Small Cell Lung Cancer What we have now?

Transcription

1 Small Cell Lung Cancer What we have now? Chunxue Bai, M.D., Ph.D. Chair, Chinese Alliance against Lung Cancer Shanghai Respiratory Research Institute Department of Pulmonary Medicine Zhongshan Hospital, Fudan University

2 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin? 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

3 Types of Lung Cancer Historically, the major pathological distinction was simply between 1)SCLC Approximately 13%, >180,000 cases/year worldwide 2) and the others which were grouped and referred to as NSCLC. SCLC characterizes as Propensity for early metastases High response to treatment Aggressive clinical course Lancet 2011; 378: ; Oncologist Sep;12(9): ; J Clin Oncol. 2006;24: ; Horn L, Pao W, Johnson DH(2010) in Harrison's Principles of Internal Medicine, Neoplasms of the lung, eds Fauci AS, Braunwald E, Kasper DL, et al.(mcgraw-hill, New York, NY), ed 18.

4 Small-cell lung cancer Staging (VALG) staging) limited-stage (LS-SCLC) Limited stage means that the cancer is only in one of the chest and can be treated with a single radiation field. This can include one lung (unless tumors are widespread throughout the lung), as well as the lymph nodes on the same side of the chest. Lymph nodes above the collarbone (clavicle) can be affected in limited stage as long as they are on the same side of the chest as the cancer. Some doctors also include lymph nodes at the center of the chest (mediastinaside l lymph nodes) even when they are closer to the other side of the chest. What is important is that the cancer is confined to an area that is small enough to be treated with radiation therapy in one port. In only about 1 out of 3 people with SCLC is the cancer limited stage when it is first found. Lung Cancer Sep;37(3): Extensive-stage (ES-SCLC) Extensive stage is used to describe cancers that have spread widely throughout the lung, to the other lung, to lymph nodes on the other side of the chest, or to distant organs (including the bone marrow). Many doctors consider SCLC that has spread to the fluid around the lung to be extensive stage as well. About 2 out of 3 people with SCLC have extensive disease when their cancer is first found.

5 Simplified algorithm for the management of SCLC *If not progressive after induction treatment Jan P van Meerbeeck, The Lancet, Volume 378, Issue 9804, 2011,

6 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

7 2015NCCN Guideline for the Surgery For less than 5% of patients with early stage lung parenchyma is limited to considering surgery

8 SCLC chemotherapy regimens

9 Randomized Trial of: (CAV) vs PE vs Alternation of (CAV/PE) in Small-Cell Lung Cancer CAV: Cyclophosphamide,Doxorubicin, and Vincristine PE: Cisplatin/Etoposide J Natl Cancer Inst Jun 19;83(12):

10 CAV vs PE vs Alternation of CAV/PE Eligibility Criteria 1) SCLC 2) untreated 3) signs of measurable or evaluable disease 4) ECOG PS 0-3 5) age<75 years 6) adequate bone marrow reserve 7) adequate liver function 8) adequate renal function 9) informed consent Exclude Criteria 1)if another active malignant disease 2)a history of myocardial infarction within the previous 3 months 3) other cardiac disease requiring medical treatment CAV: Cyclophosphamide,Doxorubicin, and Vincristine PE: Cisplatin/Etoposide J Natl Cancer Inst Jun 19;83(12):

11 Treatment Schedules and Regimens Patient eligible all : N=288 ; Study endpoints: OS, Response rate CAV arm N=97 Irradiation N=82 PE arm N=97; CAV/PE arm N=94 The median follow-up time was 39 months with a minimum of 19 months. J Natl Cancer Inst Jun 19;83(12):

12 Regime n CAV Response Response to initial chemotherapy Limited disease* Extensive disease* Overall* No. of patien CR CR + No. of No. of PR patients CR CR + PR patient CR CR + PR ts s % 51% 13% 59% 15% 55% PE 18% 77% 10% 78% 14% 78% CAV/PE 22% 88% 8% 63% 16% 76% Overall response rate: CAV vs PE:p<0.01.CAV vs CAV/PE:p<0.01 PE vs CAV/PE: P>0.05. The platinum-containing arms achieved a higher response rate than the CAVonly arm(78%pe,76%cav/pe, and 55%CAV, p <0.005) J Natl Cancer Inst Jun 19;83(12):

13 Duration of response by treatment arm ARM N Median (Months) ACV PE CAV/PE CAV/PE vs CAV CAV/PE vs PE P=0.004 p=0.081 J Natl Cancer Inst Jun 19;83(12):

