Consenso sobre el tratamiento de pacientes con CPNM, con ... · 3. Resumen de la síntesis que...

Consenso sobre el tratamiento de pacientes con CPNM, con mutación EGFR y con afectación sincrónica del sistema nervioso central

DOCUMENTO DE LECTURA Y SÍNTESIS BIBLIOGRÁFICA Versión 1.0

Junio 2017

Evaluado por: Meritxell Roca Lloret

Revisado por: María José Plazas

Síntesis de la literatura | 2

TABLA DE CONTENIDO

1. Listado de documentos revisados tras ser seleccionados en la fase de revisión bibliográfica3

2. Bloques del consenso, experto responsable y listado de preguntas a responder 14

1. Introducción (definición y magnitud del problema, epidemiologia en población Española) 14

2. Definición de asintomático/ oligosintomático/ sintomático 14

3. Diagnóstico por imagen y patrón de metástasis 14

4. Factores pronósticos 14

5. Tratamiento a diferentes escenarios clínicos 14

a. Asintomáticas o oligosintomáticas 14

b. Sintomáticas 14

c. Tratamiento sistémico 14

6. Evaluación de la respuesta y seguimiento 14

7. Algoritmo de primera línea 15

8. Carcinomatosis leptomeníngea (sólo tratamiento) 15

3. Resumen de la síntesis que podría dar respuesta a las preguntas 16

4. Síntesis de la literatura con información encontrada para las preguntas 38

1. Introducción (definición y magnitud del problema, epidemiologia en población Española) 38

2. Definición de asintomático/ oligosintomático/ sintomático 38

3. Diagnóstico por imagen y patrón de metástasis 38

4. Factores pronósticos 46

5. Tratamiento a diferentes escenarios clínicos 67

a. Asintomáticas o oligosintomáticas 71

b. Sintomáticas 83

c. Tratamiento sistémico 108

6. Evaluación de la respuesta y seguimiento 126

7. Algoritmo de primera línea 128

8. Carcinomatosis leptomeníngea (sólo tratamiento) 128

1. Listado de documentos revisados tras ser seleccionados en la fase de revisión bibliográfica

ID PMID Referencia completa del documento Tipo de estudio

Valoración general del documento:

¿Documento incluido en la síntesis? (Sí /No +porqué)

Nº de la pregunta/s en

las que se utiliza

información del documento

Procedencia Comentarios

• Alta calidad (++)

• Aceptable (+)

• Inacceptable

(-)

0 27229180

Tan DS et al. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016. J Thorac Oncol. 2016 Jul;11(7):946-63.

Review of literature

++ Sí

13

Búsqueda

16

1 27382120 Arvold ND et al. Updates in the management of brain metastases. Neuro Oncol. 2016 Aug;18(8):1043-65.


++ Sí

12

Expertos

13

16

2 28076323

Zhu Q et al. Clinical outcome of tyrosine kinase inhibitors alone or combined with radiotherapy for brain metastases from epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC). Oncotarget. 2017 Feb 21;8(8):13304-13311.

Retrospective study

+ Sí 6 Expertos

3 NA NCCN Clinical Practice Guidelines Oncology Non-small cell lung cancer. Version 2.2017 – October 26, 2016 NCCN.org

Clinical Practice

Guidelines ++ Sí

2

Expertos

6

8


9

10

11

12

13

14

4 27664245

Novello S et al. ESMO Guidelines Committee. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v1-v27.

Clinical Practice

Guidelines + Sí

2

Expertos

12

13

5 28391295

Soffietti R et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol. 2017 Feb 1;19(2):162-17

Clinical Practice

Guidelines + Sí

5

Expertos

9

11

12

13

14

6 28273734

Deuschl C et al. Diagnostic impact of integrated 18F-FDG PET/MRI in cerebral staging of patients with non-small cell lung cancer. Acta Radiol. 2016 Dec 14:284185116681041

Retrospective study

- Sí 2 Búsqueda

7 NA

Clinical Outcome Assessments in Brain Tumor Clinical Trials: Summary of a Jumpstarting Brain Tumor Drug Development Coalition Workshop

Workshop NA Sí 7 Expertos


8 25239395

O'Dowd et al. Brain metastases following radical surgical treatment of non-small cell lung cancer: is preoperative brain imaging important? Lung Cancer. 2014 Nov;86(2):185-9.

Retrospective study

+ Sí 2 Búsqueda

9 22890912

Wu Y et al. Diagnostic value of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography for the detection of metastases in non-small-cell lung cancer patients. Int J Cancer. 2013 Jan 15;132(2):E37-47.

Meta-analysis ++ Sí 2 Búsqueda

10 18556086

Sánchez de Cos J et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009 Jan;63(1):140-5.

Retrospective study

+ Sí

3

Búsqueda

20

11 18303434

Jena A et al. Magnetic resonance (MR) patterns of brain metastasis in lung cancer patients: correlation of imaging findings with symptom. J Thorac Oncol. 2008 Feb;3(2):140-4.

Retrospective study

+ Sí 3 Búsqueda

12 18707868

Na II et al. A diagnostic model to detect silent brain metastases in patients with Retrospective

study + Sí 3 Búsqueda

non-small cell lung cancer. Eur J Cancer. 2008 Nov;44(16):2411-7.

13 27892978

Sperduto PW et al. Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA). JAMA Oncol. 2016 Nov 17.

Retrospective study

+ Sí 4 Búsqueda

14 22544733

Barnholtz-Sloan JS et al. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro Oncol. 2012 Jul;14(7):910-8.

Study to develop a nomogram

+ Sí 4 Expertos


15 19942357

Sperduto PW et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61.

Retrospective study

+ Sí

4

Búsqueda

5

16 28237400

Zindler JD et al. Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer: Two externally validated nomograms. Radiother Oncol. 2017 Feb 23. pii: S0167-8140(17)30065-8.

Retrospective study

+ Sí 5 Búsqueda

17 28185793

Dinglin XX et al. Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center. Clin Lung Cancer. 2017 May;18(3):e179-e186.

Retrospective study

+ Sí 5 Búsqueda

Este artículo se seleccionó para la

pregunta 6 pero no responde a la

misma.

18 28113019

Magnuson WJ et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve J Clin Oncol. 2017 Apr 1;35(10):1070-1077

Retrospective study

+ Sí 6 Búsqueda

Este artículo se seleccionó para la pregunta 12 pero no responde a la

misma.

19 28061489

Lee MH et al. The Influence of Biomarker Mutations and Systemic Treatment on Cerebral Metastases from NSCLC Treated with Radiosurgery. J Korean Neurosurg Soc. 2017 Jan 1;60(1):21-29.

Retrospective study

+ Sí 6 Búsqueda

20 27755835

Zhang Q et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016 Nov;7(6):648-654

Retrospective study

+ Sí

6

Búsqueda

8

10


15

21 27627582

Chen Y et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase

inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016 Dec;107(12):1800-1805

Retrospective study

+ Sí

16

Búsqueda 9

8

22 27343440

Khalifa J et al. International Association for the Study of Lung Cancer Advanced Radiation Technology Committee.. Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. J Thorac Oncol. 2016 Oct;11(10):1627-43


+ Sí

8

Búsqueda

15

23 26014133

Liu et al., Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study. Radiat Oncol. 2015 May 27;10:118.

Retrospective study

+ Sí 8 Búsqueda

24 25583566

Soon YY et. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015 Feb;114(2):167-72.

Sistematic review and

Meta-analysis ++ Sí 9 Expertos

25 26823294

Schuler M et al. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016

Extensive study

+ Sí

6 Búsqueda

7


Mar;11(3):380-90. 9

14

26 25098700

Cai L et al. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer. J Neurooncol. 2014 Nov;120(2):423-30.

Retrospective study

+ Sí

6

Búsqueda

11

12

27 24281220 Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010 Dec 15;2(4):2100-37.


+ Sí

4

Búsqueda

11

12

28 28074321

Na YC et al. Predictive factors of early distant brain failure after gamma knife radiosurgery alone in patients with brain metastases of non-small-cell lung cancer. J Neurooncol. 2017 Apr;132(2):333-340

Retrospective study

+ Sí 12 Búsqueda

29 26048754

Lin CH et al. Increased survival with the combination of stereotactic radiosurgery and gefitinib for non-small cell lung cancer brain metastasis patients: a nationwide study in Taiwan. Radiat Oncol. 2015 Jun 6;10:127

Retrospective study

NO - Este artículo se

seleccionó para la pregunta 12

pero no responde a la misma.

Búsqueda

30 28363487

Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. Radiother Oncol. 2017 Mar 28. pii: S0167-8140(17)30103-2.

Retrospective study

+ Sí

10

Búsqueda

12

13


31 27237825

Jiang T et al. EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. J Thorac Oncol. 2016 Oct;11(10):1718-28.

Retrospective study

+ Sí

13

Búsqueda

14

32 27034176

Magnuson WJ et al. Impact of Deferring Radiation Therapy in Patients With Epidermal Growth Factor Receptor-Mutant Non-Small Cell Lung Cancer Who Develop Brain Metastases. Int J Radiat Oncol Biol Phys. 2016 Jun 1;95(2):673-9.

Retrospective study




Búsqueda

33 26998157

Wei H et al. Prognostic factors analysis in EGFR mutation-positive non-small cell lung cancer with brain metastases treated with whole brain-radiotherapy and EGFR-tyrosine kinase inhibitors. Oncol Lett. 2016 Mar;11(3):2249-2254

Retrospective study

+ Sí 13 Búsqueda

34 25634677

Xiang Z et al. Whole brain radiotherapy-based combined modality treatment of brain metastases from non-small cell lung cancer: a retrospective analysis of prognostic factors. Oncol Res Treat. 2015;38(1-2):35-40.

Retrospective study

+ Sí 13 Búsqueda

35 28490892

Bai H, Xiong L, Han B. The effectiveness of EGFR-TKIs against brain metastases in EGFR mutation-positive non-small-cell lung cancer. Onco Targets Ther. 2017 Apr 27;10:2335-2340.

Retrospective study

+ Sí 15 Expertos

36 28149752

Proto C et al., Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future. Transl Lung Cancer Res. 2016 Dec;5(6):563-578.


+ Sí

6

Búsqueda

15

16


37 27083334

Park K et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89.

Clinical trial + Sí 15 Expertos

38 26057469

Luo S et al. Evaluation on efficacy and safety of tyrosine kinase inhibitors plus radiotherapy in NSCLC patients with brain metastases. Oncotarget. 2015 Jun 30;6(18):16725-34.

Meta-analysis + Sí 16 Búsqueda

39 25990950

Hendriks LE et al. Safety of cranial radiotherapy concurrent with tyrosine kinase inhibitors in non-small cell lung cancer patients: A systematic review. CancerTreat Rev. 2015 Jul;41(7):634-45.


++ Sí 16 Búsqueda

40 25319074

Wang F et al. Comparison of Gefitinib versus VMP in the combination with radiotherapy for multiple brain metastases from non-small cell lung cancer. Cell Biochem Biophys. 2015 Mar;71(2):1261-5.RETR

Clinical trial




Búsqueda

41 27842767 Bunchorntavakul C et al. Drug Hepatotoxicity: Newer Agents. Clin Liver Dis. 2017 Feb;21(1):115-134





Búsqueda

42 27794414

Ohgami M et al. Drug interaction between erlotinib and phenytoin for brain metastases in a patient with nonsmall cell lung cancer.Lung Cancer. 2016 Nov;101:9-10.

Case Report - Sí 17 Búsqueda

43 24041628

Thomas-Schoemann A. et al. Drug interactions with solid tumour-targeted therapies. Crit Rev Oncol Hematol. 2014 Jan;89(1):179-96.


+ Sí 17 Búsqueda


44 28298015

Wolf A et al. Toward the complete control of brain metastases using surveillance screening and stereotactic radiosurgery. J Neurosurg. 2017 Feb 17:1-9.

Retrospective Cohort study


seleccionó para la pregunta 19 y

20 pero no responde a la

misma

Búsqueda

45 26966895

Maher HM et al. Simultaneous determination of selected tyrosine kinase inhibitors with corticosteroids and antiemetics in rat plasma by solid phase extraction and ultra-performance liquid chromatography-tandem mass spectrometry: Application to pharmacokinetic interaction studies. J Pharm Biomed Anal. 2016 May 30;124:216-27

Validation Study




Búsqueda

46 20030690

Yap KY et al. Clinically relevant drug interactions between anticancer drugs and psychotropic agents. Eur J Cancer Care (Engl). 2011 Jan;20(1):6-32.





Búsqueda

47 NA

Seiji Yano,Shigeki Nanjo, Sachiko Arai, Shinji Takeuchi, Tadaaki Yamada, Yasunori Okada, Akito Hata. Nobuyuki Katakami. OA08.03. MET Copy Number Gain Associates with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR Mutant Lung Cancer. Journal of Thoracic Oncology 2017 Vol. 12 No. 1S

Clinical trial +/- Sí 21 Búsqueda

48 28110254

Remon J et al. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era. Cancer Treat Rev. 2017 Feb;53:128-137


+/- Sí 21 Búsqueda

49 20621414 Nishikawa T et al. Early detection of Retrospective + Sí 19 Búsqueda


metachronous brain metastases by biannual brain MRI follow-up may provide patients with non-small cell lung cancer with more opportunities to have radiosurgery. Clin Neurol Neurosurg. 2010 Nov;112(9):770-4.

review

20

50 23328548

Lee SJ et. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013 Feb;8(2):185-91.

Retrospective study

+ Sí 21 Búsqueda

51 22089116

Morris PG et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012 Feb;7(2):382-5.

Retrospective study

+ Sí 21 Búsqueda

52 25247337

Hoffknecht P et al. Afatinib Compassionate Use Consortium (ACUC). Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brainmetastases or leptomeningeal disease. J Thorac Oncol. 2015 Jan;10(1):156-63

Retrospective study

+ Sí

15

Búsqueda

14

53 24679729

Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, Yu HA, Chan TA, Zhang Z, Wu AJ. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):322-9. doi: 10.1016/j.ijrobp.2014.02.022. Epub 2014 Mar 25.

Clinical trial + Sí 9 Expertos


54 26439599

Metro G et al. Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer. Expert Opin Pharmacother. 2015;16(17):2601-13.


+ Sí 16 Búsqueda

Aunque inicialmente este artículo fue seleccionado para responder a la pregunta 10, no se ha incluido ya que habla de tratamiento sistémico.

55 23993384

Lin UN et al. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol. 2013 Sep;14(10):e396-406


++/+ Sí 7 Expertos

* NA Base de datos: drug.com NA NA Sí 18 Nueva búsqueda

NA: no aplica; ++: se han cumplido todos o la mayoría de los criterios de calidad metodológica. En los puntos en que no se han cumplido, se considera muy poco probable que dicho incumplimiento pueda afectar a las

conclusiones del estudio o revisión; +: se han cumplido algunos de los criterios de calidad metodológica. Se considera poco probable que los criterios que no se han cumplido o que no se describen de forma adecuada

puedan afectar a las conclusiones; - : se han cumplido sólo unos pocos criterios de calidad metodológica, o ninguno de ellos. Se considera probable o muy probable que esto afecte a las conclusiones.

2. Bloques del consenso, experto responsable y listado de preguntas a responder

1. Introducción (definición y magnitud del problema, epidemiologia en

población Española)

2. Definición de asintomático/ oligosintomático/ sintomático

P 1. ¿Qué criterios definen al paciente asintomático y al oligosintomático? (Dr. Rafael López)

3. Diagnóstico por imagen y patrón de metástasis

P 2. ¿Cuál es la técnica de imagen de elección para diagnosticar las MTC? (Dr. Rafael López)

P 3. ¿Se deben realizar pruebas de imagen en pacientes asintomáticos para identificar MTC? (Dr. Rafael López)

4. Factores pronósticos

P 4. ¿Qué variables clínicas y radiológicas tienen impacto en el pronóstico del paciente? (Dra. Eugenia Verger)

P 5. ¿Cuál es el valor de las escalas pronósticas? (Dra. Eugenia Verger)

P 6. ¿Tienen un pronóstico diferente los pacientes con MTC dependiendo del tipo de mutación? (Dra. Eugenia

Verger)

5. Tratamiento a diferentes escenarios clínicos

P 7. ¿Cuál es la variable principal de elección para evaluar la eficacia de los tratamientos de pacientes EGFR

mutado con MTC? (Dr. Jordi Bruna)

a. Asintomáticas o oligosintomáticas P 8. ¿Se deben tratar localmente las MTC en pacientes asintomáticos? (Dr. Javier Puente)

P 9. ¿Cuál es el primer tratamiento que debe utilizarse en el paciente con MTC asintomáticas? (Dr. Javier

Puente)

b. Sintomáticas P 10. ¿Se deben tratar localmente (RT o cirugía) las MT cerebrales en pacientes sintomáticos? (Dra. Ana Laura

Ortega)

P 11. ¿Qué pacientes son tributarios al tratamiento quirúrgico? (Dr. Oscar Juan)

P 12. ¿Qué pacientes son tributarios al tratamiento radiocirugía? (Dr. Oscar Juan)

P 13. ¿Qué pacientes son tributarios al tratamiento holocraneal? (Dr. Oscar Juan)

P 14. ¿Cuál es el primer tratamiento que debe utilizarse en el paciente con MTC sintomáticas? (Dra. Ana Laura

Ortega)

c. Tratamiento sistémico P 15. ¿Existen diferencias de actividad intracraneal entre los diferentes TKI? (Dr. Alejandro Navarro)

P 16. ¿Es seguro emplear de forma simultánea los TKI con la RT? (Dr. Alejandro Navarro)

P 17. ¿Existen interacciones de los anticonvulsivantes con los TKI? (Dr. Alejandro Navarro)

P 18. ¿Existen interacciones de los corticoides con los TKI? (Dr. Alejandro Navarro)

6. Evaluación de la respuesta y seguimiento P 19. ¿Con qué periodicidad hay que evaluar las lesiones del SNC en pacientes que no han recibido tratamiento

local previo? (Dra. Adela Bartolomé)


P 20. ¿Con qué periodicidad hay que evaluar las lesiones del SNC en pacientes que han recibido tratamiento local

previo? (Dra. Adela Bartolomé)

7. Algoritmo de primera línea A partir de la información recogida en el proceso de elaboración de las recomendaciones, se realizará el

algoritmo en la reunión final del consenso.

8. Carcinomatosis leptomeníngea (sólo tratamiento)

P 21. En los pacientes con carcinomatosis leptomeníngea, ¿debe realizarse tratamiento intratecal o tratamiento

local? (Dr. Jordi Bruna)

3. Resumen de la síntesis que podría dar respuesta a las preguntas

Aquí se presenta un resumen de lo que se ha considerado más relevante para responder a cada pregunta. Se

incluyen los documentos evaluados (título, tipo de estudio y calidad del mismo) y las principales conclusiones de cada

uno, obviando el detalle de las evidencias, que podrá encontrar en la síntesis completa. Para acceder a la síntesis

completa, haga CTRL+CLIC sobre el título de cada pregunta:

Pregunta 1: ¿Qué criterios definen al paciente asintomático y al oligosintomático? (Dr. Rafael López)

En la bibliografía seleccionada no se ha encontrado una respuesta específica que pueda ayudar a responder esta pregunta.

Pregunta 2: ¿Cuál es la técnica de imagen de elección para diagnosticar las MTC? (Dr. Rafael López)

Documento 3: NCCN Clinical Practice Guidelines Oncology Non-small cell lung cancer. Version 2.2017 – October 26, 2016. Clinical Practice Guideline. Calidad: ++

Documento 4: Novello S et al. ESMO Guidelines Committee. Metastatic non small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v1-v27. Clinical Practice Guideline. Calidad: +

Imaging of the central nervous system (CNS) is most relevant in those patients with neurological symptoms or signs, however, if available, imaging of the CNS with magnetic resonance imaging (MRI, preferably with gadolinium enhancement) or CT brain with iodine contrast should be carried out at diagnosis. MRI is more sensitive than CT scan [32]. .

Documento 6: Deuschl C et al. Diagnostic impact of integrated 18F-FDG PET/MRI in cerebral staging of patients with non-small cell lung cancer. Acta Radiol. 2016 Dec. Retrospective study. Calidad: -

The sensitivity of PET in detection of BM depends on their size. 18F-FDG PET/MRI does not lead to an improvement in diagnostic accuracy in cerebral staging of NSCLC patients, as MRI alone remains the gold standard.

Documento 8: O'Dowd et al. Brain metastase following radical surgical treatment of non-small cell lung cancer: is preoperative brain imaging important? Lung Cancer. 2014 Nov;86(2):185-9.


Retrospective study. Calidad: +

Using a 5 mm detection threshold 29 (71%) of brain metastases should have been of at least 5 mm maximum diameter at time 0.Using a 2 mm detection threshold 34 (83%) would have been at least 2 mm in maximum diameter at time 0. These would be potentiallydetectable had MR brain been performed as part of the staging process. This means that 4.4% (29/646) of our patients who underwent surgery would have had their brain metastases detected by preoperative MR and this might have been as high as 5.3% (34/646) with optimal MR detection limits.

Based on our findings we suggest that, in addition to standard staging investigations, patients have brain imaging (MR or equivalent) prior to curative surgery in NSCLC regardless of preoperative stage.

Documento 9: Wu Y et al. Diagnostic value of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography for the detection of metastases in non-small-cell lung cancer patients. Int J Cancer. 2013 Jan 15;132(2):E37-47. Meta-analysis. Calidad: ++

Two studies with 546 patients evaluated the accuracy of detecting brain metastases by PET/CT on a per-patient basis.24,25 In the study of Kruger et al.,24 PET/CT was performed with contrast medium while in the study of Lee et al.,25 the CT portion of PET/CT was unenhanced. The sensitivities of these two studies were 0.27 and 0.24, and the specificities were 0.98 and 1.00, respectively. One study containing 51 patients assessed the diagnostic performance of 18F-FDG PET/CT in detecting adrenal metastases. 26 Using SUVmax > 2.7 as the diagnostic criteria, the sensitivity was 0.89 and the specificity was 0.88.

18F-FDG PET/CT is beneficial in detecting lymph node metastases and extrathoracic metastases although PET/CT showed low sensitivity in detecting brain metastases.

Pregunta 3: ¿Se deben realizar pruebas de imagen en pacientes asintomáticos para identificar MTC? (Dr. Rafael López)

Documento 10: Sánchez de Cos et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009 Jan;63(1):140-5. Retrospective study. Calidad: +

Asymptomatic patients had better performance status than symptomatic ones (p = 0.048) as well as a higher rate of synchronous brain lesions (p = 0.002), a larger number of tumors detected by cranial MRI (p < 0.001), and significantly smaller brain lesions (p = 0.005). Forty patients had metachronous brain metastasis.

The detection rate of silent brain metastasis in patients with NSCLC will probably increase, not only because of the availability of more accurate staging techniques and the increasingly widespread use of routine cranial MRI, but also because the majority of therapeutic trials (such as those investigating new angiogenesis inhibitors) exclude patients with brain involvement [12]. We therefore believe that it is very important to determine the clinical course and optimal management of these patients. Our data suggest that it is important to search for and detect brain metastasis in patients with NSCLC before neurologic signs or symptoms develop. Early detection improves prognosis and, in all probability, facilitates timely, effective treatment.

Documento 11: Jena A. et al. Magnetic resonance (MR) patterns of brain metastasis in lung cancer patients: correlation of imaging findings with symptom. J Thorac Oncol. 2008 Feb;3(2):140-4. Retrospective study. Calidad: +

The incidence of asymptomatic brain metastasis in our study was 16.5% with almost equal number of symptomatic and asymptomatic metastasis in lung cancer patients. Hence, imaging surveillance of the brain for metastasis is worthwhile to detect asymptomatic metastasis early for early institution of appropriate therapy.

Documento 12: Na II, Lee TH et al. A diagnostic model to detect silent brain metastases in patients with non-small cell lung cancer. Eur J Cancer. 2008 Nov;44(16):2411-7. Retrospective study. Calidad: +


The study was carried out in 433 patients with NSCLC who underwent chest CT, brain magnetic resonance imaging (MRI) and bone scans at an initial staging: Brain metastases were determined by MRI.

Patients were allocated to four groups according to the number of risk factors: 124 patients with none; 202 patients with one; 81 patients, with two and 26 with three. The proportions of patients with brain metastases in the four groups were 2%, 3%, 17% and 35%, respectively, and these differences were significant (P < 0.001). When analysis was performed in patients with localised disease, the number of risk factors was correlated with the prevalence of brain metastases (P = 0.013) but stage was not (P = 0.153).

MRI is more accurate for the diagnosis of brain metastases than CT, in accordance with other studies [10, 23].

Pregunta 4: ¿Qué variables clínicas y radiológicas tienen impacto en el pronóstico del paciente? (Dra. Eugenia Verger)

Documento 13: Sperduto PW et al. Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA). JAMA Oncol. 2016 Nov 17. Retrospective study. Calidad: +

Significant prognostic factors included the original 4 factors used in the DS-GPA index plus 2 new factors: EGFR and ALK alterations (Table 2) in patients with adenocarcinoma (mutation status was not routinely tested for nonadenocarcinoma).

The overall median survival for the cohort in the present study was 12 months, and those with NSCLC-adenocarcinoma and Lung-molGPA scores of 3.5 to 4.0 had a median survival of nearly 4 years.

Documento 14: arnholtz-Sloan JS et al. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro Oncol. 2012 Jul;14(7):910-8. De-identified data from 7 RadiationTherapy Oncology Group randomized trials. Study to develop a nomogram. Calidad: +

The best fitting model was the Cox proportional hazards survival model and included primary site and histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions. Thus, the nomogram was built using this model (Fig. 2).

The nomogram provides an individualized estimate of survival, rather than a group estimate. Documento 27: Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010 Dec 15;2(4):2100-37. Review of literature. Calidad: +

Three prognostic classes (RPA class I, II and III) were found to be associated with the overall survival of patients with brain metastases. This classification scheme is based on age at diagnosis, presence of extracranial disease, Karnofsky performance status (KPS), and the status of the primary cancer.

RPA class I includes patients who are younger than 65 years of age, have a KPS score of ≥70, tumor controlled at the primary site, and no extracranial disease. RPA class III patients have a KPS score of less than 70. All other patients are in RPA class II. The median survival times for the RPA classes I-III were 7.1, 4.2, and 2.3 months, respectively. This RPA classification is the most commonly used prognostic system for brain metastases, with further validation in Phase III and major institutional studies for both NSCLC and SCLC [22-25].

Documento 15: Sperduto PW et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. Retrospective study. Calidad: +

For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs,


confirming the original GPA for these diagnoses.

Pregunta 5: ¿Cuál es el valor de las escalas pronósticas? (Dra. Eugenia Verger)

Documento 5: Soffietti R et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol. 2017 Feb 1;19(2):162-174. Clinical Practice Guideline. Calidad: +

Knowledge of the most powerful prognostic factors (Karnofsky performance status [KPS], age, extracranial tumor activity, number of brain metastases, primary tumor type/molecular subtype) is crucial for predicting individual prognosis.

In this regard, several prognostic indices have been developed in order to distinguish subgroups of patients with different outcomes [2,3].

Documento 16: Zindler JD et al. Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer: Two externally validated nomograms. Radiother Oncol. 2017 May;123(2):189-194. Retrospective study. Calidad: +

Two novel clinical nomogram models were developed and validated for the prediction of respectively early death (<3 months) and long-term (>1 year) survival after SRS for patients with a maximum of four BMs of NSCLC.

These nomogram models can be used for individual probability assessments, and to avoid the limitations of previously published prognostic classification systems.

Documento 17: Dinglin XX et al. Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center. Clin Lung Cancer. 2017 May;18(3). Retrospective study. Calidad: +

It were stablished 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively.

Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy.

APA model 1 was feasible for NSCLC BM patients with unknown EGFR genotype, whereas the APA model 2 was more appropriate for patients with BM from NSCLC with known EGFR status. Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs.

Documento 15: Sperduto PW et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010 Jul 1;77(3):655-61. Retrospective study. Calidad: +

For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses.

Pregunta 6: ¿Tienen un pronóstico diferente los pacientes con MTC dependiendo del tipo de mutación? (Dra. Eugenia Verger)?

Documento 18: Magnuson WJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol. 2017 Apr 1;35(10):1070-1077. Retrospective study. Calidad: +

Multivariable analysis of patient characteristics demonstrated that SRS versus EGFR-TKI, WBRT versus EGFR-TKI, performance status, age, EGFR exon 19 mutation, and absence of


extracranial metastases were associated with improved OS (Table 2). Documento 19: Lee MHet al. The Influence of Biomarker Mutations and Systemic Treatment on Cerebral Metastases from NSCLC Treated with Radiosurgery. J Korean Neurosurg Soc. 2017 Jan 1;60(1):21-29. Retrospective study. Calidad: +

EGFR mutation (+) (exon 18–21) and ALK mutation (+) were identified as independent positive prognostic factors related to the prolonged overall survival. The prognosis of patients with brain metastases of NSCLC after GKS significantly differed according to specific biomarkers (EGFR and ALK mutations).

Documento 2: Zhu Q, et al. Clinical outcome of tyrosine kinase inhibitors alone or combined with radiotherapy for brain metastases from epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC). Oncotarget. 2017 Feb 21;8(8):13304-13311. Retrospective study. Calidad: +

We performed a subgroup analysis in our current study and found that OS (22 vs 13.5 months, P = 0.004) and cranial PFS (14 vs 9.5 months, P = 0.001) were longer for the TKI + RT group than for the TKI alone group for lung adenocarcinoma patients with BM harboring exon 21 mutations. However, there were no significant differences in OS (20.5 vs 18.5 months, P = 0.742) and cranial PFS (16.0 vs 16.0 months, P = 0.652) between the two groups for lung adenocarcinoma patients with BM harboring exon 19 mutations.

Patients with exon 21 mutations can also benefit more from TKI + RT rather than TKI alone. However, no benefit was measured from TKI + RT for patients with exon 19 deletion.


The presence of the EGFR exon 19 deletion or exon 21 L858R mutation is predictive of treatment benefit from EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy; therefore, these mutations are referred to as sensitizing EGFR mutations.108,109 However, the presence of EGFR exon 19 deletions (LREA) or exon 21 L858R mutations does not appear to be prognostic of survival for patients with NSCLC, independent of therapy.110

Documento 25: Schuler M et al. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016 Mar;11(3):380-90. Extension study. Calidad: +

Across both studies, the ORR in patients with brain metastases who were treated with afatinib was 23 of 28 (82.1%) and 12 of 20 (60.0%) in those with Del19 or L858R mutations, respectively.

In both studies, afatinib conferred longer PFS versus chemotherapy in patients with brain metastases who harbored common EGFR mutations. The outcomes were particularly promising in patients with a Del19 mutation, a subgroup for whom afatinib is the only TKI to demonstrate superior OS versus chemotherapy in this setting [21].

Documento 20: Zhang Q et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016 Nov;7(6):648-654. Retrospective study. Calidad: +

No significant difference was observed in survival between gender (male vs. female), age (< 65 years vs. ≥ 65 years), ECOG PS (0–1 vs. 2–3), EGFR mutation (19 deletion vs. other mutations), and EGFRTKIs administered (gefitinib vs. erlotinib). (N=43)

Documento 36: Proto C. et al. Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future. Transl Lung Cancer Res. 2016 Dec; 5(6): 563–578. Review of literature. Calidad: +

Exon 19 deletion was associated with better outcome in both PFS (P=0.003) and OS (P=0.025)


compared with L858R. No patient experienced grade ≥4 toxicity. Several retrospective analyses confirmed the efficacy of TKIs used alone in BM, in particular in EGFR mutated NSCLC [87-89].

