Tratamiento Multidisciplinar del CNMP Localmente Avanzado. Luis Paz-Ares

Tratamiento Multidisciplinar del CNMP Localmente Avanzado Luis Paz-Ares

Indice Definición & Estadios Estadio IIIA N2 Estadio IIIB (y N2 irresecables) Conclusiones

TNM Lababede O, Chest 2011; 139: 183-189

Indice Definición & Estadios Estadio IIIA N2 Estadio IIIB (y N2 irresecables) Conclusiones

Factores pronósticos asociados a la afectación ganglionar N2 Método de hallazgo: Rx simple: 8% sv 3a. TAC: 6% sv 5a. Cirugía: 13.5% sv 5a. Niveles afectos Nº de ganglios Localización (subaortico 20-42 % vs subcarinal 17.9% sv 5a.) Invasión extracapsular

Heterogeneity of the N2 Disease Population Guidelines Multimodality Treatment European Society for Medical Oncology 1 For resectable LA-NSCLC, especially single nodal stage N2 disease, both definitive chemoradiotherapy and induction therapy followed by surgery are options [II, A] The preferred treatment of unresectable LA-NSCLC is definitive concurrent chemotherapy and radiotherapy [I, A] National Comprehensive Cancer Network 2 Definitive concurrent chemoradiation (category 1) or induction chemotherapy ± RT followed by surgery ± CT (category 2B) American College of Chest Physicians 3 Neoadjuvant therapy followed by surgery is neither clearly better nor clearly worse than definitive chemoradiation CT, chemotherapy; LA-NSCLC, locally advanced non-small cell lung cancer; RT, radiation therapy. 1 Vansteenkiste J, et al. Ann Oncol. 2013 [Epub ahead of print]; 2 National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology: Non-Small Cell Lung Cancer. Version 2.2013; 3 Ramnath N, et al. Chest. 2013;143(5 suppl):e14s-e40s.

Algorithm for Treatment in Patients With Locoregional NSCLC ESMO Guidelines No enlarged LNs and peripheral tumour Not required if negative LNs on PET Surgery: unforeseen N2 Adjuvant chemotherapy (radiotherapy) No enlarged N2 nodes but central tumour or hilar LNs Enlarged discrete N2 LNs N0-N1 N2 N3 Potentially resectable N2 Dedicated multidisciplinary assessment Surgical multimodality treatment Extensive mediastinal N2 infiltration Not required Unresectable N2 Nonsurgical multimodality treatment ESMO, European Society of Molecular Oncology; LN, lymph node. Vansteenkiste J, et al. Ann Oncol. 2013 [Epub ahead of print].

Cuando el N2 es Resecable? ESMO definition for potentially resectable 1 Patients are defined as having potentially resectable LA-NSCLC when a dedicated multidisciplinary assessment including an experienced thoracic surgeon judges a complete resection (R0) may be feasible after induction treatment IASLC definition for complete resection 2 Microscopically proved clear margins Systematic, lobe-specific nodal dissection 3 N2 stations No extracapsular spread Highest mediastinal node negative ESMO, European Society of Molecular Oncology; IASLC, International Association for the Study of Lung Cancer. 1 Vansteenkiste J, et al. Ann Oncol. 2013[Epub ahead of print]; 2 Rami-Porta, et al. Lung Cancer. 2005;49(1):25-33.

Estadio III: QT Neoadyuvante Estudios Tratamiento Superv. media (meses) p : Pass et al 1992 QT + Cirugia (n=13) 28.7 0.095 Cirugia/RT (n=14) 15.6 Roth et al 1994 QT + Cirugia (n=28) 64 <0.008 Cirugia (n=32) 11 Rosell et al 1994 QT + Cirugia/RT (n=30) 26 <0.001 Cirugia/RT (n=30) 8

Estadio IIIA Operable: QT inducción Estudios de Fase III Rosell R et al. NEJM 1003 & Lung Cancer 1999

N2: Controversias Esquema de quimioterapia Quimioterapia vs quimioradioterapia Radioterapia Postoperatoria Cirugía vs quimioradioterapia

Phase III Focus on Induction CT or CT/RT in Stage III NSCLC Amenable to Surgery German Lung Cancer Cooperative Group trial 1 PE x 3 followed by twice-daily RT with concurrent carboplatin and vindesine, and then surgical resection vs PE x 3 followed by surgery, and then RT Median PFS 9.5 months vs 10.0 months, respectively Conclusion: preoperative chemoradiation increases pathological response and mediastinal downstaging, but does not improve survival SAKK trial 16/00 2 3 cycles of CT followed by accelerated concomitant boost RT or CT alone, with subsequent surgery for all patients CT-RT-Surgery vs CT-Surgery: Median EFS, 12.8 months vs 11.8 months, Median survival, 27.1 months vs 26.2 months, local failure, 22% vs 24% Conclusion: RT did not improve EFS or survival, nor did it reduce the local failure rate EFS, event-free survival; PE, cisplatin-etoposide. 1 Thomas M, et al. Lancet Oncol. 2008;9(7):636-648; 2 Pless M, et al. J Clin Oncol. 2013;31(suppl):abstract 7503.