14 Survival curves for all patients ARM N Median (Months) ACV PE CAV/PE CAV/PE vs CAV CAV/PE vs PE CAV vs PE P=0.027 p=0.056 P=0.805 J Natl Cancer Inst Jun 19;83(12):

15 Survival curves for patients with limited disease ARM N Median (Months) ACV PE CAV/PE CAV/PE vs CAV CAV/PE vs PE P=0.014 p=0.023 J Natl Cancer Inst Jun 19;83(12):

16 For OS, Cisplatin and etoposide regimen is superior to cyclophosphamide, epirubicin, and vincristine regimen in SCLC: results from a randomized phase III trial with 5 years' follow-up N=436 P= LS-SCLC N=214 P= ES-SCLC N=222 P=0.21 J Clin Oncol Dec 15;20(24):

17 Conclusion platinum-containing regimens(pe or CAV/PE) are superior to CAV for induction of response Either PE alone or CAV/PE is a reasonable approach for management of SCLC CAV/PE may be preferable, because CAV/PE may suppress additional CAV-sensitive clones in the treatment of SCLC Patients treated with the alternating regimen(cav/pe) achieved a significantly longer survival, but only in the LS-SCLC subset CAV: Cyclophosphamide,Doxorubicin, and Vincristine PE: Cisplatin/Etoposide J Natl Cancer Inst Jun 19;83(12):

18 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

19 The COCIS Meta-Analysis of Individual Patient Data: Carboplatin- or Cisplatin-Based Chemotherapy in First-Line Treatment of Small-Cell Lung Cancer J Clin Oncol May 10;30(14): doi: /JCO Epub 2012 Apr 2.

20 Study introduction Purpose Since treatment efficacy of cisplatin- or carboplatin-based chemotherapy in the first-line treatment of SCLC remains contentious, a meta-analysis of individual patient data was performed to compare the two treatments Patients and Methods A systematic review identified 4 randomized trials comparing cisplatin with carboplatin in the first-line treatment of SCLC. Individual patient data were obtained from coordinating centers of all eligible trials The primary end point: overall survival (OS) Secondary end points: progression-free survival (PFS), objective response rate (ORR),and treatment toxicity J Clin Oncol May 10;30(14): doi: /JCO Epub 2012 Apr 2.

21 Meta-Analysis: Characteristics of the Four Randomized Trials J Clin Oncol May 10;30(14): doi: /JCO Epub 2012 Apr 2.

22 OS by treatment arm J Clin Oncol May 10;30(14): doi: /JCO Epub 2012 Apr 2.

23 PFS by treatment arm J Clin Oncol May 10;30(14): doi: /JCO Epub 2012 Apr 2.

24 Conclusion This is the first and only individual patient data metaanalysis in which we collected all the available trials that addressed this issue and all of them have been published as full-length articles This study suggests that there was no difference between carboplatin- and cisplatin- based regiments in SCLC Although, hematologic toxicity was higher with carboplatin, while non-hematologic toxicities of nausea/vomiting, neurotoxicity, and nephrotoxicity were more common with cisplatin J Clin Oncol May 10;30(14): doi: /JCO Epub 2012 Apr 2.

25 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin? 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

26 Irinotecan plus Cisplatin Compared with Etoposide plus Cisplatin for Extensive Small-Cell Lung Cancer-JCOG9511 Noda K et.al. N Engl J Med, 2002;346(2): 85-91

27 Schedules and Regimens: JCOG9511 Study Study sample size : The planned size of the study population was 230 patients, but enrollment was terminated early because an interim analysis found a statistically significant difference in survival between the patients assigned to receive irinotecan and cisplatin and those assigned to receive etoposide and cisplatin; as a result, only 154 patients were enrolled. Noda K et.al. N Engl J Med, 2002;346(2): 85-91

28 OS & PFS OS PFS MonthIrinotecan+ DDP Etoposide+DDP Month P Value Overall Response 84.4% 67.5% 0.02 mos(month) mpfs(month) year OS(%) Year OS(%) Noda K et.al. N Engl J Med, 2002;346(2): 85-91

29 100.0% 92.20% 80.0% 60.0% 40.0% 20.0% 0.0% 3/4 Toxicity & Conclusion 65.30% 51.90% EP 26.70% 18.20% 5.30% IP 16.00% 13.30% 6.50% 0 Conclusion: Compare to EP regimen, IP regimen had -efficacy improvement -3 Months OS prolonged -2-year OS rate raised(19.5% vs 5.2%) Irinotecan plus cisplatin is an effective treatment for metastatic small-cell lung cancer Noda K et.al. N Engl J Med, 2002;346(2): 85-91