Documento 26: Cai L et al. A comparative analysis of EGFR mutation status in association with the efficacy of TKI in combination with WBRT/SRS/surgery plus chemotherapy in brain metastasis from non-small cell lung cancer. J Neurooncol. 2014 Nov;120(2):423-30. Retrospective study. Calidad: +

Patients having EGFR L858R point mutations had a longer but non-significant median overall survival (MOS), median progression-free survival for intracranial disease (MPFSI) and median progression-free survival for extracranial disease (MPFSE) compared to patients with exon 19 deletions (Table 2).

Pregunta 7: ¿Cuál es la variable principal de elección para evaluar la eficacia de los tratamientos de pacientes EGFR mutado con MTC? (Dr. Jordi Bruna )

Documento 7: Clinical Outcome Assessments in Brain Tumor Clinical Trials: Summary of Jumpstarting Brain Tumor Drug Development Coalition Workshop. Workshop. Calidad: NA NOTA: Tener en cuenta que en workshop se habló de: “…clinical trial endpoints, with a goal of advancing the development of treatments for glioblastoma…”; los outcomes que se incluyen se refieren a este tumor más que a los endpoint de elección para evaluar la eficacia de los tratamientos de pacientes EGFR mutado con MTC.

There is inconsistent measurement of these common symptoms and signs across trials. The most common symptoms at the time of diagnosis are headache, weakness, speech and communication deficits, seizures, neurocognitive issues, and behavioral issues, as documented throughout the published literature.

Recent brain tumor clinical trials have demonstrated that symptom based patient-reported outcome (PRO) measures are sensitive to tumor progression and differences in treatment arms, and may be related to overall survival (OS) and progression free survival (PFS).

Functional status (performance- outcome (PerfO), observerreported outcome (ObsRO), clinician-reported,(ClinRO), (PRO):

o Cognitive Function o Mobility/Walking o Basic activities of daily living (ADLs) o Instrumental ADLs

The importance of capturing Clinical Outcome Assessments (COAs) in brain tumor clinical trials must be relayed and emphasized to all stakeholders to help foster support for the inclusion of these measures


For both LUX-Lung 3 and LUX-Lung 6, the primary efficacy end-point was: Progression-free survival (PFS), as assessed by independent review. Key secondary end points in both studies were OS, ORR (complete response and partial response), and disease control (complete response/partial response or stable disease). Other secondary end points included patient-reported outcomes and safety.

Documento 55: Lin NU et al. Response Assessment in Neuro-Oncology (RANO) group. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol. 2013 Sep;14(10):e396-406. Review of literature. Calidad: ++/+


Overall survival has usually been the primary endpoint of phase 3 trials of brain metastases.[15,24–26]

Progression-free survival (PFS) is often used as the primary endpoint in phase 3 trials examining solid tumour metastases outside of the CNS. However, there are several reasons why intracranial PFS might not be a sufficient endpoint in brain metastasis treatment trials.

The purpose of phase 2 trials is to identify a sign of activity that would support the move to a definitive phase 3 trial. In the phase 2 setting (and as secondary endpoints in the phase 3 setting) endpoints that have been used are: Objective response, PFS, time to need for salvage therapy, neurocognitive outcomes, functional status, and quality of life.

Pregunta 8: ¿Se deben tratar localmente las MTC en pacientes asintomáticos? (Dr. Javier Puente)


Documento 22: Halifa J et al. International Association for the Study of Lung Cancer Advanced Radiation Technology Committee. Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. J Thorac Oncol. 2016 Oct;11(10):1627-43. Review of literature. Calidad: + Aunque no responde directamente a la pregunta, queda implicito que el tratamiento local es una de las primeras opciones para tratar MT asintomáticas.

Given the potential neurocognitive impairment following WBRT emerging data support that TKIs are a reasonable option for asymptomatic BM unsuitable for local ablative treatments, but further investigation is required to determine if this is the optimal option [151].

In patients not suitable for local treatments, new developments in WBRT techniques with hippocampal sparing, may reduce neurocognitive toxicity [163].

Documento 21: Chen Y et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016 Dec;107(12):1800-1805. Retrospective study. Calidad: + Studies showed that EGFR-TKIs are valid options among patients with asymptomatic BM that have arisen from NSCLC harboring sensitizing EGFR mutations. The response rate is approximately 70%, median PFS


ranges from 6.6 to 23.2 months, and OS varies from 12.9 to 19.8 months.(6,12) However, WBRT alone or in combination with surgery and SRS, has been the standard of care for BM. Documento 20: Zhang Q et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016 Nov;7(6):648-654. Retrospective study. Calidad: + NOTA: estrategia de tratamiento para pacientes sintomáticos y sintomáticos en un centro en concreto.

The following uniform treatment strategy has been applied for these patients at our cancer center. Patients with asymptomatic BM (Total patients: 33) were administered an oral EGFR-TKI (gefitinib 250 mg once daily or erlotinib 150 mg once daily) until ECLs progressed, intolerable toxicity was observed, or refusal to continue treatment. According to Response Evaluation Criteria in Solid Tumors (RECIST), if ICLs progressed alone, with stable or remissive ECLs, or an asymptomatic BM progressed to a symptomatic BM (as defined by the presence of one or more of the following symptoms: signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms), patients received brain radiotherapy and continued taking a TKI until their ECLs progressed. Radiotherapy for BM included WBRT, stereotactic radiosurgery, or both.

Documento 23: Liu S, et al. Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study. Radiat Oncol. 2015 May 27;10:118. Retrospective study. Calidad: +

Brain RT as first-line therapy was not significantly associated with BM progression-free survival (p = 0.643, HR 0.82, 95 % CI 0.39-1.81, Fig. 4).

First-line brain RT failed to improve long-term survival in TKI-naïve EGFR mutant NSCLC patients with asymptomatic BM.

Pregunta 9: ¿Cuál es el primer tratamiento que debe utilizarse en el paciente con MTC asintomáticas? (Dr. Javier Puente)


Based on the high intracranial response rates, TKIs alone have been proposed as initial treatment instead of WBRT in patients harboring activating EGFR mutations and asymptomatic brain metastases,[70–72] although this approach could be associated with a higher risk of subsequent intracranial relapse. The use of primary TKIs can avoid the adverse effects of WBRT, although it is unlikely to avoid the need for subsequent WBRT.

An alternative strategy is the use of cranial radiotherapy (SRS or WBRT) in combination with TKIs, which may improve PFS and OS compared with TKIs alone or radiotherapy with or without chemotherapy, although this is somewhat controversial and remains to be proven (class IIIa and b).[73,74]



Documento 21: Chen Y et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016 Dec;107(12):1800-1805. Retrospective study. Calidad: + NOTA: Todos los pacientes de este estudio recibieron “first-generation EGFR-TKI as first-line therapy”.

For patients who had asymptomatic BM, no statistical difference of intracranial TTP appeared between 16 patients who received WBRT and 51 patients who received EGFR-TKI alone, the median intracranial TTP was 24.7 months (95% CI, 17.5–31.9) and 20.0 months (95% CI, 16.9–23.1), respectively (P = 0.193) (Fig. 2c).

Concomitant WBRT significantly improved intracranial lesion control and prolonged intracranial TTP compared with EGFR-TKI treatment alone. A long OS for patients with EGFR-mutant lung adenocarcinoma and BM was observed in our study, and the OS was equivalent between the WBRT and EGFR-TKI alone treatment groups.


It is possible, that in patients with asymptomatic brain metastases treatment with a first-line TKI could delay the requirement for WBRT, thereby delaying or preventing exposure to the side effects of cranial irradiation.

Documento 24: Soon YY et al. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015 Feb;114(2):167-72. Systematic review and meta-analysis. Calidad: ++

For patients with asymptomatic brain metastases and are agreeable for serial imaging of intracranial disease, it could be reasonable to with hold up front cranial radiotherapy and to treat the intracranial disease with radiation upon progression.

Documento 53: Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, Yu HA, Chan TA, Zhang Z, Wu AJ. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):322-9. Retrospective study. Calidad: + NOTA: Aunque la mayoría de los pacientes incluidos en el estudio fueron pacientes asintomáticos, tambien se incluyeron pacientes sintomáticos (ver tabla 1: “baseline characteristics”).


The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.

Pregunta 10: ¿Se deben tratar localmente (RT o cirugía) las MT cerebrales en pacientes sintomáticos? (Dra. Ana Laura Ortega)

Documento 30: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. Radiother Oncol. 2017 Mar 28. pii: S0167-8140(17)30103-2. Retrospective study. Calidad: +

In this study, patients treated with first-line WBRT + TKI had significantly longer TTIP than those treated with SRS + TKI or TKI alone despite features that might be expected to result in poorer outcomes. More patients with symptomatic brain metastases had WBRT + TKI, and patients receiving SRS + TKI generally had four or fewer lesions. Some patients in the SRS-treated group had relatively rapid intracranial progression, mostly due to the development of new metastases, but small numbers in this cohort preclude identification of any prognostic factors.

Salvage SRS was used when a small number of new brain metastases were discovered, and WBRT used for progression that was more diffuse. In SRS + TKI-treated patients, 30% had salvage WBRT, which falls within the 18–32% rate reported in other studies of SRS. The choice of WBRT as salvage may be related to the development of new brain metastases rather than progression of existing lesions, which would be more likely treated with repeat SRS.


Documento 20: Zhang Q et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016 Nov;7(6):648-654. Retrospective study. Calidad: + NOTA: estrategia de tratamiento para pacientes sintomáticos y sintomáticos en un centro en concreto.


The following uniform treatment strategy has been applied for these patients at our cancer center: Patients with symptomatic BM were administered an oral TKI, together with corticosteroid and other symptomatic treatments. If the symptoms were alleviated within two weeks, TKI was continued without brain radiotherapy. If the symptoms were not relieved within two weeks, the symptoms deteriorated again after initial relief, or ICLs progressed prior to ECLs according to RECIST criteria, brain radiotherapy was commenced. Patients also continued taking a TKI until their ECLs progressed, intolerable toxicity occurred, or they refused subsequent treatment.

Pregunta 11: ¿Qué pacientes son tributarios al tratamiento quirúrgico? (Dr. Oscar Juan)


In patients with 2 or 3 brain metastases, who have a high performance status and controlled systemic disease, complete surgical resection yields results that are comparable to those obtained in single lesions (class IIIb).[11]


Documento 27: Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers(Basel). 2010 Dec 15;2(4):2100-37. Review of literature. Calidad: +

Surgery is usually limited to the dominant, symptomatic lesion in patients with multiple metastases. Surgery combined with adjuvant WBRT or stereotactic radiosurgery (SRS) have demonstrated similar survival outcome in patients with multiple lesions compared with patients with single brain metastasis in several single-institution studies [44-46]



WBRT has been considered as a standard treatment option in patients with BMs from NSCLC [3, 4] but it causes neurotoxicity which leads to leukodystrophy. SRS or surgery could be an alternative option, but only for a small subset of patients with solid or oligo-lesions.

Pregunta 12: ¿Qué pacientes son tributarios al tratamiento con radiocirugía? (Dr. Oscar Juan)


Small brain metastases represent an ideal target for SRS, owing to the generally spherical shape and distinct pathologic margins.[12].

In the past 5–10 years SRS has been increasingly used for patients with higher number of brain metastases, due to improved technology that allows the delivery of SRS with increasing speed while maintaining precision and accuracy. A prospective multicenter Japanese study investigated the use of SRS alone in 1194 patients with 1, 2 to 4 or 5 to 10 brain metastases, and found similar overall survival (OS) (10.8 mo) and treatment-related toxicity rates between the groups with 2 to 4 and 5 to 10 metastases (class IIIa).[16]

Documento 1: Arvold ND et al. Updates in the management of brain metastases. Neuro Oncol. 2016 Aug;18(8):1043-65. Review of literature. Calidad: ++

Clinical controversy remains regarding optimal patient selection for receipt of SRS alone, SRS + WBRT, and WBRT alone [36, 37]. In addition, it should be emphasized that the majority of patients treated in the landmark SRS, WBRT, and surgery trials for BM cited above were unselected NSCLC patients, and therefore caution should be applied when generalizing outcomes about local therapies from these trials to various subgroups, such as HER2+ breast cancer or ALK-rearranged NSCLC patients. A summary of several key recent studies examining survival and functional outcomes after SRS, with or without WBRT, is provided in Table 1.


For patients with multiple metastases (eg, >3), WBRT is a standard option, although SRS is also an option [445-447] WBRT is associated with measurable declines in neurocognitive function in clinical trials, particularly with increasing dose and advanced age of the patient [448].

For patients with limited metastases, randomized trials have found that the addition of WBRT to SRS decreases intracranial recurrence but does not improve survival and may increase the risk of cognitive decline.[452,453] Thus, an approach of SRS alone may strike an appropriate balance in patients with limited volume metastases.[454]

Documento 28: Na YC et al. Predictive factors of early distant brain failure after gamma knife radiosurgery alone in patients with brain metastases of non-small-cell lung cancer. J Neurooncol. 2017 Apr;132(2):333-340. Retrospective study. Calidad: +

This study suggests that GKRS alone could be considered for patients treated with EGFR-TKIs who have a stable systemic disease status and 3 or fewer brain lesions. WBRT should be considered for other patients.

Documento 30: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. Radiother Oncol. 2017 Mar 28. pii: S0167-8140(17)30103-2 . Retrospective study. Calidad: +

Salvage SRS was used when a small number of new brain metastases were discovered, and WBRT used for progression that was more diffuse.

Documento 4: Novello S et al. ESMO Guidelines Committee. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016


Sep;27(suppl 5):v1-v27. Clinical Practice Guideline. Calidad:+

For two to three metastases, SRS is recommended in patients with RPA class I–II [II, B].

Data from a prospective observational Japanese study suggested that the use of SRS may have a role in patients with more than three metastases [152]. In outpatients undergoing SRS, treatment-related side-effects occur in 8% of cases, findings that indicate SRS as a valid alternative to WBRT in fit patients [IV, C].


WBRT has been considered as a standard treatment option in patients with BMs from NSCLC [3, 4], but it causes neurotoxicity which leads to leukodystrophy.

SRS or surgery could be an alternative option, but only for a small subset of patients with solid or oligo-lesions.

Documento 27: Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010 Dec 15;2(4):2100-37. Review of literature. Calidad: +

Because of the excellent local control rates achieved by SRS, whether its addition to WBRT will lead to a survival benefit over WBRT alone has been investigated in many studies. This approach could be especially beneficial for patients who are not candidates for a craniotomy because of tumor location or existing medical contraindications (61-64).

Pregunta 13: ¿Qué pacientes son tributarios al tratamiento holocraneal? (Dr. Oscar Juan)


A recent individual patient data meta-analysis of 3 randomized trials comparing SRS alone with SRS + WBRT in patients with 1 to 4 brain metastases [35] suggested a survival advantage for SRS alone in patients aged <50 years without a reduction in the risk of new brain metastases with adjuvant WBRT; conversely, in patients aged >50 years WBRT decreased the risk of new brain metastases but did not affect survival.

Documento 30: Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. Radiother Oncol. 2017 Mar 28. pii: S0167-8140(17)30103-2 . Retrospective study. Calidad: +


Documento 0: Tan DS et al. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016. J Thorac Oncol. 2016 Jul;11(7):946-63. Review of literature. Calidad: ++

Although patients with EGFR mutant NSCLC demonstrate high response rates to whole brain radiation therapy (WBRT)110 and WBRT improves the duration of intracranial disease control


over TKIs or stereotactic radiosurgery (SRS),108 many practitioners seek to avoid the hair loss, fatigue, and other neurocognitive sequelae of WBRT in this population.

If radiation therapy is to be performed, factors that may be considered in the decision between WBRT or SRS might include the degree of symptoms, size of metastatic tumor(s), presence of hemorrhage or peritumoral edema, brainstem involvement, and number of metastases.

Documento 1: Arvold ND et al. Updates in the management of brain metastases. Neuro Oncol. 2016 Aug;18(8):1043-65. Review of literature. Calidad: ++

Clinical controversy remains regarding optimal patient selection for receipt of SRS alone, SRS + WBRT, and WBRT alone [36, 37]. A summary of several key recent studies examining survival and functional outcomes after SRS, with or without WBRT, is provided in Table 1.


For multiple metastases (eg, >3), WBRT is a standard option, although SRS is also an option [445-447]

WBRT is associated with measurable declines in neurocognitive function in clinical trials, particularly with increasing dose and advanced age of the patient [448].

For limited metastases, randomized trials have found that the addition of WBRT to SRS decreases intracranial recurrence but does not improve survival and may increase the risk of cognitive decline.[452,453] Thus, an approach of SRS alone may strike an appropriate balance in patients with limited volume metastases.[454]

Documento 31: Jiang T et al. EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. J Thorac Oncol. 2016 Oct;11(10):1718-28. Retrospective study. Calidad: +

In patients with EGFR-mutant NSCLC with BM: the addition of WBRT to EGFR TKIs did not appear to have survival benefit superior to that of EGFR TKIs alone.

In patients with BM and EGFR of wild-type or unknown status WBRT also did not bring additional benefit to chemotherapy.

Documento 4: Novello S et al. ESMO Guidelines Committee. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v1-v27. Clinical Practice Guideline. Calidad: +

When more than three brain metastases are diagnosed, WBRT is recommended in patients with RPA class I–II [II, B], although the benefit of WBRT compared with supportive care alone has not been formally studied in randomised trials [154.

The WBRT most frequent schedules are 20 Gy in 5 fractions or 30 Gy in 10 fractions, with no difference in outcome [I, A] [155].

Documento 33: Wei H et al. Prognostic factors analysis in EGFR mutation-positive non-small cell lung cancer with brain metastases treated with whole brain-radiotherapy and EGFR-tyrosine kinase inhibitors. Oncol Lett. 2016 Mar;11(3):2249-2254.. Retrospective study. Calidad: +

The Cox proportional hazards regression and classification tree models were used to explore

the prognostic factors in EGFR mutation‑positive NSCLC patients with brain metastases

following whole‑brain radiation therapy (WBRT) and EGFR‑tyrosine kinase inhibitor (EGFR‑TKI)

treatment.

The classification tree model was subsequently applied, which revealed 3 patient groups with significantly different survival times:


o Group I, age <65 years and CEA ≤10 μg/ml; o Group II, age <65 years and CEA >10 μg/ml or age ≥65 years and CEA ≤10 μg/ml o Group III, age ≥65 years and CEA >10 μg/ml

Documento 34: Xiang Z el al. Whole brain radiotherapy-based combined modality treatment of brain metastases from non-small cell lung cancer: a retrospective analysis of prognostic factors. Oncol Res Treat. 2015;38(1-2):35-40. Retrospective study. Calidad: + In the present study of brain metastases from NSCLC treated with WBRT-based combined modality therapy, the significant positive prognostic factors for overall survival included:

Good performance status, no extracranial metastasis, no cerebellar metastases, ≥ 3 cycles of chemotherapy after diagnosis of brain metastases, and combination treatment with EGFR-TKIs.

In patients with 1–3 brain metastases, significant positive prognostic factors included ≥ 3 cycles of chemotherapy and a combination of WBRT with radiation boost.

Pregunta 14: ¿Cuál es el primer tratamiento que debe utilizarse en el paciente con MTC sintomáticas? (Dra. Ana Laura Ortega)



An alternative strategy is the use of cranial radiotherapy (SRS or WBRT) in combination with TKIs, which may improve PFS and OS compared with TKIs alone or radiotherapy with or without chemotherapy, although this is somewhat controversial and remains to be proven (class IIIa and b).[73,74].



Documento 25: Schuler M et al. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016 Mar;11(3):380-90.. Extension study. Calidad: +

It is possible, that in patients with asymptomatic brain metastases treatment with a first-line

TKI could delay the requirement for WBRT, thereby delaying or preventing exposure to the side

effects of cranial irradiation.

Documento 31: Jiang T et al. EGFR TKIs plus WBRT Demonstrated No Survival Benefit Other Than That of TKIs Alone in Patients with NSCLC and EGFR Mutation and Brain Metastases. J Thorac Oncol. 2016 Oct;11(10):1718-28. Retrospective study. Calidad: +

Patients with symptomatic BM accepted EGFR TKIs plus WBRT had significantly worse iPFS than those received EGFR TKIs alone (HR = 4.232, 95% CI 1.912-9.817, P = 0.028) iPFS in symptomatic BM patients seems to favor TKIs alone.


Documento 52: Hoffknecht P et al. Afatinib Compassionate Use Consortium (ACUC). Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015 Jan;10(1):156-63.. Retrospective study. Calidad: +

Median time to treatment failure for patients with CNS metastasis was 3.6 months, and did not differ from a matched group of 100 patients without CNS metastasis. Thirty-five percent (11 of 31) of evaluable patients had a cerebral response, five (16%) responded exclusively in brain. Response duration (range) was 120 (21–395) days. Sixty-six percent (21 of 32) of patients had cerebral disease control on afatinib.

Pregunta 15: ¿Existen diferencias de actividad intracraneal entre los diferentes TKI? (Dr. Alejandro Navarro)

Documento 35: Bai H, Xiong L, Han B. The effectiveness of EGFR-TKIs against brain metastases in EGFR mutation-positive non-small-cell lung cancer. Onco Targets Ther. 2017 Apr 27;10:2335-2340. Retrospective study. Calidad: +


The difference in the intracranial efficacy outcomes by the two EGFR-TKIs was also analyzed. Out of the 95 patients receiving gefitinib, there were 33 PRs and 49 SDs. Out of the 53 patients receiving erlotinib, there were 21 PRs and 26 SDs.

As a result, it cannot be identified which TKI is superior or inferior, which is similar to some isolated reports.18,35,36 Overall, the lack of clinical data available for distinct patient populations limited the conclusions of the assessment.

Documento 20: Zhang Q et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016 Nov;7(6):648-654. Retrospective study. Calidad: +

No significant difference was observed in survival between gender (male vs. female), age (< 65 years vs. ≥ 65 years), ECOG PS (0–1 vs. 2–3), EGFR mutation (19 deletion vs. other mutations), and EGFRTKIs administered (gefitinib vs. erlotinib).

Documento 22: Halifa J et al. International Association for the Study of Lung Cancer Advanced Radiation TechnologyCommittee. Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. J Thorac Oncol. 2016 Oct;11(10):1627-43. Review of literature. Calidad: +

Tyrosine kinase inhibitors (TKIs) are low molecular weight organic compounds (less than 500 Da generally) [58], with low to moderate cerebrospinal fluid (CSF) penetration rates within the brain.[59]

Erlotinib (and its active metabolite OSI-420) has been found to have a CSF penetration rate between 2.8% and 5.1% of total plasma concentration (5.8% for OSI-420).[60–62]

As compared to erlotinib, a limited number of small cohort studies showed that other first generation TKIs have low, such as gefitinib [62,67] or very low (crizotinib 68,69) CSF penetration rates.


So, while erlotinib and gefitinib at the standard dose do not sufficiently penetrate BBB in absence of CNS involvement, when BM are evident, they probably improve their CNS concentration with a consequent improvement in central activity [67]. Furthermore the inadequate TKIs penetration across the intact BBB, could explain the frequent absence of secondary resistance mutations in BM also when they are present in extra-cranial disease sites

An open-label, single-institution, phase II study prospectively evaluated the efficacy of EGFRTKIs, erlotinib or gefitinib, in pts with BM from NSCLC harboring EGFR mutations. There were no differences in PFS and OS between the different TKIs [84].

Documento 37: Park K et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89. Clinical trial. Calidad: + NOTA: Las variables principales del estudio no están enfocadas a demostrar diferencias en la actividad intracraneal, por lo que más allá de algún indicio indirecto, el estudio no puede considerarse demostrativo de la superioridad de afatinib en la actividad intracraneal. Aunque si permite apuntar una razonable hipótesis para la reflexión y estudio, por las diferencias en las variables analizadas a favor de Afatinib en el subgrupo de pacientes con metástasis cerebrales.

To the best of our knowledge, LUX-Lung 7 is the first prospective head-to-head trial to assess an irreversible ErbB family blocker, afatinib, and a reversible EGFR tyrosine kinase inhibitor, gefitinib, as first-line treatment of patients with EGFR mutation-positive NSCLC in both Asians and non-Asian patients.


This study showed that afatinib has improved efficacy compared with gefitinib over a range of clinically relevant endpoints including progression-free survival, time-to-treatment failure, and the proportion of patients achieving an objective response.

The improvement in efficacy was noted both in patients with exon 19 deletion and Leu858Arg mutations. The adverse event profile was predictable and manageable; the discontinuation rate due to treatment-related adverse events was the same as with gefitinib.

Documento 52: Hoffknecht P et al. Afatinib Compassionate Use Consortium (ACUC). Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015 Jan;10(1):156-63. Retrospective study. Calidad: +

Afatinib appears to penetrate into the CNS with concentrations high enough to have clinical effect on CNS metastases.

Pregunta 16: ¿Es seguro emplear de forma concurrente los TKI con la RT? (Dr. Alejandro Navarro)

Documento 21: Chen Y et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016 Dec;107(12):1800-1805. Retrospective study. Calidad: +

Concomitant WBRT significantly improved intracranial lesion control and prolonged intracranial TTP compared with EGFR-TKI treatment alone. However, WBRT might specifically impair hippocampus-related functions such as memory and learning, and we found that a proportion of patients who received EGFR-TKI plus WBRT showed impaired memory. To protect against radiation-induced neurotoxicity, prospective studies are needed to identify the subsets of patients treated with EGFRTKI for whom radiotherapy can be omitted.

Documento 0: Tan DS et al. The International Association for the Study of Lung Cancer Consensus Statement on Optimizing Management of EGFR Mutation-Positive Non-Small Cell Lung Cancer: Status in 2016. J Thorac Oncol. 2016 Jul;11(7):946-63. Review of literature. Calidad: ++

NOTA: Aunque la información puede ser ítil para responder a la pregunta, no se muestran los datos de

seguridad de lose studios originales.

The study established the feasibility and tolerability of this option for patients with EGFR-mutant NSCLC, who have numerous or symptomatic brain metastases and require simultaneous urgent initiation of systemic therapy at the time of WBRT115].

Patients were not tested for EGFR mutation in this study and the combination of both WBRT and SRS has now become less favored, especially in the EGFR-mutant population, thus limiting the impact of this study on practice.

Documento 1: Arvold ND et al. Updates in the management of brain metastases. Neuro Oncol. 2016 Aug;18(8):1043-65. Review of literature. Calidad: ++ NOTA: general de metastasis cerebral.

Most studies of WBRT with concurrent systemic therapy have enrolled lung cancer patients, and further studies are needed to examine the role of adding systemic therapy to WBRT across a variety of malignancies. While TMZ is sometimes administered concurrently with WBRT for patients with BM from malignant melanoma, the limited prospective data on this subject suggest minimal benefit [88].



Phase I trial, in which NSCLC pts with BM were enrolled, evaluated the toxicity of WBRT with concurrent and maintenance erlotinib showing that erlotinib was well tolerated and the combination did not cause any significant increase in treatment related toxicity [95].

Different phase II studies evaluated the efficacy and toxicity of the concurrent approach [93,96]

A phase I trial, in which NSCLC pts with BM were enrolled, evaluated the toxicity of WBRT with concurrent and maintenance erlotinib showing that erlotinib was well tolerated and the combination did not cause any significant increase in treatment related toxicity [95]. Moreover different phase II studies evaluated the efficacy and toxicity of the concurrent approach [93,96].

The phase II trial by Ma et al. [96] studied the concomitant treatment with WBRT and gefitinib in 21 Chinese pts with BM from NSCLC to assess its impact on pts QoL and posttreatment survival. All pts received 40 Gy WBRT in 20 fractions. Gefitinib was administered during the radiation course and was continued until progression or unacceptable toxicity.

Documento 39: Hendriks LE et al. Safety of cranial radiotherapy concurrent with tyrosine kinase inhibitors in non-small cell lung cancer patients: A systematic review. Cancer Treat Rev. 2015 Jul;41(7):634-45. Systematic review. Calidad: ++

In summary, although there are arguments that EGFR–TKI can be safely applied concurrent with WBRT, there is no high-level evidence to support this. With the addition of SRS/SRT to WBRT, severe (grade 3–5) toxicities may increase, although further studies are needed [34].

Documento 38: Luo S et al. Evaluation on efficacy and safety of tyrosine kinase inhibitors plus radiotherapy in NSCLC patients with brain metastases. Oncotarget. 2015 Jun 30;6(18):16725-34.. Meta-analysis. Calidad: +

Compared with radiotherapy without TKIs (non-TKI-group), TKIs plus radiotherapy (TKI-group)

had a significant benefit on objective response rate (ORR) (RR = 1.56, 95%CI [1.25,2.03]; P

=0.0008), significantly prolonged the time to central nerves system progression (CNS-TTP)

(HR =0.58, 95% CI [0.35, 0.96]; P =0.03) and median overall survival (MOS) (HR =0.68, 95% CI

[0.47, 0.98]; P =0.04) of NSCLC patients with BM. There was no significant difference in overall

severe adverse events (Grade≥3) (RR = 1.49, 95% CI [0.88,2.54]; P = 0.14) between two groups.

TKIs plus radiotherapy significantly prolong the CNS-TTP and MOS of patients without enhancing overall severe adverse events.

Documento 54: Metro G et al. Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer. Expert Opin Pharmacother. 2015;16(17):2601-13. Meta-analysis. Calidad: +

As for TKIs, clinicians are often faced with the question if the TKI may be continued during cranial radiotherapy. Certainly, advantages of combining a TKI with cranial radiotherapy would be a possible synergistic anti-tumor effect against BMs, as well as the prevention of a systemic disease flare-up, a phenomenon that can be observed shortly after discontinuation of the TKI [83,84].

A recent systematic review of studies evaluating the use of an EGFR-TKI with concurrent cranial radiotherapy found no significant increase of neurotoxicity, with a slight increase in non-neurological severe toxicities, namely rash (9 -- 20% of patients) and mucositis 5 -- 12.5% of individuals) [85].

Pregunta 17: ¿Existen interacciones de los anticonvulsivantes con los TKI? (Dr. Alejandro Navarro)


Documento 42: Ohgami M et al. Drug interaction between erlotinib and phenytoin for brain metastases in a patient with nonsmall cell lung cancer. Lung Cancer. 2016 Nov;101:9-10. Case report. Calidad: -

When using concomitant phenytoin and erlotinib, physicians should pay attention to possible drug–drug interactions inducing unfavorable effects from both drugs—toxic symptoms in the case of phenytoin and insufficient antitumor effects in the case of erlotinib, though the combination is not contraindicated.

Documento 43: Thomas-Schoemann A et al. Drug interactions with solid tumour-targeted therapies. Crit Rev Oncol Hematol. 2014 Jan;89(1):179-96. Review of literature. Calidad: +

Enzyme inducing anti-epileptics (EIAEDs) also have a significant impact on the pharmacokinetics of gefitinib, yet to a lesser extent [97,98].

Erlotinib exposure may also be altered by concomitant administration of EIAEDs in glioblastoma patients [113]

Table 3 resumes the Pharmacokinetic drug–drug interactions described in literature. Area Under Curve (AUC).

Pregunta 18: ¿Existen interacciones de los corticoides con los TKI? (Dr. Alejandro Navarro)

Base de datos: drug.com. NOTA: En los documentos seleccionados no se ha encontrado información para responder a esta pregunta, por lo que se ha realizado una búsqueda específica en esta base de datos. Se ha buscado si los siguentes TKI (afatinib, dacomitinib, erlotinib y gefitinib) tenian interacciones con los siguiente corticoides (prednisone, metilprednisolone y dexamethasone) (ver tabla 1).

Erlotitinib y gefitinib presentan interacciones con alguno de estos cordicoides, ambos con dexamethasone.

No se han hallado interacciones entre afanitib y estos corticoides.

