Place de la radiothérapie dans les CBPC métastatiques

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1 Place de la radiothérapie dans les CBPC métastatiques Cecile Le Péchoux, 12 ème Biennale Monégasque de Cancérologie, 2016 IOT Institut d Oncologie Thoracique

2 CBPC metastatique Rapid doubling time, early development of widespread metastases Over 2/3 of patients with SCLC have metastatic disease, Backbone treatment is Platinum/etoposide based chemotherapy: 4-6 cycles What about radiation? ESMO guidelines SCLC.Ann Onc 2011, 2013; NCCN 2015

3 CBPC: Rationel pour un Traitement Local

4 M0 SCLC patients : do they exist? Landmark study of the NCIC CT CT only possible Importance of RT to eradicate resistant clones TRT improves LC, but high rate of failure M0 (and oligometastatic) SCLC patients can be divided into 3 groups according to the presence or absence of drug-resistant tumor and its location. Murray et al (JCO 1993)

5 PET-CT may contribute to select patients that may benefit from local treatment Possibly more patients with lower metastatic burden modern imaging such as PET-CT and brain MRI ~ 20% pts upstaged from LD to ED ~ 8% downstaged Use of 8th TNM classification.. Brink, 2004; Kalemkerian 2011, NCCN Guidelines 2015, ESM0 guidelines 2013

6 Treatment issues: Local treatment of primary tumor

7 MA on the role of TRT: Metastatic pts have been probably included Thoracic primary tumor is the most heterogeneous portion of the neoplasm Most probable sanctuary of drug-resistant cells Strong rationale to combine TRT to CT

8 Rationale for RT in SCLC metastatic patients Response Rate and Survival after Second line chemotherapy RR: 10% in resistant disease (i.e. progression-free interval <3 months) RR: 20-25% in sensitive disease (interval >3 months). And Survival Poor MS ~ 4-5 months SCLC ESMO guidelines 2013 and NCCN Guidelines 2015

9 Thoracic Radiotherapy in Extensive disease Randomized study evaluating the role of TRT (54 Gy with 2 daily fractions of 1.5 Gy) among patients with local CR or PR and extrathoracic CR to chemotherapy Serie of 210 pts Jeremic et al. Role of RT in the combined-modality treatment of patients with ED SCLC: A randomized study. J Clin Oncol 1999

10 Thoracic Radiotherapy in Extensive disease Randomized study evluating the role of TRT (54 Gy with 2 daily fractions of 1.5 Gy) among patients with extra-thoracic CR to chemotherapy and local CR or PR Results (Groups 1 & 2) CT-RT CT alone p N patients 55 pts 54 pts Median Time to LR 30 mo 22 mo NS 5-yr LRecurFree SR 20% 8.1% 0,062 Median Survival 17 mo 11 mo Sign 5-yr Survival 9.1% 3.7% 0,041 Jeremic et al. Role of RT in the combined-modality treatment of patients with ED SCLC: A randomized study. J Clin Oncol 1999

11 CREST Trial Design ES-SCLC, WHO platinum-based chemotherapy RANDOMIZE Any response TRT (30Gy in 10fx) PCI Stratification: Institute No TRT PCI Presence of intrathoracic disease 498 pts from 2009 to 2012 Study powered to detect a 10% improvement in 1 yr OS from randomisation Control arm:27% Kindly provided by Ben Slotman ASCO 2014, Lancet 2014

12 TRT No TRT p 1yr OS 33% 28% 0,066 1,5 yr OS 16% 9% 0,03 2 yr OS 13% 3% 0,04 Study powered to detect a 10% improvement in 1 yr OS Slotman et al, CREST trial Lancet 2014 Study powered to detect a 10% improvement in 1 yr OS from randomisation Control arm: 27%

13 Impact on treatment failure 44% 79% Slotman 2014, 2015

14 Overall survival Pts with residual intrathoracic disease (n=434) Survival Probability Thoracic RT No Thoracic RT 12 months OS - Thoracic RT : 32.5 ( 95% CI: ) 12 months OS - No Thoracic RT : 25.9 ( 95% CI: ) HR= 0.81 ( 95% CI: ) log-rank p-value HR =0.81 (95%CI ) P< Yr Survival TRT: 32,5% 1 Yr Survival no TRT: 25,9% Amélioration significative SG dans ce sous groupe de pts Months Thoracic RT No Thoracic RT Slotman IASLC 2015

