Multidisciplinary interactive session (MIS) pn2: The optimal treatment in Wilfried Ernst Erich Eberhardt

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1 Multidisciplinary interactive session (MIS) pn2: The optimal treatment in 2012 Wilfried Ernst Erich Eberhardt Department of Medicine (Cancer Res.), University Hospital Essen, West German Cancer Centre, University of Duisburg-Essen

2 Conflict of interest statement- WEE Eberhardt 1. CEO function or other direct job relationships none 2. Advisor function advisory board function Astra Zeneca, Roche, Eli Lilly, Novartis, Pfizer, BayerSchering, Sanofiaventis, Boehringer Ingelheim, BMS, GSK, Amgen 3. stocks none 4. honoraria for lectures Pierre Fabre, MerckSerono, Astra Zeneca, Roche, Eli Lilly, Novartis, Pfizer, BayerSchering, SanofiAventis, OSI, BMS, GSK, Boehringer Ingelheim, Synthon 5. research funding none 6. scientific evidence none 7. other financial relations none Folie 2 Titel

3 Case I at diagnosis T4N2 female 57 y Folie 3 Titel WEE Eberhardt MIS Geneva

4 Case I post 3 x Cis/Taxol induction CTx Folie 4 Titel WEE Eberhardt MIS Geneva

5 Case I - definitive RTx/CTx alive 65+ mo Folie 5 Titel WEE Eberhardt MIS Geneva

6 Background Stage III NSCLC is a very heterogenous disease Only a fraction of the stage III patient group are considered for combined modality approaches including surgery (potentially resectable) Folie 6 Titel WEE Eberhardt MIS Geneva

7 Background - 1 Stage III NSCLC Heterogeneity Folie 7 Titel WEE Eberhardt MIS Geneva

pretreatment prognostic factors microscopic versus macroscopic N2-disease* number of N2-nodal stations ( single vs multiple )* bulky N2-nodes* T-factor

8 pretreatment prognostic factors microscopic versus macroscopic N2-disease* number of N2-nodal stations ( single vs multiple )* bulky N2-nodes* T-factor (tumor diameter/volume, tumor infiltration) performance status weight loss serum-ldh (elevated) gender (?) age (?) * evidence given Eberhardt Geneva 2012

9 N2-factor ( necessary information ) microscopic N2-disease (only paths, media) macroscopic N2-disease (paths, media, PET, CT) bulky N2-nodes (already seen on X-ray, CT-scan) single N2-disease (media, EBUS, EUS) multiple N2-nodes involved (media) extracapsular involvement of mediastinum (media) lymphangiotic spread in the mediastinum (media) Eberhardt Geneva 2012

10 Survival of patients with N2 disease treated with primary surgery according to N2 status and number of levels involved Andre, Grunenwald et al, JCO 2000 ; 18:

11 Subsets of Stage IIIA(N 2 ) * Subset IIIA 1 IIIA 2 IIIA 3 IIIA 4 Description Incidental nodal metastases found on final pathology examination of the resection specimen Nodal (single station) metastases recognized intraoperatively Nodal metastases (single or multiple station) recognized by prethoracotomy staging (mediastinoscopy, other nodal biopsy, or PET scan) Bulky or fixed multistation N2 disease * adapted from Ruckdeschel Robinson, Ruckdeschel, Chest 2007

12 Rush et al, J Thoracic Oncol 2007 ; 2:

13 T-factor ( necessary information ) T-stage - T1, T2, T3 (CT-scan, MRI) T-factor - tumour diameter (CT-scan) T-factor - involvement of the mediastinum or mediastinal structures (CT, MRI, media) Eberhardt Geneva 2012

14 Background - 2 The standard treatment of stage III NSCLC is now considered concomittant chemoradiation Classical chemoradiation protocols are based on cisplatinum combinations WEE Eberhardt MIS Geneva

15 Agenda of the talk Single Drugs to be considered for chemoradiation protocols Carboplatin versus Carboplatin Drug combinations for chemoradiation Innovative chemoradiation protocols Induction or consolidation chemotherapy? Definitive or preoperative chemoradiation? Folie 15 Titel WEE Eberhardt MIS Geneva

16 Carboplatin Folie 16 Titel WEE Eberhardt MIS Geneva

multicenter randomized controlled trials in stage III - radiotherapy alone vs concurrent chemoradiotherapy - I - CARBO author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (3y) OS (5y; p) actox (>3 )