Pregunta 19: ¿Con qué periodicidad hay que evaluar las lesiones del SNC en pacientes que no han recibido tratamiento local previo? (Dra. Adela Bartolomé)

Pregunta 20: ¿Con qué periodicidad hay que evaluar las lesiones del SNC en pacientes que han recibido tratamiento local previo? (Dra. Adela Bartolomé)

NOTA: No se distingue entre los pacientes que han recibido tratamiento local previo y los que NO. Documento 49: Nishikawa T et al.n Early detection of metachronous brain metastases by biannual brain MRI follow-up may provide patients with non-small cell lung cancer with more opportunities to have radiosurgery. Clin Neurol Neurosurg. 2010 Nov;112 (9):770-4. Retrospective study. Calidad: + NOTA: En el artículo no se menciona la perioricidad sino que demuestran que hay que tener imagenes de las lesiones antes de que produzcan síntomas porque aumenta en 1-2 años la supervivencia.

The median critical MRIs interval (CMI) was 4.7 (range: 1.6–18.9) months. All brain metastases smaller than 30mm in maximum diameter were found when CMI was shorter than 6.0 months, although 5 or more brain metastases in number were detected even by shorter CMI than 3 months.

Early detection of MBM by biannual MRI follow-up may provide NSCLC patients with more opportunities to have less invasive treatment.

Documento 10: Sánchez de Cos et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009 Jan; 63(1):140-5. Retrospective study. Calidad: +


It is important to detect brain metastasis in patients with NSCLC before neurologic signs or symptoms develop, as early detection improves prognosis and provides patients with the opportunity of receiving timely and more effective treatment.

Park et al. [5] suggested that the preoperative screening of patients with lung adenocarcinoma using cranial MRI may facilitate the detection of brain metastasis prior to surgical resection of the primary tumor and also increase postoperative survival.

Pregunta 21: En los pacientes con carcinomatosis leptomeníngea, ¿debe realizarse tratamiento intratecal o tratamiento local? (Dr. Jordi Bruna)

Documento 47: Seiji Yano,Shigeki Nanjo, Sachiko Arai, Shinji Takeuchi, Tadaaki Yamada, Yasunori Okada, Akito Hata. Nobuyuki Katakami OA08.03. MET Copy Number Gain Associates with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR Mutant Lung Cancer. Journal of Thoracic Oncology 2017. Vol. 12 No. 1S. Clinical trial. Calidad: +/-

We found that all 32 re-biopsy specimens had the same baseline EGFR mutations and that T790M was less frequent in LMC specimens than extracranial specimens (8% vs 55%). Compared with subcutaneous tumors, T790M was less frequent in LMC which acquired resistance to gefitnib. We further established PC-9/LMCGR cells from the gefitinib-resistant LMC model and found that PC-9/LMC-GR cells were intermediately resistant to gefitinib and osimertinib (3rd generation EGFR-TKI). While EGFR-T790M was negative, MET copy number gain associated MET activation was involved in the gefitinib resistance in PC-9/LMC-GR cells. Moreover, combined use of EGFR-TKI and crizotinib, having inhibitory activity against MET, dramatically regressed LMC which already acquired resistance to gefitinib or osimertinib.

These findings suggest that combined use of MET inhibitors may be promising for controlling LMC which acquires resistance to EGFR-TKIs including osimertinib.

Documento 48: Remon J et al. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era. Cancer Treat Rev. 2017 Feb;53:128-137. Review of literature. Calidad: +/-

Intrathecal chemotherapy (ITC) in combination with systemic treatment is the mainstay of treatment for non-nodular types of LM, although its superiority compared with systemic treatment alone has not been established in randomized trials [18–23].

However, given the limited number of patients, the heterogeneity in the ITC treatment and other confounding factors it is difficult to draw robust conclusions about the efficacy of ITC in NSCLC patients and clinical trials are needed.

Radiotherapy is manly given for symptoms alleviation, CSF flow correction or for debulking to facilitate chemotherapy [13].

In a recent phase II trial with 59 patients with LM from solid tumors (including 32 NSCLC patients) and adverse prognostic factors, a combination of intensive treatment of concurrent radiotherapy (whole brain and/or spinal canal radiotherapy, 40 Gy/20f) and intrathecal methotrexate reported a median survival of 6 months and 1-year OS of 21.3%. Among NSCLC patients, clinical response rate was 87.5%, which correlated with OS (median OS 6.7 months), however, the toxicity of the combination treatment (20% severe toxicity including 15% grade 3 encephalopathy) argues against this strategy in daily clinical practice [35].

Documento 50: Lee SJ et al. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013 Feb;8(2):185-91. Retrospective study. Calidad: +


In multivariate analysis, poor ECOG performance status (p = 0.026), high protein level of CSF (p = 0.027), and high initial CSF WBC count (p = 0.015) remained significant predictors of poor prognosis for survival, whereas ITC (p < 0.001), EGFR-TKI use (p = 0.018), WBRT (p = 0.009), and VP shunt operation (p = 0.013) remained significant predictors of favorable prognosis for survival.

Results suggest that more active treatment strategies including ITC, WBRT, and EGFR-TKI use might improve clinical outcomes in NSCLC patients with LC and good performance status, low initial CSF protein and WBC counts.

Documento 51: Morris PG et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012 Feb;7(2):382-5. Retrospective study. Calidad: +

In the seven patients selected to receive IT chemotherapy, median survival was 18 months (range, 5-33 months) and appeared superior to those not selected for this treatment (p =0.001) in a landmark analysis.

Survival was not improved by WBRT.

The survival of patients selected for IT chemotherapy and those with EGFR mutations treated with TKIs highlights the importance of developing novel agents.


4. Síntesis de la literatura con información encontrada para las preguntas

1. Introducción (definición y magnitud del problema, epidemiologia en

población Española)

2. Definición de asintomático/ oligosintomático/ sintomático

Pregunta 1: ¿Qué criterios definen al paciente asintomático y al oligosintomático? (Dr. Rafael

López)

En la bibliografía seleccionada no se ha encontrado una respuesta específica que pueda ayudar a responder esta

pregunta.

3. Diagnóstico por imagen y patrón de metástasis

Pregunta 2: ¿Cuál es la técnica de imagen de elección para diagnosticar las MTC? (Dr. Rafael

López)

ID (número de identificación del documento): 3

PMID: NA

NCCN Clinical Practice Guidelines Oncology Non-small cell lung cancer. Version 2.2017 – October 26, 2016 NCCN.org

Tipo de estudio Clinical Practice Guideline

Descripción del estudio (abstract)

https://www.nccn.org/patients/guidelines/cancers.aspx#nsclc




PMID: 27664245

Novello S et al. ESMO Guidelines Committee. Metastatic non small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v1-v27



https://www.ncbi.nlm.nih.gov/pubmed/27664245

Evidencias:

Imaging of the central nervous system (CNS) is most relevant in those patients with neurological symptoms or signs, however, if available, imaging of the CNS with magnetic resonance imaging (MRI, preferably with gadolinium enhancement) or CT brain with iodine contrast should be carried out at diagnosis. MRI is more sensitive than CT scan [32].

Referencias bibliográficas: [32]. Kuhn MJ et all. MRI evaluation of “solitary” brain metastases with triple-dose gadoteridol: comparison with contrast-enhanced CT and

conventional-dose gadopentetate dimeglumine MRI studies in the same patients. Comput Med Imag Graph 1994; 18: 391–399.


PMID: 28273734

Deuschl C et al. Diagnostic impact of integrated 18F-FDG PET/MRI in cerebral staging of patients with non-small cell lung cancer. Acta Radiol. 2016 Dec 14:284185116681041

Tipo de estudio Retrospective study



Contexto:

Integrated positron emission tomography/magnetic resonance imaging (PET/MRI) systems are increasingly being available and used for staging examinations. Brain metastases (BM) are frequent in patients with non-small cell lung cancer (NSCLC) and decisive for treatment strategy.

Eighty-three consecutive patients (30 women, 53 men; mean age, 61.5 years; age range, 41–85 years) with histologically proven NSCLC were enrolled in this trial. All patients were assigned for an initial cerebral staging with 18F-FDG PET/MRI. The cerebral imaging was part of a whole-body staging with initial 18F-FDG PET/CT and subsequent whole-body 18F-FDG PET/MRI.

The study has been carried out to assess the diagnostic value of integrated 18F-2-fluoro-2-deoxy-D glucose (18F-FDG) PET/MRI in initial staging in patients with NSCLC for BM in comparison to MRI alone.

Evidencias:

Patient-based analysis: o Based on the reference standard, metastases were present in 15 out of 83 patients. Consequently,

MRI alone identified metastases in all 15 patients (100%) (Table 1). o Among the remaining 68 patients without cerebral metastatic spread, 67 (98.5 %) were correctly

identified, while in one patient MRI was rated false positive. o Furthermore, based on the PET data, 6/15 patients (40%) with cerebral metastases were correctly

identified (Figs 1 and 2*), while in the remaining nine patients, metastatic disease was missed (Fig. 3*). PET did not show any focal tracer accumulation, suspicious of cerebral metastases, in the 68 patients without cerebral tumor spread.




Lesion-based analysis:

o A total of 39 lesions were depicted and classified as malignant according to the reference standard. o All 39 lesions were visible on MRI (100%). Based on the PET component of hybrid 18F-FDG

PET/MRI datasets 15/39 metastases showed a metabolic correlate (38.5%), whereas the remaining 24 metastases were only visible on MRI (61.5%). Moreover, PET did not detect any additional metastases.

o Detectability of metastases in dependence of lesions size in PET is illustrated in Table 2. o Based on MRI alone 13 metastases smaller than 5mm were detected. Based on the PET-component

of hybrid 18F-FDG PET/MRI, 1/13 was correctly identified as a metastasis (8% sensitivity<5 mm). Considering the size range of 5–10 mm, 15 metastases were detected on MRI and three in PET (27% sensitivity). A total of 11 metastases larger than 10mm were described in MRI with a pathologic correlate in the PET-component in nine patients (82% sensitivity). PET did not detect any additional metastases.

* Para acceder a datos completos de tablas y figuras, ver .pdf completo Conclusiones:

The sensitivity of PET in detection of BM depends on their size. 18F-FDG PET/MRI does not lead to an improvement in diagnostic accuracy in cerebral staging of NSCLC patients, as MRI alone remains the gold standard.


PMID: 25239395

O'Dowd et al. Brain metastase following radical surgical treatment of non-small cell lung cancer: is preoperative brain imaging important? Lung Cancer. 2014 Nov;86(2):185-9.



https://www.ncbi.nlm.nih.gov/pubmed/?term=25239395

Contexto:

There is a lack of good quality evidence or a clear consensus of opinion internationally regarding who should receive preoperative imaging of the brain prior to radical treatment for non-small cell lung cancer (NSCLC) [1-3].



The study aimed at establishing the proportion of patients who developed brain metastases following curative surgery and to estimate how many could have been detected by preoperative magnetic resonance imaging (MR).

We performed a retrospective analysis of 646 patients who underwent surgery for lung cancer with curative intent at a regional thoracic surgical centre in the United Kingdom (between 2006 and 2011). We identified those who developed brain metastases in the postoperative period and, by using volume doubling times, estimated the size of the metastasis at the time of surgery.

Evidencias:

There was a 6.3% incidence of postoperative brain metastases, with the majority occurring within 12 months of surgery. Those who developed metastases were more likely to have adenocarcinoma and the majority had early stage malignancy (73% stage I or stage II).

Using a 5 mm detection threshold 29 (71%) of brain metastases should have been of at least 5 mm maximum diameter at time 0.Using a 2 mm detection threshold 34 (83%) would have been at least 2 mm in maximum diameter at time 0. These would be potentiallydetectable had MR brain been performed as part of the staging process. This means that 4.4% (29/646) of our patients who underwent surgery would have had their brain metastases detected by preoperative MR and this might have been as high as 5.3% (34/646) with optimal MR detection limits.

Recomendaciones:

American College of Chest Physicians (ACCP) guidelines recom-mend magnetic resonance imaging (MR) of the brain in those withclinical stage III or IV disease even if neurologically asymptomatic [1], whilst National Institute for Health and Care Excellence (NICE)and British Thoracic Society (BTS) guidelines recommend consider-ation of MR or contrast-enhanced CT of the head in patients selectedfor treatment with curative intent, particularly in stage III disease [2,3] (texto extraído de la introducción del artículo).

Whilst proportionally morestage III patients developed brain metastases, these data argue thatpreoperative brain imaging should be applied irrespective of stage.

Conclusiones:

We estimate that 71% of those who developed cerebral metas-tases might have been detected had they undergone MR brain as part of their staging (assuming a 5 mm detection threshold), potentially avoiding futile surgery in 4.4% of patients or providing anopportunity to treat oligometastatic disease.

Based on our findings we suggest that, in addition to standard staging investigations, patients have brain imaging (MR or equivalent) prior to curative surgery in NSCLC regardless of preoperative stage.

Referencias bibliográficas [1]. Detterbeck FC et. Executive summary: diagnosis and management of lung cancer, 3rd ed: american college of chest physicians evidence-based clinical practice guidelines. Chest J 2013;143(5 (Suppl.)):7S–37S. [2]. Baldwin DR et al. Diagnosis and treatment of lung cancer: summary of updated NICE guidance. Br Med J 2011:342. [3]. Lim E et al. Guidelines on the radical management of patients with lung cancer. Thorax 2010;65:1–27.


PMID: 22890912

Wu Y et al. Diagnostic value of fluorine 18 fluorodeoxyglucose positron emission tomography/computed tomography for the detection of metastases in non-small-cell lung cancer patients. Int J Cancer. 2013 Jan 15;132(2):E37-47

Tipo de estudio Meta-analysis



Contexto:

In the recent years, fluorine 18 fluorodeoxyglucose (18

F-FDG) positron emission tomography (PET)/computed tomography (CT) has emerged as a new modality for staging non-small-cell lung cancer (NSCLC) patients 4, 14.

The aim of this meta-analysis was to assess the diagnostic value of 18

F-FDG PET/CT in detecting



metastatic lesions in NSCLC patients.

Data from included studies were pooled to compare the diagnostic accuracy between PET/CT and PET or CT alone in nodal staging.

Evidencias:

Totally, 56 studies involving 8,699 patients met the inclusion criteria.

The pooled sensitivities and specificities of 18

F-FDG PET/CT were 0.72 [95% confidence interval (CI): 0.65-0.78] and 0.91 (95% CI: 0.86-0.94) in determining mediastinal nodal staging; 0.71 (95% CI: 0.60-0.80) and 0.83 (95% CI: 0.77-0.88) in intrathoracic staging; 0.78 (95% CI: 0.64-0.87) and 0.90 (95% CI: 0.84-0.94) in intrathoracic staging on a per-node basis.

For detecting extrathoracic metastases: the pooled sensitivities and specificities of 18

F-FDG PET/CT were 0.77 (95% CI: 0.47-0.93) and 0.95 (95% CI: 0.92-0.97) for all extrathoracic metastases; 0.91 (95% CI: 0.80-0.97) and 0.98 (95% CI: 0.94-0.99) for bone metastases.

Detection of brain metastases and adrenal metastases. Two studies with 546 patients evaluated the accuracy of detecting brain metastases by PET/CT on a per-patient basis.24,25 In the study of Kruger et al.,24 PET/CT was performed with contrast medium while in the study of Lee et al.,25 the CT portion of PET/CT was unenhanced. The sensitivities of these two studies were 0.27 and 0.24, and the specificities were 0.98 and 1.00, respectively. One study containing 51 patients assessed the diagnostic performance of 18

F-FDG PET/CT in detecting adrenal metastases. 26 Using SUVmax > 2.7 as the diagnostic criteria, the sensitivity was 0.89 and the specificity was 0.88.

Conclusiones:

18

F-FDG PET/CT is beneficial in detecting lymph node metastases and extrathoracic metastases although PET/CT showed low sensitivity in detecting brain metastases.

18

F-FDG PET/CT confers significantly higher sensitivity and specificity than contrast-enhanced CT (both p < 0.01) and higher sensitivity than

18F-FDG PET in staging NSCLC (p < 0.05).

Referencias bibliográficas 4. Antoch G, Stattaus J, Nemat AT, et al. Non-small cell lung cancer: dual-modality PET/CT in preoperative staging. Radiology 2003;229:526–33. 14. Cerfolio RJ, Ojha B, Bryant AS, et al. The accuracy of integrated PET-CT compared with dedicated PET alone for the staging of patients with nonsmall cell lung cancer. Ann Thorac Surg 2004;78:1017–23; discussion 23. 24. Kruger S, Mottaghy FM, Buck AK, et al. Brain metastasis in lung cancer. Comparison of cerebral MRI and 18F-FDG-PET/CT for diagnosis in the initial staging. Nuklearmedizin 2011;50. 25. Lee HY, Lee KS, Kim BT, et al. Diagnostic efficacy of PET/CT plus brain MR imaging for detection of extrathoracic metastases in patients with lung adenocarcinoma. J Kor Med Sci 2009; 24:1132–8. 26. Cho AR, Lim I, Na II, et al. Evaluation of adrenal masses in lung cancer patients using F-18 FDG PET/CT. Nucl Med Mol Imaging 2011;45:52–8.

Pregunta 3: ¿Se deben realizar pruebas de imagen en pacientes asintomáticos para identificar

MTC? (Dr. Rafael López)


PMID: 18556086

Sánchez de Cos et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009 Jan;63(1):140-5.




Contexto:

The aim of this study was to evaluate clinical course, prognostic significance, and treatment efficacy



in patients with asymptomatic brain metastasis

In a series of patients with potentially operable NSCLC and small brain lesions detected by either cranial CT or MRI, observed good survival times for both groups of patients, although survival in the MRI group was slightly higher [1].

A retrospective study of patients with cytologically and histologically diagnosed NSCLC and brain metastasis detected by cranial computed tomography or magnetic resonance imaging was performed. 12 neurologically asymptomatic patients and 69 symptomatic patients were analysed; overall survival, clinical course, and prognostic factors were considered.

Evidencias:

Of the 476 patients diagnosed with lung cancer between 1 January 1996 and 31 June 2007 who had at least 1 cranial CT or MRI study, 81 had histologically proven NSCLC and radiologically diagnosed brain metastasis. Table 1* shows the characteristics of the patients from each group.

Asymptomatic patients had better performance status than symptomatic ones (p = 0.048) as well as a higher rate of synchronous brain lesions (p = 0.002), a larger number of tumors detected by cranial MRI (p < 0.001), and significantly smaller brain lesions (p = 0.005). Forty patients had metachronous brain metastasis

Conclusiones:



In a previous study comparing the value of cranial CT and MRI in the detection of silent brain metastasis in patients with lung cancer, we found that 8.3% of patients had brain lesions and that cranial MRI detected more lesions smaller than 1 cm than did CT [15].


* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Referencias bibliográficas

[1] Yokoi K et al. Detection of brain metastasis in potentially operable non-small cell lung cancer. A comparison of CT and MRI. Chest 1999;115:714–9. [5] Park HY et. Routine screening by brain magnetic resonance imaging decreased the brain metastasis rate following surgery for lung adeno [12] Nguyen TD, DeAngelis LM. Brain metastases. Neurol Clin 2007:1173–92.carcinoma. Lung cancer 2007;58:68–72. [15] Sánchez de Cos J et al. Metástasis encefálicas silentes en la estadificación inicial del cáncer de pulmón. Arch Bronconeumol 2007;43(7):386–91.


PMID: 18303434

Jena A. et al. Magnetic resonance (MR) patterns of brain metastasis in lung cancer patients: correlation of imaging findings with symptom. J Thorac Oncol. 2008 Feb;3(2):140-4.






Contexto:

Asymptomatic brain metastasis in lung cancer patients, if detected early have been reported to show survival benefit with treatment. These asymptomatic metastasis have been found to be smaller and less in number than those with symptoms.

Database search of the cases attending a medical oncology clinic of our institute identified 175 patients of proven NSCLC (age group 32–80 years, male-to-female ratio 152:23) who were treated between 2003 and 2006.

Patients of NSCLC with large metastatic load in brain at the time of initial presentation are commonly neurologically asymptomatic: the study was aimed at investigating whether imaging pattern of brain metastasis is in any way different in the symptomatic and asymptomatic patients.

Evidencias:

Brain metastasis was seen in 62 (31.3%) patients of whom 46.7% were neurologically asymptomatic.

Patients (90.3%) with brain metastasis were in stage IV at the time of presentation.

No statistically significant correlation was found between the two groups regarding the number of lesions (p =

0.554), size of lesion (p = 0.282), site of lesion (p = 0.344), nature of lesion (p = 0.280), presence of

perilesional edema (p = 0.404), and presence or absence of intralesional hemorrhage (p = 0.09). Brain

metastases were present only in stages III and IV disease with no statistically significant difference in the

lesion pattern (Table 4).

Conclusiones:

The incidence of asymptomatic brain metastasis in our study was 16.5% with almost equal number of


symptomatic and asymptomatic metastasis in lung cancer patients. Hence, imaging surveillance of the brain for metastasis is worthwhile to detect asymptomatic metastasis early for early institution of appropriate therapy.


PMID: 18707868

Na II, Lee TH et al. A diagnostic model to detect silent brain metastases in patients with non-small cell lung cancer. Eur J Cancer. 2008 Nov;44(16):2411-7.




Contexto:

It has been suggested that diagnostic accuracy of MRI is superior to computed tomography (CT) in patients with brain metastasis. [22, 23]. Although clinical benefits of its application remain unclear in asymptomatic patients with NSCLC [10] detection of brain metastases could reduce the discomfort and the unnecessary risks caused by invasive procedures.

Extrathoracic staging of NSCLCs is important for prognostic estimation and treatment strategy. 4,5 The brain is one of the most frequent sites of extra-thoracic metastases.6

This retrospective study was carried out to identify predictive factors and to discriminate subgroups according to the risk of brain metastases in patients with NSCLC lacking neurological symptoms

The study was carried out in 433 patients with NSCLC who underwent chest CT, brain magnetic resonance imaging (MRI) and bone scans at an initial staging: Brain metastases were determined by MRI. Between April 2003 and April 2007.

Evidencias:

Amongst 17 patients with a single brain lesion, nine underwent follow-up brain MRI scans at least three months later, and progressing lesions in the brain were observed in six of them.

The 433 patients were allocated to four groups according to the number of risk factors: 124 patients with none; 202 patients with one; 81 patients, with two and 26 with three. In multivariate analysis, histopathology with non-squamous cell carcinoma, nodal stage P2 on CT and presence of bone metastases were three risk factors for brain metastases. Patients were divided into four groups according to the number (0–3) of these predictive factors.

The proportions of patients with brain metastases in the four groups were 2%, 3%, 17% and 35%, respectively, and these differences were significant (P < 0.001). When analysis was performed in patients with localised disease, the number of risk factors was correlated with the prevalence of brain metastases (P = 0.013) but stage was not (P = 0.153).

Conclusiones:

Although the results of our study could be biased by false positive interpretations of brain metastases, it should be noted that MRI is more accurate for the diagnosis of brain metastases than CT, in accordance with other studies [10, 23].

Referencias bibliográficas 4. Quinn DL, Ostrow LB, Porter DK, Shelton Jr DK, Jackson Jr DE. Staging of non-small cell bronchogenic carcinoma. Relationship of the clinical evaluation to organ scans. Chest 1986;89(2):270–5. 5. Pope RJ, Hansell DM. Extra-thoracic staging of lung cancer. Eur J Radiol 2003;45(1):31–8. 6. Hillers TK, Sauve MD, Guyatt GH. Analysis of published studies on the detection of extrathoracic metastases in patients presumed to have operable non-small cell lung cancer. Thorax 1994;49(1):14–9. [10] Yokoi K et al. Detection of brain metastasis in potentially operable non-small cell lung cancer: a comparison of CT and MRI. Chest 1999;115(3):714–9. [22] Schellinger PD et al. Diagnostic accuracy of MRI compared to CCT in patients with brain metastases. J Neurooncol 1999;44(3):275–81 [23] Davis PC et al. Diagnosis of cerebral metastases: double-dose delayed CT vs. contrastenhanced MR imaging. AJNR Am J Neuroradiol 1991;12(2):293–300.



4. Factores pronósticos

Pregunta 4: ¿Qué variables clínicas y radiológicas tienen impacto en el pronóstico del paciente?

(Dra. Eugenia Verger)


PMID: 27892978

Sperduto PW et al. Estimating Survival in Patients With Lung Cancer and Brain Metastases: An Update of the Graded Prognostic Assessment for Lung Cancer Using Molecular Markers (Lung-molGPA). JAMA Oncol. 2016 Nov 17.




Contexto:

The study is aimed at updating the current Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) for patients with non–small-cell lung cancer (NSCLC) and brain metastases, incorporating more recently reported gene and molecular alteration data for patients with NSCLC and brain metastases. This new index is called the Lung-molGPA.

To design the updated Lung-molGPA, we analyzed data from 2186 patients from 2006 through 2014 with NSCLC and newly diagnosed brain metastases (1521 adenocarcinoma and 665 nonadenocarcinoma).

Evidencias:

Significant prognostic factors included the original 4 factors used in the DS-GPA index plus 2 new factors: EGFR and ALK alterations (Table 2) in patients with adenocarcinoma (mutation status was not routinely tested for nonadenocarcinoma).

The overall median survival for the cohort in the present study was 12 months, and those with NSCLC-adenocarcinoma and Lung-molGPA scores of 3.5 to 4.0 had a median survival of nearly 4 years.

Conclusiones: The new DS-GPA has unveiled nuances in management not previously appreciated:



Recent secondary analyses applying the DS-GPA to landmark randomized trials showed that patients with good DS-PGA prognosis (score >3) achieved a survival benefit with the addition of WBRT to SRS [12,13] contrary to the current clinical trend to avoid WBRT;

The survival benefit of ALK alterations found by the Lung-molGPA has been reported by others [14], contrary to the findings of a study that did not use the DS-GPA [15].

In recent years, patient survival and physicians’ ability to predict survival in NSCLC with brain metastases has improved significantly. The updated Lung-molGPA incorporating gene alteration data into the DS-GPA is a user-friendly tool that may facilitate clinical decision making and appropriate stratification of future clinical trials.

Referencias bibliográficas 12. Sperduto PW, Shanley R, Luo X, et al. Secondary analysis of RTOG 9508, a phase 3 randomized trial of whole-brain radiation therapy versus WBRT plus stereotactic radiosurgery in patients with 1-3 brain metastases; poststratified by the graded prognostic assessment (GPA). Int J Radiat Oncol Biol Phys. 2014;90(3):526-531.

[13]. Aoyama H et al. Japanese Radiation Oncology Study Group 99-1 (JROSG 99-1) Investigators. Stereotactic radiosurgery with or without

whole-brain radiotherapy for brain metastases: secondary analysis of the JROSG 99-1 randomized clinical trial. JAMA Oncol. 2015;1(4): 457-464. [14]. Johung KL et al. Extended survival and prognostic factors for patients with ALK-rearranged non-small cell lung cancer and brain metastasis. J Clin Oncol. 2015;2016;34(2): 123-129. [15]. Yamamoto M et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387-395


PMID: 22544733

Barnholtz-Sloan JS et al. A nomogram for individualized estimation of survival among patients with brain metastasis. Neuro Oncol. 2012 Jul;14(7):910-8. De-identified data from 7 RadiationTherapy Oncology Group randomized trials

Tipo de estudio Study to develop a nomogram



Contexto:

The study was aimed at developing and internally validate a prognostic nomogram for estimation of survival among patients with brain metastasis.

De-identified data for 2367 patients with brain metastasis from 7 Radiation Therapy Oncology Group randomized trials were used. De-identified data were provided by RTOG for 7 brain metastasis randomized clinical trials spanning over 20 years.

The prognostic accuracy for survival from 3 statistical approaches (Cox proportional hazards regression, recursive partitioning analysis [RPA], and random survival forests) was calculated using the concordance index.

A nomogram for 12- month, 6-month, and median survival was generated using the most parsimonious model.The nomogram provides individualized estimates of survival, compared with current RPA and Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) group estimates.

Evidencias:

Of the 2350 patients available for study, 2273 were deceased (96.7%). Characteristics of these patients are shown in Table 1* along with the number of patients with missing information by variable of interest.

The majority of patients had lung cancer, controlled primary disease, no surgery, Karnofsky performance score (KPS) ≥ 70, and multiple brain metastases and were in RPA class II or had a Diagnosis-Specific Graded Prognostic Assessment (DS-GPA) score of 1.25–2.5. The overall median survival was 136 days (95% confidence interval, 126–144 days).

The best fitting model was the Cox proportional hazards survival model and included primary site and



histology, status of primary disease, metastatic spread, age, KPS, and number of brain lesions. Thus, the nomogram was built using this model (Fig. 2).

* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Conclusiones

In conclusion, we have developed a tool for assessing individualized survival estimates for patients with brain metastasis. The nomogram provides an individualized estimate of survival, rather than a group estimate. This tool should be useful to patients and health care teams for counseling patients with respect to prognosis. Future directions include external validation in a new dataset and expanding its development in patient cohorts with much greater rates of resection and/or radiosurgery.


PMID: 24281220

Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers (Basel). 2010 Dec 15;2(4):2100-37.

Tipo de estudio Review of literature



Contexto: The study reviewed the treatment of Brain Metastasis from Lung Cancer. Evidencias:



Prognostic Factors: A retrospective recursive partitioning analysis (RPA) was performed based on three consecutive Radiation Therapy Oncology Group (RTOG) trials, which included approximately 1200 patients with brain metastases [21].

Three prognostic classes (RPA class I, II and III) were found to be associated with the overall survival of patients with brain metastases. This classification scheme is based on age at diagnosis, presence of extracranial disease, Karnofsky performance status (KPS), and the status of the primary cancer. RPA class I includes patients who are younger than 65 years of age, have a KPS score of ≥70, tumor controlled at the primary site, and no extracranial disease. RPA class III patients have a KPS score of less than 70. All other patients are in RPA class II. The median survival times for the RPA classes I-III were 7.1, 4.2, and 2.3 months, respectively. This RPA classification is the most commonly used prognostic system for brain metastases, with further validation in Phase III and major institutional studies for both NSCLC and SCLC [22-25].

Despite the common adaptation of RPA classification, clinicians are still faced with the dilemma of tailoring treatments to individual patients because factors such as the number or volume of brain metastases were not included in the RPA initially, estimation of systemic disease was not consistently reliable, etc. As newer data came out, a new prognostic index, the graded prognostic assessment (GPA), was generated based on data from five randomized RTOG studies involving brain metastases [26]. Please refer to Table 2* for details of the GPA scoring system. The median survival times according to GPA score were: GPA 0–1, 2.6 months; GPA 1.5–2.5, 3.8 months; GPA 3, 6.9 months; and GPA 3.5–4.0, 11.0 months (p < 0.05).

The GPA prognostic index was further validated based on specific diagnosis at the primary site due to the heterogeneous response of brain metastases to various treatment approaches based on histology and the various patterns of systemic disease and response to systemic therapy for different types of primary tumor [27]. For both NSCLC and SCLC, all four prognostic factors remained significant, confirming the prognostic value of the original GPA for lung cancer.

* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Referencias bibliográficas [21]. Gaspar et al.. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int. J. Radiat. Oncol. Biol. Phys. 1997, 37, 745-751. [22]. Gaspar et al. Validation of the RTOG recursive partitioning analysis (RPA) classification for brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 2000, 47, 1001-1006. [23]. Kepka et al. M. Results of whole-brain radiotherapy for patients with brain metastases from lung cancer: The RTOG RPA intra-classes analysis. Acta Oncol. 2005, 44, 389-398. [24]. Videtic et al. Validation of the RTOG recursive partitioning analysis (RPA) classification for small-cell lung cancer-only brain metastases. Int. J. Radiat. Oncol. Biol. Phys. 2007, 67, 240-243. [25]. Gülbas et al. The use of recursive partitioning analysis grouping in patients with brain metastases from non-small-cell lung cancer. Jpn. J. Clin. Oncol. 2006, 36, 193-196. [26]. Sperduto A. et al. A new prognostic index and comparison to three other indices for patients with brain metastases: An analysis of 1960 patients in the RTOG database. Int. J. Radiat. Oncol. Biol. Phys. 2008, 70, 510-514. [27]. Sperduto, P. et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: A multi-institutional analysis of 4,259 patients. Int. J. Radiat. Oncol. Biol. Phys. 2010, 77, 655-661.


