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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

SCLC: Future Directions

Michael Perry, MD, FACP

small cell lung cancer
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
small cell lung cancer1
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.)
small cell lung cancer2
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)
small cell lung cancer staging
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.
sclc prognostic factors
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
sclc current standards pdq
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)
sclc current standards nccn
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
sclc current standards mcp
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
limited stage sclc results
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
sclc current standards pdq1
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
sclc current standards nccn1
SCLC Current Standards: NCCN
  • Extensive Stage:
    • Chemotherapy with etoposide/cisplatin or etoposide/carboplatin (+/- ifosfamide) for 4-6 cycles.
sclc current standards mcp1
SCLC Current Standards: MCP
  • Extensive stage: Clinical trial or etoposide/cisplatin (carboplatin)
extensive stage sclc results
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
sclc current standards pdq2
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
sclc current standards nccn2
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)
sclc current standards mcp2
SCLC Current Standards: MCP
  • Recurrent disease: Clinical trial or topotecan
sclc problems
SCLC Problems
  • Drug resistance
  • Radio-resistance
  • Minimal residual disease detection
  • Toxicity of therapy
  • Second primaries
special problems issues
Special Problems/Issues
  • Surgery
  • The elderly
  • High dose chemotherapy
  • BID RT
  • Brain metastases
sclc surgery
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
sclc the elderly
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)
sclc radiotherapy
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?
sclc brain metastases
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
sclc brain metastases1
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
sclc brain metastases2
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
sclc chemotherapy
SCLC: Chemotherapy
  • No improvement in survival with:
    • High dose chemotherapy
    • Increased dose intensity
    • Addition of a third agent
sclc chemotherapy1
SCLC: Chemotherapy
  • CPT-11
    • Topoisomerase I inhibitor
    • Activity in preclinical models
    • May be synergistic with other agents (Cisplatin)
    • Radiosensitizer?
cpt 11 cddp for es sclc phase iii schema
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

slide30

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

summary of jcog phase iii trial
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
sclc cpt 11
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
sclc asco 2002
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)
sclc asco 20021
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
sclc asco 20022
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).
calgb ecog rtog phase i trial
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)
sclc new initiatives
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
sclc conclusions
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.
sclc future directions1

SCLC: Future Directions

Michael Perry, MD, FACP