17 multicenter randomized controlled trials in stage III - radiotherapy alone vs concurrent chemoradiotherapy - I - CARBO author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (3y) OS (5y; p) actox (>3 ) DUTCH Cb d (2y) 37(2y) N/R 28(2y) 20(2y) N/R 2 E 9 E CALGB * Cb wk N/R (4y) 13 (4y) (p 0.74) 4 E 12 E E = esophagitis; * all pts had induction PVbl 17 Eberhardt et al, Nat Clin Pract Oncol April 2006

18 Carboplatin as a single agent is NOT a radiation sensitizer Folie 18 Titel WEE Eberhardt MIS Geneva

19 multicenter randomized controlled trials in stage III - sequential vs concurrent chemoradiotherapy - II author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (3y) OS (5y; p) actox (>3 ) LAMP CarT ind Ind + CarTcc Cc + CarT cons N/R N/R N/R 3 E 19 E 28 E CALGB CarT cc CarT ind + CarTcc N/R N/R N/R (p 0.1) 31 E 35 E E = esophagitis 19 Eberhardt et al, Nat Clin Pract Oncol April 2006

20 Cisplatin Folie 20 Titel WEE Eberhardt MIS Geneva

multicenter randomized controlled trials in stage III - radiotherapy alone vs concurrent chemoradiotherapy - I - CIS author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (3y) OS (5y; p) actox (>3 )

21 multicenter randomized controlled trials in stage III - radiotherapy alone vs concurrent chemoradiotherapy - I - CIS author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (3y) OS (5y; p) actox (>3 ) GOCCNE P d N/R 6 E 16 E EORTC P wk P d (2y) 30(2y) 31(2y) N/R N/R) (p 0.36) (p 0.009) 0 E 2 E N/R Turkish P 3wk (1y) 15(1y) N/R 2 10 N/R (p ) 8 E 10 E HOG P 3wk N/R (p 0.36) 3 E 3 E E = esophagitis 21 Eberhardt et al, Nat Clin Pract Oncol April 2006

22 Cisplatin as a single agent is a radiation sensitizer both in weekly as in three-weekly schedules Folie 22 Titel WEE Eberhardt MIS Geneva

23 Sequential chemotherapy and radiotherapy WEE Eberhardt MIS Geneva

24 multicenter randomized controlled trials in stage III - radiotherapy alone vs sequential chemoradiotherapy - author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (3y) OS (5y; p) actox (>3 ) CALGB PVbl (0.012) 7 3 Intergroup 8808, PVbl bid N/R N/R (0.04) CEBI, 1992/ VCPC (1y) 15(1y) N/R (<0.02) 3 5 SLCSG, PE N/R 3(4y) 7(4y) p (0.16) Eberhardt et al, Nat Clin Pract Oncol April 2006

25 Sequential radiotherapy prior to chemotherapy already gives some modest survival improvement Benefit: systemic control WEE Eberhardt MIS Geneva

26 Concurrent versus sequential chemoradiotherapy WEE Eberhardt MIS Geneva

27 multicenter randomized controlled trials in stage III - sequential vs concurrent chemoradiotherapy - I author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (3y) OS (5y; p) actox (>3 ) WJLCG MVPind MVPcc N/R N/R N/R N/R (0.04) 2 E 3 E RTOG Pvin Pvin cc Peor cc N/R N/R 32 2y 35 2y 24 2y y (p 0.05) 17 4y (p 0.3) 30* 48* 62* BROCAT CarT ind CarT ind + Tcc N/R N/R (p 0.08) 8 E 16 E GLOT-GFPC PN ind ccpe+ PN y 55 4y y 21 4y (p 0.24) 3 E 32 E E = esophagitis *nonhematological tox 27 Eberhardt et al, Nat Clin Pract Oncol April 2006

28 (A) Hazard ratio (HR) plots for survival, (B) progression-free survival, (C) local progression and (D) distant progression. Aupérin A et al. JCO 2010;28: by American Society of Clinical Oncology

29 (A) Hazard ratio (HR) plots for survival, (B) progression-free survival, (C) local progression and (D) distant progression. Aupérin A et al. JCO 2010;28: by American Society of Clinical Oncology

30 (A) Survival curves and (B) progression-free survival curves. Aupérin A et al. JCO 2010;28: by American Society of Clinical Oncology

31 Hazard ratio plots according to (A) the type of chemotherapy for survival and (B) progressionfree survival and according to (C) the patient characteristics for survival and (D) progressionfree survival. Aupérin A et al. JCO 2010;28: by American Society of Clinical Oncology

32 Hazard ratio plots according to (A) the type of chemotherapy for survival and (B) progressionfree survival and according to (C) the patient characteristics for survival and (D) progressionfree survival. Aupérin A et al. JCO 2010;28: by American Society of Clinical Oncology