PMID: 19942357





Contexto:

The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis- Specific Graded Prognostic Assessment [DS-GPA])

A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11



institutions. The significant prognostic factors were determined and used to define the DS-GPA prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment.

Evidencias:

The patient characteristics are listed in Table 1.

Table 2 lists the results of the multivariate analysis of the prognostic factors for each primary site.

The significant prognostic factors varied by diagnosis.

For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. The definitions of the DS-GPA prognostic indexes are listed in Table 3.


Median survival by GPA score and diagnosis Table 4 lists the median survival, in months (95% confidence intervals) by diagnosis and diagnosis-specific GPA score for patients with newly diagnosed BMs.

Treatment comparison Table 5 lists the results of the multivariate analysis of the risk of death and median survival by treatment and diagnosis. For BM patients with NSCLC, all other treatments were statistically significantly superior to WBRT.


Conclusiones:

The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.

The study emphasise the heterogeneity of patients with BMs and offer diagnosis-specific prognostic factors, indexes, and the outcomes that can be expected from the various treatment options.

Pregunta 5: ¿Cuál es el valor de las escalas pronósticas? (Dra. Eugenia Verger)


PMID: 28391295



Descripción del estudio




(abstract)

Evidencias:

The majority of patients who develop brain metastases have a limited life expectancy, as the appearance of the disease in the brain is frequently a hallmark of disseminated end stage disease, but patients with a limited disease may have a more favorable outcome with the use of intensive therapies. Knowledge of the most powerful prognostic factors (Karnofsky performance status [KPS], age, extracranial tumor activity, number of brain metastases, primary tumor type/molecular subtype) is crucial for predicting individual prognosis.

In this regard, several prognostic indices have been developed in order to distinguish subgroups of patients with different outcomes [2,3].

Referencias bibliográficas: [2] Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group

(RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys. 1997;37(4):745–751. [3]. Sperduto PW, Chao ST, Sneed PK, et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys. 2010;77(3):655–661.


PMID: 28237400

Zindler JD et al. Individualized early death and long-term survival prediction after stereotactic radiosurgery for brain metastases of non-small cell lung cancer: Two externally validated nomograms. Radiother Oncol. 2017 May;123(2):189-194.




Contexto:

To predict survival in BM patients, several prognostic models have been published in the past decades [2–4].

The most commonly used is the Recursive Partitioning Analysis (RPA), which is a relatively simple scoring system, initially developed in patients who were treated with whole brain radiotherapy (WBRT), and subsequently validated for other treatment modalities [5]

Commonly used clinical models for survival prediction after stereotactic radiosurgery (SRS) for brain metastases (BMs) are limited by the lack of individual risk scores and disproportionate prognostic groups. In this study, two nomograms were developed to overcome these limitations.

Evidencias:

495 patients with BMs of NSCLC treated with SRS for a limited number of BMs in were identified and divided in a training cohort (n = 214, patients treated in one hospital) and an external validation cohort n = 281, patients treated in three other hospitals). Clinical data were collected from all patients with newly diagnosed BMs treated with linear accelerator-based SRS between December 2002 and March 2015 in four participating Dutch Radiation Oncology centers.

Using the training cohort, nomograms were developed for prediction of early death (<3 months) and long-term survival (>12 months) with prognostic factors for survival (Fig. 1*).. Accuracy of prediction was defined as the area under the curve (AUC) by receiver operating characteristics analysis for prediction of early death and long term survival.

Prognostic factors for survival were: WHO performance status, presence of extracranial metastases, age, GTV largest BM, and gender. Number of brain metastases and primary tumor control were not prognostic factors for survival.



In the external validation cohort, the nomogram predicted early death statistically significantly better (p < 0.05) than the unfavorable groups of the RPA, DS-GPA, GGS, SIR, and Rades 2015 (AUC = 0.70 versus range AUCs = 0.51–0.60 respectively). With an AUC of 0.67, the other nomogram predicted 1 year survival statistically significantly better (p < 0.05) than the favorable groups of four models (range AUCs = 0.57–0.61), except for the SIR (AUC = 0.64, p = 0.34). The models are available on www.predictcancer.org.

* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Conclusiones:

In conclusion, two novel clinical nomogram models were developed and validated for the prediction of respectively early death (<3 months) and long-term (>1 year) survival after SRS for patients with a maximum of four BMs of NSCLC.

These nomogram models can be used for individual probability assessments, and to avoid the limitations of previously published prognostic classification systems. The nomograms can be found at www.predictcancer. org

Bibliografia: [2] Zindler JD, Rodrigues G, Haasbeek CJ, et al. The clinical utility of prognostic scoring systems in patients with brain metastases treated with

radiosurgery. Radiother Oncol 2013;106:370–4. [3] Nieder C, Mehta MP. Prognostic indices for brain metastases – usefulness and challenges. Radiat Oncol 2009;4:10. [4] Rodrigues G, Bauman G, Palma D, et al. Systematic review of brain metastases prognostic indices. Pract Radiat Oncol 2013;3:101–6. [5] Gaspar L, Scott C, Rotman M, et al. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. Int J Radiat Oncol Biol Phys 1997;37:745–51.

ID (número de identificación del documento: 17

PMID: 28185793

Dinglin XX et al. Establishment of an Adjusted Prognosis Analysis Model for Initially Diagnosed Non-Small-Cell Lung Cancer With Brain Metastases From Sun Yat-Sen University Cancer Center. Clin Lung Cancer. 2017 May;18(3)




http://www.predictcancer.org/



Contexto:

The most widely used prognostic index for cancer patients with BM over the last decade was the RPA (recursive partition analysis) index, which was based on 4 stratified factors (Karnofsky performance score (KPS), age, presence or absence of extracranial metastases, and the control status of the primary tumor)[6], originally described by the Radiation

Therapy Oncology Group (RTOG) [7]. And GPA (Graded Prognostic Assessment) was another popularly used index which had considered the number of brain lesion as the extra prognostic factors for brain metastases on the basis of RPA [8].

Evidencias:

We retrospectively screened patients with BM at the initial diagnosis of NSCLC who received treatment at Sun Yat-Sen University Cancer Center from August 1994 to December 2011. Using the same inclusion and exclusion criteria, an additional non-overlapping cohort of 321 patients from January 2012 to August 2015 was used as a validation cohort. A total of 1158 consecutive patients (837 in derivation cohort and 321 in validation cohort) with newly diagnosed BMs from NSCLC were enrolled.

It were stablished 2 prognostic models (APA 1 and 2) for the whole group of patients and for those with known epidermal growth factor receptor (EGFR) genotype, respectively.

Six factors were independently associated with survival time: Karnofsky performance status, age, smoking history (replaced by EGFR mutation in APA 2), local treatment of intracranial metastases, EGFR-tyrosine kinase inhibitor treatment, and chemotherapy. Patients in the derivation cohort were stratified into low- (score, 0-2), moderate- (score, 3-5), and high-risk (score 6-7) groups according to the median survival time (16.6, 10.3, and 5.2 months, respectively; P < 0.001). The results were further confirmed in the validation cohort. (Table 2 and table 3*)

Conclusiones:

Our study showed that the APA model 1 was feasible for NSCLC BM patients with unknown EGFR genotype, whereas the APA model 2 was more appropriate for patients with BM from NSCLC with known EGFR status.

Compared with recursive partition analysis and graded prognostic assessment, APA seems to be more suitable for initially diagnosed NSCLC with BMs.

Referencias bibliográficas [6] Gaspar L et al.. Recursive partitioning analysis (RPA) of prognostic factors in three Radiation Therapy Oncology Group (RTOG) brain metastases trials. International journal of radiation oncology, biology, physics 1997;37(4):745-751. [7] Nieder C and Mehta MP. Prognostic indices for brain metastases--usefulness and challenges. Radiat Oncol 2009;4:10. [8] Sperduto PW et al. A new prognostic index and comparison to three other indices for patients with brain metastases: an analysis of 1,960 patients in the RTOG database. International journal of radiation oncology, biology, physics 2008;70(2):510-514.


PMID: 19942357





Contexto:

The purpose of the present study was to identify significant diagnosis-specific prognostic factors and indexes (Diagnosis- Specific Graded Prognostic Assessment [DS-GPA])

A retrospective database of 5,067 patients treated for BMs between 1985 and 2007 was generated from 11 institutions. The significant prognostic factors were determined and used to define the DS-GPA



prognostic indexes. The DS-GPA scores were calculated and correlated with the outcomes, stratified by diagnosis and treatment.

Evidencias:

The patient characteristics are listed in Table 1.

Table 2 lists the results of the multivariate analysis of the prognostic factors for each primary site.

The significant prognostic factors varied by diagnosis.

For non-small-cell lung cancer and small-cell lung cancer, the significant prognostic factors were Karnofsky performance status, age, presence of extracranial metastases, and number of BMs, confirming the original GPA for these diagnoses. The definitions of the DS-GPA prognostic indexes are listed in Table 3.


Median survival by GPA score and diagnosis Table 4 lists the median survival, in months (95% confidence intervals) by diagnosis and diagnosis-specific GPA score for patients with newly diagnosed BMs.

Treatment comparison Table 5 lists the results of the multivariate analysis of the risk of death and median survival by treatment and diagnosis. For BM patients with NSCLC, all other treatments were statistically significantly superior to WBRT.


Conclusiones:

The prognostic factors for BM patients varied by diagnosis. The original GPA was confirmed for non-small-cell lung cancer and small-cell lung cancer. New DS-GPA indexes were determined for other histologic types and correlated with the outcome, and statistical separation between the groups was confirmed. These data should be considered in the design of future randomized trials and in clinical decision-making.

The study emphasise the heterogeneity of patients with BMs and offer diagnosis-specific prognostic factors, indexes, and the outcomes that can be expected from the various treatment options.

Pregunta 6: ¿Tienen un pronóstico diferente los pacientes con MTC dependiendo del tipo de

mutación? (Dra. Eugenia Verger)?


PMID: 28113019

Magnuson WJ, et al. Management of Brain Metastases in Tyrosine Kinase Inhibitor-Naïve Epidermal Growth Factor Receptor-Mutant Non-Small-Cell Lung Cancer: A Retrospective Multi-Institutional Analysis. J Clin Oncol.

2017 Apr 1;35(10):1070-1077.





Contexto:

All patients with EGFRmutant lung adenocarcinoma who developed brain metastases between January 1, 2008, and December 31, 2014, were identified. A total of 351 patients from six institutions with EGFR-mutant NSCLC developed brain metastases and met inclusion criteria for the study.

Patients with EGFR-mutant NSCLC may have a higher likelihood of being diagnosed with brain metastases because of prolonged survival from targeted systemic agents and the increased quality of CNS imaging [5,6].

This multi-institutional analysis sought to determine the optimal management of patients with EGFR-mutant NSCLC who develop brain metastases and have not received EGFR-TKI.

Evidencias:

Multivariable analysis of patient characteristics demonstrated that SRS versus EGFR-TKI, WBRT versus EGFR-TKI, performance status, age, EGFR exon 19 mutation, and absence of extracranial metastases were associated with improved OS (Table 2).

Referencias bibliográficas

[5]. Eichler AF et al: The biology of brain metastases-translation to new therapies. Nat Rev Clin Oncol 8:344-356, 2011

[6]. Fink KR, Fink JR: Imaging of brain metastases. Surg Neurol Int 4:S209-S219, 2013 (suppl 4)


PMID: 28061489

Lee MHet al. The Influence of Biomarker Mutations and Systemic Treatment on Cerebral Metastases from NSCLC Treated with Radiosurgery. J Korean Neurosurg Soc. 2017 Jan 1;60(1):21-29.


Descripción del https://www.ncbi.nlm.nih.gov/pubmed/28061489




estudio (abstract)

Contexto:

We retrospectively reviewed the medical records of 817 patients who underwent GKS for brain metastases from NSCLC between January 2002 and December 2012 at our institute. Among these patients, 134 patients with pretreatment data available for epidermal growth factor receptor (EGFR) mutation, K-ras mutation, and anaplastic lymphoma kinase (ALK) mutation were included in analysis.

The study was to analyzes outcomes and identify prognostic factors in patients with cerebral metastases from non-small cell lung cancer (NSCLC) treated with gamma knife radiosurgery (GKS) particularly, focusing on associations of biomarkers and systemic treatments.

Representative biomarkers including epidermal growth factor receptor (EGFR) mutation (exon 18–21 K-ras mutation, and anaplastic lymphoma kinase (ALK) mutation status were investigated.

The mutational analyses of EGFR (exon 18–21) and K-ras (exon 2, 3) were performed by using directional sequencing of PCR fragments amplified from genomic DNA.

Evidencias:

EGFR mutation (+) (exon 18–21) and ALK mutation (+) were identified as independent positive prognostic factors related to the prolonged overall survival.

Conclusiones:

The prognosis of patients with brain metastases of NSCLC after GKS significantly differed according to specific biomarkers (EGFR and ALK mutations).

Results show that target agents combined with GKS was related to significantly longer overall survival, and salvage treatment-free survival.


PMID: 28076323

Zhu Q, et al. Clinical outcome of tyrosine kinase inhibitors alone or combined with radiotherapy for brain metastases from epidermal growth factor receptor (EGFR) mutant non small cell lung cancer (NSCLC). Oncotarget. 2017 Feb 21;8(8):13304-13311




Contexto:

This study compared treatment outcomes between TKI monotherapy and TKI administration combined with brain radiotherapy (TKI + RT) in 133 non-small cell lung cancer (NSCLC) patients with brain metastasis (BM). 67 were treated with TKI + RT (63 received WBRT while four received SRS) and 66 received TKI alone.

It also evaluated the association of different epidermal growth factor receptor (EGFR) mutation subtypes with treatment outcome.

Evidencias:

Exon 19 deletions and exon 21 mutations (L858R) account for about 90% of these mutations [20, 21]. Previous studies showed different ORR between the two subtypes for patients with BM receiving TKI alone [11, 21, 22]. A phase 2 trial revealed a longer PFS (P = 0.003) and OS (P = 0.025) in lung adenocarcinoma patients harboring exon 19 deletions with BM than in patients harboring exon 21 mutations [11]. Interestingly, NSCLC patients with exon 19 deletions have more and smaller brain lesions with smaller brain edema than patients with wild-type EGFR. No significant difference was found between patients with exon 21 point mutations and those with wild-type EGFR [23] (texto extraído de la discusión).



We performed a subgroup analysis in our current study and found that OS (22 vs 13.5 months, P = 0.004) and cranial PFS (14 vs 9.5 months, P = 0.001) were longer for the TKI + RT group than for the TKI alone group for lung adenocarcinoma patients with BM harboring exon 21 mutations. However, there were no significant differences in OS (20.5 vs 18.5 months, P = 0.742) and cranial PFS (16.0 vs 16.0 months, P = 0.652) between the two groups for lung adenocarcinoma patients with BM harboring exon 19 mutations.

As shown in Figure 1, for patients with exon 21 mutations, female, KPS (≥ 70), number of brain metastases (> 3), and extracranial metastasis, the TKI + RT group faired better than the TKI group in terms of cranial PFS.

In the case of patients with exon 21 mutation, female, KPS (≥ 70) and extracranial metastasis, median OS in TKI + RT group was longer than those treated with TKI alone.

When EGFR mutations occurred in exon 21, the TKI group again showed inferior results than the TKI + RT group, with a shorter cranial PFS (9.5 vs 14 months, P = 0.001) and OS (13.5 vs 22 months, P = 0.004).

For patients with exon 19 deletions, there were no significant differences between the two groups in terms of cranial PFS (16.0 vs 16.0 months, P = 0.652) and OS (18.5 vs 20.5 months, P = 0.742) (Figure 3*).

Median cranial, progression free survival (PFS) and overall survival (OS) were longer for the TKI + RT group (n = 67) than TKI alone group (n = 66).

Intracranial metastasis correlated with a better median OS than extracranial metastasis. For patients with exon 21 mutations, TKI + RT yielded a better median OS and cranial PFS than TKI alone.

There were no significant differences in median OS and cranial PFS between the two treatment groups for patients with exon 19 deletions (Figure 1).

* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Conclusiones

EGFR-mutant NSCLC patients with BM could benefit more from TKI combined with brain radiation than from TKI monotherapy.

Patients with exon 21 mutations can also benefit more from TKI + RT rather than TKI alone. However,


no benefit was measured from TKI + RT for patients with exon 19 deletion.


PMID: NA


Tipo de estudio Clinical Practice Guidelines



Evidencias:

The predictive effects of the drug-sensitive EGFR mutations— Exon 19 del (LREA deletion) and L858R—are well defined. Patients with these mutations have a significantly better response to erlotinib, gefitinib, or afatinib [154]

Retrospective studies have shown an objective response rate of approximately 80% with a median progression-free survival (PFS) of 13 months to single-agent therapy in patients with a bronchioloalveolar variant of adenocarcinoma and a sensitizing EGFR mutation.[108]

A prospective study has shown that the objective response rate in North American patients with non-squamous NSCLC and sensitizing EGFR mutations (53% Exon 19 del [LREA deletion], 26% L858R, and 21% other mutations) is 55% with a median PFS of 9.2 months.[109]

Data suggest that EGFR mutations can occur in patients with adenosquamous carcinoma, which is harder to discriminate from squamous cell carcinoma in small specimens [122].

Conclusion:

The presence of the EGFR exon 19 deletion or exon 21 L858R mutation is predictive of treatment benefit from EGFR tyrosine kinase inhibitor (EGFR-TKI) therapy; therefore, these mutations are referred to as sensitizing EGFR mutations.108,109 However, the presence of EGFR exon 19 deletions (LREA) or exon 21 L858R mutations does not appear to be prognostic of survival for patients with NSCLC, independent of therapy.110

Referencias bibliográficas [108] Miller VA et al. Molecular characteristics of bronchiolo alveolar carcinoma and adenocarcinoma, bronchiolo alveolar carcinoma subtype,

predict response to erlotinib. J Clin Oncol 2008;26:1472-1478. [109] Sequist LV et al. First-line gefitinib in patients with advanced non-small-cell lung cancer harboring somatic EGFR mutations. J Clin Oncol 2008;26:2442-2449. 110. Tsao MS, Sakurada A, Cutz JC, et al. Erlotinib in lung cancer - molecular and clinical predictors of outcome. N Engl J Med 2005;353:133-144. [122] 122. Paik PK, et al. Response to erlotinib in patients with EGFR mutant advanced non-small cell lung cancers with a squamous or squamous-like component. Mol Cancer Ther 2012;11:2535-2540. [154] Langer CJ. Epidermal growth factor receptor inhibition in mutationpositive non-small-cell lung cancer: is afatinib better or simply newer? J Clin Oncol 2013;31:3303-3306.


PMID: 26823294

Schuler M et al. First-Line Afatinib versus Chemotherapy in Patients with Non-Small Cell Lung Cancer and Common Epidermal Growth Factor Receptor Gene Mutations and Brain Metastases. J Thorac Oncol. 2016 Mar;11(3):380-90.

Tipo de estudio Extension study



Contexto:

For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n= 35 and n =46, respectively). Post hoc analyses of clinical outcomes was undertaken in the




combined data set (n = 81).

Together, the phase III LUX-Lung 3 and LUX-Lung 6 trials represent the largest prospective data set on EGFR mutation–positive patients with NSCLC treated with a TKI. The trials are feasible and facilitates robust subanalyses in clinically relevant patient subgroups. Both trials permitted the enrollment of patients with clinically asymptomatic and controlled brain metastases.

In this study it has been performed subgroup analyses of the efficacy of first-line treatment with afatinib or platinum based chemotherapy in these patients. Analysis was undertaken in both the individual trials.

For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81).

Given the observation that afatinib confers an OS benefit in patients with Del19,21 we also undertook an analysis in patients with Del19 and L858R mutations separately.

Evidencias:

In both LUX-Lung 3 and 6, ORR was significantly greater with afatinib than with chemotherapy in patients with brain metastases and common EGFR mutations (Table 2).

Across both studies, the ORR in patients with brain metastases who were treated with afatinib was 23 of 28 (82.1%) and 12 of 20 (60.0%) in those with Del19 or L858R mutations, respectively (see Fig. Supplemental Digital Content 1*, which demonstrates PFS and best response with respect to mutation type in individual patients).

Conclusiones

In summary, the findings of the current analysis lend further support to the efficacy of afatinib in asymptomatic brain metastases secondary to NSCLC harboring common EGFR mutations, and they add valuable insights into a clinically unmet need.

In both studies, afatinib conferred longer PFS versus chemotherapy in patients with brain metastases who harbored common EGFR mutations. The outcomes were particularly promising in patients with a Del19 mutation, a subgroup for whom afatinib is the only TKI to demonstrate superior OS versus chemotherapy in this setting [21].


Referencias bibliográficas [1] Sequist LV et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. [2] Wu YL et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15: 213–222. 20. [21] Yang JC et al. Afatinib versus cisplatinbased chemotherapy for EGFR mutation-positive lung adenocarcinoma (LUX-Lung 3 and LUX-Lung 6): analysis of overall survival data from two randomised, phase 3 trials. Lancet Oncol. 2015;16:141–151.


PMID: 27755835

Zhang Q et al. Effects of epidermal growth factor receptor-tyrosine kinase inhibitors alone on EGFR-mutant non-small cell lung cancer with brain metastasis. Thorac Cancer. 2016 Nov;7(6):648-654.


Descripción del estudio (abstract


Contexto:

We reviewed clinical data from the electronic medical record database of the Guangdong Lung Cancer Institute from January 2009 to April 2012. Forty-three eligible patients were treated according to this strategy.

Epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) are remarkably effective for treating EGFR-mutant non-small cell lung cancer (NSCLC). However, the individual role of EGFR-TKIs in patients with brain metastasis (BM) arising from EGFR-mutant NSCLC remains unclear.

Patients with BM secondary to NSCLC and harboring EGFR-activating mutations were retrospectively screened. Patients who received gefitinib or erlotinib to control both extracranial lesions (ECLs) and intracranial lesions (ICLs) were eligible.

Evidencias:

Forty-three eligible patients were treated according to this strategy. The characteristics of these patients are summarized in Table 1.





PMID: 28149752

Proto C. et al. Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future. Transl Lung Cancer Res. 2016 Dec; 5(6): 563–578.



https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5233868/

Contexto:

Although their role is not well defined, the reported objective response rate (ORR) and the good tolerance make EGFR-tyrosine kinase inhibitors (TKIs) an interesting valid alternative for NSCLC patients with BM, especially for those harboring EGFR mutations.

Evidencias:

The BM responses to gefitinib, even without irradiation, were reported in a third phase II trial [86] in which 41



pts with BM from EGFR mutated lung adenocarcinoma were enrolled. The ORR was 87.8%, median PFS and OS were 14.5 months (95% CI, 10.2–18.3 months) and 21.9 months (95% CI, 18.5–30.3 months), respectively.

Exon 19 deletion was associated with better outcome in both PFS (P=0.003) and OS (P=0.025) compared with L858R. No patient experienced grade ≥4 toxicity. Several retrospective analyses confirmed the efficacy of TKIs used alone in BM, in particular in EGFR mutated NSCLC [87-89].

Conclusiones:

First and second generation EGFR-TKIs represent a valid therapeutic option in NSCLC pts with BM (Table 1*), especially in patients with activating EGFR mutations. .

* Para acceder a datos completos de tablas y figuras, ver .pdf completo.

Referencias bibliográficas [86] Iuchi T et al. Phase II trial ofgefitinib alone without radiation therapy for Japanese patients with brain metastases from EGFR mutant lung adenocarcinoma. Lung Cancer 2013;82:282-7. [87]. Hotta K, Kiura K, Ueoka H, et al. Effect of gefitinib (`Iressa', ZD1839) on brain metastases in patients withadvanced non-small-cell lung cancer. Lung Cancer 2004;46:255-61. [88]. Porta R, Sanchez-Torres JM, Paz-Ares L, et al. Brain metastases from lung cancer responding to erlotinib: the importance of EGFR mutation. Eur Respir J 2011;37:624-31. [89] Kim JE et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer b2009;65:351-4.


PMID: 25098700





Contexto:

The study was aimed at identifying the efficacy of an epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI) using whole brain radiotherapy (WBRT)/ stereotactic radiosurgery (SRS)/surgery in brain metastases from patients with non-small cell lung cancer (NSCLC).

A total of 282 patients with NSCLC brain metastases who underwent WBRT/SRS/ surgery alone or in combination with TKI were enrolled in our study from 2003–2013.

Evidencias:

Patients having EGFR L858R point mutations had a longer but non-significant median overall survival (MOS), median progression-free survival for intracranial disease (MPFSI) and median progression-free survival for extracranial disease (MPFSE) compared to patients with exon 19 deletions (Table 2).



Conclusiones:

Patients harboring EGFR mutations not only had significant improvement in PFSE with TKI plus conventional treatment compared to EGFR negative patients, but also had a non-significantly better outcome of OS and PFSI.

5. Tratamiento a diferentes escenarios clínicos

Pregunta 7: ¿Cuál es la variable principal de elección para evaluar la eficacia de los tratamientos de

pacientes EGFR mutado con MTC? (Dr. Jordi Bruna)


PMID: NA

Clinical Outcome Assessments in Brain Tumor Clinical Trials: Summary of Jumpstarting Brain Tumor Drug Development Coalition Workshop

Tipo de estudio Workshop


http://braintumor.org/wp-content/assets/Endpoints-Workshop-2-Summary-Final.pdf

Tener en cuenta que en workshop se habló de: “…clinical trial endpoints, with a goal of advancing the development of treatments for glioblastoma…”; los outcomes que se incluyen se refieren a este tumor más que a los endpoint de elección para evaluar la eficacia de los tratamientos de pacientes EGFR mutado con MTC. Contexto To summarize the discussion sessions in the Brain Tumor Clinical Trial Endpoints Workshop on Clinical Outcome Assessments (COAs) held on October 15, 2014 in Bethesda, MD Evidencias Determining Brain Tumor Specific Signs, Symptoms, and Functions for Use in Clinical Outcome Assessments (Panel 1)

Up to 90 percent of patients are unable to return to work from the time of their diagnosis due to the symptoms of brain tumors. There is increasing recognition of the importance of evaluating the impact of therapy on patient-focused outcomes as a measure of clinical benefit.

Recent brain tumor clinical trials have demonstrated that symptom based patient-reported outcome (PRO) measures are sensitive to tumor progression and differences in treatment arms, and may be related to overall survival (OS) and progression free survival (PFS).

http://braintumor.org/wp-content/assets/Endpoints-Workshop-2-Summary-Final.pdf


Recent brain tumor clinical trials suggest that neurocognitive function may predict OS and PFS, as a decline in function often precedes imaging evidence of tumor progression.

The relationships between symptoms, signs, and functions are complex, and there is a need to continue to analyze these relationships to determine what is being caused by the treatment and what is being caused by the tumor.

There is the need for a concise, prioritized list of symptoms, signs, and functions for which new COAs need to be developed.

Across currently used brain tumor PRO instruments, there is great redundancy in symptoms included, the most common being headache and pain, the second being short-term memory; followed by expressive aphasia, or difficulty speaking; hemiparesis or hemiplegia (sometimes worded "weakness" on the instruments), and seizures.

There is inconsistent measurement of these common symptoms and signs across trials. The most common symptoms at the time of diagnosis are headache, weakness, speech and communication deficits, seizures, neurocognitive issues, and behavioral issues, as documented throughout the published literature. Other medications, including corticosteroids, anticonvulsants, and chemotherapy can affect signs and symptoms.

Three general areas designated as priority areas to consider when developing COAs at the workshop include: 1. Concomitant Medication Use

Presence/Absence at diagnosis

Dose

Duration

Changes in dose and duration 2. Symptoms (PROs)

Headache/Pain

Seizures

Patient’s perceived cognition i. Concentration ii. Memory iii. Executive

Aphasia (difficult speaking)

Mood (depression / anxiety)

Paresis / Plegia (weakness) 3. Functional status (performance- outcome (PerfO), observerreported outcome (ObsRO), clinician-

reported,(ClinRO), (PRO):

Cognitive Function

Mobility/Walking

Basic activities of daily living (ADLs)

Instrumental ADLs

Assessment of Patient Symptoms, Signs, Neurocognition, and Limitations in Functional Activities in Clinical Trials for Malignant Gliomas (Panel 2)

Patients and the clinicians in the trial must understand that COAs are important and a key endpoint, and that the collection of the data supporting these measures is critical to trial success.

A major hurdle to the use of QoL as a regulatory endpoint is the difficulty in its measurement, as it is a term with a different meaning to everyone. Commonly used QoL measures include some domains that are of little relevance to drug development and domains that have little impact on patient outcomes. In light of these issues, there is a preference for the use of a symptom inventory instead of assessing QoL, as symptoms are more proximal to the disease and the treatment effect, and can often be measured more directly.

A limitation in the use and understanding of current PRO measures included in brain tumor trials is that


these instruments assess both the impact of the disease itself on the symptoms or signs as well as the effect of the treatment. There is debate about the need to separate these assessments.

A COA that fits the following parameters is needed:

‒ Ability to assess specific disease-related symptoms. ‒ Have good psychometric properties. ‒ Is feasible in the clinical trail context. ‒ Has the ability to detect a well-defined, meaningful change in that patient population.

There is a need for more targeted endpoint measures. While existing instruments may not be perfect, analysis of these measures may identify something suitable and useful for implementation now, while concurrently developing new instruments with better measurement properties.

There is a need to use instruments that are specific to the brain tumor subpopulations being evaluated.

No available measure is sufficient to address all the symptoms that were identified by Panel 1 as important. We need to look at the data we have from previous clinical studies and determine which symptoms, signs, and functions track with the disease and what is the minimally, clinically important difference for these symptoms, signs and functions.

It is essential to capture cognition and neurologic function, as they are the outputs of the organ in which the disease is occurring and the treatments are targeting.

Moving forward, we need to determine how:

‒ To take the instruments we have now that are working and incorporate them into clinical trials; ‒ To improve on those existing instruments; ‒ To plan/develop next generation instruments that would more accurately assess the priority

symptoms.

Step 1 (also known as “low-hanging fruit”) - Incorporation of the symptom sub-scale of MD Anderson Symptom Inventory Brain Tumor Module (MDASI-BT) and the Clinical Trial Battery for neurocognition into clinical trials whenever possible.

Step 2 - Refinement of current COAs along with a consolidation of symptom PROs into a single, universally used instrument.

Step 3 – Follow the development of new COAs such as the NANO, National Comprehensive Cancer Network/Functional Assessment of Cancer Therapy-Brain Symptom Index (NFBrSI-24), and brain tumor specific EORTC instrumental ADL

Creating Clinical Trial Designs that Incorporate Clinical Outcome Assessments (Panel 3)

There is a need to collaborate and build consensus within the community to identify the best clinical trial designs incorporating COAs going forward. (…)

Conclusions

Ideally, this group will utilize existing clinical trial data and existing (MDASI) and emerging (NFBrSI-24) tools and work towards the development of a symptom PRO measure in which the items correspond to the other concepts of interest being measured in the trial.

Prior consensus among neuropsychologists has led to the Clinical Trial Battery, a PerfO, being the standard neurocognitive test used in brain tumor clinical trials. However, there is a need to address and develop standards for how and when the test is administered, as well as how the results are analyzed and interpreted.


The importance of capturing COAs in brain tumor clinical trials must be relayed and emphasized to all stakeholders to help foster support for the inclusion of these measures


PMID: 26823294





Contexto:

For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n= 35 and n =46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81).

Together, the phase III LUX-Lung 3 and LUX-Lung 6 trials represent the largest prospective data set on EGFR mutation–positive patients with NSCLC treated with a TKI [1-2].

