Stato dell arte del. Antonio ROSSI, MD. Division of Medical Oncology, S.G. MOSCATI HOSPITAL, AVELLINO - ITALY

Transcription

1 Stato dell arte del trattamento del microcitoma Antonio ROSSI, MD Division of Medical Oncology, S.G. MOSCATI HOSPITAL, AVELLINO - ITALY

2 Truly has become small. Last session/day in all meetings One chemo talk, 1 RT talk, 1 surgery (?) Decreasing incidence 22% to 15% As many patients with ihmesothelioma Only 2 lines of therapy Few patients considered for 2 nd line Small on the budget. Decreasing research.small returns Decreasing publications ASCO one

3

4 SCLC: C: Staging g (VALG) Limited stage disease Confined to one hemithorax and Stadio regional lymph nodes, including 80% ipsilateral supraclavicular lymph 70% nodes 60% 50% 40% Stadio Extensive stage disease Extend beyond one hemitorax and/or malignant pleural effusion 30% 20% 10% 0% LS-SCLC ES-SCLC Patel AM, et al. Mayo Clin Proc 1993; 68:

5 IASLC Lung Cancer Database: SCLC Small Cell LungCancer: Stage Distribution by Continent, 13,290 Cases Limited 1500 Extensive Percent of total small cell cases contributed Europe Australia N. America Asia (58%) (6%) (34%) (2%) TNM Only Shepherd F, et al. J Thorac Oncol 2007; 2:

6 TNM7: Small Cell Lung Cancer Shepherd F, et al. J Thorac Oncol 2007; 2: TNM6 TNM7 Survival by clinical sixth edition of TNM, and IASLC proposed p TNM stage

7

8

9 Historical surgical options in SCLC It is a lung cancer ( 50s 60s) Do not touch, it is a SCLC! ( 70s early 80s) Renewed interest ( 90s) No randomized trials!

10 8,791 patients with L SCLC, 915 (10.4%) had undergone surgical resection Stage % of pts Median survival (months) I vs II vs III vs (p = ) ASCO 2011, abstr. 7021

11 5 y S 31% 5 y S 3.08%

12 Primary surgery in SCLC It is advised in very limited disease (Stage I: T 1 2,N 0,M 0 ) Adjuvant chemotherapy should follow the surgery Postoperative radiotherapy could be advised only when a nonradical resection was accomplished? Problems to perform a randomized trial: Little number of patients (LD stage I:5%) Accurate staging (Mediastinoscopy)

13

14 SCLC: treatment of limited disease Chemotherapy is the back boneof of therapy Radiation adds about 5% to survival Concurrent therapy increases toxicity compared to sequential

15

16 Studies using Cis based CT had a significant advantage in OS favoring early RT Studies using non Cis based CT had no significant difference in OS A small but significant improvement in 2 yrs OS for early vslate lt RT A greater difference was evident for hyperfractionated RT and Cis based dct Two year overall survival riskio ratio forest plot for early vs. late thoracic radiation therapy Fried DB, J Clin Oncol 2004; 22:

17 Timing of Radiotherapy Looked at time of starting any therapy and end of radiotherapy (SER) Significantly ifi higher h 5 yr survival rate in shorter SER arms (RR = 0.62 p=0.0003) 1.83% decreased survival for each week added to time from the shortest SER De Ruysscher et al JCO 2006

18 Timing of Radiotherapy Differences ee in chemotherapy e compliance between arms within studies mostly explains the heterogeneity of the effect of early radiotherapy on survival Benefit of early radiotherapy in terms of 5 yr survival only in trials where chemotherapy compliance is similar in both arms De Ruysscher et al WCLC 2011

19 The primary end point was complete response rate: early 36% versus late 38% The primary end point was complete response rate: early 36% versus late 38% Neutropenic fever occurred more commonly in the early TRT arm than the late TRT arm (21.6% versus 10.2%; p = 0.02)

20 LD SCLC At what time to combine CT and RT A substantial proportion of patients with LD SCLC present with bulky tumors that wouldrequire largeradiationtargetradiation target volumeswith concomitantincreasesincreases in acute or chronic toxic effects. The complexity of administering TRT concurrently with the first cycle of chemotherapy The complexity of administering TRT concurrently with the first cycle of chemotherapy could result in some delay in treatment initiation.