QT/RT Cx v QT/RT: INT 0139 Cisplatin, 50 mg/m 2 IVPB d1, 8, 29, 36 Etoposide, 50 mg/m 2 IVPB d1-5, 29-33 Thoracic RT, 45 Gy (1.8 Gy/d), begin d1 No progression at re-evaluation Surgical Resection Continue RT to 61 Gy without interruption CONSOLIDATION cisplatin plus etoposide X 2 cycles Albain K et al; Lancet 2009

QT/RT Cx v QT/RT: INT 0139

QT Cx v QT RT: EORTC 08941 EORTC 08941 Unresectable IIIA-N2 3 cycles platinum-based chemotherapy OR-mR: randomisation SD-PD Off study Thoracic Radiotherapy (TRT) Surgical resection (S) Postoperative Radiotherapy (PORT) if R1-2 resection von Meerbeeck, J et al. JNCI 2007

Patients (%) QT Cx v QT RT: EORTC 08941 Radiotherapy Surgery FU; median 73 67 MS (95%CI) 17.5 (16 23) 16.4 (13 19) 100 80 5-year (%) 14.0 15.7 HR (95%CI) 1 1.06 (0.84 1.35) 60 40 20 0 Surgery (n=167) Radiotherapy (n=165) 0 12 24 36 48 60 72 84 96 108 120 Months Overall survival for all 579 patients = 15.4 months PORT = post-operative radiotherapy FU = follow-up; MS = median survival van Meerbeeck JP, et al. J Natl Cancer Inst 2007;99:442 50

QT/RT Cx v QT/RT: INT 0139

7504: Surgery for NSCLC stages T1-3N2M0 having preoperative pathologically verified N2 involvement: A prospective randomized multinational phase III trial by the Nordic Thoracic Oncology Group Sørensen JB et al Prospective, randomised, Phase III study Objective: To explore the role of surgery in NSCLC with N2 involvement when preceded by induction chemotherapy Key patient inclusion criteria Previously untreated NSCLC Stage IIIA/N2 (T1-3N2M0, but N2 localisations and numbers not recorded) (n=341) R 1:1 Paclitaxel 225 mg/m 2 + carboplatin AUC6 q3w for 3 cycles (n=170) Stratification T-stage; histology; centre Paclitaxel 225 mg/m 2 + carboplatin AUC6 q3w for 3 cycles (n=171) Surgery RT RT Primary endpoint OS RT was given 4 weeks after surgery or immediately after chemotherapy and included either 2 Gy x 30 fractions, 5F/W, total 60 Gy or 1.7 Gy bid for 18 days, 10F/W, total 61.2 Gy Sørensen et al. J Clin Oncol 31, 2013 (suppl; abstr 7504)

7504: Surgery for NSCLC stages T1-3N2M0 having preoperative pathologically verified N2 involvement: A prospective randomized multinational phase III trial by the Nordic Thoracic Oncology Group Sørensen JB et al Key results 170 patients were randomised to surgery and 171 to no surgery (median age 61 years, range 33-76; 59% male; 43% had PS 0; 19%, 60%, and 22% had stages T1N2M0, T2N2M0 and T3N2M0, respectively; 50% adenocarcinoma; 29% squamous cell carcinoma) Surgery was possible in 132/170 patients in surgery group (78%): 121/170 (71.2%) had complete resection; 11/170 (6.4%) had incomplete resection n Surgery No surgery HR (95% CI) p value Overall, median (months) ADC Non-ADC T1N2 ADC T1N2 Non-ADC T1N2 T2N2 T3N2 341 169 172 61 32 29 205 75 17.3 20.3 14.9 31.7 15.4 13.4 14.9 12.7 17.7 18.4 14.9 12.5 0.866 0.606 1.154 0.472 0.346 (0.154 0.780) 0.492 (0.195 1.244) 0.218 0.002 0.394 0.009 0.008 0.126 0.767 0.930 Key conclusions There was a statistical benefit of surgery for T1N2 overall and in ADC but not for non-adc and also for ADC overall, for T1N2 and T3N2 but not for ADC T2N2 This trials suggests that surgery may be an option in N2 disease if ADC, questionable in T1N2 non-adc and was not proven indicated for T2N2 and T3N2 non-adc Sørensen et al. J Clin Oncol 31, 2013 (suppl; abstr 7504)