30 What about the IP vs EP regimens both in the United States and Europe?

31 Study Design and Regimens 2006 Unitited States Study Untreated ES-SCLC R 2:1 N= mg/m 2 D1/ 120mg/m 2 D1-3 Q3w N= mg/m 2 D1,8/ 65mg/m 2 D1,8 Q3w N= 221 Primary End Point: OS Second end Point: RR, TTP,toxicity Hanna N et.al.j Clin Oncol 2006;24:

32 OS & TTP OS TTP P=0.74 P=0.37 Hanna N et.al.j Clin Oncol 2006;24: IP(Irinotecan +DDP) EP(Etoposide+DDP) Overall Response mos(month) mpfs(month) year OS(%)

33 Hanna N et.al.j Clin Oncol 2006;24: Grade 3 Or 4 Toxicitis Toxicity Dose Comparasion Irinotecan+ DDP N=216 Etoposide+DD P N=106 P Value Neutropenia 36.2% 86.5% < Febrile neutropenia 3.7% 10.4% Anemia 4.8% 11.5% 0.03 Thrombocytopenia 4.3% 19.2% < Diarrhea 21.3% Conclusion: Why did this study fail to confirm the positive JCOG results? Explanation? one might be Hanna tested a different dose and schedule of IP Another may be related to pharmacogenomic differences that may exist between North American and Japanese patients

34 Study Design and Regimens SWOG S0124 untreated ES-SCLC R 1:1 80mg/m 2 D1/ 100mg/m 2 D1-3 Q3w N= mg/m 2 D1 / 60mg/m 2 D1,8,15 Q4w N= 324 Primary end point: OS Second end point: ORR,PFS Lara Jr PN et.al J Clin Oncol 2009;27:

35 OS & PFS PFS OS IP(Irinotecan+DDP) N=324 EP(Etoposide+DDP) N=327 ORR,%(95% CL) 60(54-65) 57(53-63) mos, mos(range) 9.9( ) 9.1( ) 0.71 mpfs, mos(range) 5.7( ) 5.2( ) year OS, % year PFS, % 7 6 Lara Jr PN et.al J Clin Oncol 2009;27:

36 Pharmacogenomic Results-SNPs ABCB1 (C3435T) T/T was associated with an increased risk of irinotecan-associated 3grade diarrhea -OR: 3.9(95% CI ;P=0.01) UGT1A1 (G-3156A) A/A & ABCB1 was associated with increased risk of irinotecan-associated Combined grade 3 neutropenia and diarrhea - ABCB1 OR:5.0( ;P=0.03) -UGT1A1 OR:7.6(0.9-63;P=0.06) None of the genotypes seemed to be associated with efficacy outcomes Lara Jr PN et.al J Clin Oncol 2009;27:

37 Summary This large North American trial SWOG S0124 also failed to confirm the previously reported survival benefit observed with IP in Japanese patients, Explanation? S0124 and JCOG study pharmacogenomic differences of population, such as with genetic polymorphism in UDPglucuronosyltransferase (UGT1A1) enzyme that metabolized irinotecan JCOG 9511 also had imbalances in the distribution of patient characteristics which, although not statistically significant, may have favored the experimental arm in the context of a small trial Lara Jr PN et.al J Clin Oncol 2009;27:

38 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin? 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

39 Study Design and Regimens AUC of 5,D1 Untreated I-IV SCLC Enrollment: R N=614 1:1 159 mg/m2 (stage I IIIB) or 125mg/m2 (stage IV), D1-3 2 mg, D1,8 Q3w, Max 6 Cycles N= 309 Primary Endpoint: OS AUC of 5, D4 CEV :carboplatin plus etoposide plus vincristine TEC : placlitaxel plus etoposide plus carboplatin 125 mg/m2 (stage I IIIB) or mg/m2 (stage IV), D mg/m2, Q3w, Max 6 Cycles N= 305 J Natl Cancer Inst Aug 6;95(15):