The trials are feasible and facilitate robust subanalyses in clinically relevant patient subgroups. Both trials permitted the enrollment of patients with clinically asymptomatic and controlled brain metastases. Evidencias:

For both LUX-Lung 3 and LUX-Lung 6, the primary efficacy end-point was: Progression-free survival (PFS), as assessed by independent review. Key secondary end points in both studies were OS, ORR (complete response and partial response), and disease control (complete response/partial response or stable disease). Other secondary end points included patient-reported outcomes and safety.

Referencias bibliográficas [1] Sequist LV et al. Phase III study of afatinib or cisplatin plus pemetrexed in patients with metastatic lung adenocarcinoma with EGFR mutations. J Clin Oncol. 2013;31:3327–3334. [2] Wu YL et al. Afatinib versus cisplatin plus gemcitabine for first-line treatment of Asian patients with advanced non-small-cell lung cancer harbouring EGFR mutations (LUX-Lung 6): an open-label, randomised phase 3 trial. Lancet Oncol. 2014;15: 213–222. 20.


PMID: 23993384

Lin NU et al. Response Assessment in Neuro-Oncology (RANO) group. Challenges relating to solid tumour brain metastases in clinical trials, part 1: patient population, response, and progression. A report from the RANO group. Lancet Oncol. 2013 Sep;14(10):e396-406




Evidencias:

The primary goal of phase 3 trials is to show a benefit greater than standard of care, either through improved survival or quality of life. Overall survival has usually been the primary endpoint of phase 3 trials of brain metastases.[15,24–26]

Development of treatments that prolong overall survival by a clinically meaningful extent is a worthy goal, shared by both patients and health-care providers. However, patients with brain metastases often have




coexisting extracranial disease that can have a major effect on survival, independent of intracranial disease control.

Progression-free survival (PFS) is often used as the primary endpoint in phase 3 trials examining solid tumour metastases outside of the CNS. However, there are several reasons why intracranial PFS might not be a sufficient endpoint in brain metastasis treatment trials: In studies of stereotactic radiosurgery with or without whole-brain radiotherapy, PFS has been felt to be inadequate to capture the risk–benefit profile of the two treatment groups because of concerns about neurocognitive decline associated with whole-brain radiotherapy. Progression can also be diffi cult to define after stereotactic radiosurgery because radiographical findings might instead show effects of radiation and radionecrosis. PFS can be affected by the ability (or lack thereof) of the studied treatment to affect extracranial progression. In the case of radiotherapy trials, concurrent or subsequent systemic therapies (if effective in the CNS) might confound interpretation of results.

The purpose of phase 2 trials is to identify a sign of activity that would support the move to a definitive phase 3 trial. In the phase 2 setting (and as secondary endpoints in the phase 3 setting) endpoints that have been used are:

o Objective response, PFS, time to need for salvage therapy, neurocognitive outcomes, functional status, and quality of life. All of these endpoints, when applied to patients with brain metastases, have several strengths, limitations, and unresolved issues.

Referencias bibliográficas: [15] Aoyama H et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA 2006; 295: 2483–91. [24] Murray KJ, et al. A randomized phase III study of accelerated hyperfractionation versus standard in patients with unresected brain metastases: a report of the Radiation Therapy Oncology Group (RTOG) 9104. Int J Radiat Oncol Biol Phys 1997; 39: 571–74. [25] Andrews DW, Scott CB, Sperduto PW, et al. Whole brain radiation therapy with or without stereotactic radiosurgery boost for patients with one to three brain metastases: phase III results of the RTOG 9508 randomised trial. Lancet 2004; 363: 1665–72. 26 Suh JH, Stea B, Nabid A, et al. Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 2006; 24: 106–14.

[26] Suh JH et al. Phase III study of efaproxiral as an adjunct to whole-brain radiation therapy for brain metastases. J Clin Oncol 2006; 24: 106–14.

a. Asintomáticas o oligosintomáticas

Pregunta 8: ¿Se deben tratar localmente las MTC en pacientes asintomáticos? (Dr. Javier Puente)


PMID: NA





Evidencias:




PMID: 27343440

Halifa J et al. International Association for the Study of Lung Cancer Advanced Radiation Technology Committee. Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. J Thorac Oncol. 2016 Oct;11(10):1627-43.




NOTA: Aunque no responde directamente a la pregunta, queda implicito que el tratamiento local es una de las primeras opcions para tartar MT asintomáticas. Evidencias:

Given the potential neurocognitive impairment following WBRT emerging data support that TKIs are a reasonable option for asymptomatic BM unsuitable for local ablative treatments, but further investigation is required to determine if this is the optimal option [151].

Chemotherapy alone for newly diagnosed NSCLC with asymptomatic BM results in significant intracranial response rates, with no impact of delayed WBRT on patient outcome [28,152,153].

In patients not suitable for local treatments, new developments in WBRT techniques with hippocampal sparing, may reduce neurocognitive toxicity [163].

Referencias bibliográficas [28]. Barlesi F et al. Pemetrexed and cisplatin as first-line chemotherapy for advanced non-small-cell lung cancer (NSCLC) with asymptomatic inoperable brain metastases: a multicenter phase II trial (GFPC 07- 01). Ann Oncol. 2011 Nov;22(11):2466–70. [151]. Soon Y et al. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015 Feb;114(2):167–72.



[152]. Lee DH et al. Primary chemotherapy for newly diagnosed nonsmall cell lung cancer patients with synchronous brain metastases compared with whole-brain radiotherapy administered first : result of a randomized pilot study. Cancer. 2008 Jul 1;113(1):143–9. [153]. Robinet G et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann Oncol. 2001 Jan;12(1):59–67. [163]. Gondi V et al. Preservation of Memory With Conformal Avoidance of the Hippocampal Neural Stem-Cell Compartment During Whole-Brain Radiotherapy for Brain Metastases (RTOG 0933): A Phase II Multi-Institutional Trial. J Clin Oncol. 2014 Oct 27;32(34):3810


PMID: 27627582

Chen Y et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016 Dec;107(12):1800-1805.




Contexto:

The study is aimed at comparing the outcomes of first-line epidermal growth factor receptor-tyrosine kinase inhibitor (EGFR-TKI) alone with EGFR-TKI plus whole-brain radiotherapy (WBRT) for the treatment of brain metastases (BM) in patients with EGFR-mutated lung adenocarcinoma.

A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study Evidencias:

For EGFR-mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT achieved a

higher response rate of BM and significant improvement in intracranial progression-free survival compared

with EGFR-TKI alone.

Concomitant (EGFR-TKI treatment) WBRT achieved a significantly increased intracranial TTP, with 1-year

and 3-year intracranial control rates of 83.5% and 33.4%.

For patients who had asymptomatic BM, no statistical difference of intracranial TTP appeared between 16 patients who received WBRT and 51 patients who received EGFR-TKI alone, the median intracranial TTP was 24.7 months (95% CI, 17.5–31.9) and 20.0 months (95% CI, 16.9–23.1), respectively (P = 0.193) (Fig. 2c*).

Studies showed that EGFR-TKIs are valid options among patients with asymptomatic BM that have arisen from NSCLC harboring sensitizing EGFR mutations. The response rate is approximately 70%, median PFS ranges from 6.6 to 23.2 months, and OS varies from 12.9 to 19.8 months.(6,12) However, WBRT alone or in combination with surgery and SRS, has been the standard of care for BM.

* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Referencias bibliográficas 6 Park SJ, Kim HT, Lee DH et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012; 77: 556–60. 12 Jamal-Hanjani M, Spicer J. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptormutant nonsmall cell lung cancer metastatic to the brain. Clin Cancer Res 2012; 18: 938–44.


PMID: 27755835





Descripción del estudio (abstract


NOTA: estrategia de tratamiento para pacientes sintomáticos y sintomáticos en un centro en concreto. Contexto:


We reviewed clinical data from the electronic medical record database of the Guangdong Lung Cancer Institute from January 2009 to April 2012. Patients with BM secondary to NSCLC and harboring EGFR-activating mutations were retrospectively screened. Patients who received gefitinib or erlotinib to control both extracranial lesions (ECLs) and intracranial lesions (ICLs) were eligible. Forty-three eligible patients were treated according to this strategy.

Evidencias:

Patients who received gefitinib or erlotinib to control both extracranial lesions (ECLs) and intracranial lesions (ICLs) were eligible. If ECLs remained stable or remissive while ICLs progressed; asymptomatic BM progressed to symptomatic BM; BM symptoms were not alleviated within two weeks; or BM symptoms deteriorated after initial release, patients received brain radiotherapy or other local treatments and continued taking TKIs until ECLs progression occurred.

The following uniform treatment strategy has been applied for these patients at our cancer center. o 1- Patients with asymptomatic BM (Total patients: 33) were administered an oral EGFR-TKI

(gefitinib 250 mg once daily or erlotinib 150 mg once daily) until ECLs progressed, intolerable toxicity was observed, or refusal to continue treatment. According to Response Evaluation Criteria in Solid Tumors (RECIST), if ICLs progressed alone, with stable or remissive ECLs, or an asymptomatic BM progressed to a symptomatic BM (as defined by the presence of one or more of the following symptoms: signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms), patients received brain radiotherapy and continued taking a TKI until their ECLs progressed. Radiotherapy for BM included WBRT, stereotactic radiosurgery, or both.

o 2- Patients with symptomatic BM (Total patients: 10) were administered an oral TKI, together with corticosteroid and other symptomatic treatments. If the symptoms were alleviated within two weeks, TKI was continued without brain radiotherapy. If the symptoms were not relieved within two weeks, the symptoms deteriorated again after initial relief, or ICLs progressed prior to ECLs according to RECIST criteria, brain radiotherapy was commenced. Patients also continued taking a TKI until their ECLs progressed, intolerable toxicity occurred, or they refused subsequent treatment.

For all patients, if the ECLs progressed before the ICLs, or both progressed in parallel, TKI treatment was halted. Physicians adopted subsequent systemic and local brain treatments.

Total of patients: 43. (see table). First line TKI treatment = 27 and second line 16.



Conclusiones:

This study shows that EGFR-TKIs are active against both ICLs and ECLs in patients with EGFRmutant NSCLC. EGFR-TKIs alone appear to be an effective and tolerable option for patients with BM arising from EGFR-mutant NSCLC. Because of the special anatomic structure of the brain, the efficacy of TKIs in ICLs and ECLs should be evaluated separately to maximize the benefits of TKI treatment. Moreover, a prospective study comparing the efficacy between EGFR-TKIs and WBRT in patients with EGFR-mutant NSCLC with BM is warranted.


PMID: 26014133

Liu S, et al. Radiotherapy for asymptomatic brain metastasis in epidermal growth factor receptor mutant non-small cell lung cancer without prior tyrosine kinase inhibitors treatment: a retrospective clinical study. Radiat Oncol. 2015 May 27;10:118.




Contexto:

There were 628 patients diagnosed with EGFR mutant NSCLC between October 2005 and December 2011. Treatment outcomes had been retrospectively evaluated in 96 patients with asymptomatic BM without prior TKI treatment. 39 patients received first-line brain RT, 23 patients received delayed brain RT, and 34 patients did not receive brain RT.

EGFR-mutant NSCLC patients with asymptomatic brain metastasis who do not require urgent symptom relief, the proper treatment schedule is not well established.



This study is to assess the appropriate timing of brain radiotherapy (RT) for asymptomatic BM in EGFR mutant NSCLC patients.

Evidencias:

The patient characteristics are detailed in Table 1*.

With a median follow-up of 26 months, the 2-year OS was 40.6 %. Univariate analyses revealed that ECOG performance status (p = 0.006), other distant metastases (p = 0.002) and first line systemic treatment (p = 0.032) were significantly associated with overall survival (OS). Multivariate analyses revealed that other sites of distant metastases (p = 0.030) were prognostic factor. The timing of brain RT was not significantly related to OS (p = 0.246). The 2-year BM progression-free survival (PFS) was 26.9 % (table 2*).

Brain RT as first-line therapy was not significantly associated with BM progression-free survival (p = 0.643, HR 0.82, 95 % CI 0.39-1.81, Fig. 4).

Conclusiones

First-line brain RT failed to improve long-term survival in TKI-naïve EGFR mutant NSCLC patients with asymptomatic BM.

* Para acceder a datos completos de tablas y figuras, ver .pdf completo.


Pregunta 9: ¿Cuál es el primer tratamiento que debe utilizarse en el paciente con MTC

asintomáticas? (Dr. Javier Puente)


PMID: 28391295





Evidencias:



Referencias bibliográficas [70] Berger LA et al. CNS metastases in nonsmall- cell lung cancer: current role of EGFR-TKI therapy and future perspectives. Lung Cancer.

2013;80(3):242–248. [71]. Jamal-Hanjani M et al. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptormutant non-small cell lung cancer metastatic to the brain. Clin Cancer Res. 2012;18(4):938–944. [72]. Zimmermann S et al. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev. 2014;40(6):716–722. [73]. Soon YY et al. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015;114(2):167–172. [74]. Jiang T, Min W, Li Y, et al. Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-analysis. Cancer Med. 2016;5(6):1055–1065.


PMID: NA





Evidencias:





PMID: 27627582

Chen Y et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016 Dec;107(12):1800-1805.




NOTA: Todos los pacientes de este estudio recibieron “first-generation EGFR-TKI as first-line therapy”. Contexto:


A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study Evidencias:

For EGFR-mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT achieved a

higher response rate of BM and significant improvement in intracranial progression-free survival compared

with EGFR-TKI alone.



Concomitant (EGFR-TKI treatment) WBRT achieved a significantly increased intracranial TTP, with 1-year

and 3-year intracranial control rates of 83.5% and 33.4%.

For patients who had asymptomatic BM, no statistical difference of intracranial TTP appeared between 16 patients who received WBRT and 51 patients who received EGFR-TKI alone, the median intracranial TTP was 24.7 months (95% CI, 17.5–31.9) and 20.0 months (95% CI, 16.9–23.1), respectively (P = 0.193) (Fig. 2c*).

Studies showed that EGFR-TKIs are valid options among patients with asymptomatic BM that have arisen from NSCLC harboring sensitizing EGFR mutations. The response rate is approximately 70%, median PFS ranges from 6.6 to 23.2 months, and OS varies from 12.9 to 19.8 months.(6,12) However, WBRT alone or in combination with surgery and SRS, has been the standard of care for BM.

Conclusiones:

Concomitant WBRT significantly improved intracranial lesion control and prolonged intracranial TTP compared with EGFR-TKI treatment alone. A long OS for patients with EGFR-mutant lung adenocarcinoma and BM was observed in our study, and the OS was equivalent between the WBRT and EGFR-TKI alone treatment groups.

* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Referencias bibliográficas 6 Park SJ, Kim HT, Lee DH et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 21 mutation. Lung Cancer 2012; 77: 556–60. 12 Jamal-Hanjani M, Spicer J. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptormutant nonsmall cell lung cancer metastatic to the brain. Clin Cancer Res 2012; 18: 938–44.


PMID: 26823294





Contexto:

Together, the phase III LUX-Lung 3 and LUX-Lung 6 trials represent the largest prospective data set on EGFR mutation–positive patients with NSCLC treated with a TKI (...).

In thi study it has been performed subgroup analyses of the efficacy of first-line treatment with afatinib or platinum based chemotherapy in these patients. Analysis was undertaken in both the individual trials.

For both LUX-Lung 3 and LUX-Lung 6, prespecified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes was undertaken in the combined data set (n = 81).

Evidencias:

In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060).

In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly



improved the objective response rate versus chemotherapy in patients with brain metastases.

Several observations in this analysis suggest that patients with NSCLC and asymptomatic brain metastases can benefit from treatment with afatinib.

Conclusiones

In summary, the findings of the current analysis lend further support to the efficacy of afatinib in asymptomatic brain metastases secondary to NSCLC harboring common EGFR mutations, and they add valuable insights into a clinically unmet need.

It is possible, that in patients with asymptomatic brain metastases treatment with a first-line TKI could

delay the requirement for WBRT, thereby delaying or preventing exposure to the side effects of cranial

irradiation.


PMID: 25583566

Soon YY et al. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015 Feb;114(2):167-72.

Tipo de estudio Systematic review and meta-analysis



Contexto:

This study aimed at determining if upfront cranial radiotherapy improves intracranial disease control and survival outcomes in EGFR mutant NSCLC with brain metastases relative to TKIs alone.

It has been carried out a bibliographic research in MEDLINE and various conference proceedings from 2008 to July 2014 for eligible studies where patients received upfront cranial radiotherapy or TKIs alone. 12 non-comparative observational studies (n = 363) with severe methodological limitations have been found.

Evidencias:

The results of this meta-analysis are consistent with the findings of qualitative reviews summarising the clinical evidence on the effects of WBRT and TKI in NSCLC [33–35].

This review suggests that based on the high intracranial disease response rates, TKI alone may be used first before WBRT in patients with NSCLC harboring activating EGFR mutations and asymptomatic brain metastases. However, the review authors also acknowledge that the strength of evidence supporting this treatment strategy is weak and should be tested in a randomised fashion.

The quality of the data was heterogeneous as several important informations such as number of brain metastases, status of extra-cranial disease control, use of salvage local or systemic therapies and health-related quality of life outcomes were not consistently reported. Thirdly, the chance of publication bias is fairly high because we feel that negative studies involving use of TKI alone are unlikely to be published.

Conclusiones

For patients with asymptomatic brain metastases and are agreeable for serial imaging of intracranial disease, it could be reasonable to with hold up front cranial radiotherapy and to treat the intracranial disease with radiation upon progression.

Referencias bibliográficas [33]Jamal-Hanjani et al. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptor mutant



nonsmall cell lung cancer metastatic to the brain. Clin Cancer Res 2012;18: 938–44. [34] Bartolotii M et al. EGF receptor tyrosine kinase inhibitors in the treatment of brain metastases from non-small cell lung cancer. Expert Rev Anticancer Ther 2012;11:1429–35. [35] Zimmermann et al. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev 2014;40:716–22.


PMID: 24679729

Gerber NK, Yamada Y, Rimner A, Shi W, Riely GJ, Beal K, Yu HA, Chan TA, Zhang Z, Wu AJ. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys. 2014 Jun 1;89(2):322-9.

Tipo de estudio Clinical trial



NOTA: Aunque la mayoría de los pacientes incluidos en el estudio fueron pacientes asintomáticos, tambien se incluyeron pacientes sintomáticos (ver tabla 1: “baseline characteristics”). Contexto:

Radiation therapy (RT) is the principal modality in the treatment of patients with brain metastases (BM). However, given the activity of EGFR tyrosine kinase inhibitors in the central nervous system, it is uncertain whether upfront brain RT is necessary for patients with EGFR-mutant lung adenocarcinoma with BM.

Methods: Using an institutional query system, we identified all patients with BMs and lung adenocarcinoma who harbored EGFR mutations and were treated at our institution from 2006 to 2012.

222 patients were identified. Exclusion criteria included prior erlotinib use, presence of a de novo erlotinib resistance mutation, or incomplete data. Of the remaining 110 patients, 63 were treated with erlotinib, 32 with whole brain RT (WBRT), and 15 with stereotactic radiosurgery (SRS).

Table 1: baseline characteristics



Evidencias:

The median overall survival (OS) for the whole cohort was 33 months. There was no significant difference in OS between the WBRT and erlotinib groups (median, 35 vs 26 months; P=0.62), whereas patients treated with SRS had a longer OS than did those in the erlotinib group (median, 64 months; P=0.004).

The median time to intracranial progression was 17 months. There was a longer time to intracranial

progression in patients who received WBRT than in those who received erlotinib upfront (median, 24 vs 16

months, P=0.04). Patients in the erlotinib or SRS group were more likely to experience intracranial

failure as a component of first failure, whereas WBRT patients were more likely to experience failure

outside the brain (P=0.004).

First site of progression by treatment type (table 2).

Conclusiones

The survival of patients with EGFR-mutant adenocarcinoma with BM is notably long, whether they


receive upfront erlotinib or brain RT. We observed longer intracranial control with WBRT, even though the WBRT patients had a higher burden of intracranial disease. Despite the equivalent survival between the WBRT and erlotinib group, this study underscores the role of WBRT in producing durable intracranial control in comparison with a targeted biologic agent with known central nervous system activity.


b. Sintomáticas

Pregunta 10: ¿Se deben tratar localmente (RT o cirugía) las MT cerebrales en pacientes

sintomáticos? (Dra. Ana Laura Ortega)


PMID: 28363487

Doherty MK et al. Treatment options for patients with brain metastases from EGFR/ALK-driven lung cancer. Radiother Oncol. 2017 Mar 28. pii: S0167-8140(17)30103-2




Contexto:

This retrospective study included all patients with brain metastases from EGFR- or ALK-driven NSCLC treated at Princess Margaret Cancer Centre up to August 2015

This study evaluated the impact of first-line whole brain radiotherapy (WBRT), stereotactic radiotherapy (SRS) or TKI alone on outcomes of patients with brain metastases from EGFR/ALK-driven NSCLC.

This single center retrospective review included 184 patients with brain metastases from EGFR/ ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS).

Evidencias:

In our institutional practice, patients with symptomatic brain metastases or a large burden of intracranial disease generally would be selected for WBRT, while those with fewer lesions would be offered the choice of SBRT with close surveillance. Asymptomatic patients with very small or multiple small brain metastases generally would be offered the choice of TKI alone or up-front WBRT + TKI.

First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone

in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms.

Conclusiones:


Salvage SRS was used when a small number of new brain metastases were discovered, and WBRT used for progression that was more diffuse. In SRS + TKI-treated patients, 30% had salvage WBRT, which falls within the 18–32% rate reported in other studies of SRS. The choice of WBRT as salvage may be



related to the development of new brain metastases rather than progression of existing lesions, which would be more likely treated with repeat SRS.

The results of our study are consistent with a previous report of patients treated with either erlotinib, SRS or WBRT for EGFR-driven NSCLC, in which WBRT-treated patients had longer TTIP, but similar OS to those treated with TKI alone [19].

Referencias bibliográficas [19] Gerber NK et al.. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 2014;89:322–9.


PMID: NA





Evidencias:


PMID: 27755835



Descripción del https://www.ncbi.nlm.nih.gov/pubmed/27755835




estudio (abstract

NOTA: estrategia de tratamiento para pacientes sintomáticos y sintomáticos en un centro en concreto. Contexto:


Patients with BM secondary to NSCLC and harboring EGFR-activating mutations were retrospectively screened. Patients who received gefitinib or erlotinib to control both extracranial lesions (ECLs) and intracranial lesions (ICLs) were eligible.


Evidencias:


The following uniform treatment strategy has been applied for these patients at our cancer center. o 1- Patients with asymptomatic BM were administered an oral EGFR-TKI (gefitinib 250 mg once

daily or erlotinib 150 mg once daily) until ECLs progressed, intolerable toxicity was observed, or refusal to continue treatment. According to Response Evaluation Criteria in Solid Tumors (RECIST), if ICLs progressed alone, with stable or remissive ECLs, or an asymptomatic BM progressed to a symptomatic BM (as defined by the presence of one or more of the following symptoms: signs of increased intracranial pressure, headache, nausea and vomiting, cognitive or affective disturbances, seizures, and focal neurologic symptoms), patients received brain radiotherapy and continued taking a TKI until their ECLs progressed. Radiotherapy for BM included WBRT, stereotactic radiosurgery, or both.

o 2- Patients with symptomatic BM were administered an oral TKI, together with corticosteroid and other symptomatic treatments. If the symptoms were alleviated within two weeks, TKI was continued without brain radiotherapy. If the symptoms were not relieved within two weeks, the symptoms deteriorated again after initial relief, or ICLs progressed prior to ECLs according to RECIST criteria, brain radiotherapy was commenced. Patients also continued taking a TKI until their ECLs progressed, intolerable toxicity occurred, or they refused subsequent treatment.

For all patients, if the ECLs progressed before the ICLs, or both progressed in parallel, TKI treatment was halted. Physicians adopted subsequent systemic and local brain treatments.

Conclusiones:

This study shows that EGFR-TKIs are active against both ICLs and ECLs in patients with EGFRmutant NSCLC. EGFR-TKIs alone appear to be an effective and tolerable option for patients with BM arising from EGFR-mutant NSCLC. Because of the special anatomic structure of the brain, the efficacy of TKIs in ICLs and ECLs should be evaluated separately to maximize the benefits of TKI treatment. Moreover, a prospective study comparing the efficacy between EGFR-TKIs and WBRT in patients with EGFR-mutant NSCLC with BM is warranted.


Pregunta 11: ¿Qué pacientes son tributarios al tratamiento quirúrgico? (Dr. Oscar Juan)


PMID: 28391295


Tipo de estudio

Clinical Practice Guideline



Evidencias:

There is limited class I evidence for survival benefit of surgical resection in addition to WBRT, and this is likely to be restricted to the subgroup of patients with controlled systemic disease and good performance status.[4-6]

The impact of surgical techniques on the complication rate and functional outcome as well as on the risk of local relapse in patients with single brain metastasis has been recently reviewed (class IIIb).9

In patients with 2 or 3 brain metastases, who have a high performance status and controlled systemic disease, complete surgical resection yields results that are comparable to those obtained in single lesions (class IIIb).[11]

Referencias bibliográficas: [4]Patchell RA et al. A randomized trial of surgery in the treatment of single metastases to the brain. N Engl J Med. 1990;322(8):494–500. [5]. Vecht CJ et al. Treatment of single brain metastasis: radiotherapy alone or combined with neurosurgery? Ann Neurol. 1993;33(6):583–590. 6. [6]. Mintz AH et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a singlecerebral metastasis Cancer. 1996;78(7):1470–1476 9. Patel AJ, Suki D, Hatiboglu MA, et al. Impact of surgical methodology on the complication rate and functional outcome of patients with a single brain metastasis. J Neurosurg. 2015;122(5):1132–1143. [11] Pollock BE et al. Properly selected patients with multiple brain metastases may benefit from aggressive treatment of their intracranial disease Neurooncol. 2003;61(1):73–80


PMID: NA





Evidencias:





[234] Howington JA, Blum MG, Chang AC, et al. Treatment of stage I and II non-small cell lung cancer: Diagnosis and management of lung cancer,

3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e278S-313S. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23649443. [235]. Handforth C, Clegg A, Young C, et al. The prevalence and outcomes of frailty in older cancer patients: a systematic review. Ann Oncol 2015;26:1091-1101. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25403592. [236]. Caillet P, Laurent M, Bastuji-Garin S, et al. Optimal management of elderly cancer patients: usefulness of the Comprehensive Geriatric Assessment. Clin Interv Aging 2014;9:1645-1660. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25302022. [237]. Pallis AG, Gridelli C, Wedding U, et al. Management of elderly patients with NSCLC; updated expert's opinion paper: EORTC Elderly Task Force, Lung Cancer Group and International Society for Geriatric Oncology. Ann Oncol 2014;25:1270-1283. Available at: http://www.ncbi.nlm.nih.gov/pubmed/24638905. [238]. Brunelli A, Kim AW, Berger KI, Addrizzo-Harris DJ. Physiologic evaluation of the patient with lung cancer being considered for resectional surgery: Diagnosis and management of lung cancer, 3rd ed: American College of Chest Physicians evidence-based clinical practice guidelines. Chest 2013;143:e166S-190S. Available at: http://www.ncbi.nlm.nih.gov/pubmed/23649437. [239]. Turner G, Clegg A, British Geriatrics S, et al. Best practice guidelines for the management of frailty: a British Geriatrics Society, Age UK and Royal College of General Practitioners report. Age Ageing 2014;43:744-747. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25336440


PMID: 24281220

Chi A, Komaki R. Treatment of brain metastasis from lung cancer. Cancers(Basel). 2010 Dec 15;2(4):2100-37.




Contexto:

The study reviewed the treatment of Brain Metastasis from Lung Cancer. Evidencias: Surgery

http://www.ncbi.nlm.nih.gov/pubmed/23649443






The results from the following three studies suggest that patients with a single brain metastasis and positive prognostic features, such as the control of extracranial disease and young age, will benefit more from surgical resection followed by WBRT compared with WBRT alone:

Patients began WBRT 36 Gy/12 fractions within 14 days after surgery, whereas patients in the WBRT alone arm began radiotherapy within 48 hours of biopsy or study entry. The recurrence rates at the site of original metastasis for the surgery arm and the WBRT alone arm were 20% and 52%, respectively. The length of time from treatment to the recurrence of the original brain metastasis was significantly shorter for the WBRT alone arm than the surgical arm (median 21 versus >59 weeks, p < 0.0001). The median survival after surgery and adjuvant WBRT was much longer at 40 weeks versus 15 weeks with WBRT alone (p < 0.01). In addition, the patients in the surgical group maintained functional independence (KPS score of ≥70) much longer than the patients treated with radiation alone (median, 38 weeks versus 8 weeks, p < 0.005) [41].

The results from this study were confirmed in another study by Noordijk et al. [42], which demonstrated a median survival advantage with the addition of surgery (10 versus 6 months, p = 0.04). This survival advantage was most pronounced in patients with stable extracranial disease and patients ≤60 years old. In contrast, a study of 84 patients by Mintz et al. failed to demonstrate any survival advantage with surgery plus radiation.

This survival advantage was most pronounced in patients with stable extracranial disease and patients ≤60 years old. In contrast, a study of 84 patients by Mintz et al. failed to demonstrate any survival advantage with surgery plus radiation [43].

Surgery is usually limited to the dominant, symptomatic lesion in patients with multiple metastases. Surgery combined with adjuvant WBRT or stereotactic radiosurgery (SRS) have demonstrated similar survival outcome in patients with multiple lesions compared with patients with single brain metastasis in several single-institution studies [44-46] The benefit of adding WBRT after complete surgical resection of a single lesion (based on MRI at 2–5 days after surgery) was investigated by Patchell et al. [47].

The overall median follow up was 43 weeks in the observation group and 48 weeks in the radiation group. Postoperative WBRT was found to have superior local control (90% versus 54%; p < 0.001), distant intracranial control (86% versus 63%; p < 0.01), and overall intracranial control (82% versus 30%; p < 0.001) rates when compared with those who underwent surgical resection alone. However, no overall survival benefit was seen, despite the fact that patients who underwent WBRT were less likely to die from neurological causes than patients in the observation group (14% versus 44%; p = 0.003).

The results of this study have recently been confirmed by a randomized Phase III study in Europe, EORTC 22952-26001 [48]. In this study, 359 patients were enrolled with non-progressing primary tumors that had metastasized to the brain. For all patients, brain metastases were initially treated with surgery or radiosurgery. Subsequently, the patients were randomized to prophylactic WBRT or observation. The median survival was 9.5 versus 10 months, respectively. Overall survival was 10.7 versus 10.9 months, respectively. However, WBRT was associated with superior progression-free survival (PFS), intracranial control, and fewer neurologic deaths. This may suggest an overall improvement in patients’ quality of life when WBRT is added to surgical resection.

Referencias bibliográficas [41] Patchell, R.A et al. A randomized trial of surgery in the treatment of single metastases to the brain. New Engl. J. Med. 1990, 322, 494-500. [42].Noordijk, E.M. et al.The choice of treatment of single brain metastasis should be based on extracranial tumor activity and age. Int. J. Radiat. Oncol. Biol. Phys. 1994, 29, 711-717. [43].Mintz, A.H. et al. A randomized trial to assess the efficacy of surgery in addition to radiotherapy in patients with a single cerebral metastasis. Cancer 1996, 78, 1470-1476. [44].Paek, S.H. et al. Reevaluation of surgery for the treatment of brain metastases: Review of 208 patients with single or multiple brain metastases treated at one institution with modern neurological techniques. Neurosurgery 2005, 56, 1021-1034. [45].Stark, A.M. et al. Surgical treatment for brain metastases: Prognostic factors and survival in 177 patients. Neurosurg. Rev. 2005, 28, 115-119. 46. Bindal, R.K. et al..Surgical treatment of multiple brain metastases. J. Neurosurg. 1993, 79, 748-754. [47] Patchell, R.A. et al. Postoperative radiotherapy in the treatment of single metastases to the brain: A randomized trial. JAMA 1998, 280, 1485-1489. [48].Kocher, M. et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral

metastases – results of the EORTC 22952-26001 study. J. Clin. Oncol. 2011, in press.



