Estadificación del cáncer de pulmón

Mariano ProvencioServicio de Oncología MédicaHospital Universitario Puerta de Hierro

Agenda

Orientación al diagnósticoMétodos de diagnósticoMediastino Ebus/mediastinoscopia

HistologíaEstudio extensión PET mediastino PET y otras

AdyuvanciaNeoadyuvancia

Mariano Provencio

Cáncer de pulmónMétodos diagnósticos

Confirmación Citología de esputo Broncoscopia con biopsia Biopsia trans-bronquial

Éxito en 79-95% PAAF trans torácica de lesiones pulmonares

Sensibilidad del 95-100% Complicaciones: neumotórax en el 15%

Mediastinoscopia con biopsia No más del 3% se debe llegar a otras pruebas o no dx previo

cirugía

En general, estos dos marcadores suelen ser suficientes“judicious use of IHQ”

Early and locally advanced non-small-cell lung cancer (NSCLC): ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up†

Ann Oncol. 2013;24(suppl_6):vi89-vi98. doi:10.1093/annonc/mdt241Ann Oncol | © The Author 2013. Published by Oxford University Press on behalf of the European Society for Medical Oncology. All rights reserved. For permissions, please email: journals.permissions@oup.com.

PET-TC en CPNM

Fischer B, et al. N Eng J Med 2009;361:32-9

Abordajes Mediastinoscopia Cervical Estándar

Carlens en 1959. SUPRAESTERNAL 3 cm Plano de disección digital. Pretraqueal ,paratraqueal,

subcarinal S 80%, E 90%,

Ann Thorac Surg 2002;74:1720-1723

Toracoscopia video-asistida (VATS)Diagnóstico y terapéuticoDiagnóstico definitivo 96% Indicaciones

Biopsia de ganglios Biopsia de TM Resección de T. pequeños Resección de quistes Informacion adicional: Invasión, carcinomatosis, derrame

Estudio N Sensibilidad VPN

EBUS MED. EBUS MED.

Ernst* 66 87% 68% 78% 59%

Yasufuku** 190 81% 79% 91% 90%

Ernst A et, al. J Thorac Oncol 2008;3:577Yasufuku K, et al. J Thorac Cardiovasc Surg 2011;142:1393

*Diferencias significativas **Diferencias no significativas

EBUS vs. Mediastinoscopia

Variable Estadificación quirúrgica (EQ)

EUS y EBUS seguidos de EQ p

Sensibilidad 79% 94% 0,02

VPN 86% 93% 0,18

Toracotomías innecesarias 21 (18%) 9 (7%) 0,02

Complicaciones 7 6 0,78

Estudio randomizado de pacientes con CPNM T1-T3 con adenopatías > 1 cm, PET +, T central o sospecha N1:

• Estadificación quirúrgica (118)• EUS + EUS y si negativos, estadificación quirúrgica (123)

Annema JT, et al. JAMA 2010;304:2245-52

Estudio ASTER

Health Technol Assess. 2012;16(18):1-75

PET staging

PETHigh negative predictive value (94%)

Fails to identify microscopic N2 diseaseCarcinoid, bronchiololaveolar

Lower positive predictive value (75%-79%), false-positive in: GranulomasAspergillomasActive tuberculosisAbscessesSarcoidosis

Mediastinoscopy

Mariano Provencio

Focal Extrapulmonary abnormality and PET

350 NSCLC with PET/CTAdditional evaluations were performed on all patients with single focal extrapulmonary abnormalities:

21% (72/350) (no IIIB, or multifocal, ...IV)A diagnosis was obtained in 69 patients37 (54%) with solitary metastases32 (46%) lesions unrelated to lung cancer19% unsuspected malignancy81% benign tumor or inflammatory

Etiology of solitary PET positive should be determined (axillary, spleen, spinal, pancreas)

Mariano Provencio Lardinois D J Clin Oncol October 2005

Extrathoracic staging: adrenal glands

In 5-10% of patients with NSCLC, CT reveals enlarged adrenal glands at initial presentation:

2/3 are benign

PET: 95%- 100% sensitivity, 80-100% specificity

94 p with adrenal masses, the sensitivity, specificity and accuracy of PET for detection of metastatic disease was: 93, 90 and 92% (Kumar J Nucl Med 2004)

However:Vigilance required for small lesions (<1 cm)False-positive have also been reported

