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SCLC: Future Directions

SCLC: Future Directions . Michael Perry, MD, FACP. Small Cell Lung Cancer. Demographics: 15-25% of 177,000 lung cancer cases or 26,550-44,250 cases/year Major risk factor: smoking Characteristics: Typically an endobronchial lesion with hilar adenopathy Considered metastatic at diagnosis.

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SCLC: Future Directions

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  1. SCLC: Future Directions Michael Perry, MD, FACP

  2. Small Cell Lung Cancer • Demographics: • 15-25% of 177,000 lung cancer cases or 26,550-44,250 cases/year • Major risk factor: smoking • Characteristics: • Typically an endobronchial lesion with hilar adenopathy • Considered metastatic at diagnosis

  3. Small Cell Lung Cancer • Biologic behavior • Rapid doubling time • High growth fraction • Early metastases • Acquired drug resistance • Paraneoplastic syndromes (SIADH, Cushing’s, Eaton-Lambert, Anti-Hu, etc.)

  4. Small Cell Lung Cancer • Molecular characteristics • Deletion of 3p (90%) • Loss of retinoblastoma gene at 13q14 (90%) • Mutations of p53 (75-100%) • Amplification of myc-dominant oncogenes (30%) • Bcl-2 Expression (95%) • VEGF expression(>100 fold variation)

  5. Small Cell Lung Cancer: Staging • Limited disease: disease confined to one hemi-thorax, including ipsilateral mediastinal, hilar, or supraclavicular nodes (originally the amount of disease that could be incorporated into a “tolerable” radiation port). Now ~33% of SCLC. • Extensive disease: any disease beyond the above. Now ~ 67% of SCLC.

  6. SCLC: Prognostic Factors • Good prognosis • Limited stage disease • Female gender • Performance status of 0,1 • Poor prognosis • CNS or liver involvement • Performance status of 2 or greater

  7. SCLC Current Standards: PDQ • Limited stage: • Combination chemotherapy • Etoposide/cisplatin • Thoracic radiation therapy • 4,000-4,500 cGy • Prophylactic cranial irradiation (PCI) • For Complete Response (CR) or Very Good Partial Response (VGPR)

  8. SCLC Current Standards: NCCN • Limited stage: • Combination chemotherapy: Etoposide/cisplatin or Etoposide/carboplatin for 4-6 cycles • Concurrent RT: either 1.5 Gy bid or 1.8 Gy/day to at least 54 Gy, starting with cycle 1 or 2. • PCI: 24 Gy in 8 FX to 36 Gy in 18 FX

  9. SCLC Current Standards: MCP • Limited stage: Clinical trial or etoposide/cisplatin (or carboplatin) with thoracic RT starting with cycle 3 for a total of 5 cycles

  10. Limited Stage SCLC: Results • Overall response rates of 65-90% • Complete response rates of 45-75% • Median survival of 18-24 months • 40-50% 2 year survival • 20-25% 5 year survival

  11. SCLC Current Standards: PDQ • Extensive stage: • Combination chemotherapy • CAV (cyclophosphamide/doxorubicin/vincristine) • CAE (cyclophosphamide/doxorubicin/etoposide) • Etoposide/cisplatin or etoposide/carboplatin • ICE (Ifosfamide/carboplatin/etoposide) • Prophylactic cranial irradiation (PCI) • For CR or VGPR

  12. SCLC Current Standards: NCCN • Extensive Stage: • Chemotherapy with etoposide/cisplatin or etoposide/carboplatin (+/- ifosfamide) for 4-6 cycles.

  13. SCLC Current Standards: MCP • Extensive stage: Clinical trial or etoposide/cisplatin (carboplatin)

  14. Extensive Stage SCLC: Results • Overall response rates of 70-85% • Complete response rates of 20-30% • Median survival of 6-12 months • 2 year survival uncommon

  15. SCLC Current Standards: PDQ • Progressive disease: • Clinical trial • Palliative symptom management, including localized RT or clinical trial or second-line chemotherapy (PS 0-2) • Relapse: • “Salvage radiation therapy” • Second line chemotherapy (topotecan or CAV) or Best Supportive Care

  16. SCLC Current Standards: NCCN • Relapse: • Second line chemotherapy or Best Supportive Care • Progressive disease: • Palliative symptom management • localized RT • or clinical trial • or second-line chemotherapy (PS 0-2)

  17. SCLC Current Standards: MCP • Recurrent disease: Clinical trial or topotecan

  18. SCLC Problems • Drug resistance • Radio-resistance • Minimal residual disease detection • Toxicity of therapy • Second primaries

  19. Special Problems/Issues • Surgery • The elderly • High dose chemotherapy • BID RT • Brain metastases

  20. SCLC: Surgery • Not helpful for established diagnosis • May be done for solitary pulmonary nodules where histologic diagnosis not yet obtained. • In this setting, CT and RT are usually given

  21. SCLC: The Elderly* • Single agent therapy or low dose therapy is less effective than conventional IV therapy at standard doses • *(Or poor performance score or co-existing illnesses)

  22. SCLC: Radiotherapy • The ECOG study of BID RT resulted in improved survival, but at the cost of increased esophagitis. It has not taken the world by storm due to scheduling • Intensity modulated RT (IMRT) is the latest best thing. Is it more likely to reduce toxicity than improve local control? • Radiosensitizers?

