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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
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 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
• 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
• 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
• 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
• 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
• 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
• 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: 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: NCCN
• Extensive Stage:
– Chemotherapy with etoposide/cisplatin or
etoposide/carboplatin (+/- ifosfamide) for
4-6 cycles.
SCLC Current Standards: MCP
• Extensive stage: Clinical trial or
etoposide/cisplatin (carboplatin)
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: 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: 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: MCP
• Recurrent disease: Clinical trial or
topotecan
SCLC Problems
• Drug resistance
• Radio-resistance
• Minimal residual disease detection
• Toxicity of therapy
• Second primaries
Special Problems/Issues
• Surgery
• The elderly
• High dose chemotherapy
• BID RT
• Brain metastases
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*
• 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
• 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
• 40% of brain metastases
• Standard therapy is whole brain
radiation
• In NSCLC there are promising results
with temozolomide and motexafin with
RT
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 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
• No improvement in survival with:
– High dose chemotherapy
– Increased dose intensity
– Addition of a third agent
SCLC: Chemotherapy
• CPT-11
– Topoisomerase I inhibitor
– Activity in preclinical models
– May be synergistic with other agents
(Cisplatin)
– Radiosensitizer?
Japan Clinical Oncology Group Trial
Parameter
VP-16/DDP
Response rate 67.5% (56-78%)
CPT-11/DDP
84.4% (74-92%)
p=.02
2.6% NS
CR
Prog-free surv
9.1%
Med surv
9.4 m (8.1-10.8)
1-year surv
2-yr surv
37.7%
6.9m (6.1-7.3)
p=.003
12.8 m (11.7-15.2)
p=.002
58.4% NS
5.2%
19.5% NS
4.8 m (4.3-5.5)
CPT-11/CDDP for ES-SCLC
Phase III Schema
Stratification
PS (0, 1, 2)
R
A
N
D
O
M
I
Z
A
T
I
O
N
CPT-11 60 mg/m2 d1, 8, 15
q4wk
CDDP 60 mg/m2 d1
VP-16 100 mg/m2 d1-3
q3wk
CDDP 80 mg/m2 mg/m2 d1
Noda et al NEJM 346:85-91, 2002
Overall Survival
1
0.9
0.8
Survival Proportion
CP
(95% C.I.)
CP
EP
MST (mo)
% 1-yr. survival
% 2 yr. survival
0.7
0.6
EP
(95% C.I.)
12.8
58.4 (47.4-69.4)
19.5 (10.0-27.8)
9.5
37.7 (26.8-48.5)
5.5 (1.0-12.0)
0.5
0.4
P=0.0021 (unadjusted one-sided log rank test)
0.3
0.2
0.1
0
0
200
400
600
800
Days after Randomization
1000
1200
1400
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
• 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
• 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 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 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
• Cisplatin 60 mg/M2 with irinotecan 406-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
• 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
• 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 Directions
Michael Perry, MD, FACP