TAC: lacks a high sensitivity or specificity

MRI: may be helpful in distinguishing benign, fat-containing adrenal adenomas from adrenal metastases

Mariano ProvencioGupta NC, Clinical Lung Cancer 3; 59-64, 2001

Carcinoma bronquioloalveolar en varón de 75a

SUV 1.7

Carcinoma bronquioloalveolar mucinoso en mujer de 61a

Stage 1b cervical cancer . Obstet Gynecol 2015

QUIMIOTERAPIA ADYUVANTE EN CPNM: EPIDEMIOLOGÍA

SPV a 5 años en pacientes con CPNM según el estadio clínico

Estadio TNM SPV 5a Recidiva local / a distancia

I A T1N0M0 67 % 10 % / 15 %I B T2N0M0 57 % 10 % / 30 %II A T1N1M0 55 %

12 % / 40 %II B T2N1M0

T3N0M0

39 %38 %

III A T3N1M0

T1-3N2M0

25 %23 %

15 % / 60 %

Mountain 1997, Feld, 1984, Martini 1990, Thomas 1990

The beginning of the adjuvant history

BMJ, 1995

Adjuvant QTTrrial Stage Treatment Pt No 5-yr HR P value

ALPI I-III SurgMVP

603606

45%50%

0.96 0.59

BLT I-IIIA SurgCis-based

189192

58%60%

1.02 0.90

IALT I-III SurgCis-based

935932

40%44.5%

0.86 <0.03

ANITA IB-IIIA SurgCis-vin

433407

43%51%

0.80 0. 017

NCI-C IB-II SurgCis-vin

240242

54%69%

0.69 0.04

CALGB IB SurgCarb-pac

171173

57%59%

0.80 0.10

Author Year Type Data Nº trials N HR

Hotta 2004 Published data 11* 5716 0.87

Sedrakyan 2004 Published data 19 7200 0.87

Berghmans 2005 Published data 17 7644 0.85

Bria 2005 Published data 11 + 1 MA 6494 0.93

Hamada 2005 Individual patient data 6** 2003 0.74

Pignon (LACE) 2006 Individual patient data 5 4584 0.89

NSCLC MA 2010 Individual patient data 34 8447 0.864% at 5y

*Recent trials only ; **UFT trials only

Meta-analysis in ADJ setting

Hotta – JCO 2004 * Sedraykan – J Thorax Cardiov S 2004 * Berghmans – Lung Cancer 2005Bria – JCO 2005 * Hamada – JCO 2005 * Pignon – JCO 2008 * NSCLC MA – Lancet 2010

Pignon. JCO 2008; 21: 3552-9

“LACE” METANALISIS

Pignon. JCO 2008; 21: 3552-9

Benefit 5 years: 5.4 % Benefit 5 years: 5.8 %

“LACE” METANALISIS

LACE Meta-analysis of Adjuvant Chemo:Chemotherapy Effect and Stage

Pignon JP, et al. J Clin Oncol. 2008;26:3552-3559.

Stage IA 104/347 1.40 (0.95-2.06)Stage IB 515/1371 0.93 (0.78-1.10)Stage II 893/1616 0.83 (0.73-0.95)Stage III 878/1247 0.83 (0.72-0.94)

CategoryNo. Deaths/No. Patients

HR for OS (Chemo vs Control) HR (95% CI)

Chemotherapy Better Control Better0.5 1.0 1.5 2.0 2.5

Test for trend: P = .04

CALGB 9633: Survival by Tumor Size

Tumor ≥ 4 cm Tumor < 4 cm

Strauss GM, et al. J Clin Oncol. 2008;26:5043-5051.

Mos

Surv

ival

Pro

babi

lity

1.0

0.8

0.6

0.4

0.2

00 20 100 12060

Chemotherapy (n = 99)Control (n = 97)

8040Mos

Surv

ival

Pro

babi

lity

1.0

0.8

0.6

0.4

0.2

00 20 100 12060

Chemotherapy (n = 63)Control (n = 71)

