Cooperative Group Research Endeavors in Small-cell Lung Cancer: Current and Future Directions

Current and Future Directions

Randeep Sangha; Primo N. Lara, Jr.; Alex A. Adjei; Paul Baas; Hak Choy; Laurie E. Gaspar; Glenwood Goss; Nagahiro Saijo; Joan H. Schiller; Everett E. Vokes; David R. Gandara

Disclosures

Clin Lung Cancer. 2009;10(5) 

In This Article

Southwest Oncology Group

The premier effort of the SWOG research portfolio in SCLC is the recently reported S0124 phase III trial, a study in which CALGB, ECOG, and NCCTG also participated as part of the Intergroup.[38] This protocol duplicated the treatment regimen of a small phase III study conducted by JCOG (JCOG 9511) demonstrating the superiority of the cisplatin/irinotecan combination over cisplatin/etoposide in patients with chemotherapy-naive ES-SCLC with respect to RR, PFS, and OS.[39] After an interim analysis, the trial was closed to further accrual, with only 154 patients entered. Because of its small sample size and possible effects from pharmacogenomic differences between Japanese and North American populations, further confirmatory studies were prompted.

In a comparative North American and Australian phase III trial directed by the Hoosier Oncology Group, 331 patients were randomized to receive a modified dose schedule of cisplatin/irinotecan or cisplatin/etoposide.[40] The modified treatment regimens were intended to improve delivery, reduce toxicity, and be more consistent with the dosages and schedules administered in the United States.[31] In this trial, there were no differences in outcome between cisplatin/irinotecan and cisplatin/etoposide. Because of the differing dose schedules, questions remained regarding the validity of cisplatin/irinotecan as an optimal regimen for ES-SCLC.

The Southwest Oncology Group sought to conduct a confirmatory, appropriately powered trial (S0124) by designing a similar study to JCOG 9511 by using identical cisplatin/irinotecan and cisplatin/etoposide treatment doses and schedules, thereby determining whether the results were reproducible and relevant to a Western population.[38] Correlative studies were incorporated to seek out the possible role of population-related pharmacogenomic variability in irinotecan metabolism due to genetic polymorphisms. Over a 4-year time span, 671 patients were randomized to receive a maximum of 4 cycles of either cisplatin 60 mg/m2 on day 1 plus irinotecan 60 mg/m2 on days 1, 8, and 15 every 28-days or cisplatin 30 mg/m2 on day 1 plus etoposide 100 mg/m2 on days 1–3 every 21-days. Patients were stratified based on performance status, number of metastatic sites, weight loss, and lactate dehydrogenase levels. The primary endpoint was OS. Cisplatin/irinotecan efficacy outcomes were similar to cisplatin/etoposide, with an ORR of 60% versus 57%, median PFS of 5.8 months versus 5.2 months (P = .07), and a median OS of 9.9 months versus 9.1 months (P = .71), respectively.[38]

Evaluation of the adverse events between the S0124 and JCOG9511 trials demonstrated a significantly higher hematologic toxicity in Japanese patients compared with North American patients with either treatment regimen (P ≤ .02), but the incidence of nonhematologic toxicities did not differ significantly. Of those enrolled in the S0124 trial, 142 patient samples were analyzed for pharmacogenetic variability of select genes in irinotecan metabolism performed on genomic DNA from peripheral blood mononuclear cells. Intriguingly, significant correlations for genetic polymorphisms and hematologic and gastrointestinal toxicities were found.[38]

Thus, S0124 did not confirm the results of JCOG9511 in a Western population. The putative mechanisms underlying the differences in efficacy and toxicity are hypothesized to be related to allelic variants of genes involved in irinotecan metabolism. SWOG has confirmed that in North America, platinum/etoposide remains the standard of care for previously untreated ES-SCLC.

The Southwest Oncology Group also recently reported S0435, a phase II study investigating the role of sorafenib in ES-SCLC.[41] Sorafenib, an oral multikinase inhibitor with effects on tumor proliferation and angiogenesis, is FDA-approved for the treatment of advanced renal cell and hepatocellular carcinoma. Patients with ES-SCLC treated with only 1 previous platinum-based chemotherapy regimen were stratified according to platinum sensitivity and treated with sorafenib 400 mg orally twice daily on a continuous basis for a 28-day cycle. Of 80 evaluable patients, 3 patients with platinum-sensitive disease had a partial response (PR; 8%), whereas only 1 patient with platinum-resistant disease had a PR (2%). The stable-disease rates were similar between both groups (32% and 31%, respectively). Median PFS was 2 months for both strata, and OS was 7 months for platinum-sensitive patients and 5 months for platinum-resistant patients. Given these results and the general tolerability of sorafenib, further study of this agent in SCLC is warranted.

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