Stato dell arte del trattamento del microcitoma Antonio ROSSI, MD Division of Medical Oncology, S.G. MOSCATI HOSPITAL, AVELLINO - ITALY
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
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; 68:475 482
IASLC Lung Cancer Database: SCLC Small Cell LungCancer: Stage Distribution by Continent, 13,290 Cases 4000 3500 3000 2500 2000 Limited 1500 Extensive 1000 500 0 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; 2:1067 1077
TNM7: Small Cell Lung Cancer Shepherd F, et al. J Thorac Oncol 2007; 2:1067 1077 TNM6 TNM7 Survival by clinical sixth edition of TNM, and IASLC proposed p TNM stage
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!
8,791 patients with L SCLC, 915 (10.4%) had undergone surgical resection Stage % of pts Median survival (months) I 65.8 45.9 vs. 15.9 II 13.4 39.4 vs. 13.7 III 20.8 21.8 vs. 11.5 (p = 0.0001) ASCO 2011, abstr. 7021
5 y S 31% 5 y S 3.08%
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)
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
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: 4837 4845
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
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
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)
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.
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
Intergroup study CALGB 30610 RTOG 0538 45 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
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%
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
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
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 84 7.3 27 EP + ifosfamide 87 9.0 36 EP 62 10.5 38 vs EP + paclitaxel 71 95 9.5 37 EP vs 109 9.3 29 EP + epidoxorubicin + cyclophosphamide 117 10.5 40 EP vs EP + paclitaxel 282 283 9.9 10.6 37 38 0.045 Myelosuppression 0.588 0.0067 [*] 0.169 [*] 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
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
Progression Free Survival Overall Survival
Objective response Overall survival
Hemoglobin nadir Leukocyte nadir Platelet nadir
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
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
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
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 5 395 69 25.1 40.3 2006 ETO 100 mg/m 2 d 1 3 TOPO os 1.7 mg/m 2 d 1 5 vs. Q3W Q3W 389 63 24.1 39.3 Fink, 2012 CDDP 75 mg/m 2 d 5 CDDP 75 mg/m 2 d 1 334 45.5 24.3 40.9 ETO 100 mg/m 2 d 1 3 TOPO 1.0 mg/m 2 d 1 5 vs. Q3W Q3W 346 55.55 27.4 44.9 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
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 1 77 67.5 4.8 9.4 ETO 100 mg/m 2 dd 1 3 Q3W IRI 60mg/m² dd 1, 8, 15 Q4W vs. 77 84.4 6.9 12.8 Hanna, 2006 CDDP 60 mg/m 2 d 1 CDDP 30 mg/m² dd 1, 8 110 43.6 10.2 ETO 120 mg/m 2 dd 1 3 Q3W IRI 65 mg/m² dd 1, 8 Q3W vs. 221 48 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. 7.1 85 8.5 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. 324 57 60 5.2 5.7 9.1 9.9 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. 202 46.3 39.1 6.2 5.4 9.7 10.2 Schmittel, 2011 CBDCA AUC 5 d 1 CBDCA AUC 5 d 1 110 52 6.0 9.0 ETO 140 mg/m 2 d 1 3 Q3W IRI 50 mg/m 2 d 1, 8, 15 Q4W vs. 106 54 6.0 10.0
Pts: 2,027 ORR RR 1.04 (0.95 1.13) OS HR 0.81 (0.71 0.93) PFS HR 0.90 (0.76 1.07) 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
Overall Survival Progression Free Survival
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
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 0.87 1.00; p = 0.05) or PFS (HR 0.98, 95% CI 0.91 1.06; 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
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
PCI Meta Analysis 7 RCTs with 987 SCLC patients in complete remission RR of death for PCI was 0.84 (95% CI 0.73 0.97; 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: 476 484
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: 664 672
AIOM guidelines 2013 Algorithm 4: SCLC
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 52 23 32 IV Topotecan 54 15 25 Eckardt 3 Oral Topotecan 153 18.3 33 IV Topotecan 151 21.9 35 O Brien 3 BSC 67 13.9 Topotecan 70 7 25.9 von Pawel 3 CAV 104 18.3 24.7 Topotecan 107 24.3 25
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
Jotte R, et al. ASCO 2011
AIOM guidelines 2013 Algorithm 5: SCLC second line
27 October 30 October 2013 Sydney, Australia WCLC 2013
SCLC: Targeted Therapies SCLC Sara Pilotto
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