40 OS & PFS CEV(standard arm ) 1-yr OS rate, range OS 48% (95% CI 42% to 53%) 2-yr OS rate, range 16% (95% CI 42% to 53%) TEC(experimental arm) 51% PFS (95% CI 46% to 57%), 20% (95% CI 16% to 25%) 3-yr OS rate, range 9% (95% CI 6% to 13%) 17% (95% CI 12% to 21%) mos, stage I IIIA 16.9 months 18.7 months mos, stage IIIB, mos, stage I IIIB mos, stage IV J Natl Cancer Inst Aug 6;95(15):

41 J Natl Cancer Inst Aug 6;95(15): Toxicity

42 CONCLUSION Patients with previously untreated SCLC who received paclitaxel, etoposide, and carboplatin showed improving overall and progression-free survival and less frequent hematologic toxicities than those who received the standard therapy J Natl Cancer Inst Aug 6;95(15):

43 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin? 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

44 Description of trial of maintenance chemotherapy in small-cell lung cancer Lung Cancer Nov;70(2): doi: /j.lungcan Epub 2010 Feb 25.

45 Meta-analysis Results A meta-analysis of 21randomized studies including 3,687 SCLC patients which showed no benefit with maintenance therapy OS(HR:0.93;95%CI, ; P =0.05) or PFS(HR:0.98;95%CI, ; P =0.63) Overall, maintenance therapy in unselected, onprogressing SCLC is not an effective strategy A survival advantage is suggested for maintenance chemotherapy and interferonalpha, but its clinical impact needs to be confirmed by further studies Lung Cancer Nov;70(2): doi: /j.lungcan Epub 2010 Feb 25.

46 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin? 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

47 Management of relapsed SCLC Re-treatment With Frontline Regimen Non-Cross-Reacting Second Line Regimen Radiation (Thoracic Radiation,Prophylactic Cranial Irradiation) Lancet 2011; 378: ;

48 Re-treatment With Frontline Regimen Frontline chemotherapy Relapse Retreated with Frontline chemotherapy Conclusions Retreated with Frontline chemotherapy SCLC Results: second response:23 N=37 (62%,6 CR, 17 PR) Frontline with CDE(cyclophosphamide, doxoru 1 st line 23CR:18 second response The outcome for second-line Relapse therapy for SCLC bicin and etoposide 1 st line 14PR: 5 second response Results: 23 (CR) 14(PR). P<0.01 was poor and benefit appeared to be limited to Median response duration was 1 st line response 34 week) duration>34weeks 19pts: 15 those patients with good PS and rechallenged second response(in other 18pts,8 second response, P<0.05 Retreated with Frontline with platinum-based chemotherapy chemotherapy Retrospective analysis: Results: The median age:63. mpfs:4.3 months SCLC: Platinum-based N=161 rechallenge should be mos: 5.8 months. (ECOG-PS) 0, 1 and Relapse The overall RR:22.9%. (34.5% vs 2(in12.5%, considered 62.5% and 25% pts), as a standard comparator in 17.5%, future p: 0.06) and Median time to SL OS (9.2 months vs 5.8 months, p chemotherapy was 6.9 months. randomized controlled trials of second = 0.08) line for patients with. sensitive disease who were rechallenged with chemotherapy platinum-based chemotherapy Eur J Cancer Clin Oncol Sep;23(9): Lung Cancer 72 (2011)

49 Topotecan Versus Cyclophosphamide, Doxorubicin, and Vincristine for the Treatment of Recurrent Small-Cell Lung Cancer

50 Study design and Regimens PS (0-2) LS-SCLC or ESSCLC after previous therapy TTP>60d Minimum 4weeks interval between a prior surgery or immunotherapy and study entry adequate marrow, liver, and renal function R Topotecan 1.5 mg/m2 IV D1-5, Q3w, N=107 CAV Cyclophosphamide 1,000mg/m2, d1,doxor ubicin 45mg/m2, d1 and vincristine 2 mg,d1 Q3W N=104 Primary end point: Response rate Second end point: OS J Clin Oncol Feb;17(2):

51 Toxicity & OS Number (%) of Patients and Courses with Grade 3/4 Hematologic Toxicity Topotecan N=107(ITT) CAV N=104 (ITT P value Grade 4 neutropenia 37.8% 51.4% Grade4 thrombocytopenia 9.8% 1.4% grade 3/4 anemia 17.7% 7.2% Survival in weeks. Regimen: Hycamtin; CAV. J Clin Oncol Feb;17(2):

