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Small Cell Lung Cancer: What's New in 2003 ... Phase II

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Small Cell Lung Cancer: What's New in 2003 ... Phase III trial of 400 patients (66% lung cancer) randomized to WBRT /-motexafin ... – PowerPoint PPT presentation

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Title: Small Cell Lung Cancer: What's New in 2003 ... Phase II


1
SCLC Future Directions
  • Michael Perry, MD, FACP

2
Small Cell Lung Cancer Whats New in
2003Bristol Myers Squibb/ImClone Systems Lung
Cancer Summit
  • Michael C. Perry, MD, FACP
  • University of Missouri/Ellis Fischel Cancer
    Center

3
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

4
Small Cell Lung Cancer
  • Biologic behavior
  • Rapid doubling time
  • High growth fraction
  • Early metastases
  • Acquired drug resistance
  • Paraneoplastic syndromes (SIADH, Cushings,
    Eaton-Lambert, Anti-Hu, etc.)

5
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 (gt100 fold variation)

6
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.

7
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

8
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)

9
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

10
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

11
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

12
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

13
SCLC Current Standards NCCN
  • Extensive Stage
  • Chemotherapy with etoposide/cisplatin or
    etoposide/carboplatin (/- ifosfamide) for 4-6
    cycles.

14
SCLC Current Standards MCP
  • Extensive stage Clinical trial or
    etoposide/cisplatin (carboplatin)

15
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

16
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

17
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)

18
SCLC Current Standards MCP
  • Recurrent disease Clinical trial or topotecan

19
SCLC Problems
  • Drug resistance
  • Radio-resistance
  • Minimal residual disease detection
  • Toxicity of therapy
  • Second primaries

20
Special Problems/Issues
  • Surgery
  • The elderly
  • High dose chemotherapy
  • BID RT
  • Brain metastases

21
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

22
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)

23
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?

24
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

25
SCLC Brain metastases
  • ASTRO 2002Greek 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

26
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, WBRTM 4.0 ms
  • Time to progression
  • WBRT 4.3ms Vs 3.8 ms
  • Median time to progression MRTgt RT

27
SCLC Chemotherapy
  • No improvement in survival with
  • High dose chemotherapy
  • Increased dose intensity
  • Addition of a third agent

28
SCLC Chemotherapy
  • CPT-11
  • Topoisomerase I inhibitor
  • Activity in preclinical models
  • May be synergistic with other agents (Cisplatin)
  • Radiosensitizer?

29
Japan Clinical Oncology Group Trial
30
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)
RANDOMI ZATION
VP-16 100 mg/m2 d1-3 CDDP 80 mg/m2 mg/m2 d1
q3wk
Noda et al NEJM 34685-91, 2002
31
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 (10.0-2
7.8) 5.5 (1.0-12.0)
0.7
0.6
0.5
Survival Proportion
0.4
P0.0021 (unadjusted one-sided log rank test)
0.3
0.2
0.1
0
0
200
400
600
800
1000
1200
1400
Days after Randomization
32
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

33
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

34
SCLC ASCO 2002
  • Three drugs versus two for Extensive stage
  • CALGB 9732 Phase III 587 ptsPaclitaxel plus
    etoposide/cisplatin increased toxicity without
    survival advantage (Abstract 1169)
  • SWOG Phase II 82 pts Paclitaxel plus
    carboplatin /topotecanmedian survival of 12 mos,
    1-year 50 (33 gr4, 7 deaths), (Abstract 1184)

35
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

36
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).

37
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)

38
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

39
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.

40
SCLC Future Directions
  • Michael Perry, MD, FACP
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