15 Toxicité RTT de consolidation acceptable Less acute grade 3 and 4 toxic events in CT than in CTRT group (P <.00001). No difference in late grade 3 and grade 4 toxicities between CTRT and CT. Jeremic Study Jeremic J Clin Oncol 1999; Slotman Lancet 2014

16 CREST Trial In pts with M1 disease with any response after CT,TRT led to a significant improvement in PFS (P<0.001) nearly 50% reduction in the risk of intrathoracic progression (P<0.001), significant difference in OS and PFS in patients who had residual intrathoracic disease after CT Conclusion: Consolidation RT to pts with good response or partial response to CT. Ongoing analysis Still more than 40% of pts had local recurrence after TRT Higher dose to thorax Treatment of other metastatic sites?...

17 Treatment issues: Role of radiation for extra-cranial metastases

18 SCHEMA RTOG 0937 S T R A T I F Y 1. CR vs PR to ChT 2. 1 vs 2-4 metastatic lesions 3. <65 vs >65 years R A N D O M I Z E Arm 1: -PCI (25 Gy/10 fr) Arm 2: -PCI -RT Chest and metastatic lesions (45 Gy/15 fr or Gy/10 fr) Required sample size: 154 pts Statistical hypothesis: 1-yr survival 30% improved to 45% Activated in 2010 Gore Elisabeth, Coordinator

19 RTOG 0937 Closed to accrual based on planned interim analysis (86/97 patients analysed) with MFU 9 mo Control Arm PCI arm Investigational Arm PCI + consolidation extra cranial RT N patients 42 pts 44 pts 1 yr Survival 60.1% 50.8% (p=0,21) 1 yr rate of any progress Gr 4 and 5 toxicities 79.6% 75% 1 1/1 MF 9 mo, Observed OS exceeded predicted OS. Consolidative RT to thorax and extracranial mets delayed progression, did not improve OS Gore E, ASTRO 2015

20 Irradiation prophylactique cérébrale (IPC) Risque de rechute cérébrale : problème majeur dans les CPC 45% à 2 ans chez des pts mis en RC Chimiothérapie peu efficace comme prophylaxie d une dissémination cérébrale (barrière cérébro-méningée) mais efficace sur lésions objectivables (RO : 70 %) SM après découverte de métastases cérébrales (MC) malgré traitement : 4.5 mois Arriagada et al, JNCI 1995

21 PCI increases survival in responders Metaanalysis of Aupérin et al 85% LD SCLC, 15% ED SCLC Phase III EORTC study. Slotman et al 100% ED SCLC Overall Survival 3 yrs OS: 15.3% versus 20.7% in the PCI group At risk 1,00 0,90 0,80 0,70 0,60 0,50 0,40 0,30 0,20 0,10 0,00 (p=0.01) No PCI PCI M o n th s sin ce ran d o m izatio n Auperin et al, NEJM 1999 Slotman et al, NEJM 2007

22 Survie à 1 an: IPC ou pas d IPC Control Arm PCI Arm p Seto, ASCO 2014 Median OS 5,4 mo 6,7mo <0,003 MA No PCI PCI p Median OS 5,3 mo 5,9 mo =0,01 Aupérin, NEJM 1999 Slotman, NEJM 2007

23 Treatment algorythm for SCLC Combined CT-RT ** Proposition: changement standard + TRT in case of extra thoracic response and thoracic PR *if no confirmation of solitary metastasis is obtained, RT may be added after 1st response evaluation and may be omitted in case of obvious metastatic involvement ** or concomitant CTRT SCLC ESMO guidelines 2011,2013

24 Take home message Etoposide and platinum remains the backbone of 1st line treatment As in non metastatic SCLC, progress in the outcome of M1 patients better integration of CT and RT: EP+ TRT+PCI in responders (good and partial response) sequentially after 4-6 cycles of CT with low toxicity PCI to responders, Japanese final results awaited Need to pursue clinical trials in SCLC+++ Use the new TNM classification!

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