Proposed Pathway & Evidence for Small Cell Lung Cancer– UPDATE IN PROGRESS

Limited Stage

NCCN:

Category 1: Cisplatin-etoposide

Category 2A: all other regimens listed below

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Cisplatin(80)-Etoposide(100) /
  • Saito JCO 2006 (n=49): single arm phase II study evaluating 1 cycle of cis-etop + RT for induction therapy followed by cis(60)-irinotecan(60)d1,8,15 q28d x 3 cycles. Results: median survival 23 mo, 2 year survival: 49%, 3 year survival: 29.7%, PFS was 11.8mo, major toxicity was neutropenia, febrile neutropenia, infection, diarrhea and electrolyte imbalance.
  • Takeda JCO 2002: evaluated concurrent vs sequential RT with cis-etop as their chemotherapy regimen. The concurrent arm was superior to the sequential RT arm. Median survival (27.2 vs 19.7 mo, p=0.097), however hematologic toxicity was higher in the concurrent arm (9% vs 4%).
  • Sundstrom JCO 2002 (n=436): cis(75)-etop100d1,etop oral 200d2-4 vs cyclophos-epirubicin-vincristine showed cis-etop to be superior in median survival (14.5 vs 9.7mo, p=0.001), although there were no major differences in QOL between the two groups.
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NP+ / Cisplatin(60)-etoposide(120) /
  • Turrisi NEJM 1999 (n=417): compared once daily RT vs twice daily RT with cis-etop in both comparator groups. Median survival was better in the twice daily RT group (23 vs 19mo, p=0.04), and grade 3 esophagitis was more frequent in the twice-daily RT group (27% vs 11%, p<0.0001)
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NP / Carboplatin-Etoposide /
  • Skarlos Ann Oncol 2001 (n=81): compared early vs late concurrent RT with carbo-etop in both comparator groups. The early concurrent RT group had better median survival (17.5 vs 17mo, p=NS), the late concurrent RT group had better response rate (92.5% vs 76%, p=0.07) and PFS (10.5 vs 9.5mo, p=NS)
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+NP = non-preferred

Extensive Stage

NCCN: Category 2A: all regimens listed below

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Preferred / Cisplatin(80)-etoposide(100) /
  • Noda NEJM 2002 (n=154): cis-irinot was found to be superior to cis(80)-etop(100) d1-3 at 12.8 vs 9.4mo (p=0.002), 2 year survival was 19.5% vs 5.2%, severe life threatening myelosuppression was higher in cis-etop, whereas diarrhea was higher in the cis-irinot group.
  • Hanna JCO 2006 (n=221): cis(30) d1,8 – irinot(65) d1,8 was found to be no different to cis(60)-etop(120)d1-3 with respect to median overall survival (9.3 vs 10.2mo, p=0.74), response rates (48% vs 43.6%), PFS (4.1 vs 4.6mo), whereas there was more myelosuppression in the cis-etop group and more vomiting and diarrhea in the cis-irinot group.
  • Lara JCO 2009 (n=651): cis(60)-irinot(60)d1,8,15 q28d vs cis(80)-irinot(100)d1-3 q21d showed similar results with response rates of 60% vs 57% (p=0.56) respectively, PFS of 5.8 vs 5.2 mo (p=0.07), and median survival of 9.9 vs 9.1 mo (p=0.71). the Irinotecan regimen showed more diarrhea, whereas the etoposide regimen showed more myelosuppression.
  • Lima JCO 2010 (n=3,086): 8 study meta-analysis of cis-etop vs cis-irinotecan found the irinotecan regimens were favored for overall survival (HR 0.87, 95% CI 0.78-0.97, p=0.02) and PFS (HR 0.83, 95% CI 0.73-0.95, p=0.006). The Irinotecan regimens also produced more diarrhea (p<0.0001) and but less myelosuppression (p<0.001).
  • Despite the findings in the Noda study and the meta-analysis, NCCN advocates for cis-etop to be the preferred regimen.
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Preferred / Carboplatin(6)-etoposide(100) /
  • Schmittel Ann Oncol 2006 (n=70): carbo-irinot was superior to carbo-etop(140) d1-3 for PFS (9 vs 6 mo, p=0.03) and response rate (67% vs 59%, p=0.24). Myelosuppression was more common in carbo-etop and diarrhea was more common in carbo-irinot.
  • Overall survival was not assessed.
  • They used a different a different dose for the etop than in the TEC care plans.
  • NCCN lists this as an option, but has no reference for this particular dose evaluating true endpoints (only had a phase II study that evaluated dose tolerability’s – not efficacy)
  • For patients that cannot tolerate cisplatin AND irinotecan
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Preferred / Cisplatin(60)-irinotecan(60) /
  • See Noda study in cis-etop section above.
  • For patients that cannot tolerate etoposide (myelosuppression)
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NP / Cisplatin(80)-etoposide(80) /
  • No comparator studies to other regimens.
  • Ihde JCO 1994 (n=90): phase II study compared cis(80)-etop(80) to a high dose cis-etop (67% higher dose) found no survival advantage of the higher dose regimen with more toxicity (febrile neutropenia, weight loss, leukopenia and thrombocytopenia).
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NP / Carboplatin(5)-irinotecan(50) /
  • For patients that cannot tolerate cisplatin
  • See Schmittel study above under Carbo-etop row.
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Subsequent Chemotherapy