PMID: 25098700





Contexto:



Evidencias:

In the non-TKI group (WBRT/SRS/surgery), less than 3 BMs number, less than 3 cm in maximum diameter of a BM lesion, no extracranial disease, T stage equal to or less than 1, and N0 were favorable factors influencing median overall survival (MOS). (Table 3)

Conclusiones:

WBRT has been considered as a standard treatment option in patients with BMs from NSCLC [3, 4] but it causes neurotoxicity which leads to leukodystrophy. SRS or surgery could be an alternative option, but only for a small subset of patients with solid or oligo-lesions.

Referencias bibliográficas [3] Diener-West M, Dobbins TW, Phillips TL, Nelson DF (1989) Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int J Radiat Oncol Biol Phys 16(3):669–673. [4] Borgelt B, Gelber R, Kramer S, Brady LW, Chang CH, Davis LW, Perez CA, Hendrickson FR (1980) The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6(1):1–9.



Pregunta 12: ¿Qué pacientes son tributarios al tratamiento con radiocirugía? (Dr. Oscar Juan)


PMID: 28391295


Tipo de estudio

Clinical Practice Guideline



Evidencias:

Small brain metastases represent an ideal target for SRS, owing to the generally spherical shape and distinct pathologic margins.[12]. The dose is inversely related to tumor size. Maximal tolerated doses of SRS have been described in the Radiation Therapy Oncology Group (RTOG) 9005 study,13

Single dose SRS in the treatment of a limited number (1–3) of newly diagnosed brain metastases has yielded a local control (defined as shrinkage or arrest of growth) at 1 year of 80%–90% with symptoms improvement and median survival of 6–12 months (class IIIa).14 Patients with a single lesion, controlled extracranial disease, and KPS of 70% or greater have longer survival.15,16 Metastases from radioresistant tumors, such as melanoma and renal cell carcinoma, respond to SRS as do metastases from radiosensitive tumors.17 Older patients (≥80 y) respond as well as younger patients.18 The outcome following gamma-knife or linear accelerator (Linac)–based procedures is similar.

In the past 5–10 years SRS has been increasingly used for patients with higher number of brain metastases, due to improved technology that allows the delivery of SRS with increasing speed while maintaining precision and accuracy. A prospective multicenter Japanese study investigated the use of SRS alone in 1194 patients with 1, 2 to 4 or 5 to 10 brain metastases, and found similar overall survival (OS) (10.8 mo) and treatment-related toxicity rates between the groups with 2 to 4 and 5 to 10 metastases (class IIIa).[16] Cumulative volume of metastases, rather than the number, was reported as a significant prognostic factor.[16]

Referencias bibliográficas: [12] Baumert BG et al. A pathology-based substrate for target definition in radiosurgery of brain metastases. Int J Radiat Oncol Biol Phys.

2006;66(1):187–194. 13. Shaw E, Scott C, Souhami L, et al. Single dose radiosurgical treatment of recurrent previously irradiated primary brain tumors and brain metastases: final report of RTOG protocol 90-05. Int J Radiat Oncol Biol Phys. 2000;47(2):291–298. 14. Lippitz B, Lindquist C, Paddick I, et al. Stereotactic radiosurgery in the treatment of brain metastases: the current evidence. Cancer Treat Rev. 2014;40(1):48–59. 15. Karlsson B, Hanssens P, Wolff R, et al. Thirty years’ experience with Gamma Knife surgery for metastases to the brain. J Neurosurg. 2009;111(3):449–457. 16. Yamamoto M, Serizawa T, Shuto T, et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol. 2014;15(4):387–395. 17. Manon R, O’Neill A, Knisely J, et al. Eastern Cooperative Oncology Group. Phase II trial of radiosurgery for one to three newly diagnosed brain metastases from renal cell carcinoma, melanoma, and sarcoma: an Eastern Cooperative Oncology Group study (E 6397). J Clin Oncol. 2005;23(34):8870–8876. 18. Watanabe S, Yamamoto M, Sato Y, et al. Stereotactic radiosurgery for brain metastases: a case-matched study comparing treatment results for patients 80 years of age or older versus patients 65-79 years of age. J Neurosurg. 2014;121(5):1148–1157. [16] Yamamoto M et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional Bprospective observational study. Lancet Oncol. 2014;15(4):387–395.

ID (número de

identificación del

documento: 1

PMID:

27382120

Arvold ND et al. Updates in the management of brain metastases. Neuro Oncol. 2016 Aug;18(8):1043-65.






Evidencias:

There may be patient subgroups that derive differential benefits from SRS versus SRS + WBRT,

but for now the clinical trial data, while underpowered, largely suggest no OS difference between

these 2 approaches, and prospective trials are required to test hypotheses from the secondary studies

cited above.

Clinical controversy remains regarding optimal patient selection for receipt of SRS alone, SRS +

WBRT, and WBRT alone [36, 37]. In addition, it should be emphasized that the majority of patients

treated in the landmark SRS, WBRT, and surgery trials for BM cited above were unselected NSCLC

patients, and therefore caution should be applied when generalizing outcomes about local therapies from

these trials to various subgroups, such as HER2+ breast cancer or ALK-rearranged NSCLC patients. A

summary of several key recent studies examining survival and functional outcomes after SRS, with or

without WBRT, is provided in Table 1

Referencias Bibliograficas [36] Sahgal A. Point/counterpoint: Stereotactic radiosurgery without whole-brain radiation for patients with a limited number of brain metastases: the current standard of care? Neuro Oncol. 2015;17(7):916–918. [37]. Mehta MP. The controversy surrounding the use of whole-brain radiotherapy in brain metastases patients. Neuro Oncol. 2015;



17(7):919–923.


PMID: NA





Evidencias:

For patients with multiple metastases (eg, >3), WBRT is a standard option, although SRS is also an option [445-447] WBRT is associated with measurable declines in neurocognitive function in clinical trials, particularly with increasing dose and advanced age of the patient [448].

For patients with limited metastases, randomized trials have found that the addition of WBRT to SRS decreases intracranial recurrence but does not improve survival and may increase the risk of cognitive decline.[452,453] Thus, an approach of SRS alone may strike an appropriate balance in patients with limited volume metastases.[454]

Referencias bibliográficas: [445]. Reck M et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii27-39. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25115305. [446]. Tsao MN et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012;4:CD003869.. [447]. Chang WS et al. Analysis of radiosurgical results in patients with brain metastases according to the number of brain lesions: is stereotactic radiosurgery effective for multiple brain metastases? J Neurosurg 2010;113 Suppl:73-78. [448]. Wolfson AH et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:77-84. [452]. Aoyama H et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic

radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 2007;68:1388-1395. [453]. Chang EL et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10:1037-1044.


PMID: 28074321

Na YC et al. Predictive factors of early distant brain failure after gamma knife radiosurgery alone in patients with brain metastases of non-small-cell lung cancer. J Neurooncol. 2017 Apr;132(2):333-340.




Contexto:

Although a previous randomized controlled trial revealed that the use of up-front WBRT plus SRS did not improve survival when compared with SRS alone [6], some patients will experience early distant brain failure and consequently will require WBRT early in the course of their treatment.

The objective of this study was to elucidate the predictive factors for early distant brain failure in patients with brain metastases of non-small-cell lung cancer (NSCLC) who were treated with gamma knife radiosurgery (GKRS) without previous whole-brain radiotherapy (WBRT) or surgery.

A total of 495 patients with brain metastases of primary lung cancer were treated with GKRS at our institute between October 6, 2009 and December 31, 2015.

The primary end-point was early distant brain failure, defined as the detection of newly developed




metastatic lesions on magnetic resonance imaging (MRI) 3 months after GKRS.

Factors such as tumor pathology subtype, concurrent systemic chemotherapy, epidermal growth factor receptor (EGFR) mutation status, use of EGFR tyrosine kinase inhibitors (TKIs), systemic disease status, presence of a metastatic lesion only in delayed MRI, and volume and number of metastases were analyzed

Evidencias:

There were no statistically significant differences with respect to pathologic subtype, concurrent systemic chemotherapy, EGFR mutation, and early distant brain failure. Patients treated with EGFR-TKIs (p = 0.004), with a stable systemic disease status (p = 0.028) and 3 or fewer brain lesions (p = 0.000) experienced a significantly lower incidence of early distant brain failure.

Conclusiones:

This study suggests that GKRS alone could be considered for patients treated with EGFR-TKIs who have a stable systemic disease status and 3 or fewer brain lesions. WBRT should be considered for other patients.

Referencias bibliográficas [6]. Aoyama el al. (2006) Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. Jama 295:2483–2491.


PMID: 28363487





Contexto:


This single center retrospective review included 184 patients with brain metastases from EGFR/ ALK-driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS).

Evidencias:

First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms.

Median TTIP was longer in the WBRT group at 50.5 months than SRS or TKI groups at 12 and 15

months (p = 0.0038).

No significant difference was seen in median OS: 21.6 months in the WBRT group, 23.9 months in the SRS group and 22.6 months in the TKI group (p = 0.67).



Conclusiones:

In this study, patients treated with first-line WBRT + TKI had significantly longer TTIP than those

treated with SRS + TKI or TKI alone despite features that might be expected to result in poorer outcomes.

More patients with symptomatic brain metastases had WBRT + TKI, and patients receiving SRS + TKI

generally had four or fewer lesions. Some patients in the SRS-treated group had relatively rapid intracranial

progression, mostly due to the development of new metastases, but small numbers in this cohort preclude

identification of any prognostic factors.

Salvage SRS was used when a small number of new brain metastases were discovered, and WBRT

used for progression that was more diffuse.

Referencias bibliográficas [19] Gerber NK et al.. Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 2014;89:322–9.


PMID: 27664245

Novello S et al. ESMO Guidelines Committee. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v1-v27




Evidencias:

For two to three metastases, SRS is recommended in patients with RPA class I–II [II, B]. There is currently no evidence that adding upfront whole brain radiotherapy (WBRT) to surgery or to SRS has an impact on OS [I, A] [151].

Data from a prospective observational Japanese study suggested that the use of SRS may have a role in patients with more than three metastases [152]. The observational study enrolled 1194 eligible patients with 1–10 newly diagnosed brain metastases in a 3-year period, with the largest tumour <10 ml in volume and <3 cm in longest diameter; total cumulative volume ≤15 ml, and a KPS score of 70 or higher, with all patients undergoing standard SRS [152]. Median OS after SRS was 13.9 months (95% CI: 12.0–15.6) in the 455 patients with a single metastasis, 10.8 months (95% CI: 9.4–12.4) in the 531 patients with 2–4 tumours and 10.8 months (95% CI: 9.1–12.7) in the 208 patients with 5–10 tumours. OS was similar in patients with 2–4 tumours and in those with 5–10. In outpatients undergoing SRS, treatment-related side-effects occur in 8% of cases, findings that indicate SRS as a valid alternative to WBRT in fit patients [IV, C].

SRS, with or without WBRT, has recently been further investigated in an individual patient data meta-analysis of three phase III trials [153]. The age of the patient significantly influenced survival (P = 0.04), with SRS alone favoured in patients aged 50 or younger, and with no significant survival differences.

Referencias bibliográficas: [151]. Soon Y et al. Surgery or radiosurgery plus whole brain radiotherapy versus surgery or radiosurgery alone for brain metastases. Cochrane



Database Syst Rev 2014; 3: CD009454. [152]. Yamamoto M et al. Stereotactic radiosurgery for patients with multiple brain metastases (JLGK0901): a multi-institutional prospective observational study. Lancet Oncol 2014; 15: 387–395. [153]. Sahgal A et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys 2015; 91: 710–717. 152. [154]. Mulvenna PM et al. Whole brain radiotherapy for brain metastases from non-small lung cancer: quality of life (QoL) and overall survival


PMID: 25098700





Contexto:


Although the standard management has been optimized over time with the development of stereotactic radiosurgery (SRS) combined with systemic chemotherapy and more accurate patient selection for appropriate treatment options now depends on a better definition of prognostic factors, outcomes of BM from NSCLC remain poor, with a short median survival time of 7–8 months [5].


Evidencias:

Radiotherapy was performed on a majority of patients (70 %), in which WBRT accounted for 54 % and SRS for 16 %.

Conclusiones:

WBRT has been considered as a standard treatment option in patients with BMs from NSCLC [3, 4], but it causes neurotoxicity which leads to leukodystrophy.

SRS or surgery could be an alternative option, but only for a small subset of patients with solid or oligo-lesions.

Referencias bibliográficas [3] Diener-West M et al. (1989) Identification of an optimal subgroup for treatment evaluation of patients with brain metastases using RTOG study 7916. Int J Radiat Oncol Biol Phys 16(3):669–673. [4] Borgelt B et al. (1980) The palliation of brain metastases: final results of the first two studies by the Radiation Therapy Oncology Group. Int J Radiat Oncol Biol Phys 6(1):1–9 [5] Moscetti L et al. (2007) Up-front chemotherapy and radiation treatment in newly diagnosed nonsmall cell lung cancer with brain metastases: survey by outcome research network for evaluation of treatment results in oncology. Cancer 109(2):274–281. doi:10.1002/cncr.22399

ID (número de

identificación del

documento): 27

PMID:

24281220

Chi A, Komaki R. Treatment of brain metastasis from lung cancer.

Cancers(Basel). 2010 Dec 15;2(4):2100-37.




Descripción del

estudio (abstract)


Contexto:

This article reviewed the treatment of Brain Metastasis from Lung Cancer.

Evidencias:

In recent years, SRS has emerged as an effective alternative to surgery for up to four small brain

metastases. This is mainly due to the pseudospherical shape, well-defined margin, and the relatively

small size of brain metastases at presentation [49].

As the lesions increase in size, the dose fall-off becomes less rapid, thus increasing the dose to the

volume of normal brain immediately adjacent to the tumor. This increases the risk of edema and radiation

necrosis, which may require surgery six months or longer after SRS. As a result, SRS is typically delivered

to small lesions up to 4 cm in size [50]. The maximum tolerated dose (MTD) was determined in an RTOG

Phase I dose escalation trial, RTOG 90-05, based on tumor size [51]. In this study, the MTD was found to be

24 Gy for lesions ≤2 cm, 18 Gy for lesions 2.1–3 cm, and 15 Gy for lesions 3.1–4 cm in maximum diameter.

Each dose level was associated with incidence rates of grade 3–5 CNS toxicity of 14%, 20%, and 8%,

respectively. The biological effects of SRS on tumors are largely unknown.

Among various studies, patients with good functional performance status, no active systemic

disease, and longer time from the diagnosis of primary lung cancer often had better prognosis and

lived longer (Table 4)

Because of the excellent local control rates achieved by SRS, whether its addition to WBRT will lead to a

survival benefit over WBRT alone has been investigated in many studies. This approach could be especially

beneficial for patients who are not candidates for a craniotomy because of tumor location or existing medical

contraindications:

Three randomized studies have evaluated the efficacy of WBRT alone versus WBRT + SRS. Most

patients had lung tumor histology in two of the published studies [61, 62]. In the first randomized study

by Kondziolka et al. [61], the local control rate at one year was found to be significantly better when SRS was

added to WBRT in a small number of patients (92% versus 0%, p = 0.0016). However, no survival benefit was

found with the addition of SRS. This study defined local recurrence as any increase in lesion size on MRI

rather than the more usually employed RECIST (revised response evaluation criteria in solid tumors) system.

In addition, this study was not controlled for corticosteroid use, radiation changes, or other factors possibly

affecting the lesion size on MRI. Therefore, this study is difficult to interpret.

The largest study done to date is the randomized controlled Phase III trial (RTOG-9508) of WBRT alone

versus WBRT and SRS (Table 5). This RTOG trial enrolled 333 patients with one to three brain metastases



and a KPS of ≥70 [62]. The primary end point was overall survival. No statistically significant difference in

overall survival was found between the WBRT and SRS and the WBRT alone arms (6.5 and 5.7 months,

respectively, p = 0.1356). However, WBRT and SRS led to a significant decrease in local recurrence at one

year despite the fact that 19% of the patients initially assigned to the SRS boost arm did not receive SRS for

various reasons (18 versus 29%, p = 0.01). In planned subgroup analysis, increased median survival (6.5

versus 4.9 months; p = 0.039) was associated with WBRT and SRS in patients with a single brain metastasis.

An SRS boost also resulted in improvement in KPS and decreased steroid use at six months, suggesting an

improvement in the quality of life with the addition of the SRS boost. This is a very important observation, as

the primary objective of treatment in patients with brain metastases is the improvement of their quality of life

since their overall survival is often very poor. In an unplanned subgroup analysis, an OS benefit was

associated with RPA class I, tumor size ≥2 cm, and squamous/NSCLC histology.

However, these three cohorts are exploratory subsets that required an adjusted p value of 0.0056 to

reach significance [63]. On multivariate analysis using Cox regression, however, RPA class I for both single

and multiple lesions and lung primary histology for multiple lesions were found to be significant beneficial

prognostic factors. Overall, this study is considered by most to be a negative trial with regard to major end

points for multiple metastases.

The third study is a three-arm study (SRS, SRS and WBRT, and WBRT alone) from Brown University,

reported in abstract form [64]. Superior local control and fewer brain metastases were reported with the

addition of an SRS boost. However, no p value was reported, nor was any attempt made to stratify for further

surgery, which would have made this a six-arm trial (the size of this trial would not be large enough to support

a meaningful analysis for this reason). Furthermore, the SRS dose was unconventional because the tumor

dose was not individualized based on tumor size or volume. All of these methodological flaws made this study

difficult to interpret.

Referencias bibliográficas [49]. Suh, J.H. Stereotactic radiosurgery for the management of brain metastases. N. Engl. J. Med. 2010, 362, 1119-1127.

[51] Fuks, Z.; Kolesnick, R. Engaging the vascular component of the tumor response. Cancer Cell2005, 8, 89-91.

[61]. Kondziolka, D. et al. Stereotactic radiosurgery plus whole brain radiotherapy versus radiotherapy alone for patients with multiple brain

metastases. Int. J. Radiat. Oncol. Biol. Phys. 1999, 45, 427-434.

[62]. Andrews, D.W. et al. Whole brain radiation therapy with and without stereotactic radiosurgery boost for patients with one to three brain

metastases: Phase III results of the RTOG 9508 randomized trial. Lancet 2004, 363, 1665-1672.

[63]. Elveen, T. et al. Summary of RTOG 95-08 phase III randomized trial of whole brain radiation with or without stereotactic radiosurgery boost,

including presentation of a clinical case study. Am. J. Oncol. Rev. 2004, 3, 592-600.

[64]. Chougule, P.B. et al. Randomized treatment of brain metastases with gamma knife radiosurgery, whole brain radiotherapy or both. Int. J.

Radiat. Oncol. Biol. Phys. 2000, 48, S114.


Pregunta 13: ¿Qué pacientes son tributarios al tratamiento holocraneal? (Dr. Oscar Juan)


PMID: 28391295


Tipo de estudio

Clinical Practice Guidelines



Evidencias:

Three large phase III trials [31–33] and a meta-analysis [34] demonstrated that omission of WBRT in patients with a limited number of brain metastases after either complete surgery or SRS results in significantly worse local and distant control in the brain, but does not affect functionally independent and overall survival (class I).

The American [31] and the Japanese [32] trials included patients with both stable and progressive systemic disease, while the European trial [33] was restricted to patients with stable systemic disease, that is, those who could maximally benefit in terms of survival from improved intracranial control.

A recent individual patient data meta-analysis of 3 randomized trials comparing SRS alone with SRS + WBRT in patients with 1 to 4 brain metastases [35] suggested a survival advantage for SRS alone in patients aged <50 years without a reduction in the risk of new brain metastases with adjuvant WBRT; conversely, in patients aged >50 years WBRT decreased the risk of new brain metastases but did not affect survival.

Referencias bibliográficas: [31]Patchell RA et al. Postoperative radiotherapy in the treatment of single metastases to the brain: a randomized trial. JAMA. 1998;280(17):1485–1489. [32]. Aoyama H et al. Stereotactic radiosurgery plus whole-brain radiation therapy vs stereotactic radiosurgery alone for treatment of brain metastases: a randomized controlled trial. JAMA. 2006;295(21):2483–2491. [33]. Kocher M et al. Adjuvant whole-brain radiotherapy versus observation after radiosurgery or surgical resection of one to three cerebral metastases: results of the EORTC 22952-26001 study. J Clin Oncol. 2011;29(2):134–141. [34]. Tsao Me et al.. A meta-analysis evaluating stereotactic radiosurgery, whole-brain radiotherapy, or both for patients presenting with a limited number of brain metastases. Cancer. 2012;118(9):2486–2493. [35]. Sahgal A, Aoyama H, Kocher M, et al. Phase 3 trials of stereotactic radiosurgery with or without whole-brain radiation therapy for 1 to 4 brain

metastases: individual patient data meta-analysis. Int J Radiat Oncol Biol Phys. 2015;91(4):710–717.


PMID: 28363487





Contexto:

Brain metastases in EGFR/ALK-driven NSCLC frequently pose treatment dilemmas. Tyrosine kinase inhibitors (TKIs) can control extracranial disease, but radiotherapy is often required for intracranial control.


This single center retrospective review included 184 patients with brain metastases from EGFR/ ALK-




driven NSCLC, and analyzed effect of treatment choice on time to intracranial progression (TTIP) and overall survival (OS).

Evidencias:

First-line treatment for brain metastases consisted of WBRT in 120 patients, SRS in 37 and TKI alone in 27. WBRT-treated patients had more brain metastases, and more baseline symptoms.

Median TTIP was longer in the WBRT group at 50.5 months than SRS or TKI groups at 12 and 15 months (p = 0.0038).

No significant difference was seen in median OS: 21.6 months in the WBRT group, 23.9 months in the SRS group and 22.6 months in the TKI group (p = 0.67).

Conclusiones:


Salvage SRS was used when a small number of new brain metastases were discovered, and WBRT

used for progression that was more diffuse.

Referencias bibliográficas [19] Gerber NK et al..Erlotinib versus radiation therapy for brain metastases in patients with EGFR-mutant lung adenocarcinoma. Int J Radiat Oncol Biol Phys 2014;89:322–9.


PMID: 27229180





Evidencias:

Although patients with EGFR mutant NSCLC demonstrate high response rates to whole brain radiation therapy (WBRT)110 and WBRT improves the duration of intracranial disease control over TKIs or stereotactic radiosurgery (SRS),108 many practitioners seek to avoid the hair loss, fatigue, and other neurocognitive sequelae of WBRT in this population.

If radiation therapy is to be performed, factors that may be considered in the decision between WBRT or SRS might include the degree of symptoms, size of metastatic tumor(s), presence of hemorrhage or peritumoral edema, brainstem involvement, and number of metastases.

Referencias Bibliograficas [108] Mak KS et al. Significance of targeted therapy and genetic alterations in EGFR, ALK, or KRAS on survival in patients with non-small cell lung cancer treated with radiotherapy for brain metastases. Neuro Oncol. 2015;17:296–302. [110] Gow CH et al. Radiotherapy in lung adenocarcinoma with brain metastases: effects of activating epidermal growth factor receptor mutations on clinical response. Clin Cancer Res. 2008;14:162–168.

ID (número de identificación del

PMID:

Arvold ND et al. Updates in the management of brain metastases. Neuro



documento: 1 27382120 Oncol. 2016 Aug;18(8):1043-65.




Evidencias:

There may be patient subgroups that derive differential benefits from SRS versus SRS + WBRT, but for now the clinical trial data, while underpowered, largely suggest no OS difference between these 2 approaches, and prospective trials are required to test hypotheses from the secondary studies cited above.

Clinical controversy remains regarding optimal patient selection for receipt of SRS alone, SRS + WBRT, and WBRT alone [36, 37]. A summary of several key recent studies examining survival and functional outcomes after SRS, with or without WBRT, is provided in Table 1.

Referencias Bibliograficas [36] Sahgal A. Point/counterpoint: Stereotactic radiosurgery without whole-brain radiation for patients with a limited number of brain metastases: the current standard of care? Neuro Oncol. 2015;17(7):916–918. [37]. Mehta MP. The controversy surrounding the use of whole-brain radiotherapy in brain metastases patients. Neuro Oncol. 2015; 17(7):919–923.


PMID: NA








Evidencias:

For multiple metastases (eg, >3), WBRT is a standard option, although SRS is also an option [445-447]

WBRT is associated with measurable declines in neurocognitive function in clinical trials, particularly with increasing dose and advanced age of the patient [448].

For limited metastases, randomized trials have found that the addition of WBRT to SRS decreases intracranial recurrence but does not improve survival and may increase the risk of cognitive decline.[452,453] Thus, an approach of SRS alone may strike an appropriate balance in patients with limited volume metastases.[454]

Referencias bibliográficas: [445]. Reck M et al. Metastatic non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol 2014;25 Suppl 3:iii27-39. Available at: http://www.ncbi.nlm.nih.gov/pubmed/25115305. [446]. Tsao MN et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012;4:CD003869.. [447]. Chang WS et al. Analysis of radiosurgical results in patients with brain metastases according to the number of brain lesions: is stereotactic radiosurgery effective for multiple brain metastases? J Neurosurg 2010;113 Suppl:73-78. [448]. Wolfson AH et al. Primary analysis of a phase II randomized trial Radiation Therapy Oncology Group (RTOG) 0212: impact of different total doses and schedules of prophylactic cranial irradiation on chronic neurotoxicity and quality of life for patients with limited-disease small-cell lung cancer. Int J Radiat Oncol Biol Phys 2011;81:77-84. [452]. Aoyama H et al. Neurocognitive function of patients with brain metastasis who received either whole brain radiotherapy plus stereotactic

radiosurgery or radiosurgery alone. Int J Radiat Oncol Biol Phys 2007;68:1388-1395. [453]. Chang EL et al. Neurocognition in patients with brain metastases treated with radiosurgery or radiosurgery plus whole-brain irradiation: a randomised controlled trial. Lancet Oncol 2009;10:1037-1044.


PMID: 27237825





Contexto:

This is arguably the first large-scale retrospective study to investigate the epidemiology and role of WBRT in advanced NSCLC patients with BM.

Patients with pathologically confirmed lung cancer at the Thoracic Cancer Institute, Tongji University from February 2012 to May 2015 were retrospectively collected.

A total of 230 patients with NSCLC with EGFR mutation and BM were identified. Within this group, 116 patients received EGFR TKIs alone (as first-line therapy in 91 cases) and 51 patients received EGFR TKIs plus WBRT therapy (as first-line treatment in 30 cases).

Evidencias:

Compared with TKIs alone, EGFR TKIs plus WBRT had no superior intracranial progression-free survival (PFS) (6.9 versus 7.4 months [p = 0.232]) and systemic PFS (7.5 versus 7.9 months [p = 0.546]) but were associated with worse overall survival (OS) (21.6 versus 26.4 months [p = 0.049]) in NSCLC with EGFR mutation and BM.

Chemotherapy plus WBRT was shown to have an intracranial PFS (5.2 versus 5.9 months [p = 0.339]) and OS (10.5 versus 11.0 months [p = 0.977]) similar to those with chemotherapy alone in patients with EGFR of unknown or wild-type status.

In multivariate analysis, EGFR mutation was found to be an independent risk factor for BM (hazard ratio = 1.476, p = 0.039) and also a significant independent prognostic factor for OS in patients with NSCLC with BM (hazard ratio = 0.601, p = 0.028).



Conclusiones:


In patients with BM and EGFR of wild-type or unknown status WBRT also did not bring additional benefit to chemotherapy.


PMID: 27664245

Novello S et al. ESMO Guidelines Committee. Metastatic non-small-cell lung cancer: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2016 Sep;27(suppl 5):v1-v27




Evidencias:

When more than three brain metastases are diagnosed, WBRT is recommended in patients with RPA

class I–II [II, B], although the benefit of WBRT compared with supportive care alone has not been formally

studied in randomised trials. The role of WBRT has been questioned by data from a phase III non-inferiority

study, in which patients were randomised to either BSC including dexamethasone plus WBRT 20 Gy in 4 Gy

fractions or to the same BSC without WBRT. This trial (QUARTZ) demonstrated no difference between the

treatment arms regarding the relief of symptoms, steroid use, OS, QoL or quality-adjusted life years, but full

publication is awaited [154].

The WBRT most frequent schedules are 20 Gy in 5 fractions or 30 Gy in 10 fractions, with no

difference in outcome [I, A] [155]. In patients with asymptomatic brain metastases who have not yet received

prior systemic therapy (i.e. chemotherapy, TKIs) however, treatment with upfront systemic chemotherapy

and deferred WBRT should be considered [II, B] [156, 157].

Referencias bibliográficas: [154] Mulvenna PM et al. Whole brain radiotherapy for brain metastases from non-small lung cancer: quality of life (QoL) and overall survival (OS) results from the UK Medical Research Council QUARTZ randomised clinical trial (ISRCTN 3826061). J Clin Oncol 2015; 33(20 Suppl); abstr 8005. [155] Tsao MN et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev 2012;

4: CD003869.

[156]. Robinet G et al. Results of a phase III study of early versus delayed whole brain radiotherapy with concurrent cisplatin and vinorelbine

combination in inoperable brain metastasis of non-small-cell lung cancer: Groupe Français de Pneumo-Cancérologie (GFPC) Protocol 95-1. Ann

Oncol 2001; 12: 59–67.

[157]. Lim SH et al. A randomized phase III trial of stereotactic radiosurgery (SRS) versus observation for patients with asymptomatic cerebral oligo-metastases in non-small-cell lung cancer. Ann Oncol 2015; 26: 762–768.


PMID: 26998157

Wei H et al. Prognostic factors analysis in EGFR mutation-positive non-small cell lung cancer with brain metastases treated with whole brain-radiotherapy and EGFR-tyrosine kinase inhibitors. Oncol Lett. 2016 Mar;11(3):2249-2254.




Contexto:

The purpose of the present study was to analyze and assess the prognostic factors in EGFR mutation‑




positive NSCLC patients with brain metastases following WBRT and EGFR‑TKI treatment, using. The

Cox proportional hazards

The Cox proportional hazards regression and classification tree models were used to explore the

prognostic factors in EGFR mutation‑positive NSCLC patients with brain metastases following whole‑

brain radiation therapy (WBRT) and EGFR‑tyrosine kinase inhibitor (EGFR‑TKI) treatment.

A total of 66 EGFR mutation‑positive NSCLC patients with brain metastases were retrospectively

reviewed. Between January 2005 and July 2014.

Univariate and multivariate analyses by Cox proportional hazards regression were then performed. The classification tree model was applied in order to identify prognostic groups of the patients. In the survival analysis, age, carcinoembryonic antigen (CEA) and status of the primary tumor were prognostic factors for progression free survival (P=0.006, 0.014 and 0.005, respectively) and overall survival (P=0.009, 0.013 and 0.009, respectively).

Evidencias: The classification tree model was subsequently applied, which revealed 3 patient groups with significantly different survival times:

Group I, age <65 years and CEA ≤10 μg/ml;

Group II, age <65 years and CEA >10 μg/ml or age ≥65 years and CEA ≤10 μg/ml

Group III, age ≥65 years and CEA >10 μg/ml. Conclusiones:

The major prognostic predictors for EGFR mutation‑positive NSCLC patients with brain metastases

following and EGFR‑TKI were age and CEA. Age (≥65 years) and CEA (>10 μg/ml) were considered to

be the adverse prognostic factors.


PMID: 25634677

Xiang Z el al. Whole brain radiotherapy-based combined modality treatment of brain metastases from non-small cell lung cancer: a retrospective analysis of prognostic factors. Oncol Res Treat. 2015;38(1-2):35-40.