52 Response & Conclusion Topotecan N=107(ITT) CAV N=104 (ITT) Response to treatent No. % No. % P Value Currently, Topotecan is the only agent with approval for the treatment of relapsed SCLC, it could improve quality of life and symptom control mttp, weeks Responders Complete response Partial response Total % CI Nonresponders Stable disease Progressive disease Not assessable Total Topotecan was at least as effective as CAV in the treatment of patients with recurrent SCLC and resulted in improved control of several symptoms Total patients mos, weeks J Clin Oncol Feb;17(2):

53 Phase III trial comparing BSC alone with BSC+oral topotecan in patients with relapsed SCLC PS (0-2) Liver matastics After previous chemo TTP ( 60 Ot>60d) R 1:1 Topotecan 2.3 mg/m 2 /d PO D1-5 + BSC N=71 Primary end point: OS BSC N=70 Age midian:60/59;ed:68%/61%;ps0-1:73%/67%;1 st therapy TTP:84d/90d O'Brien M, et al. Lung Ca 2005; 49:S54(abstract O-157)

54 Results: OS Cumulative Proportion Alive Topotecan+ BSC Topotecan +BSC N=71 mos. weeks BSC N=70 6 month-os, % O'Brien M, et al. Lung Ca 2005; 49:S54(abstract O-157)

55 OS subgroup Conclusion Chemotherapy with oral topotecan is associated with prolongation of survival and quality of life benefit in patients with relapsed SCLC O'Brien M, et al. Lung Ca 2005; 49:S54(abstract O-157)

56 The Content Introduction 1 Surgery & Platinum-Based Therapy 2 Carboplatin or Cisplatin? 3 Substitution of Partner Chemotherapy in the Frontline (Irinotecan in SCLC) 4 Dose Intensification (Triple Chemotherapy) 5 Maintenance Therapy 6 Management of relapsed SCLC 7 Role of Radiotherapy 8

57 Role of Radiation Therapy in the Combined-Modality Treatment of Patients With Extensive Disease Small- Cell Lung Cancer: A Randomized Study N=206 ACC HFX RT : accelerated hyperfractionated radiation therapy CE: carboplatin and etoposide J Clin Oncol Jul;17(7):

58 mos 5-yr OS Rate : CHT/ACC HFX vs CHT(P=0.041) Results: For 206 assessable patients, the median survival time (MST) was 9 months and the 5-year survival rate was 3.4% CHT: chemotherapy; ACC HFX RT : accelerated hyperfractionated radiation therapy J Clin Oncol Jul;17(7):

59 Grade 3 Acute Toxicity Acute high-grade toxicity was higher in group 2(chemotherapy)than in group 1(ACC HFX RT ) J Clin Oncol Jul;17(7):

60 2 Meta-analysis Results: addition of radiotherapy to chemotherapy Meta-analysis(NEJM) Meta-analysis(JCO) Patients No Trial included Main Results CRT vs Chemo: 3-yr OS,%: [5.4%] RR=0.86(95%CI, ; P =0.001) for LS- SCLC Especially Age<55 pts: RR=0.72(95%CI, ) CRT vs Chemo: 2-ye OS, %: [5.4%], P=0.05 These two studies established the benefit of thoracic radiation in LS-SCLC 1.Pignon JP,ArriagadaR,IhdeDC, N Engl JMed.1992;327: WardeP,PayneD. ClinOncol.1992;10:890 5.

61 Meta-analysis: Cranial irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission PCI Control No PCI P value Relative risk of death 0.84 (95% confidence interval=0.73 to 0.97) P= year survival rate,% Disease-free survival (relative risk=0.75, 95% confidence interval=0.65 to 0.86) P<0.001 Brain metastasis risk Trend in favour of earlier administration of cranial irradiation after the initiation of induction treatment P=0.01 Prophylactic cranial irradiation significantly improves survival and disease-free survival for patients with SCLC in complete remission Further clinical trials are needed to confirm the potential greater benefit on brain metastasis rate suggested when cranial irradiation is given earlier or at higher doses The Prophylactic Cranial Irradiation Overview Collaborative Group. Cranial Irradiation for preventing brain metastases of small cell lung cancer in patients in complete remission Cochrane Database Syst Rev 2000; 4: CD002805

62 Take-Home Message For less than 5% of patients with early stage lung parenchyma is limited to considering surgery Platinum doublet chemotherapy is a standard treatment for SC-SCLC and ES-SCLC Chemotherapy with topotecan is associated with benefit of survival and quality of life in patients with relapsed SCLC Dose Intensification also showed the efficacy in SCLC Consequently, the 5-year survival rate remains low at <7% overall, and most patients survive for only 1 year or less after diagnosis

63 Thank you!