Chemotherapy for Small-Cell Lung Cancer

Chemotherapy for Small-Cell Lung Cancer Nevin Murray MD British Columbia Cancer Agency Vancouver, Canada 1 ASCO Lung Cancer Abstracts 1980-2003 450 400 350 300 250 200 150 100 50 0 All NSCLC SCLC 80 82 84 86 88 90 92 94 96 98 00 02 19 19 19 19 19 19 19 19 19 19 20 20 20 04 Abstracts Submitted to X WCLC Total Abstracts: 1158  SCLC Abstracts: 55 (4.7%)  Randomized SCLC Trials: 7  SCLC vs NSCLC Are the Therapeutic Principles different? First-line chemotherapy? Second-line chemotherapy? 4 Advanced SCLC vs NSCLC Common Chemotherapy Themes      Combination chemotherapy superior to monotherapy (single drug regimens). Two drug regimens not inferior to three or four drug regimens. High-dose chemotherapy disproved/not proven. Optimal duration of chemotherapy 4 cycles. Second-line chemotherapy principles similar. SCLC versus NSCLC Metastatic Disease Outcomes with Standard Chemotherapy Regimens SCLC M edian S urvival 35-45 w eeks 1-Y r S urvival 2-Y r S urvival 30-40% 10-15% N SCLC 35-45 w eeks 30-40% 10-15% What are the characteristics of the optimal induction regimen? 7 Chemotherapy Issues         Regimen(drugs) of choice. Number of Drugs (1 vs 2 vs 3) Is a platinum necessary? Cisplatin versus Carboplatin. Duration of Treatment Sequencing. Second-line chemotherapy effects. Combination with Targeted Agents. Limited versus Extensive SCLC    Quantitatively and qualitatively different. Curative versus palliative potential. Influence of stage on the impact of treatment innovations. Monotherapy Vs Combination Chemotherapy   Medical Research Council Lung Cancer Working Party: etoposide 50 mg po bid x 10 days vs CAV or EV. Souhami RL et al. : etoposide 100 mg po bid x 5 days vs CAV/EP. Drug Diversity Acquisition Methods      Standard Regimen with Drug Addition. Alternating Combinations. Asymmetric Sequences of Combinations. Weekly Chemotherapy. Sequential Monotherapies. CAV vs EP vs CAV/EP: SECSG Trial for Extensive Stage SCLC CAV x 6 (18 weeks) CAV/EP (6) (18 weeks) EP (4) (12 weeks) Roth B, et al. J Clin Oncol 10:282-291, 1992 Cisplatin and Etoposide is Superior to Cyclophosphamide,Epirubicin and Vincristine: Phase III, Norway Median Surv EP = 14.5m Extensive Stage CEV=9.7m EP x 5 versus CEV x 5: 436 patients Sundstrom S, et al. J Clin Oncol 20:4665-4672, 2002 Loehrer P et al. JCO 13:2574, 1995 Etoposide-cisplatin versus etoposide, ifosfamide, cisplatin.  Response rate: EP 67%, VIP 73%, NS  Median Survival: EP 7.3 mos, VIP 9.0 mos, P = 0.045  Reck M, et al. JNCI 2003;95:1118-27 Randomized Trial of 4 Vs 8 Cycles Induction (Ctx-Vcr-VP16) Followed by Chemotherapy or Symptomatic Treatment at Relapse In d u c tio n T re a tm e n t C yc le # A t R e la p se In d u c tio n M e d ia n R e s p o n s e S u rviva l TTP R esponse A t R e la p se 4 4 8 8 S ym p to m a tic C a re O n ly M e th o tre xa te D o xo ru b ic in S ym p to m a tic C a re O n ly M e th o tre xa te D o xo ru b ic in 61% 61% 63% 63% 30 w k 23w k 3 8 w k 2 3 w k 2 5 .6 % 38 w k 31w k 4 2 w k 3 1 w k 1 8 .7 % Spiro SG, et al. Br J Cancer 59:578-583, 1989 CAV vs EP vs CAV/EP: SECSG Trial for Extensive Stage SCLC CAV x 6 (18 weeks) CAV/EP (6) (18 weeks) EP (4) (12 weeks) Roth B, et al. J Clin Oncol 10:282-291, 1992 Consolidation with Topotecan after Cisplatin/ Etoposide in ED-SCLC: ECOG Randomized Phase III Study - E7593 R Response/ A SD N PE (N=402): D 2 (d1) Cisplatin 60 mg/m O Etoposide 120 mg/m2 (d1-3) M Q21d x 4 cycles I Z E Topotecan (N=112) 1.5 mg/m2/d (d15) Q21d x 4 cycles Observation (N=111) PD Off study Schiller JH, et al. J Clin Oncol 2001;19:2114-2122. Characteristics of Optimal Induction Regimen for Extensive SCLC   Platin-based two-drug regimen (Platin plus etoposide or irinotecan) for four chemotherapy cycles. Four cycles of cyclophosphamidebased regimen is suboptimal. Combined Modality Therapy for Extensive Stage SCLC   Prophylactic Cranial Irradiation for Complete Responders: Yes Thoracic Irradiation Therapy    Routine Therapy: No Bulky Mediastinal Masses: Sometimes Regional Extensive Stage: Yes Second-line Chemotherapy for Small-Cell Lung Cancer: Issues 1. What evidence exists that any chemotherapy beyond induction treatment is of any benefit? 2. How do we select relapsed SCLC patients for 2nd line chemotherapy? 3. Is combination chemotherapy superior to single agent chemotherapy? 4. How do we decide which regimen to recommend? Second-line Chemotherapy for Small-Cell Lung Cancer: Issues 1. What evidence exists that any chemotherapy beyond induction treatment is of any benefit? 2. How do we select relapsed SCLC patients for 2nd line chemotherapy? 