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: [email protected].
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!! [email protected]
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