Contexto:

In previous reports, several prognostic factors were identified for patients with brain metastasis from NSCLC, including age, performance status, number of brain metastases, and extracranial metastases [16, 17].

The prognostic factors for patients with brain metastases from non-small cell lung cancer treated with whole brain radiotherapy (WBRT)-based combined modality therapy were investigated.

The present study was approved by the Institutional Review Board. Between March, 2007 and December, 2012, a total of 135 patients underwent WBRT for brain metastases from lung cancer at Ningbo Medical Center, Lihuili Hospital, including 80 males and 55 females, ranging in age from 31 to 77 years (mean age 54 years).

Evidencias:

The mean survival time was 9.3 months, and the 1-year and 2-year survival rates were 46.3 and 16.1%, respectively in patients receiving radiation boost, systemic chemiotherapy and EGFR-TKIs, respectively.



In univariate analysis, improved survival was associated with age < 60 years, no extracranial metastasis.

Karnofsky performance score ≥ 70, ≥ 3 cycles of chemotherapy after diagnosis of brain metastases, combined treatment with EGFR-TKIs, and no metastases in the cerebellum.

In multivariate analysis, the above prognostic factors maintained significance with the exception of age. In an additional analysis of the 58 patients with 1–3 brain metastases, combination of WBRT with radiation boost was associated with better survival.

Conclusiones: In the present study of brain metastases from NSCLC treated with WBRT-based combined modality therapy, the significant positive prognostic factors for overall survival included:

Good performance status, no extracranial metastasis, no cerebellar metastases, ≥ 3 cycles of chemotherapy after diagnosis of brain metastases, and combination treatment with EGFR-TKIs.

In patients with 1–3 brain metastases, significant positive prognostic factors included ≥ 3 cycles of chemotherapy and a combination of WBRT with radiation boost

Referencias bibliográficas [16]. Sperduto PW et al. Diagnosis-specific prognostic factors, indexes, and treatment outcomes for patients with newly diagnosed brain metastases: a multi-institutional analysis of 4,259 patients. Int J Radiat Oncol Biol Phys 2010; 77: 655–661. [17]. Rades D et al.Two radiation regimens and prognostic factors for brain metastases in nonsmall cell lung cancer patients. Cancer 2007; 110: 1077–1082. [18]. Gerdan L et al. Brain metastasis from non-small cell lung cancer (NSCLC): prognostic importance of the number of involved extracranial organs. Strahlenther Onkol 2014; 190: 64–67.

Pregunta 14: ¿Cuál es el primer tratamiento que debe utilizarse en el paciente con MTC

sintomáticas? (Dra. Ana Laura Ortega)


PMID: 28391295

Soffietti R et al. Diagnosis and treatment of brain metastases from solid tumors: guidelines from the European Association of Neuro-Oncology (EANO). Neuro Oncol. 2017 Feb 1; 19(2):162-174




Evidencias:



Referencias bibliográficas [70] Berger LA et al. CNS metastases in nonsmall- cell lung cancer: current role of EGFR-TKI therapy and future perspectives. Lung Cancer.

2013;80(3):242–248. [71]. Jamal-Hanjani M et al. Epidermal growth factor receptor tyrosine kinase inhibitors in the treatment of epidermal growth factor receptormutant non-small cell lung cancer metastatic to the brain. Clin Cancer Res. 2012;18(4):938–944. [72]. Zimmermann S et al. Indications and limitations of chemotherapy and targeted agents in non-small cell lung cancer brain metastases. Cancer Treat Rev. 2014;40(6):716–722. [73]. Soon YY et al. EGFR tyrosine kinase inhibitors versus cranial radiation therapy for EGFR mutant non-small cell lung cancer with brain metastases: a systematic review and meta-analysis. Radiother Oncol. 2015;114(2):167–172. [74]. Jiang T, Min W, Li Y, et al. Radiotherapy plus EGFR TKIs in non-small cell lung cancer patients with brain metastases: an update meta-



analysis. Cancer Med. 2016;5(6):1055–1065.


PMID: NA





Evidencias:


PMID: 26823294





Contexto:

Together, the phase III LUX-Lung 3 and LUX-Lung 6 trials represent the largest prospective data set on EGFR mutation–positive patients with NSCLC treated with a TKI (...).




In thi study it has been performed subgroup analyses of the efficacy of first-line treatment with afatinib or platinum based chemotherapy in these patients. Analysis was undertaken in both the individual trials.

For both LUX-Lung 3 and LUX-Lung 6, pre-specified subgroup analyses of progression-free survival (PFS), overall survival, and objective response rate were undertaken in patients with asymptomatic brain metastases at baseline (n = 35 and n = 46, respectively). Post hoc analyses of clinical outcomes were undertaken in the combined data set (n = 81).

Evidencias:

In both studies, there was a trend toward improved PFS with afatinib versus chemotherapy in patients with brain metastases (LUX-Lung 3: 11.1 versus 5.4 months, hazard ratio [HR] = 0.54, p = 0.1378; LUX-Lung 6: 8.2 versus 4.7 months, HR = 0.47, p = 0.1060).

In combined analysis, PFS was significantly improved with afatinib versus with chemotherapy in patients with brain metastases (8.2 versus 5.4 months; HR, 0.50; p = 0.0297). Afatinib significantly improved the objective response rate versus chemotherapy in patients with brain metastases.

Conclusiones

It is possible, that in patients with asymptomatic brain metastases treatment with a first-line TKI could

delay the requirement for WBRT, thereby delaying or preventing exposure to the side effects of cranial

irradiation.


PMID: 27237825





Contexto:

Patients with pathologically confirmed lung cancer at the Thoracic Cancer Institute, Tongji University from February 2012 to May 2015 were retrospectively collected.

This is arguably the first large-scale retrospective study to investigate the epidemiology and role of WBRT in advanced NSCLC patients with BM.



A total of 230 patients with NSCLC with EGFR mutation and BM were identified. Within this group, 116 patients received EGFR TKIs alone (as first-line therapy in 91 cases) and 51 patients received EGFR TKIs plus WBRT therapy (as first-line treatment in 30 cases).

Evidencias:

Compared with TKIs alone, EGFR TKIs plus WBRT had no superior intracranial progression-free survival (iPFS) (6.9 versus 7.4 months [p = 0.232]) and systemic PFS (7.5 versus 7.9 months [p = 0.546]) but were associated with worse overall survival (OS) (21.6 versus 26.4 months [p = 0.049]) in NSCLC with EGFR mutation and BM.

Patients with symptomatic BM accepted EGFR TKIs plus WBRT had significantly worse iPFS than those received EGFR TKIs alone (HR = 4.232, 95% CI 1.912-9.817, P = 0.028) iPFS in symptomatic BM patients seems to favor TKIs alone.

The imbalance of subsequent WBRT therapy among the two groups will inevitably happened and contribute to longer OS in the EGFR-TKI alone group, since the progression from brain frequently happened in the situation of acquired resistance of EGFR-TKIs and patients already received WBRT and EGFR-TKI could not tolerate WBRT again [32].

Conclusiones:


Referencias bibliográficas: 32. Zhuang HQ, Sun J, Yuan ZY, et al. Radiosensitizing effects of gefitinib at different administration times in vitro. Cancer Sci 2009;100:1520-5.


PMID: 25247337

Hoffknecht P et al. Afatinib Compassionate Use Consortium (ACUC).. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015 Jan;10(1):156-63.






Contexto:

Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis.

Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program.

Evidencias:

Patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation.


Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol.

Conclusiones:


Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR–TKI-sensitive NSCLC and CNS metastasis.

c. Tratamiento sistémico

Pregunta 15: ¿Existen diferencias de actividad intracraneal entre los diferentes TKI? (Dr. Alejandro

Navarro)


PMID: 28490892

Bai H, Xiong L, Han B. The effectiveness of EGFR-TKIs against brain metastases in EGFR mutation-positive non-small-cell lung cancer. Onco Targets Ther. 2017 Apr 27;10:2335-2340



https://www.ncbi.nlm.nih.gov/pubmed/PMC5415007

Contexto:

Brain metastases are usual in non-small-cell lung cancer (NSCLC) with poor prognosis and few available therapeutic options.

This retrospective study aims to evaluate the efficacy of epidermal growth factor receptor-tyrosine kinase inhibitors (EGFR-TKIs) against brain metastases from NSCLC harboring activating EGFR mutation.

From January 2006 to June 2016, 1,076 NSCLC patients with brain metastases were screened in Shanghai

https://www.ncbi.nlm.nih.gov/pubmed/PMC5415007


Chest Hospital.

A total of 148 patients with brain metastases from EGFR mutation-positive NSCLC were analyzed retrospectively (97 with multiple intracranial lesions and 51 with a single intracranial lesion; 101 with metastatic brain symptoms and 47 without metastatic brain symptoms).

The patients were orally given gefitinib (250 mg) or erlotinib (150 mg) once a day until intracranial disease progression, death, or intolerable side effects.

Evidencias:

No patient achieved CR in the study. Among them, for intracranial diseases, 54 achieved PR, 75 obtained SD, and 19 had PD.

The difference in the intracranial efficacy outcomes by the two EGFR-TKIs was also analyzed. Out of the 95 patients receiving gefitinib, there were 33 PRs and 49 SDs. Out of the 53 patients receiving erlotinib, there were 21 PRs and 26 SDs.

There was no statistical difference in the median PFS (11.3 vs 10.8 months, P=0.2030) and OS (13.8 vs 13.5 months, P=0.3185) between the gefitinib and the erlotinib group.

Conclusiones:

As a result, it cannot be identified which TKI is superior or inferior, which is similar to some isolated reports.18,35,36 Overall, the lack of clinical data available for distinct patient populations limited the conclusions of the assessment.

Referencias bibliográficas: [18] Park SJ et al. Efficacy of epidermal growth factor receptor tyrosine kinase inhibitors for brain metastasis in non-small cell lung cancer patients harboring either exon 19 or 2l mutation. Lung cancer. 2012;77:556–560. [34] Kim ST et al. Randomized phase II study of gefitinib versus erlotinib in patients with advanced non-small cell lung cancer who failed previous chemotherapy. Lung Cancer. 2012;75:82–88. [35]. Kim JE, Lee DH, Choi,Y et al. Epidermal growth factor receptor tyrosine kinase inhibitors as a first-line therapy for never-smokers with adenocarcinoma of the lung having asymptomatic synchronous brain metastasis. Lung Cancer. 2009;65:351–354. [36]. Heon S, Yeap BY, Britt GJ, et al. Development of central nervous system metastases in patients with advanced non-small cell lung cancer and somatic EGFR mutations treated with gefitinib or erlotinib. Clin Cancer Res. 2010;16:5873–5882.


PMID: 27755835







Contexto:

The individual role of EGFR-TKIs in patients with brain metastasis (BM) arising from EGFR-mutant NSCLC remains unclear.



Evidencias:


TKI treatment resulted in a response rate of 69.6%, an intracranial tumor response rate of 73.9%, and a median PFS of 7.1 months, which suggests that selected patients with BM would benefit greatly from TKI treatment. Because EGFR mutations have been shown to be better predictors of EGFR-TKI efficacy than EGFR protein expression, EGFR gene copy number, and clinical characteristics, we selected patients according to EGFR mutation status [10, 21, 22].

Conclusiones:

In conclusion, this study shows that EGFR-TKIs are active against both ICLs and ECLs in patients with EGFR mutant NSCLC. EGFR-TKIs alone appear to be an effective and tolerable option for patients with BM arising from EGFR-mutant NSCLC.

Referencias bibliográficas [10]. Mok TS et al. Gefitinib or carboplatin-paclitaxel in pulmonary adenocarcinoma. N Engl J Med 2009; 361: 947–57. [21]. Sholl LM et al. EGFR mutation is a better predictor of response to tyrosine kinase inhibitors in nonsmall cell lung carcinoma than FISH, CISH, and immunohistochemistry. Am J Clin Pathol 2010; 133: 922–34. [22]. Dahabreh IJ et al. Somatic EGFR mutation and gene copy gain as predictive biomarkers for response to tyrosine kinase inhibitors in non-small cell lung cancer. Clin Cancer Res 2010; 16: 291–303.


PMID: 27343440

Halifa J et al. International Association for the Study of Lung Cancer Advanced Radiation TechnologyCommittee. Brain Metastases from NSCLC: Radiation Therapy in the Era of Targeted Therapies. J Thorac Oncol. 2016 Oct;11(10):1627-43.

Tipo de estudio Review of litersture



Evidencias:

Tyrosine kinase inhibitors (TKIs) are low molecular weight organic compounds (less than 500 Da generally) [58], with low to moderate cerebrospinal fluid (CSF) penetration rates within the brain.[59]

Erlotinib (and its active metabolite OSI-420) has been found to have a CSF penetration rate between 2.8% and 5.1% of total plasma concentration (5.8% for OSI-420).[60–62]

As compared to erlotinib, a limited number of small cohort studies showed that other first generation TKIs have low, such as gefitinib [62,67] or very low (crizotinib 68,69) CSF penetration rates.


[58]. Hojjat-Farsangi M. Small-molecule inhibitors of the receptor tyrosine kinases: promising tools for targeted cancer therapies. Int J Mol Sci. 2014



Jan;15(8):13768–801 [59]. Baik CS et al. Targeted Therapy for Brain Metastases in EGFR-Mutated and ALK-Rearranged Non-Small-Cell Lung Cancer. J Thorac Oncol. 2015 Sep;10(9):1268–78. [60].Togashi Y et al. Pharmacokinetics of erlotinib and its active metabolite OSI-420 in patients with nonsmall cell lung cancer and chronic renal failure who are undergoing hemodialysis. J Thorac Oncol. 2010 May;5(5):601–5. [61]. Deng Y et al. The concentration of erlotinib in the cerebrospinal fluid of patients with brain metastasis from non-small-cell lung cancer. Mol Clin Oncol. 2014 Jan;2(1):116–20. [62].Togashi Y et al. Cerebrospinal fluid concentration of gefitinib and erlotinib in patients with non-small cell lung cancer. Cancer Chemother Pharmacol. 2012 Sep;70(3):399–405. [67]. Zhao J, et al. Cerebrospinal fluid concentrations of gefitinib in patients with lung adenocarcinoma. Clin Lung Cancer. 2013 Mar;14(2):188–93. 68. Costa DB, Kobayashi S, Pandya SS, Yeo W-L, Shen Z, Tan W, et al. CSF concentration of the anaplastic lymphoma kinase inhibitor crizotinib. J Clin Oncol. 2011 May 20;29(15):e443–5. 69. Metro G, Lunardi G, Floridi P, Pascali JP, Marcomigni L, Chiari R, et al. CSF Concentration of Crizotinib in Two ALK-Positive Non-Small-Cell Lung Cancer Patients with CNS Metastases Deriving Clinical Benefit from Treatment. J Thorac Oncol. 2015 May;10(5):e26–7.


PMID: 28149752

Proto C. et al. Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future. Transl Lung Cancer Res. 2016 Dec; 5(6): 563–578



https://www.ncbi.nlm.nih.gov/pubmed/?term=PMC5233868

Contexto:

Today erlotinib and gefitinib, together with the second generation TKI afatinib, are recognized as the standard first line therapy in NSCLC pts with activating EGFR mutations, instead of conventional cytotoxic chemotherapy

Evidencias:

Randomized studies showed that in this setting they were able to obtain an ORR of 60–80%, a PFS ranging from 10 to 13 months and an OS of 13–20 months [41-43; 56-65]

Nevertheless, despite their small molecular weight, both erlotinib and gefitinib seem to reach limited concentrations into cerebrospinal fluid (CSF). In fact, at standard dose CSF levels are lower than plasma levels [68-72]. Available data do not favor one EGFR-TKI over another but the concentration and the penetration in CSF are significantly higher with erlotinib than gefitinib [73-75].

The limited CNS exposure to TKIs can explain the high incidence of BM in EGFR mutated NSCLC despite the good control of extracranial disease during EGFRTKIs therapy. However, BM occurrence can damage the integrity of BBB and favor TKIs penetration [77].

So, while erlotinib and gefitinib at the standard dose do not sufficiently penetrate BBB in absence of CNS involvement, when BM are evident, they probably improve their CNS concentration with a consequent improvement in central activity [67]. Furthermore the inadequate TKIs penetration across the intact BBB, could explain the frequent absence of secondary resistance mutations in BM also when they are present in extra-cranial disease sites

Complete and sustained responses following BM treatment with erlotinib and gefitinib have been reported in several case reports [103-106].

An open-label, single-institution, phase II study prospectively evaluated the efficacy of EGFRTKIs, erlotinib or gefitinib, in pts with BM from NSCLC harboring EGFR mutations. There were no differences in PFS and OS between the different TKIs [84].

Conclusiones:

In many studies they are able to obtain similar activity to local treatments, with a beneficial toxicity profile (Table 1).

https://www.ncbi.nlm.nih.gov/pubmed/?term=PMC5233868


Referencias bibliográficas [*] para acceder a la bibliografia completa ver . el pdf.


PMID: 27083334

Park K et al. Afatinib versus gefitinib as first-line treatment of patients with EGFR mutation-positive non-small-cell lung cancer (LUX-Lung 7): a phase 2B, open-label, randomised controlled trial. Lancet Oncol. 2016 May;17(5):577-89.




NOTA: Las variables principales del estudio no están enfocadas a demostrar diferencias en la actividad intracraneal, por lo que más allá de algún indicio indirecto, el estudio no puede considerarse demostrativo de la superioridad de afatinib en la actividad intracraneal. Aunque si permite apuntar una razonable hipótesis para la reflexión y estudio, por las diferencias en las variables analizadas a favor de Afatinib en el subgrupo de pacientes con metástasis cerebrales. Contexto:

The irreversible ErbB family blocker afatinib and the reversible EGFR tyrosine kinase inhibitor gefitinib are approved for fi rstline treatment of EGFR mutation-positive non-small-cell lung cancer (NSCLC).

The study was aimet at comparing the efficacy and safety of afatinib and gefitinib in this setting.

This multicentre, international, open-label, exploratory, randomised controlled phase 2B trial (LUX-Lung 7) was done at 64 centres in 13 countries. Treatment-naive patients with stage IIIB or IV NSCLC and a common EGFR mutation (exon 19 deletion or Leu858Arg) were randomly assigned (1:1) to receive



afatinib (40 mg per day) or gefitinib (250 mg per day) until disease progression, or beyond if deemed benefi cial by the investigator.

Randomisation, stratified by EGFR mutation type and status of brain metastases, was done centrally using a validated number generating system implemented via an interactive voice or web-based response system with a block size of four. Clinicians and patients were not masked to treatment allocation; independent review of tumour response was done in a blinded manner. Coprimary endpoints were progression-free survival by independent central review, time-to-treatment failure, and overall survival. Effi cacy analyses were done in the intention-to-treat population and safety analyses were done in patients who received at least one dose of study drug

Evidencias

Progression-free survival (median 11.0 months [95% CI 10.6–12.9] with afatinib vs 10·9 months [9.1–11·5] with geftinib; hazard ratio [HR] 0.73 [95% CI 0.57–0·95], p=0.017)

Time-to-treatment failure (median 13.7 months [95% CI 1.9–15.0] with afatinib vs 11.5 months [10.1–13.1] with gefitinib; HR 0.73 [95% CI 0.58–0.92], p=0.0073) were significantly longer with afatinib than with gefitinib. Overall survival data are not mature.

The proportion of patients who achieved an objective tumour response was signifi cantly higher with afatinib than with gefitinib by independent review (112 [70%] of 160 patients given afatinib vs 89 [56%] of 159 patients given gefitinib; odds ratio 1·87 [95% CI 1·18–2·99]; p=0·0083; table 2) with a longer median duration of response for patients treated with afatinib than gefitinib (10·1 months [IQR 5·6–16·8] vs 8·4 months [6·2–13·1], respectively) (table 2).

The most common treatment-related grade 3 or 4 adverse events were diarrhoea (20 [13%] of 160 patients given afatinib vs two [1%] of 159 given gefi tinib) and rash or acne (15 [9%] patients given afatinib vs fi ve [3%] of those given gefi tinib) and liver enzyme elevations (no patients given afatinib vs 14 [9%] of those given gefi tinib).

Serious treatment-related adverse events occurred in 17 (11%) patients in the afatinib group and seven (4%) in the gefitinib group. Ten (6%) patients in each group discontinued treatment due to drug-related adverse events. 15 (9%) fatal adverse events occurred in the afatinib group and ten (6%) in the gefi tinib group. All but one of these deaths were considered unrelated to treatment; one patient in the gefi tinib group died from drug-related hepatic and renal failure.

Conclusiones:

To the best of our knowledge, LUX-Lung 7 is the first prospective head-to-head trial to assess an


irreversible ErbB family blocker, afatinib, and a reversible EGFR tyrosine kinase inhibitor, gefitinib, as first-line treatment of patients with EGFR mutation-positive NSCLC in both Asians and non-Asian patients.

This study showed that afatinib has improved efficacy compared with gefitinib over a range of clinically relevant endpoints including progression-free survival, time-to-treatment failure, and the proportion of patients achieving an objective response.

The improvement in efficacy was noted both in patients with exon 19 deletion and Leu858Arg mutations. The adverse event profile was predictable and manageable; the discontinuation rate due to treatment-related adverse events was the same as with gefitinib.


PMID: 25247337

Hoffknecht P et al. Afatinib Compassionate Use Consortium (ACUC).. Efficacy of the irreversible ErbB family blocker afatinib in epidermal growth factor receptor (EGFR) tyrosine kinase inhibitor (TKI)-pretreated non-small-cell lung cancer patients with brain metastases or leptomeningeal disease. J Thorac Oncol. 2015 Jan;10(1):156-63.




Contexto:

Afatinib is an effective first-line treatment in patients with epidermal growth factor receptor (EGFR)-mutated non–small-cell lung cancer (NSCLC) and has shown activity in patients progressing on EGFR-tyrosine kinase inhibitors (TKIs). First-line afatinib is also effective in patients with central nervous system (CNS) metastasis.

Here we report on outcomes of pretreated NSCLC patients with CNS metastasis who received afatinib within a compassionate use program.

Evidencias:

Patients were enrolled and 541 treated with afatinib. One hundred patients (66% female; median age, 60 years) had brain metastases and/or leptomeningeal disease with 74% having documented EGFR mutation.


Data from one patient with an impressive response showed an afatinib concentration in the cerebrospinal fluid of nearly 1 nMol.

Conclusiones:


Afatinib may therefore be an effective treatment for heavily pretreated patients with EGFR-mutated or EGFR–TKI-sensitive NSCLC and CNS metastasis.

Pregunta 16: ¿Es seguro emplear de forma concurrente los TKI con la RT? (Dr. Alejandro Navarro)

ID (número de identificación del

PMID:

Chen Y et al. First-line epidermal growth factor receptor (EGFR)-tyrosine kinase inhibitor alone or with whole-brain radiotherapy for brain



documento): 21 27627582 metastases in patients with EGFR-mutated lung adenocarcinoma. Cancer Sci. 2016 Dec;107(12):1800-1805.




Contexto:


A total of 1665 patients were screened from 2008 to 2014, and 132 were enrolled in our study

Evidencias:

For EGFR-mutated lung adenocarcinoma patients with BM, treatment with concomitant WBRT

achieved a higher response rate of BM and significant improvement in intracranial progression-free survival

compared with EGFR-TKI alone.

Concomitant (EGFR-TKI treatment) WBRT achieved a significantly increased intracranial TTP, with 1-

year and 3-year intracranial control rates of 83.5% and 33.4%.

Neurocognitive toxicity: at early follow-up, significantly more patients in the EGFR-TKI plus WBRT group had impairments in memory (delayed recall and recall) and learning (recognition) than in the EGFR-TKI alone group. On the contrary, in the >2 years survivors, the percentage of those suffering from impaired memory function had declined by more than half.

A phase II trial carried out in a molecularly unselected population also showed that the combination of

erlotinib and WBRT was both safe and efficacious, with an ORR of 86% and no increase in neurotoxicity

[20].

Conclusiones:

Concomitant WBRT significantly improved intracranial lesion control and prolonged intracranial TTP compared with EGFR-TKI treatment alone. However, WBRT might specifically impair hippocampus-related functions such as memory and learning, and we found that a proportion of patients who received EGFR-TKI plus WBRT showed impaired memory. To protect against radiation-induced neurotoxicity, prospective studies are needed to identify the subsets of patients treated with EGFRTKI for whom radiotherapy can be omitted.

Referencias bibliográficas [20]. Welsh JW et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 2013; 31: 895–902.

ID (número de

identificación del

documento: 0

PMID:

27229180



Descripción del

estudio (abstract)


NOTA: Aunque la información puede ser ítil para responder a la pregunta, no se muestran los datos de




seguridad de lose studios originales.

Evidencias:

The combinatorial effect of TKIs with WBRT has been tested in two prospective trials. A multi-institutional phase II study combined erlotinib with WBRT in 40 patients with NSCLC. The ORR was 86% and the median survival was 11.8 months, but in patients with a known EGFR mutation, it was 19.1 months [115]. The study established the feasibility and tolerability of this option for patients with EGFR-mutant NSCLC, who have numerous or symptomatic brain metastases and require simultaneous urgent initiation of systemic therapy at the time of WBRT.

Therapy Oncology Group conducted a phase III trial of WBRT and SRS, given alone or with either temozolamide or erlotinib, for patients with NSCLC with one to three brain metastases.[116] The study closed early on account of poor accrual and because the three arms were not statistically different. Grade 3 to 5 toxicity rates were 41% to 49% in the two arms incorporating concurrent drug treatment. Patients were not tested for EGFR mutation in this study and the combination of both WBRT and SRS has now become less favored, especially in the EGFR-mutant population, thus limiting the impact of this study on practice.

Referencias Bibliograficas [115] Welsh JW et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell lung cancer. J Clin Oncol. 2013;31:895–902. [116] Sperduto PW et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol Biol Phys. 2013;85: 1312–1318.

ID (número de

identificación del

document: 1

PMID:

27382120

Arvold ND et al. Updates in the management of brain metastases. Neuro

Oncol. 2016 Aug;18(8):1043-65.




NOTA: general de metastasis cerebral.

Evidencias:

Randomized trials to date have not demonstrated an OS benefit from adding systemic therapy to WBRT [84, 85].

With regard to other endpoints such as radiographic response rate, progression-free survival, and time to neurologic deterioration, results are mixed. However, toxicity is generally increased when adding systemic therapy.[84] While a recent Phase II study of concurrent WBRT with erlotinib among NSCLC patients showed low toxicity rates,[86] a larger, randomized Phase III trial (RTOG 0320) reported grades 3–5 toxicity rates of 41%–49% in the arms receiving either temozolomide (TMZ) or erlotinib concurrently with WBRT, compared with 11% receiving WBRT alone [87].It has been speculated that the shorter survival observed among the 2 concurrent chemotherapy arms of the RTOG trial may be attributable to higher rates of toxicity, but the trial was underpowered to prove this assertion.

Most studies of WBRT with concurrent systemic therapy have enrolled lung cancer patients, and further studies are needed to examine the role of adding systemic therapy to WBRT across a variety of malignancies. While TMZ is sometimes administered concurrently with WBRT for patients with BM from malignant melanoma, the limited prospective data on this subject suggest minimal benefit [88].

In addition, a Phase II randomized trial of concurrent TMZ with WBRT for patients with BM from breast



cancer showed no improvement in objective response rate, progression-free survival, or OS.[89] Ongoing randomized studies include a study of WBRT with or without lapatinib for patients with BM from HER2-positive breast cancer [90,91].

Referencias Bibliograficas [84]. Tsao MN et al. Whole brain radiotherapy for the treatment of newly diagnosed multiple brain metastases. Cochrane Database Syst Rev.

2012;4:CD003869.

[85]. Mehta MP et al. The role of chemotherapy in the management of newly diagnosed brain metastases: a systematic review and evidence-based

clinical practice guideline. J Neurooncol. 2010;96(1):71–83.

[86]. Welsh JW et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapy for patients with brain metastases from non-small-cell

lung cancer. J Clin Oncol. 2013; 31(7):895–902.

[87]. Sperduto PW et al. A phase 3 trial of whole brain radiation therapy and stereotactic radiosurgery alone versus WBRT and SRS with

temozolomide or erlotinib for non-small cell lung cancer and 1 to 3 brain metastases: Radiation Therapy Oncology Group 0320. Int J Radiat Oncol

Biol Phys. 2013;85(5):1312–1318.

[88]. Margolin K et al. Temozolomide and whole brain irradiation in melanoma metastatic to the brain: a phase II trial of the Cytokine Working

Group. J Cancer Res Clin Oncol. 2002;128(4):214–218.

[89]. Cao K et al. Phase II randomized study of whole-brain radiation therapy with or without concurrent temozolomide for brain metastases from

breast cancer. Ann Oncol. 2015;26(1):89–94.

[90] National Cancer Institute. Whole-brain radiation therapy with or without lapatinib ditosylate in treating patients with brain metastasis from HER2-

positive breast cancer In: ClinicalTrials.gov [Internet]. Bethesda, MD: National Library of Medicine (US). 2012-[cited 2015 Jul 27]. Available from:

http://clinicaltrials.gov/show/NCT01622868. NLM Identifier: NCT01622868.

[91]. Lin NU et al. A phase I study of lapatinib with whole brain radiotherapy in patients with human epidermal growth factor receptor 2 (HER2)-

positive breast cancer brain metastases. Breast Cancer Res Treat. 2013;142(2): 405–414. .


PMID: 28149752

Proto C. et al. Epidermal growth factor receptor tyrosine kinase inhibitors for the treatment of central nervous system metastases from non-small cell lung cancer: the present and the future. Transl Lung Cancer Res. 2016 Dec; 5(6): 563–578.




Contexto:

Here, we review literature data about EGFR-TKIs use in pts with BM from NSCLC, analyzing the most relevant aspects concerning their role and effectiveness compared to current standard treatment.

Evidencias:

Different data about the association of TKIs and WBRT exist. A resume is reported in Table 1*.

Several preclinical studies have been carried out [118-122].

‒ Phase I trial, in which NSCLC pts with BM were enrolled, evaluated the toxicity of WBRT with concurrent and maintenance erlotinib showing that erlotinib was well tolerated and the combination did not cause any significant increase in treatment related toxicity [95].

‒ Different phase II studies evaluated the efficacy and toxicity of the concurrent approach [93,96].

‒ A phase I trial, in which NSCLC pts with BM were enrolled, evaluated the toxicity of WBRT with concurrent and maintenance erlotinib showing that erlotinib was well tolerated and the combination did not cause any significant increase in treatment related toxicity [95]. Moreover different phase II studies evaluated the efficacy and toxicity of the concurrent approach [93,96].

‒ The phase II trial by Ma et al. [96] studied the concomitant treatment with WBRT and gefitinib in

21 Chinese pts with BM from NSCLC to assess its impact on pts QoL and posttreatment survival. All pts received 40 Gy WBRT in 20 fractions. Gefitinib was administered during the radiation course and was continued until progression or unacceptable toxicity.

The great majority of toxicities were grade 2 and QoL was significantly improved following treatment. Erlotinib achieved similar results in a single-arm phase II trial [93] in which 40 NSCLC pts with BM, not selected for EGFR mutations, were treated with standard dose TKIs and concurrent WBRT.



The ORR was 86%, median OS was 11.8 months (95% CI, 7.4–19.1 months) and the combination resulted well tolerated with no grade 4 toxicity, limited neurotoxicity and only 3 cases of grade 3 rash (3%). EGFR status was known in 17 pts and median OS was 9.3 vs. 19.1 months in EGFR WT vs. mutated pts respectively. These data are promising and concomitant treatment was well tolerated, with important

activity and improvement in QoL. Conclusiones:

First and second generation EGFR-TKIs represent a valid therapeutic option in NSCLC pts with BM (Table 1*), especially in pts with activating EGFR mutations. EGFR-TKIs in combination with other treatment options, such as surgery, radiotherapy, chemotherapy, monoclonal antibodies and immunotherapy, may further improve results.

* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Referencias bibliográficas [93]. Welsh JW et al. Phase II trial of erlotinib plus concurrent whole-brain radiation therapyfor patients with brain metastases from non-small-cell lung cancer. J Clin Oncol 2013;31:895-902. [95] Lind JS et al. Phase I study of concurrent whole brain radiotherapy and erlotinib for multiple brain metastases from non-small-cell lung cancer. Int J Radiat Oncol Biol Phys 2009;74:1391-6. [96] Ma S bet al. Treatment of brain metastasis from non-small cell lung cancer with whole brain radiotherapy and Gefitinib in a Chinese population. Lung Cancer 2009;65:198-203. [118]. Chinnaiyan P et al. Mechanisms of enhanced radiation response following epidermal growth factor receptor signaling inhibition by erlotinib (Tarceva). Cancer Res 2005;65:3328-35. [119]. Akimoto T et al. Inverse relationship between epidermal growth factor receptor expression and radiocurability of murine carcinomas. Clin Cancer Res 1999;5:2884-90. [120]. Qin D et al. Effect of brain irradiation on blood-CSF barrier permeability of chemotherapeutic agents. Am J Clin Oncol 1997;20:263-5. [121]. Qin D et al. Improved efficacy of chemotherapy for glioblastoma by radiation-induced opening of blood-brain barrier: clinical results. Int J Radiat Oncol Biol Phys 2001;51:959-62. [122]. DeAngelis LM et al. Radiation-induced dementia in patients cured of brain metastases. Neurology 1989;39:789-96.


PMID: 25990950

Hendriks LE et al. Safety of cranial radiotherapy concurrent with tyrosine kinase inhibitors in non-small cell lung cancer patients: A systematic review. Cancer Treat Rev. 2015 Jul;41(7):634-45.

Tipo de estudio Systematic review



Contexto:

To our knowledge, the present study was the first to systematically review the literature in order to evaluate the safety of concurrent cranial radiotherapy and TKI.

The literature search was performed following the PICO method. This search was used to identify studies in Pub Med, EMBASE, Web of Science and the Cochrane Library from 2001 until the search date in November 2014. Additionally, clinicaltrials.gov was searched to identify unpublished or ongoing clinical trials.

Based on the exclusion criteria, 11 articles and 3 conference proceedings were eligible to include in this review

Evidencias:

The following studies were analyzed (Table 2):



Evidencias: All toxicity outcomes are summarized in Table 4.


Conclusiones:

In summary, although there are arguments that EGFR–TKI can be safely applied concurrent with WBRT, there is no high-level evidence to support this. With the addition of SRS/SRT to WBRT, severe (grade 3–5) toxicities may increase, although further studies are needed [34].

Referencias bibliográficas [*]para acceder a las referencias ver el pdf completo.



PMID: 26057469

Luo S et al. Evaluation on efficacy and safety of tyrosine kinase inhibitors plus radiotherapy in NSCLC patients with brain metastases. Oncotarget. 2015 Jun 30;6(18):16725-34.

Tipo de estudio Meta-analysis



Contexto:

The study was designed to evaluate the efficacy and safety of tyrosine kinase inhibitors (TKIs) plus radiotherapy in patients with brain metastases (BM) of non-small cell lung cancer.

Methods: Medline PubMed, Google Scholar, Web of Science, Oxford Journals Collection, clinical trials and current controlled trials were searched to identify relevant publications. After screening literature and undertaking quality assessment and data extraction, the meta-analysis was performed using RevMan5.3 software.

Evidencias:

Eight controlled trials (980 participants) were included in the study.

Compared with radiotherapy without TKIs (non-TKI-group), TKIs plus radiotherapy (TKI-group) had a

significant benefit on objective response rate (ORR) (RR = 1.56, 95%CI [1.25,2.03]; P =0.0008),

significantly prolonged the time to central nerves system progression (CNS-TTP) (HR =0.58, 95% CI

[0.35, 0.96]; P =0.03) and median overall survival (MOS) (HR =0.68, 95% CI [0.47, 0.98]; P =0.04) of NSCLC

patients with BM. There was no significant difference in overall severe adverse events (Grade≥3) (RR =

1.49, 95% CI [0.88,2.54]; P = 0.14) between two groups.

Conclusiones:

This meta-analysis showed TKI-group produced superior response rate when compared with non-TKI-group. TKIs plus radiotherapy significantly prolong the CNS-TTP and MOS of patients without enhancing overall severe adverse events.


PMID: 26439599

Metro G et al. Pharmacotherapeutic options for treating brain metastases in non-small cell lung cancer. Expert Opin Pharmacother. 2015;16(17):2601-13.

Tipo de estudio Expert opinion



Contexto:

An interesting question in clinical practice is whether systemic treatment could be safely combined with concurrent radiotherapy, particularly WBRT.

Evidencias:

As for chemotherapy, this approach has been demonstrated to have an acceptable toxicity profile [19,28], potentially increasing the anti-tumor activity against BMs [28].

As for TKIs, clinicians are often faced with the question if the TKI may be continued during cranial radiotherapy. Certainly, advantages of combining a TKI with cranial radiotherapy would be a possible synergistic anti-tumor effect against BMs, as well as the prevention of a systemic disease flare-up, a phenomenon that can be observed shortly after discontinuation of the TKI [83,84].




A recent systematic review of studies evaluating the use of an EGFR-TKI with concurrent cranial radiotherapy found no significant increase of neurotoxicity, with a slight increase in non-neurological severe toxicities, namely rash (9 -- 20% of patients) and mucositis 5 -- 12.5% of individuals) [85].

Conclusiones:

No firm conclusion can be drawn on the activity of such an approach, as studies were mainly conducted in a molecularly unselected population, with only few patients being tested for an activating mutation in the EGFR gene.

In clinical practice, the extent of extra-cranial disease, and therefore concerns about a flareup phenomenon upon discontinuation of the TKI, may guide treatment decision on whether the TKI should be continued during cranial radiotherapy.

Referencias bibliográficas [28] Dinglin XX, et al. Pemetrexed and cisplatin combination with concurrent whole brain radiotherapy in patients with brain metastases of lung adenocarcinoma: a single-arm phase II clinical trial. J Neurooncol 2013;112(3):461-6 [83]. Chaft JE et al. Disease flare after tyrosine kinase inhibitor discontinuation in patients with EGFR-mutant lung cancer and acquired resistance to erlotinib or gefitinib: implications for clinical trial design. Clin Cancer Res 2011;17:6298-303 [84]. Pop O et al. Disease flare after treatment discontinuation in a patient with EML4-ALK lung cancer and acquired resistance to crizotinib. J Thorac Oncol 2012;7(8):e1-2 [85]. Hendriks LE, et al. Safety of cranial radiotherapy concurrent with tyrosine kinase inhibitors in non-small cell lung cancer patients: a systematic review. Cancer Treat Rev 2015;41:634-45

Pregunta 17: ¿Existen interacciones de los anticonvulsivantes con los TKI? (Dr. Alejandro Navarro)


PMID: 27794414

Ohgami M et al. Drug interaction between erlotinib and phenytoin for brain metastases in a patient with nonsmall cell lung cancer. Lung Cancer. 2016 Nov;101:9-10

Tipo de estudio Case Report



Contexto:

Erlotinib, a substrate drug metabolized by the CYP3A4 enzyme, is an epidermal growth factor receptor tyrosine kinase inhibitor used to treat nonsmall cell lung cancer (NSCLC).

Concomitant use of erlotinib and the antiepileptic drug phenytoin, an inducer of CYP3A4, may result in a drug-drug interaction accompanied by changes in the blood concentrations of both drugs.

In this case report it was determinded the blood concentration of each drug to confirm the interaction between phenytoin and erlotinib in a case of NSCLC with brain metastases.

Evidencias:

The phenytoin blood concentration (8.2-10.0μg/mL) gradually increased 3-fold (to 24.2μg/mL) 7 months after the start of erlotinib (150mg/d) co-administration.

The erlotinib blood concentration which was maintained at 0.15-0.37μg/mL under phenytoin co-administration, increased 12-fold (to 1.77μg/mL) after the stoppage of phenytoin co-administration.

The change in phenytoin blood concentration, which was increased by erlotinib co-administration, is similar to that previously described by Grenader et al [6].

Conclusions

When using concomitant phenytoin and erlotinib, physicians should pay attention to possible drug–drug interactions inducing unfavorable effects from both drugs—toxic symptoms in the case of phenytoin and insufficient antitumor effects in the case of erlotinib, though the combination is not



contraindicated.

It is recommended to switch to non-enzyme-inducing antiepileptic drugs when erlotinib gives first medication priority. Therapeutic drug monitoring for both phenytoin and erlotinib may be alternative way to optimize the relevant dose amounts when phenytoin cannot be switched to non-enzyme-inducing antiepileptic drugs.

Referencias bibliográficas [6] Grenader T et al. Significant drug interaction: phenytoin toxicity due to erlotinib. Lung Cancer. 2007; 57: 404-6.


PMID: 24041628

Thomas-Schoemann A et al. Drug interactions with solid tumour-targeted therapies. Crit Rev Oncol Hematol. 2014 Jan;89(1):179-96.




Contexto:

Drug interactions are an on-going concern in the treatment of cancer, especially when targeted therapies, such as tyrosine kinase inhibitors (TKI).

We would like to provide the first comprehensive overview of Drug–drug interactions (DDIs) that involve targeted therapies approved by the Food and Drug Administration for the treatment of solid tumours for more than 3 years and medicinal herb or drugs.

The indications, targeted kinases and dosage of these targeted therapies (sorafenib, sunitinib, erlotinib, gefitinib, imatinib, lapatinib, everolimus, temsirolimus) are summarised in Table 1.

Evidencias:



Enzyme inducing anti-epileptics (EIAEDs) also have a significant impact on the pharmacokinetics of gefitinib, yet to a lesser extent [97,98].

Erlotinib exposure may also be altered by concomitant administration of EIAEDs in glioblastoma patients [113]

Table 3 resumes the Pharmacokinetic drug–drug interactions described in literature. Area Under Curve (AUC)


[97] Chun S et al. Gefitinib–phenytoin interaction is not correlated with the c-erythromycin breath test in healthy male volunteers. Br J Clin


Pharmacol 2009;68:226–37. [98] Reardon DA et al. Phase 1 trial of gefitinib plus sirolimus in adults with recurrent malignant glioma. Clin Cancer Res 2006;12:860–8. [113] van den Bent MJ et al. Randomized phase II trial of erlotinib versus temozolomide or carmustine in recurrent glioblastoma: EORTC brain tumor group study 26034. J Clin Oncol 2009;27:1268–74.

Pregunta 18: ¿Existen interacciones de los corticoides con los TKI? (Dr. Alejandro Navarro)

ID (número de identificación del documento): NA

PMID: NA

Drugs.com

Tipo de estudio NA


https://www.drugs.com/drug_interactions.php

NOTA: En los documentos seleccionados no se ha encontrado información para responder a esta pregunta, por lo que se ha realizado una búsqueda específica en esta base de datos. Se ha buscado si los siguentes TKI (afatinib, dacomitinib, erlotinib y gefitinib) tenian interacciones con los siguiente corticoides (prednisone, metilprednisolone y dexamethasone) (ver tabla 1). Contexto: Drugs.com provides accurate and independent information on more than 24,000 prescription drugs, over-the-counter medicines and natural products. This material is provided for educational purposes only and is not intended for medical advice, diagnosis or treatment. Data sources include Micromedex® (updated June 2nd, 2017), Cerner Multum™ (updated June 5th, 2017), Wolters Kluwer™ (updated June 6th, 2017) and others.

Evidencias En la tabla no se incluye dacomitinib ya que este no se encontaba en la base de datos (no aprobado). Tabla 1: Interacciones

dexamethasone prednisone metilprednisolone

afatinib No se encuentra en la lista de

interacciones No se encuentra en la lista de interacciones

No se encuentra en la lista de interacciones

erlotinib

Moderate drug interaction: Dexamethasone may reduce the

blood levels of erlotinib, which may make the medication less

effective in treating your condition.



gefitinib

Moderate drug interaction: Dexamethasone may reduce the

blood levels and effects of gefitinib.



Conclusiones:

Solamente erlotitinib y gefitinib presentan interacciones con alguno de estos cordicoides, ambos con dexamethasone.

https://www.drugs.com/drug_interactions.php


6. Evaluación de la respuesta y seguimiento

Pregunta 19: ¿Con qué periodicidad hay que evaluar las lesiones del SNC en pacientes que no han

recibido tratamiento local previo? (Dra. Adela Bartolomé)

Pregunta 20: ¿Con qué periodicidad hay que evaluar las lesiones del SNC en pacientes que han

recibido tratamiento local previo? (Dra. Adela Bartolomé)

NOTA: No se distingue entre los pacientes que han recibido tratamiento local previo y los que NO.


PMID: 20621414

Nishikawa T et al.n Early detection of metachronous brain metastases by biannual brain MRI follow-up may provide patients with non-small cell lung cancer with more opportunities to have radiosurgery. Clin Neurol Neurosurg. 2010 Nov;112 (9):770-4.




NOTA: En el artículo no se menciona la perioricidad sino que demuestran que hay que tener imagenes de las lesiones antes de que produzcan síntomas porque aumenta en 1-2 años la supervivencia. Contexto

This retrospective study evaluated the optimal brain magnetic resonance image (MRI) follow-up interval for non-small cell lung cancer (NSCLC) patients to detect radiosurgically manageable metachronous brain metastases.

We reviewed the database of the NSCLC patients in our institute, Kishiwada City Hospital, between January 2002 and December 2007. The records of 551 patients with primary NSCLC, were reviewed. The initial brain MRI was performed within one month after diagnosis of NSCLC, and the follow-up brain MRI interval was at the discretion of physicians.

The interval between the last MRI in which brain metastases were not found and the first MRI in which brain metastases were found was defined as the critical MRIs interval (CMI). The relationship between CMI and the maximum size or number of MBM was evaluated.

Evidencias

Among reviewed patients, the initial MRI of 38 patients showed brain metastases and 29 patients were diagnosed as MBM. In theseMBMpatients, the median interval from diagnosis of NSCLC to diagnosis of brain metastases was 8.9 months.

The median CMI was 4.7 (range: 1.6–18.9) months. All brain metastases smaller than 30mm in maximum diameter were found when CMI was shorter than 6.0 months, although 5 or more brain metastases in number were detected even by shorter CMI than 3 months.

Conclusiones

Early detection of MBM by biannual MRI follow-up may provide NSCLC patients with more opportunities to have less invasive treatment.


PMID: 18556086

Sánchez de Cos et al. Non-small cell lung cancer and silent brain metastasis. Survival and prognostic factors. Lung Cancer. 2009 Jan; 63(1):140-5.






Contexto:

The aim of this study was to evaluate clinical course, prognostic significance, and treatment efficacy in patients with asymptomatic brain metastasis

In a series of patients with potentially operable NSCLC and small brain lesions detected by either cranial CT or MRI, observed good survival times for both groups of patients, although survival in the MRI group was slightly higher [1].

A retrospective study of patients with cytologically and histologically diagnosed NSCLC and brain metastasis detected by cranial computed tomography or magnetic resonance imaging was performed. 12 neurologically asymptomatic patients and 69 symptomatic patients were analysed; overall survival, clinical course, and prognostic factors were considered.

Evidencias:

Of the 476 patients diagnosed with lung cancer between 1 January 1996 and 31 June 2007 who had at least 1 cranial CT or MRI study, 81 had histologically proven NSCLC and radiologically diagnosed brain metastasis. Table 1* shows the characteristics of the patients from each group.

Asymptomatic patients had better performance status than symptomatic ones (p = 0.048) as well as a higher rate of synchronous brain lesions (p = 0.002), a larger number of tumors detected by cranial MRI (p < 0.001), and significantly smaller brain lesions (p = 0.005). Forty patients had metachronous brain metastasis

Conclusiones:



In a previous study comparing the value of cranial CT and MRI in the detection of silent brain metastasis in patients with lung cancer, we found that 8.3% of patients had brain lesions and that cranial MRI detected more lesions smaller than 1 cm than did CT [15].


* Para acceder a datos completos de tablas y figuras, ver .pdf completo. Referencias bibliográficas

[1] Yokoi K et al. Detection of brain metastasis in potentially operable non-small cell lung cancer. A comparison of CT and MRI. Chest 1999;115:714–9. [5] Park HY et. Routine screening by brain magnetic resonance imaging decreased the brain metastasis rate following surgery for lung adeno [12] Nguyen TD, DeAngelis LM. Brain metastases. Neurol Clin 2007:1173–92.carcinoma. Lung cancer 2007;58:68–72. [15] Sánchez de Cos J et al. Metástasis encefálicas silentes en la estadificación inicial del cáncer de pulmón. Arch Bronconeumol 2007;43(7):386–91.



7. Algoritmo de primera línea A partir de la información recogida en el proceso de elaboración de las recomendaciones, se realizará el

algoritmo en la reunión final del consenso.

8. Carcinomatosis leptomeníngea (sólo tratamiento)

Pregunta 21: En los pacientes con carcinomatosis leptomeníngea, ¿debe realizarse tratamiento

intratecal o tratamiento local? (Dr. Jordi Bruna)


PMID: NA

Seiji Yano,Shigeki Nanjo, Sachiko Arai, Shinji Takeuchi, Tadaaki Yamada, Yasunori Okada, Akito Hata. Nobuyuki Katakami OA08.03. MET Copy Number Gain Associates with Gefitinib Resistance in Leptomeningeal Carcinomatosis of EGFR Mutant Lung Cancer. Journal of Thoracic Oncology 2017. Vol. 12 No. 1S



http://www.jto.org/article/S1556-0864(16)31510-6/pdf

Contexto:

The purpose of this study is to clarify the mechanism of EGFR-TKI resistance in LMC and establish novel therapeutic strategy.

We examined EGFR mutations, including T790M gatekeeper mutation, in 32 re-biopsy specimens from 12 LMC and 20 extracranial lesions (e.c., lung metastasis and malignant pleural effusions) of EGFR mutant lung cancer patients who became refractory to EGFR-TKI treatment. To clarify molecular mechanisms of acquired EGFR-TKI resistance in LMC, we utilized in vivo imaging model of LMC with EGFR mutant lung cancer cell line PC-9/ffluc and induced acquired resistance to gefitinib by continuous oral treatment.

Evidencias:

We found that all 32 re-biopsy specimens had the same baseline EGFR mutations and that T790M was less frequent in LMC specimens than extracranial specimens (8% vs 55%). Compared with subcutaneous tumors, T790M was less frequent in LMC which acquired resistance to gefitnib. We further established PC-9/LMCGR cells from the gefitinib-resistant LMC model and found that PC-9/LMC-GR cells were intermediately resistant to gefitinib and osimertinib (3rd generation EGFR-TKI). While EGFR-T790M was negative, MET copy number gain associated MET activation was involved in the gefitinib resistance in PC-9/LMC-GR cells. Moreover, combined use of EGFR-TKI and crizotinib, having inhibitory activity against MET, dramatically regressed LMC which already acquired resistance to gefitinib or osimertinib.

Conclusions:

These findings suggest that combined use of MET inhibitors may be promising for controlling LMC which acquires resistance to EGFR-TKIs including osimertinib.


PMID: 28110254

Remon J et al. Leptomeningeal carcinomatosis in non-small cell lung cancer patients: A continuing challenge in the personalized treatment era. Cancer Treat Rev. 2017 Feb;53:128-137




Contexto: Standard treatment is yet to be established due to the lack of randomized clinical trials with definitive conclusions. This situation is explained by low incidence rates, the rapidly progressing nature of the disease, and the heterogeneous LM

http://www.jto.org/article/S1556-0864(16)31510-6/pdf



population Intrathecal chemotherapy

Intrathecal chemotherapy (ITC) in combination with systemic treatment is the mainstay of treatment for non-nodular types of LM, although its superiority compared with systemic treatment alone has not been established in randomized trials [18–23].

Recently, some retrospective data have reported its efficacy among NSCLC patients [24,25]. A recent pooled analysis, evaluated 589 NSCLC patients receiving ITC, with 37 patients receiving ITC only, while 552 patients received multiple interventions, such as ITC, whole-brain radiotherapy (WBRT), epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs), systemic chemotherapy or best supportive care. The study reported a re-evaluated cytological, clinical and radiographic rates of 55% (53- 60%; n=49), 64% (53-79%; n=58), and 53% (n=32), respectively, and median OS of 6.0 months. The median survival time of patients who received ITC only (7.5 months) was much longer than that of patients who received multiple interventions (3.0-5.0 months) [26]. However, given the limited number of patients, the heterogeneity in the ITC treatment and other confounding factors it is difficult to draw robust conclusions about the efficacy of ITC in NSCLC patients and clinical trials are needed. In another study in NSCLC patients, cytological response after ITC was reported to be a prognostic factor (median survival of 5.5 months for cytological responders versus 1.4 months for non-responders, p=0.075). PS and clinical improvement after ITC were also significant prognostic factors [25]. However, predictive value of cytological conversion remains controversial.

Intact blood-brain and blood-CSF barriers limit penetration into the CSF of most anticancer drugs, giving CSF exposure of usually less than 5% of the plasma concentration [4]. Three drugs are routinely used for intrathecal application: methotrexate, Ara-C (liposomal cytarabine), and thiotepa (Table 3).


Methotrexate is the drug with the broadest experience in treating LM, however the precise schedule of

administration and the duration of treatment has not been established. The most common doses of methotrexate are 10-15 mg twice weekly for 4 to 6 weeks as treatment induction. If negative cytology is achieved after induction, induction therapy once weekly is continued for another month before switching to monthly maintenance ITC [9,13] (Table 3).

However, the RANO group reported that CSF response definitions vary widely across trials [10]. It has been suggested that at each ITC, CSF should be taken and analyzed to monitor the disease response in parallel with the patient’s clinical course. In patients without cytology clearance and clinically stable or improved outcomes, it may be advisable to continue the induction ITC for 1 month before switching to maintenance ITC. Termination of ITC may be indicated in cases of clinical or CSF cytology deterioration [9,13], however the duration of the maintenance treatment is not consensual. A leukoencephalopathy after methotrexate may occur, especially if methotrexate is administered after rather than before radiotherapy. Thus in combined treatments, methotrexate ITC should be administered 2 or 3 weeks before WBRT [9]. Also, in 10-50% of cases reversible chemical aseptic meningitis may occur after IT liposomal cytarabine that can be overcome with oral steroids. Renal impairment may increase the risk of methotrexate toxicity [9].

Radiotherapy

Radiotherapy is manly given for symptoms alleviation, CSF flow correction or for debulking to facilitate chemotherapy [13]. It is appropriate for patients with nodular type leptomeningeal disease. WBRT is typically used in cases of concurrent brain metastases or major meningeal cerebral involvement.

Focal radiotherapy is used for meningeal nodular spinal or cerebral lesions or in symptomatic areas (fossa posterior or cauda equine) even in the absence of imaging abnormalities [9].

However, use of WBRT in NSCLC patients with LM needs to be better defined in clinical trials given its impact on patients’ quality of life. In a retrospective cohort of NSCLC patients with LM (n=212), the median OS for patients who underwent WBRT for LM was longer than in those patients who did not (10.9 months versus 2.4 months, p=0.002) [6]. On the other hand, a recent study showed no difference in OS between patients treated with WBRT (n=46) and those who were not (n=59, p=0.84), with a median OS for the whole cohort of 3 months [24]. Another retrospective study reported limited efficacy of WBRT alone as palliative treatment (median OS of 2 months) in 27 breast and lung cancer patients unsuitable for chemotherapy. The absence of cranial nerve dysfunction was the only significant prognostic factor for OS for with WBRT (median 3.7 vs. 19.4 weeks, p<0.001) [34].

In a recent phase II trial with 59 patients with LM from solid tumors (including 32 NSCLC patients) and adverse prognostic factors, a combination of intensive treatment of concurrent radiotherapy (whole brain and/or spinal canal radiotherapy, 40 Gy/20f) and intrathecal methotrexate reported a median survival of 6 months and 1-year OS of 21.3%. Among NSCLC patients, clinical response rate was 87.5%, which correlated with OS (median OS 6.7 months), however, the toxicity of the combination treatment (20% severe toxicity including 15% grade 3 encephalopathy) argues against this strategy in daily clinical practice [35].

Prognostic factors should be taken into consideration to identify patients who are likely to benefit from WBRT. Concomitant strategies with ITC should be balanced against toxicity risks and are not considered as standard due to the toxicity profile.

Referencias bibliográficas [4] E. Le Rhun, S et al. Chamberlain, Carcinomatous meningitis: Leptomeningeal metastases in solid tumors, Surg Neurol Int. 4 (2013) S265- b288. doi:10.4103/2152-7806.111304. [9] F. Mack, B.G. et al. Therapy of leptomeningeal metastasis in solid tumors, Cancer Treat. Rev. 43 (2016) 83–91. doi:10.1016/j.ctrv.2015.12.004. [10] M. Chamberlain, R et al. Leptomeningeal metastasis: a Response Assessment in Neuro-Oncology critical review of endpoints and response criteria of published randomized clinical trials, Neuro-Oncology. 16 (2014) 1176–1185. doi:10.1093/neuonc/nou089 [13] Central Nervous System Cancers. NCCN version 1.2016(www.nccn.org), (n.d.). [18] R.N. Hitchins, D.R. et als, J.A. Levi, A prospective randomized trial of single-agent versus combination chemotherapy in meningeal carcinomatosis, J. Clin. Oncol. 5 (1987) 1655–1662. [19] S.A. Grossman, D.M. Finkelstein, J.C. Ruckdeschel, D.L. Trump, T. Moynihan, D.S. Ettinger, Randomized prospective comparison of intraventricular methotrexate and thiotepa in patients with previously untreated neoplastic meningitis. Eastern Cooperative Oncology Group, J. Clin. Oncol. 11 (1993) 561–569.


[20] M.J. Glantz, et al. Randomized trial of a slow-release versus a standard formulation of cytarabine for the intrathecal treatment of lymphomatous meningitis, J. Clin. Oncol. 17 (1999) 3110–3116. [21] M.J. Glantz, et al. A randomized controlled trial comparing intrathecal sustainedrelease cytarabine (DepoCyt) to intrathecal methotrexate in patients with neoplastic meningitis from solid tumors, Clin. Cancer Res. 5 (1999) 3394– 3402. [22] W. Boogerd, M.J.et al. The relevance of intraventricular chemotherapy for leptomeningeal metastasis inbreast cancer: a randomised study, Eur. J. Cancer. 40 (2004) 2726–2733. doi:10.1016/j.ejca.2004.08.012. [23] M.J. Glantz, A. Van Horn, R. Fisher, M.C. Chamberlain, Route of intracerebrospinal fluid chemotherapy administration and efficacy of therapy in neoplastic meningitis, Cancer. 116 (2010) 1947–1952. doi:10.1002/cncr.24921. [34] C. Gani, A.C. et al. Outcome after whole brain radiotherapy alone in intracranial leptomeningeal carcinomatosis from solid tumors, Strahlenther Onkol. 188 (2012) 148–153. doi:10.1007/s00066-011-0025-8. [35] Z. Pan, G. et al. Concurrent radiotherapy and intrathecal methotrexate for treating leptomeningeal metastasis from solid tumors with adverse prognostic factors: A prospective and single-arm study, Int. J. Cancer. 139 (2016) 1864–1872. doi:10.1002/ijc.30214.


PMID: 23328548

Lee SJ et al. Leptomeningeal carcinomatosis in non-small-cell lung cancer patients: impact on survival and correlated prognostic factors. J Thorac Oncol. 2013 Feb;8(2):185-91.




Contexto:

The incidence of leptomeningeal carcinomatosis (LC) has increased in patients with metastatic non-small-cell lung cancer (NSCLC) because of recent improvements in survival [4, 9].

The aim of this study was to identify the clinical features and prognostic factors of NSCLC patients with LC.

One hundred and forty-nine consecutive NSCLC patients with cytologically proven LC diagnoses between 2001 and 2009 at Samsung Medical Center were retrospectively reviewed

Evidencias: Treatment for LC consisted of:

intrathecal chemotherapy (ITC) alone in 44 patients,ITC plus systemic therapy in 18 patients, ITC plus radiotherapy in 29 patients, all three treatments in 18 patients, and other treatments without ITC in 20 patients. wenty patients received only supportive care.

The median follow-up duration was 34 months and the median overall survival from diagnosis of LC was 14 weeks (95% confidence interval [CI] 12, 16).

In univariate analysis, encephalopathy, Eastern Cooperative Oncology Group (ECOG) performance status, low initial cerebrospinal fluid (CSF) glucose, high initial CSF protein, high initial CSF white blood cell count, treatment with ITC, systemic therapy with epidermal growth factor receptor tyrosine kinase inhibitors or cytotoxic chemotherapy, whole-brain radiotherapy (WBRT), ventriculoperitoneal (VP) shunt operations, and negative cytologic conversion after ITC were identified as variables that had prognostic influence on survival.

In multivariate analysis, poor ECOG performance status (p = 0.026), high protein level of CSF (p = 0.027), and high initial CSF WBC count (p = 0.015) remained significant predictors of poor prognosis for survival, whereas ITC (p < 0.001), EGFR-TKI use (p = 0.018), WBRT (p = 0.009), and VP shunt operation (p = 0.013) remained significant predictors of favorable prognosis for survival.

Conclusiones:

Even though the prognosis of LC from NSCLC is poor, small subsets of these patients survive longer.

Results suggest that more active treatment strategies including ITC, WBRT, and EGFR-TKI use might improve clinical outcomes in NSCLC patients with LC and good performance status, low initial CSF protein and WBC counts.



Referencias bibliográficas [4]. Herrlinger U, Förschler H, Küker W, et al. Leptomeningeal metastasis: survival and prognostic factors in 155 patients. J Neurol Sci 2004;223:167–178. [9]. Pentheroudakis G, Pavlidis N. Management of leptomeningeal malignancy. Expert Opin Pharmacother 2005;6:1115–1125.


PMID: 22089116

Morris PG et al. Leptomeningeal metastasis from non-small cell lung cancer: survival and the impact of whole brain radiotherapy. J Thorac Oncol. 2012 Feb;7(2):382-5.




Contexto:

Leptomeningeal metastasis (LM), or leptomeningeal carcinomatosis, is a devastating complication of non-small cell lung cancer (NSCLC), and the optimal therapeutic approach remains challenging.

A retrospective review was carried out to assess the impact of whole brain radiotherapy (WBRT), intrathecal therapy (IT), and epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) on outcomes.

Patients with newly diagnosed LM from NSCLC from January 2002 to December 2009 were identified through institutional databases and medical records reviewed.

Evidencias:

We identified 125 patients (45 men, 80 women) with LM from NSCLC, median age 59 years (range, 28-87 years). Almost all (123 [98%]) patients have died and median overall survival was 3.0 months (95% confidence interval, 2.0-4.0).

No differences in survival were seen between patients who were treated with WBRT (n =46) and those who were not (n =59, p =0.84) in a landmark analysis.

In the seven patients selected to receive IT chemotherapy, median survival was 18 months (range, 5-33 months) and appeared superior to those not selected for this treatment (p =0.001) in a landmark analysis.

The median survival of the nine patients with known EGFR mutations (all of whom received TKIs at some point) was 14 months (range, 1-28 months).

Conclusiones:

Survival was not improved by WBRT.

The survival of patients selected for IT chemotherapy and those with EGFR mutations treated with TKIs highlights the importance of developing novel agents.

NOTA: Además de enviar este documento a los expertos, se les enviará un documento individualizado que incluya

solamente el resumen de la síntesis y la síntesis de su bloque en concreto.


Consenso sobre el tratamiento de pacientes con CPNM, con ... · 3. Resumen de la síntesis que...

Documents

Transcript of Consenso sobre el tratamiento de pacientes con CPNM, con ... · 3. Resumen de la síntesis que...