3. Is combination chemotherapy superior to single agent chemotherapy? 4. How do we decide which regimen to recommend? Factors Predictive For Benefit from 2nd Line Chemotherapy for SCLC      Response to first-line chemotherapy Time to progression from first-line Performance Status Presence or Absence of Co-morbidities Adequacy of first-line chemotherapy SCLC: Second-line Treatment  Sensitive disease  Relapse > 3 months after completing first-line therapy No response to or relapse < 3 months after completing first-line therapy Supportive care or investigational therapy most appropriate.  Refractory disease   Second-line Chemotherapy for Small-Cell Lung Cancer: Issues 1. What evidence exists that any chemotherapy beyond induction treatment is of any benefit? 2. How do we select relapsed SCLC patients for 2nd line chemotherapy? 3. Is combination chemotherapy superior to single agent chemotherapy? 4. How do we decide which regimen to recommend? Phase III Study: Topotecan vs. CAV Study Design and Demographics     Phase III randomized, multicenter comparison of topotecan vs. CAV Progressive or recurrent, limited- or extensivestage SCLC Recurrence must be at least 60 days after last treatment with first-line chemotherapy Bidimensionally measurable disease with independent validation of response von Pawel J, et al. J Clin Oncol 1999; 17: 658-667 Phase III Study: Topotecan vs. CAV Stratification Stratification: Performance status Extent of disease at relapse Cycles repeated q 21 days  4 courses for SD 6 courses for CR/PR R A N D O M I Z E Topotecan: 1.5 mg/m2/day IV × 5 days CAV: Cyclophosphamide: 1.0 g/m2 Doxorubicin: 45 mg/m2 Vincristine: 2 mg von Pawel J, et al. J Clin Oncol 1999; 17: 658-667 Phase III Study: Topotecan vs. CAV Time to Event Median response* duration (weeks) Median time to progression (weeks) Median survival (weeks) 6-month survival (%) Topotecan N = 107 14 13 25 47 CAV N = 104 15 12 25 45 P value .30 .552 .795 — 12-month survival (%) *Response measured from time of first response 14 14 — von Pawel J, et al. J Clin Oncol 1999; 17: 658-667 Combination versus Single Agent 2nd Line Chemotherapy of Epithelial Cancers   Single agent 2nd line chemotherapy is standard for most cancers. Exceptions: Randomized Trials showing superior survival with 2 versus 1 drug in previously treated patients with epithelial cancers. 1. 2. Breast Cancer: Capecitabine plus docetaxel > docetaxel O’Shaughnessy J, et al J Clin Oncol 20:2812, 2002 Colon Cancer: 5FU/leukovorin plus oxaliplatin > 5FUleukovorin or oxaliplatin. Rothenberg et al. ESMO 2002 Combination Chemotherapy Regimens     Select patients with 0-1 PS and long DFI (>6-12 mos). Long DFI patients may receive original induction regimen. Avoid 3 drug combinations outside a clinical trial. Avoid regimens based on alkylating agents. Second-line Chemotherapy for Small-Cell Lung Cancer: Issues 1. What evidence exists that any chemotherapy beyond induction treatment is of any benefit? 2. How do we select relapsed SCLC patients for 2nd line chemotherapy? 3. Is combination chemotherapy superior to single agent chemotherapy? 4. How do we decide which regimen to recommend? Resistance Biology of Lymphomas versus Epithelial Cancers Alkylating agents have activity as second line or salvage therapy of lymphomas and germ cell cancers. For epithelial neoplasms, alkylating agents may be used in some first-line chemotherapy regimens but alkylators have little activity in the second-line setting 37 Response Rate of Combination Chemotherapy for 2nd Line Rx of SCLC 1 st L in e 2 nd L in e N u m b e r R e sp o n se P a tie n ts R a te 342 43% C yc lo p h o s p h a m id e -b a se d R e g im e n s: VAC, CMV, CAV, CAMP, CAE C isp la tin E to p o sid e C yc lo p h o s p h a m id e b a se d R e g im e n s: VAC, CAV, CMV, CMC, CAE V a rio u s 272 18% Andersen M, et al. Cancer Treatment Rev 17:427, 1990 Second-Line Chemotherapy for SCLC Convenience vs Toxicity vs Cost C onvenience Toxicity C ost S ingle A gent E toposide orally bid for 10 days Topotecan 1.5m g/m 2 IV for 5 days ` Topotecan 2.3 m g/m 2 orally for 5 days ++++ + ++++ + ++ + ++ ++++ ++++ C om binations C yclophospham ide, doxorubicin, V cr C arboplatin plus etoposide C arboplatin plus paclitaxel E toposide, ifosfam ide, and cisplatin +++ ++ +++ + ++ ++ ++ +++ + + +++ ++ C hem otherapy drug acquisition costs for one cycle: +, < $250; ++, $250-1,000; +++, $1,000-2,000; ++++, > $2,000. Targeted Therapy for Relapsed SCLC 1. Monoclonal Antibody to Gastrin Releasing Peptide 2. Immunotoxin Therapy: NCAM or CD56 antibody (N109) congugated with ricin or Maytansinoid toxin. 3. Antisense bcl-2 (Genasense) plus paclitaxel. 4. Imatinib for SCLC.