NCCN:

Category 1: Topotecan (oral or IV) for relapses >2-3 mo up to 6 months

Category 2A: all other regimens listed below

Not preferred or discouraged: bevacizumab and erlotinib

Pathway Preference / Regimen / Evidence / Total Cost
Clinic Margin
Relapse in <2 mo, PS 0-2:
Preferred / Paclitaxel(80) wkly x 6 q8wks /
  • Yamamoto AntiCancer Res 2006 (n=21): pac(80) wkly x 6 q8wks- phase II single arm study in relapsed SCLC patients (relapse in less than 4 weeks) found a response rate of 23.8% (95% CI 5.59 to 42.03), median survival of 5.8mo, 1 year survival rates of 13.4%, and life-threatening toxicity in 1 patient (5%)
  • Smit Br J Ca 1998 (n=21): pac(175) q21d- phase II single arm study in previously treated SCLC patients found a partial response rate of 29%, median survival of 100 days and life-threatening toxicity in 4/21 patients (19%)
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NP / Gemcitabine (1000) q28d /
  • Van der Lee Ann Oncol 2001 (n=38): phase II single arm study in previously treated SCLC patients (relapsed in less than 90 days) found an overall response rate of 13% (95% CI 6-27%), PFS varied from 4-20wks, median survival was 17 wks (range 4-84 wks), most common adverse events were leucopenia (18%) and thrombocytopenia (29%).
  • Masters JCO 2003 (n=42): phase II single arm study in previously treated SCLC patients: gem d1,8,15 q21days. If the patients tolerated the first cycle with no grade 3 or 4 toxicities, they were increased to gem(1250) on subsequent cycles. This study evaluated both refractory patients: relapsed in less than 90 days & “relapsed” patient: relapsed in greater than 90 days). Median survival in the refractory patients was 6.9 mo (n=18) and 7.3 mo for “relapsed” patients. The major toxicities were hematological and neurologic.
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NP / Docetaxel(100) q21d /
  • Abstract available Smyth Eur J Cancer 1994 (n=28): phase II single arm study in previously treated SCLC patients (relapsed in less than 90 days) found a partial response rate of 25%, with duration of response lasting 3.5-12.6 months, and major toxicities were neutropenia, alopecia and asthenia.
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Relapse in 2-6 months
Preferred / Topotecan(1.5) d1-5 /
  • Von Pawel JCO 1999 (n=107): evaluated patients with previously treated (>60 days prior) SCLC were randomized to topotecan or CAV (cyclophos-doxorubicin-vincristine). PFS was 13.3 wks for topotecan vs 12.3 wks for CAV (p=0.552), median survival was 25 wks vs 24.7 wks (p=0.795); dyspnea, anorexia, hoarseness, fatigue and interference with daily activity were superior in the topotecan group over CAV, myelosuppression was greater in the topotecan group however.
  • Eckardt JCO 2007 (n=304): topotecan IV vs oral topotecan (2.3) d1-5 found similar efficacy and tolerability. Median survival of IV to oral was 35 vs 33 wks (with HR 0.98), 1 and 2-year survival rates were 29.2% vs 32.6% and 7.1 vs 12.4% respectively, similar myelosuppression, nausea, alopecia and fatigue between the groups.
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NP / Oral Topotecan /
  • O’Brien JCO 2006 (n=71): topotecan ORAL was found to be superior to BSC for patients with previously treated SCLC (>60 days ago) who could not tolerate IV chemotherapy. Median survival was 25.9 wks with topotecan, but only 13.9 wks with BSC (p=0.01), and myelosuppression was more common in the topotecan group. Patients on topotecan also had slower QOL deterioration and greater symptom control.
  • See Eckardt reference above.
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NP / Topotecan(4) d1,8,15 /
  • No evidence in NCCN to use this treatment regimen for subsequent SCLC.
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NP / Gemcitabine (1000 x1, then 1250) q21d /
  • See Masters JCO 2003 in the above gemcitabine row.
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Relapse in > 6 months
Preferred / Use the original regimen (references: Postmus Eur J Cancer 1987, and Giaccone Eur J Cancer 1987)
  • NCCN discourages the use of Avastin (bevacizumab) in SCLC at this time, a phase II study with carbo-irinotecan-bev-RT followed by maintenance bev produced unacceptable high incidence of tracheoesophagel fistulaes and was stopped early, whereas randomized phase III studies are ongoing.
  • NCCN does not consider the use of Tarceva (erlotinib) in SCLC

08-2011