8040

HR: 0.6990% CI: 0.48-0.99P = .043

HR: 1.1290% CI: 0.75-1.07P = .32

Visión crítica estudios adyuvancia

Requieren largo seguimiento para extraer conclusiones ciertas

Más recientes ensayos

IALT: se paró el reclutamiento con 60% 65% seguimiento del previsto

Cumplimiento: IALT: 31% reciben menos de 3 ciclos, 9% nada ALPI: 26%, 8% ninguno

Radioterapia: ALPI: 43% IALT: 27% NCIC-BR10: 0% ANITA: 28%

¿Por qué más beneficio? Poblaciones más

seleccionadas IALT: 339 pacientes /año BR10: 80 pacientes/año

Tipo de cirugía IALT: 35% neumonectomía BR10: 25%

Disección ganglionar completa o muestreo: Desconocida en todos, salvo ALPI: 57% vs 43%

The IALT; NEJM 04

• Diferentes esquemas a elegir, por no haber consenso en:• La dosis de cisplatino• El doblete de referencia basado en cisplatino• Los estadios elegibles para la quimioterapia adyuvante• La radioterapia postoperativa

• CISPLATINO: 80 mg/m2 cada 3 sem. x 4 cicloso 100 mg/m2 cada 4 sem. x 3 ó 4 c.o 120 mg/m2 cada 4 sem. x 3 ciclos

+• NAVELBINE: 30 mg/m2 /semanal• ETOPÓSIDO: 100 mg/m2 x 3 días por ciclo• VINBLASTINA: 4 mg/m2 /semanal• VINDESINA: 3 mg/m2 /semanal

ESTUDIO IALT

The IALT; NEJM 04

40.4%34.3%935Control

44.5%39.4%I: 36%II: 25%III: 39%

932

CDDP +VP16 (56%pts)NVB (27%)VLB/VDS (17%)

Superviv. global

SLEEstadioNúmero

pacientesEsquema

Seguimiento 56 meses

I: 37%II: 24%III: 39%

DESARROLLO: 3300 pacientes previstos / 1867 finalRESULTADOS

p<0,003 p<0,03

ESTUDIO IALT

Douillard JY, et al. Lancet Oncology 2006; 7:719-27, 2006

43,8 meses vs 65,8 meses; beneficio del 8% en supervivencia; no en IB

Evaluación cuantitativa de los resultados de un ensayo clínico

Riesgo Relativo 0,43 (IC 95%; 0,36-0,68)

Reducción Relativa Riesgo

53% (IC 95%,38-44)

R Absoluta del Riesgo

40% (IC 95%, 28,6-50)

Número Necesario a tratar

3 (IC 95%, 2-4)

ANITA N1 S GLOBALRiesgo Relativo 0,89 (IC 95%, 0,81-0,98)

Reducción Relativa Riesgo

11% (IC 95%,1.6%-14,2%)

R Absoluta del Riesgo

7,9% (IC 95%, 1,6%-14,2%)

Número NT 13 (IC 95%, 6-62)

ANITA QT vs Observación Sv. Global

Riesgo Relativo 0,81 (IC 95%, 0,70-0,94)

Reducción Relativa Riesgo

19% (IC 95%,6-30)

R Absoluta del Riesgo

5,9% (IC 95%, 1,5-8,5)

Número Necesario a tratar

21 (IC 95%, 12-68)

NEJM- MOSAIC-SLE

Riesgo Relativo 0,87 (IC 95%, 0,81-0,95)

Reducción Relativa Riesgo

13% (IC 95%,0-19)

R Absoluta del Riesgo

10% (IC 95%; 4-16)

Número NT 10 (IC 95%,7-25)

ANITA QT vs Observación SLE (60m)

Pre or Neoadjuvant QT

Why neoadjuvant chemotherapy?

Front-line attack of micrometastasis

Better compliance

Downstaging in about 50% of cases

Improvement resectability

Increase R0

Assess response

Study biology of disease and treatment effects

Phase III neoadyuvant trials: “The old fashion”

Brandon et al. Thorac Surg Clin 2008

“New” randomized trials in NEON Stage

I-IIARR(%)

Compliance Neumonectomy/Lobectomy/Exploratory

Post-opmortality

DFS(mo)

OS(mo)

5yOS(%)