33 concurrent chemotherapy and radiotherapy is superior to sequential chemotherapy and single modality radiotherapy Benefit: local control WEE Eberhardt MIS Geneva

34 combined modality therapy for stage III NSCLC - conclusion I - definitive concurrent platinum-based CTx/RTx has become a standard approach to inoperable stage III (N2) NSCLC pts broadest evidence does exist with cisplatin-based combinations - either cisplatin/etoposide or cisplatin/vinca-alkaloid as concurrent CTx regimen stage III (N2) still subsumes a very heterogenous group of patients for the majority of patients concurrent CTx/RTx may be the standard of care 34 Eberhardt Geneva 2012

35 Consolidation versus Induction? WEE Eberhardt MIS Geneva

36 . Pignon J et al. JCO 2008;26: by American Society of Clinical Oncology

37 combined modality treatment of stage III NSCLC - concurrent and consolidation chemotherapy - Concurrent chemoradiotherapy Consolidation chemotherapy 37 Eberhardt Geneva 2012

38 multicenter randomized controlled trials in stage - concurrent and consolidation chemotherapy - I author pts (n) CTx RTx (Gy ) LRC ( 3y ) LRC (5y) OS (med) OS (5y; %) Albain x PE cc + 2 x PE 61 N/R N/R % Concurrent chemotherapy: 92 % Consolidation chemotherapy: 75 % 38 Eberhardt Geneva 2012

39 . Hanna N et al. JCO 2008;26: by American Society of Clinical Oncology

40 . Hanna N et al. JCO 2008;26: by American Society of Clinical Oncology

41 . Hanna N et al. JCO 2008;26: by American Society of Clinical Oncology

42 Concurrent CRT +/- consolidation with vinorelbine oral + CDDP in stage III NSCLC Radiotherapy 66 Gy 6.5 weeks Cycle 1 Cycle 2 Arm A: consolidation CT + BSC Cycle 3 Cycle / Screening Cisplatin 20 mg/m² day 1-4 NAVELBINE ORAL 50 mg/m² R 6 weeks max. 8 weeks CDDP 80 mg/m² d1, 22 NAVELBINE ORAL 60 mg/m² d1, 8 80 mg/m² d22, 29 Arm B: BSC alone Cycle 3 Cycle Study Registration for both Arms End of treatment Tumor Assessment Huber, Flentje, Fietkau et al: GILT-Trial

43 combined modality treatment of stage III NSCLC induction chemotherapy and concurrent chemoradiotherapy - Induction chemotherapy Concurrent chemoradiotherapy 43 Eberhardt Geneva 2012

44 multicenter randomized trials in stage III NSCLC - CALGB randomized phase-ii of induction CTx followed by C/RTx - Pts (n) CTx ( mg/m² ) ( P 80+ ) RT ( 66Gy ) + CTx ( mg/m² ) RR (%) medos ( mo ) Gem 1250 d Pac 225 d 1,22 Nav 25 d 1,8,15,22,29 Gem 600 d 43,50,64,71 Pac 135 d 43,64 Nav 15 d 43,50,64, Vokes et al, JCO

45 . Vokes E E et al. JCO 2002;20: by American Society of Clinical Oncology

46 . Vokes E E et al. JCO 2002;20: by American Society of Clinical Oncology

47 multicenter randomized controlled trials in stage III - induction vs consolidation chemotherapy - II author pts (n) CTx RTx (Gy) LRC ( 3y ) LRC (5y) OS (med) OS (1y; %) acto x (3/4 ) Fournel x PT ind + 3 x PVrb cc cc 3 x PVrb + 2 x PTcons N/R N/R E 19 E E = esophagitis 47 Eberhardt Geneva 2012

48 New drugs to combine WEE Eberhardt MIS Geneva

Phase 3 Study in Patients with Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer Other than

NSCLC predominantly non-squamous Without pleural or percardial effusion Stratifikation Geschlecht PS Stadium IIIa vs

$43 TRT: 66 Gy in 33 fractions (daily 2 Gy fx; Mon-Fri) Folic Acid, Vitamin B12, Dexamethasone concurrent Etoposide: 50$ Recovery period 3-5 weeks mg/m2, D1, 22, 43, and 64 Supplemented with folic acid, vitamin B12, and dexamethasone per

Recovery period 3-5 weeks mg/m2, D1, 22, 43, and 64 Supplemented with folic acid, vitamin B12, and dexamethasone per

mg/m2 iv D1- D5 and D29-D33, Cisplatin: 50 mg/m2 iv on D1, 8, 29, and 36 OR (2) Vinorelbine: 30 mg/m2 iv on D1, 8, 22,