21 all Cell age Sma g Cancer mited Sta Lung Lim CONVERT study Once daily Thoracic Irradiation D1 D3 D22 D24 D43 D45 D64 D66 rsd, RT 66Gy/45D/33F PR,CR PCI Registration Randomisation PS 0 2 No age limit D1 D3 Twice daily Thoracic Irradiation D22 D24 D43 D45 D64 D66 RT 45Gy/19D/30F Restage Chemotherapy Radiotherapy If<SD No PCI OD XRT C O N V E R T BD

22 Intergroup study CALGB RTOG Gy BID (1.5 Gy/fx) 3 weeks from day 1 Control TRT arm Limited SCLC PS 0 1 PE X 4 PCI Cycle 1 or 2 TRT 61.2 Gy Concomitant Boost (QD 1.8 Gy/fx for 16 days than BID 1.8 Gy /fx for 9 days) 5 weeks from day 1 Re assess 70 Gy QD (2.0 Gy/fx) 7 weeks from day 1 Primary endpoints = OS VS. Experimental TRT arm

23

24 ED SCLC: 1 st Line Therapy The combination of platinum and etoposide (PE) became the standard of care for SCLC in the 1990s when this regimen was shown to be as effective as cyclophosphamide anthracycline vincristine anthracycline based combinations such as CAV, but with less toxicities PE results in ORR 60 80% (10 20% CR), median OS 8 10 months, 1 year S 35%, 2 year S 5 10%

25 ED SCLC 1 st Line Therapy Attempts to improve outcomes in first line ED SCLC 1. Addition of a third active agent 2. Increase dose intensity with or without stem cell transplant 3. Platinum compound 4. New chemotherapeutics: h topotecan, ii irinotecan, pemetrexed 5. Maintenance therapy

26 ED SCLC 1 st Line Therapy Attempts to improve outcomes in first line ED SCLC 1. Addition of a third active agent 2. Increase dose intensity with or without stem cell transplant 3. Platinum compound 4. New chemotherapeutics: h topotecan, ii irinotecan, pemetrexed 5. Maintenance therapy

27 ED SCLC Treatment Multidrug Cisplatin + Etoposide Combinations Reference Regimen No. of Pts MST (mo) 1 Yr Survival (%) p Value Loehrer et al, 1995 Mavroudis et al, 2001 Pujol et al, 2001 Niell et al, 2005 EP vs EP + ifosfamide EP vs EP + paclitaxel EP vs EP + epidoxorubicin + cyclophosphamide EP vs EP + paclitaxel Myelosuppression [*] [*] Toxicity related death rate = 9% Addi i f hi d ( ) i EP i ff i (OS) d ll i d Addition of a third (or more) active agent to EP ineffective (OS) and generally associated with toxicity. Outside of a clinical trial setting, this approach has to be discouraged

28 ED SCLC 1 st Line Therapy Attempts to improve outcomes in first line ED SCLC 1. Addition of a third active agent 2. Increase dose intensity with or without stem cell transplant 3. Platinum compound 4. New chemotherapeutics: h topotecan, ii irinotecan, pemetrexed 5. Maintenance therapy

29 Progression Free Survival Overall Survival

30

31 Objective response Overall survival

32 Hemoglobin nadir Leukocyte nadir Platelet nadir

33 ED SCLC 1 st Line Therapy Attempts to improve outcomes in first line ED SCLC 1. Addition of a third active agent 2. Increase dose intensity with or without stem cell transplant 3. Platinum compound 4. New chemotherapeutics: h topotecan, ii irinotecan, pemetrexed 5. Maintenance therapy

34 OVERALL SURVIVAL PROGRESSION FREE SURVIVAL The choice of the platinum compound for first line treatment of patients with SCLC in The choice of the platinum compound for first line treatment of patients with SCLC in clinical practice should take into account the expected toxicity profile, age, the patient s organ function, and the patient s comorbidities

35 ED SCLC 1 st Line Therapy Attempts to improve outcomes in first line ED SCLC 1. Addition of a third active agent 2. Increase dose intensity with or without stem cell transplant 3. Platinum compound 4. New chemotherapeutics: h topotecan, ii irinotecan, pemetrexed 5. Maintenance therapy

36 ED SCLC Treatment Platinum + Etoposide vs. Platinum + Topotecan Author Platinum/etoposide arm Platinum/topotecan arm No.pts ORR TTP OS (%) (wks) (wks) Eckardt, CDDP 80 mg/m 2 d 1 CDDP 60 mg/m 2 d ETO 100 mg/m 2 d 1 3 TOPO os 1.7 mg/m 2 d 1 5 vs. Q3W Q3W Fink, 2012 CDDP 75 mg/m 2 d 5 CDDP 75 mg/m 2 d ETO 100 mg/m 2 d 1 3 TOPO 1.0 mg/m 2 d 1 5 vs. Q3W Q3W Platinum/Topotecan is noninferior to Platinum/Etoposide in efficacy but for the slightly worse toxicity profile it is not a first line standard treatment in this setting