  23. SCLC: Brain metastases • 40% of brain metastases • Standard therapy is whole brain radiation • In NSCLC there are promising results with temozolomide and motexafin with RT

  24. SCLC: Brain metastases • ASTRO 2002:Greek study of 129 patients, (80%) lung cancer • WBRT with or without concurrent and sequential Temozolomide • Improved radiographic responses, time to neurologic progression and medial survival with combined modality Rx

  25. SCLC: Brain metastases • ASTRO 2002: Mehta et al, U Wisconsin • Phase III trial of 400 patients (66% lung cancer) randomized to WBRT +/-motexafin • Median survival: • WBRT 5.2 ms, WBRT+M 4.0 ms • Time to progression: • WBRT 4.3ms Vs 3.8 ms • Median time to progression M+RT> RT

  26. SCLC: Chemotherapy • No improvement in survival with: • High dose chemotherapy • Increased dose intensity • Addition of a third agent

  27. SCLC: Chemotherapy • CPT-11 • Topoisomerase I inhibitor • Activity in preclinical models • May be synergistic with other agents (Cisplatin) • Radiosensitizer?

  28. Japan Clinical Oncology Group Trial

  29. CPT-11/CDDP for ES-SCLCPhase III Schema CPT-11 60 mg/m2 d1, 8, 15 CDDP 60 mg/m2 d1 q4wk Stratification PS (0, 1, 2) RANDOMIZATION VP-16 100 mg/m2 d1-3 CDDP 80 mg/m2 mg/m2 d1 q3wk Noda et al NEJM 346:85-91, 2002

  30. Overall Survival 1 0.9 CP EP (95% C.I.) (95% C.I.) CP 0.8 EP MST (mo) 12.8 9.5 % 1-yr. survival 58.4 (47.4-69.4) 37.7 (26.8-48.5) % 2 yr. survival 19.5 (10.0-27.8) 5.5 (1.0-12.0) 0.7 0.6 0.5 Survival Proportion 0.4 P=0.0021 (unadjusted one-sided log rank test) 0.3 0.2 0.1 0 0 200 400 600 800 1000 1200 1400 Days after Randomization

  31. Summary of JCOG Phase III Trial • Study terminated early at 2nd interim analysis with 154 patients • CPT-11/CDDP yielded remarkably better survival than standard EP • Treatment compliance identical in the two arms • Toxicity profiles differed • CPT-11/CDDP - New Japanese standard • CPT-11/CDDP- New US Option

  32. SCLC: CPT-11 • Carboplatin can replace cisplatin • Can be combined with etoposide, giving inhibition of topoisomerase I and II • Other possible chemotherapy combinations: ifosfamide, paclitaxel, or docetaxel, navelbine, or gemcitabine • Novel combinations: cyclosporine, MTA, or phenobarbital

  33. SCLC: ASCO 2002 • Three drugs versus two for Extensive stage: • CALGB 9732 Phase III 587 pts:Paclitaxel plus etoposide/cisplatin= increased toxicity without survival advantage (Abstract 1169) • SWOG Phase II 82 pts: Paclitaxel plus carboplatin /topotecan=median survival of 12 mos, 1-year 50% (33% gr4, 7% deaths), (Abstract 1184)

  34. SCLC: ASCO 2002 • Three drugs versus two for Extensive stage: • Italian group: Cisplatin/gemcitabine versus etoposide/cisplatin/gemcitabine. More toxicity and more benefit with three drugs? (abstract 1219) • Conclusion? It is doubtful that three drugs will be significantly better than two, and at the risk of increased toxicity

  35. SCLC: ASCO 2002 • Phase II Study of STI 571 (Gleevec) in SCLC-no objective responses in 19 pts, although only 4/14 were + for CD117 (abstract 1171) • Increased initial dose of cyclophosphamide did not increase survival in limited stage disease (abstract 1172) • Phase I trial of monoclonal Ab conjugate, BB-10901 (abstract 1232).

  36. CALGB-ECOG-RTOG Phase I Trial • Cisplatin 60 mg/M2 with irinotecan 40-6-Mg/M2 days 1 and 8, every 21 days for 4 cycles • Thoracic radiotherapy as either 4,500 cGy (twice daily) or 7,000 cGy (once daily)

  37. SCLC: New Initiatives • CPT-11 in extensive disease-confirmatory studies • CPT-11 with RT in limited disease • Other new agents: paclitaxel, docetaxel, vinorelbine, gemcitabine • Higher doses of RT • New targets: VEGFR, VEGF, COX-2, Bcl-2, Gastrin • CALGB strategy: DDP/CPT-11 +MTT

  38. SCLC: Conclusions • Increments of 5% in survival will not be sufficient for cure. • Improvements in conventional CT and/or RT will be small. • New therapies for brain mets, PCI? • New approaches are needed-targeted agents, radiopharmaceuticals, vaccines, etc.

  39. SCLC: Future Directions Michael Perry, MD, FACP

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