Phase III Trials Focus on Surgery in INT 0139 1 Stage III NSCLC Resectable stage IIIA pn2 disease MOS: 23.6 months (CT-RT followed by surgery) vs 22.2 months (CT-RT) EORTC 8941 2 Unresectable stage IIIA pn2 disease MOS: 17.5 months (CT-RT) vs 16.4 months (CT followed by surgery) Nordic Thoracic Oncology Group 3 MOS: 17 months (CT-surgery-RT) vs 15 months (CT-RT) CT, chemotherapy; EORTC, European Organisation for Research and Treatment of Cancer; MOS, median overall survival; RT, radiotherapy. 1 Albain KS, et al. Lancet. 2009;374(9687):379-386; 2 van Meerbeeck JP, et al. J Natl Cancer Inst. 2007;99(6):442-450; 3

Indice Definición & Estadios Estadio IIIA N2 Estadio IIIB (y N2 irresecables) Conclusiones

Slide 7 Presented By Karen Kelly at 2014 ASCO Annual Meeting

QT/RT Secuencial v Concurrente Slide 11

QT/RT Secuencial v Concurrente Metanálisis Slide 12

Survival, % Concurrent CT/RT Is the Standard of Care in Fit Patients With Stage III NSCLC (Level 1 Evidence) Meta-analysis 1 Absolute benefit in OS at 5 years: 4.5% (RT+concurrent CT) RTOG 9410 2 MOS: 17 months (RT+concurrent CT) RTOG 0617 3 MOS: 28.7 vs 19.5 months (SD vs HD RT) 100 80 60 40 20 30.3 HR=0.84 [0.74-0.95], P=0.004 35.6 18.1 RT + concurrent CT RT + sequential CT 23.8 12.8 18.4 10.6 0 0 1 2 3 4 5 Time Since Randomisation, years 15.1 HD, high-dose; SD, standard-dose. 1 Auperin A, et al. J Clin Oncol. 2010;28(13):2181-2190; 2 Curran WJ, et al. J Natl Cancer Inst. 2011;103(19):1452-1460; 3 Bradley JD, et al. J Clin Oncol. 2013;31(suppl):abstract 7501.

QT/RT Secuencial v Concurrente Factores Condicionantes Survival, % PS Weight loss Comorbidity Pulmonary function tests Volume of normal lung receiving 20 Gy (V20) 100 80 60 40 20 0 Overall Survival by V20 SWOG 0023 n Deaths Median OS, months V20 35% 363 181 24 V20 > 35% 81 53 12 P=0.0006 0 12 24 36 48 60 Months After Registration

Estrategias Potenciales de Optimización de QT/RT Tratamiento sístemico: Combinaciones de QT Inducción, Consolidación, Mantenimiento Agentes biológicos Tratamiento Local Escalada de dosis de RT Optimizaciones técnicas de RT (IMRT, Gating, Protonterapia)

Esquema de QT Slide 29 Presented By Karen Kelly at 2014 ASCO Annual Meeting

Optimización de QT/RT QT Inducción Slide 16

Optimización de QT/RT QT Consolidación Slide 17

Optimización de QT/RT QT Mantenimiento Slide 18

Optimización de QT/RT QT Mantenimiento: START Trial Slide 19

Attempts to improve systemic therapy: JMIG PROCLAIM Stage III unresectable Locally advanced NSCLC Rand 1:1 Stratify by: - PS 0 vs 1 - Gender - IIIA vs IIIB -PET scan use N: 600 pts R * 21 days ** 28 days 3 cycles* of pemetrexed + cisplatin + radiation therapy (66 Gy in 33) sequenced to 4 cycles of pemetrexed Primary Endpoint : Survival Superiority design 80% Powered to detect Hazard Ratio=0.74 2 cycles** of etoposide + cisplatin + radiation therapy (66 Gy in 33) sequenced to 2 cycles of platinum doublet consolidation

Attempts to improve systemic therapy: JMIG PROCLAIM The primary objective was overall survival The study is ongoing toward the final primary efficacy endpoint. The enrollment terminated prior to reaching the targeted 600 patients due to futility (Aug 2012) Data on safety have been presented during WCLC 2013

Dose escalation & Cetuximab RTOG 0617 trial

RTOG 0617 trial Effect of Cetuximab Cetuximab vs non-cetuximab arms: MST 23.1 vs 23.5 months, OS at 18-month 60.8% vs 60.2%

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Dose escalation & Cetuximab RTOG 0617 trial

Dose escalation: RTOG 0617 trial MST rates for SD and HD arms: 28.7 vs 19.5 months, 18-month OS rate 66.9% vs 53.9% (p=0.0007, HR=1.56)

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Indice Definición & Estadios Estadio IIIA N2 Estadio IIIB (y N2 irresecables) Conclusiones

Conclusiones CNMP LA: Enfermedad heterogénea con pronóstico diverso, y opciones de tratamiento diferenciales. Abordaje multidisciplinar Considerar Cx en N2 resecable y operable QT/RT concurrente o secuencial dependiendo del tumor y paciente Estrategias a evaluar Optimización de RT Basadas en las características moleculares

Slide 36 Presented By Karen Kelly at 2014 ASCO Annual Meeting