49 Phase 3 Study in Patients with Unresectable, Locally Advanced, Stage III Non-Small Cell Lung Cancer Other than Predominantly Squamous Cell Histology Study design Pemetrexed: 500 locally advanced, unresectable/inoperable Stage III NSCLC predominantly non-squamous Without pleural or percardial effusion Stratifikation Geschlecht PS Stadium IIIa vs IIIb PET ja/nein R A N D O M I S I E R U N G Pemetrexed: 500 mg/m2, D1, 22, and 43 Cisplatin: 75 mg/m2, on D1, 22, and 43 TRT: 66 Gy in 33 fractions (daily 2 Gy fx; Mon-Fri) Folic Acid, Vitamin B12, Dexamethasone concurrent Etoposide: 50 mg/m2, D1-D5, and D29-D33 Cisplatin: 50 mg/m2, on D1, 8, 29, and 36 TRT: 66 Gy in 33 fractions (daily 2Gy fx; Mon-Fri) Recovery period 3-5 weeks mg/m2, D1, 22, 43, and 64 Supplemented with folic acid, vitamin B12, and dexamethasone per local regulatory guideline consolidation Cytotoxic chemotherapy platinum-baseddoublet of choice: (1) Etoposide: 50 mg/m2 iv D1- D5 and D29-D33, Cisplatin: 50 mg/m2 iv on D1, 8, 29, and 36 OR (2) Vinorelbine: 30 mg/m2 iv on D1, 8, 22, and 29, Cisplatin: 75 mg/m2 on D1 and 22 OR (3) Paclitaxel: 200 mg/m2 iv on D1 and 22, Carboplatin: AUC=6 iv on D1 and

50 Preoperative chemoradiotherapy? WEE Eberhardt MIS Geneva

51 % Alive Intergroup 0139/RTOG 9309 Overall Survival by Treatment Arms 100 Dead/Total 75 CT/RT/S 145/202 CT/RT 155/ Logrank p = 0.24 Hazard ratio = 0.87 (0.70, 1.10) Months from Randomization Albain et al, The Lancet 2009

1+8) / Paclitaxel (175 mg/m2 T 1) C/Hf-RTx : Cis/Nav (50/20 mg/m2 T 2+9) / 1.

52 D E S I G N N S C L C IIIA / III B - randomized Phase-III study EsPaTü - inoperable B B IIIA IIIB CTx- CTx- CTx - C/hf-RTx (45 Gy) Restaging operable (PET-CT) (Angio-CT) (PET) CTx : Cisplatin (50 mg/m2 T 1+8) / Paclitaxel (175 mg/m2 T 1) C/Hf-RTx : Cis/Nav (50/20 mg/m2 T 2+9) / 1.5 Gy bid/5 x per wk/3 wks = 45 Gy B: Boost-C/RTx: Cis/Nav (40/15 mg/m2 T 2+9(Nav))/20 or 26 Gy a 2 Gy (Arm A) T: Thoracotomy ( Arm B ) 52 T

53 combined modality therapy for lung cancer - competing risks in stage III - ongoing tumor-free and long-term survival NED treatment-induced / toxic event * TOX local / locoregional relapse* PD systemic relapse outside the brain* PD brain relapse PD second cancer / second primary SC event due to significant comorbidities ( natural death hazard ) * Potentially Influenced by chemotherapy 53 Eberhardt Geneva 2012

54 Conclusions II Concurrent chemotherapy and radiotherapy is the standard of care for inoperable stage III NSCLC with proven N2-disease Based on experience in stage IV and stage II the number of CTX cycles should preferably between three and four to achieve systemic control Either induction or consolidation can be given to cc CTx/RTx Largest evidence for drug combinations exists for cisplatin and etoposide as well as cisplatin and vinorelbine/vinca (concurrent) Treatment descision in the individual patient should be made on the existing dominant risks (local, loco-regional, systemic) treatment feasibility and compliance is one of the prominent issues and dose reductions should be avoided Folie 54 Titel WEE Eberhardt MIS Geneva

55 Future World Lung Cancer Conference JULY 3-7, Save the date! October 27-31, 2013 Folie 55 Titel

Tratamiento Multidisciplinar de Estadios Localmente Avanzados en Cáncer de Pulmón

Tratamiento Multidisciplinar de Estadios Localmente Avanzados en Cáncer de Pulmón Santiago Ponce Aix Servicio Oncología Médica Hospital Universitario 12 de Octubre Madrid Stage III: heterogenous disease