ChEST NEOCG

129 46% 35 86% 10% / 64% / 12% - 48* 68* 67

IB-T3N1 Sur 141 55% - 24% / 57% / 16% - 35 25 60

LU22 NEOPlat+

258 66% 49 75% 25% / 60% / 6% 4% 26 54 44

IA-T3N1 Sur 261 62% - 31% / 56% / 6% 4% 25 55 45

S9900 NEOCbP

169 67% 41 80% 16% / 78% / 3% 5% 33 62 50

IB-T3N1 Sur 167 68% - 16% / 77% / 4% 3% 20 41 41

NATCH NEOCbP

199 76% 53 90% 23% / 72% / 4% 5% 31.5 55.2 46.6

IA-T3N1 Sur 210 74% - 26% / 65% / 5% 5.5% 25.1 48.9 44

ADJCbP

210 77% - 60% 24% / 69% / 5% 7.5% 26 50.3 45.5

*IIB/IIIA Scagliotti - ASCO 2008 * Gilligan – Lancet Oncol 2007 * Pisters - JCO 2010 * Felip –JCO 2010

Meta-analyses / Systematic reviewsBerghmans 2005 Nakamura 2006 Burdett 2006 Gilligan 2007 Song 2010

Dautzenberg, 1990Pass, 1992Roth, 1998Rosell, 1999Depierre, 2002JCOG, 2003

Pass, 1992Roth, 1998Rosell, 1999Depierre, 2002JCOG, 2003

Dautzenberg, 1990

Roth, 1998Rosell, 1999Depierre, 2002JCOG, 2003S9900, 2006Sorensen, 2005

Dautzenberg, 1990

Roth, 1998Rosell, 1999Depierre, 2002JCOG, 2003S9900, 2006Sorensen, 2005MRC LU22, 2007

Dautzenberg, 1990

Roth, 1998Rosell, 1999Depierre, 2002JCOG, 2003S9900, 2006Sorensen, 2005MRC LU22, 2007Zhou, 2001Liao, 2003Li, 2003Yao, 2004Ch.E.S.T, 2008

6 trials / 590 pt. 5 trials / 564 pt. 7 trials / 988 pt. 8 trials / 1507 pt 13 trials / 3224 pt.

HR=0.66 (95%IC 0.48-0.93)

HR 5y=0.85, p=0.12 (+ at 1,3y)

HR=0.82 ; p=0.026% at 5 years

HR=0.88 ; p=0.075% at 5 years

HR=0.84 ; p .0001English, HR=0.83

Berghmans – Lung Can 2005 * Nakamura – Lung Can 2006 * Burdett- JTO 2006 * Gilligan – Lan Oncol 2007 * Song – JTO 2010

NEO vs ADJ CT in early stage NSCLC

Lim –JTO 2009

Indirect comparision ADJ vs NEO OS (p=0.91) / DFS (p=0.7))

ADJ HR 0.80, NEO HR0.81

32 trials (22 ADJ / 10 NEO. 10000 p)

In resectable NSCLC, ADJ / NEO CT administration similar impact on survival benefit

Phase III “Targeted” Therapy Adjuvant Trials

Trial Stage Therapy Target N Primary Endpoint

JBR.19[1] IB-IIIA Gefitinib x 2 yrs 503 OSRADIANT[2] I-IIIA Erlotinib x 2 yrs EGFR-IHC+ 945 DFSMAGRIT[3] IB-IIIA Vaccine x

27 mosMAGE-A3 2270 DFS

E1505[4] IB (≥ 4 cm)-IIIA

Chemo ±bevacizumab

1500 OS

1. Goss GD, et al. ASCO 2010. Abstract LBA7005. 2. ClinicalTrials.gov. NCT00373425. 3. ClinicalTrials.gov. NCT00480025. 4. ClinicalTrials.gov. NCT00324805.

ADJUVANT study design (NCT01405079)

Presented By Yi-Long Wu at 2017 ASCO Annual Meeting

Primary endpoint: DFS (ITT population)

Presented By Yi-Long Wu at 2017 ASCO Annual Meeting

PORT. Lancet 1998; 352: 257-263

ADYUVANCIA: “PORT”

Thanks!! mprovenciop@gmail.com

ADJ or NEO in early-stage disease?

Adjuvant CISPLATIN chemotherapy remains the standard of care for patients with resected stage II/IIIA NSCLC

Personalized medicine: having enough tumor material essential, the use of ADJ could be improved by the integration of molecular biomarkers and pharmacogenomics approaches

Neo-adjuvant therapy likely equivalent. A subset of pts may benefit from a NEO strategy, but this is yet to be defined

The NEO approach offers a unique opportunity to test new drugs