37 ED SCLC Treatment Platinum + Etoposide vs. Platinum + Irinotecan Author Platinum/etoposide arm Platinum/irinotecan arm No.pts ORR (%) PFS (mo) OS (mo) Noda, 2002 CDDP 80 mg/m 2 d 1 CDDP 60 mg/m² d ETO 100 mg/m 2 dd 1 3 Q3W IRI 60mg/m² dd 1, 8, 15 Q4W vs Hanna, 2006 CDDP 60 mg/m 2 d 1 CDDP 30 mg/m² dd 1, ETO 120 mg/m 2 dd 1 3 Q3W IRI 65 mg/m² dd 1, 8 Q3W vs n.r. 9.3 Hermes, 2008 CBDCA AUC 4 d 1 ETO os 120 mg/m 2 dd 1 5 Q3W CBDCA AUC 4 d 1 IRI 175 mg/m² d 1 Q3W 104 vs. 105 n.r. n.r Lara, 2009 CDDP 80 mg/m 2 d 1 ETO 100 mg/m 2 d 1 3 Q3W CDDP 60 mg/m 2 d 1 IRI 60 mg/m² dd 1, 8, 15 Q4W 327 vs Zatloukal, 2010 CDDP 80 mg/m 2 d 1 ETO 100 mg/m 2 d 1 3 Q3W CDDP 80 mg/m 2 d 1 IRI 65 mg/m 2 d 1, 8 Q3W 203 vs Schmittel, 2011 CBDCA AUC 5 d 1 CBDCA AUC 5 d ETO 140 mg/m 2 d 1 3 Q3W IRI 50 mg/m 2 d 1, 8, 15 Q4W vs

38 Pts: 2,027 ORR RR 1.04 ( ) OS HR 0.81 ( ) PFS HR 0.90 ( ) 07) Favours PI Favours PE The significant heterogeneity found may be due to the pharmacogenomic differences between study populations and race, as well as differences in the studied treatment regimens and their pharmacokinetics. An IPD is awaited to confirm these findings

39 Overall Survival Progression Free Survival

40

41 ED SCLC 1 st Line Therapy Attempts to improve outcomes in first line ED SCLC 1. Addition of a third active agent 2. Increase dose intensity with or without stem cell transplant 3. Platinum compound 4. New chemotherapeutics: h topotecan, ii irinotecan, pemetrexed 5. Maintenance therapy

42 ED SCLC: 1 st Line Therapy Mi Maintenance therapy? 21 RCTs (12 CT, 6 IFs, 4 biological agents), 3,688 SCLC patients No statistically significant advantage for maintenance in terms of: OS (HR 0.93, 95% CI ; p = 0.05) or PFS (HR 0.98, 95% CI ; p = 0.63) Survival advantage for OS (p = 0.02) but not for PFS in CT and IFs trials Is this clinically meaningful? Rossi A et al Lung Cancer 2010

43 ED SCLC 1 st Line Therapy Attempts to improve outcomes in first line ED SCLC 1. Addition of a third active agent 2. Increase dose intensity with or without stem cell transplant 3. Platinum compound 4. New chemotherapeutics: h topotecan, ii irinotecan, pemetrexed 5. Maintenance therapy

44 PCI Meta Analysis 7 RCTs with 987 SCLC patients in complete remission RR of death for PCI was 0.84 (95% CI ; p = 0.01) 5.4% survival improvement at 3 years (15.3% no PCI to 20.7% PCI) Decreased cumulative risk of brain metastases by 25.3% (58.6% to 33.3% PCI. P < 0.001) Benefit was also seen in the small number of patients with Extensive Stage Auperin A, N Engl J Med 1999; 341:

45 PCI in ED SCLC Multicenter RCT by EORTC 286 patients with ED SCLC achieving any response to chemotherapy Median OS increased by 1.3 months (5.4 months in no PCI to 6.7 months in PCI; p = 0.003) OS at 1 year increased from 13.3% to 27.1% Decreased symptomatic brain metastases from 41.3% to 16.8% (p < 0.001) Slotman B, N Engl J Med 2007; 357:

46 AIOM guidelines 2013 Algorithm 4: SCLC

47

48 ED SCLC 2 nd Line Therapy Topotecan is approved for 2nd line therapy but response is low and survival is poor Study Phase Regimen No.pts RR (%) MST (wks) von Pawel 2 Oral Topotecan IV Topotecan Eckardt 3 Oral Topotecan IV Topotecan O Brien 3 BSC Topotecan von Pawel 3 CAV Topotecan

49 Phase III 2 nd Line SCLC: ACT 1 Trial Key entry criteria i SCLC Extensive or Limited disease Sensitive or Refractory disease 1 prior chemotherapy regimen ECOG PS 0 1 ZE DOMI RAN Amrubicin 40 mg/m2 day 1 3 Q3W Topotecan 1.5 mg/m 2 day 1 5 Q3W Primary endpoint: Overall Survival Secondary endpoints: ORR, PFS, TTP, QoL, Safety Analyses: Interim (deaths = 294), Final (deaths = 490) Jotte R, et al. ASCO 2011

50 Jotte R, et al. ASCO 2011

51 AIOM guidelines 2013 Algorithm 5: SCLC second line

52 27 October 30 October 2013 Sydney, Australia WCLC 2013

53 SCLC: Targeted Therapies SCLC Sara Pilotto

54 SCLC: State of the Art TNM staging g should be used, particularly to stratify patients with LD SCLC Patient withvery limited SCLC (T1 2N0M0) may beconsidered for surgical resection LD SCLC patient with good performance status shouldbe treated with concurrent PE and thoracic radiotherapy PCIin responders Standard 1st line therapy remains the combination of PE Topotecan is the only drug approved for 2nd line therapy Very limited progress achieved over the last several years