Phase II study of maintenance sunitinib following irinotecan and carboplatin as first-line treatment for patients with extensive-stage small-cell lung cancer.

BACKGROUND: Inhibition of angiogenesis may be effective in the treatment of small-cell lung cancer (SCLC). Sunitinib, an oral agent that inhibits the VEGF signaling pathway, may delay progression in sequence with chemotherapy. This phase II trial was designed to evaluate the role of sunitinib monotherapy following 6 cycles of irinotecan and carboplatin in patients with newly diagnosed extensive-stage (ES) SCLC. METHOD: Patients aged ≥18 years with previously untreated ES-SCLC were eligible. Additional criteria included: ECOG PS 0-1, no active brain metastases, and adequate organ function. Patients received 28-day cycles of irinotecan (60 mg/m(2), days 1, 8, 15) and carboplatin (AUC=4, day 1), and were assessed for response every 8 weeks. After 6 cycles of chemotherapy, patients with stable disease or responding disease proceeded to sunitinib monotherapy (25 mg orally daily) until disease progression or unacceptable toxicity. The primary endpoint was 1-year overall survival (OS). RESULTS: Between 2/09 and 10/09, 34 patients (median age 65 years [range, 41-80]) were enrolled. 53% of patients were male, 47% had ECOG PS 0.21 patients (62%) completed 6 cycles of chemotherapy, and 17 (50%) initiated sunitinib monotherapy (median duration: 9 weeks; range, 2-28+weeks). After a median follow-up of 50 weeks (range: 37-68 weeks), 22 (62%) of the patients remain alive. The objective response rate with chemotherapy was 59%, and an additional 20% had stable disease. 1-year OS was 54% and median time to progression was 7.6 months. Grade 3/4 toxicity was rare during sunitinib monotherapy. CONCLUSIONS: This phase II trial provides support for further study of sunitinib maintenance therapy following platinum-doublet chemotherapy in patients with ES-SCLC. The 1 year OS of 54% is encouraging, and a randomized trial would be appropriate to assess sunitinib's impact following chemotherapy.

A randomized phase II trial of pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab in the first-line treatment of elderly patients with advanced non-small cell lung cancer.

PURPOSE: To assess time to progression (TTP) in elderly patients with previously untreated nonsquamous non-small cell lung cancer treated with pemetrexed/gemcitabine/bevacizumab or pemetrexed/carboplatin/bevacizumab. METHODS: Eligible patients were aged 70 years or older with newly diagnosed stage IIIB/IV nonsquamous non-small cell lung cancer; Eastern Cooperative Oncology Group performance status 0 to 1; adequate organ function; and no active central nervous system metastasis. Patients were randomized 1:1 to cohort A (pemetrexed 500 mg/m2 IV, gemcitabine 1500 mg/m2 IV, and bevacizumab 10 mg/kg IV; days 1 and 15 of 28-day cycles) or cohort B (pemetrexed 500 mg/m2 IV, carboplatin area under the concentration-time curve =5 IV, and bevacizumab 15 mg/kg IV; day 1 of 21-day cycles). After six cycles, stable/responding patients continued bevacizumab until disease progression. RESULTS: Between March 2007 and December 2009, 110 patients (median age, 76 years; 88% stage IV) were treated for medians of 2.5 cycles (cohort A) and 6 cycles (cohort B). Overall response rate was 35% in both cohorts, with stable disease rates of 33% (A) and 45% (B). TTP by cohort was 4.7 and 10.2 months with median OS 7.5 and 14.8 months, respectively. Severe toxicities included the following: neutropenia (A, 51% and B, 45%), fatigue (A, 36% and B, 18%), anemia (A, 22% and B, 7%), infection (A, 25% and B, 7%), thrombocytopenia (A, 11% and B, 31%), and thromboembolism (A, 7% and B, 7%). Three potential treatment-related deaths occurred in cohort A (sepsis, thrombocytopenia, and myocardial infarction) and two in B (sepsis and pulmonary hemorrhage). CONCLUSIONS: Treatment with pemetrexed/carboplatin/bevacizumab was associated with improved TTP and OS in this elderly population and should be further evaluated. Treatment-related toxicities were expected and usually manageable, although deaths occurred with both regimens.

Predicting the risk of chemotherapy toxicity in older patients: the Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score.

BACKGROUND: Tools are lacking to assess the individual risk of severe toxicity from chemotherapy. Such tools would be especially useful for older patients, who vary considerably in terms of health status and functional reserve. METHODS: The authors conducted a prospective, multicentric study of patients aged ≥70 years who were starting chemotherapy. Grade 4 hematologic (H) or grade 3/4 nonhematologic (NH) toxicity according to version 3.0 of the Common Terminology Criteria for Adverse Events was defined as severe. Twenty-four parameters were assessed. Toxicity of the regimen (Chemotox) was adjusted using an index to estimate the average per-patient risk of chemotherapy toxicity (the MAX2 index). In total, 562 patients were accrued, and 518 patients were evaluable and were split randomly (2:1 ratio) into a derivation cohort and a validation cohort. RESULTS: Severe toxicity was observed in 64% of patients. The Chemotherapy Risk Assessment Scale for High-Age Patients (CRASH) score was constructed along 2 subscores: H toxicity and NH toxicity. Predictors of H toxicity were lymphocytes, aspartate aminotransferase level, Instrumental Activities of Daily Living score, lactate dehydrogenase level, diastolic blood pressure, and Chemotox. The best model included the 4 latter predictors (risk categories: low, 7%; medium-low, 23%; medium-high, 54%; and high, 100%, respectively; P(trend) < .001). Predictors of NH toxicity were hemoglobin, creatinine clearance, albumin, self-rated health, Eastern Cooperative Oncology Group performance, Mini-Mental Status score, Mini-Nutritional Assessment score, and Chemotox. The 4 latter predictors provided the best model (risk categories: 33%, 46%, 67%, and 93%, respectively; P(trend) < .001). The combined risk categories were 50%, 58%, 77%, and 79%, respectively; P(trend) < .001). Bootstrap internal validation and independent sample validation demonstrated stable risk categorization and P(trend) < .001. CONCLUSIONS: The CRASH score distinguished several risk levels of severe toxicity. The split score discriminated better than the combined score. To the authors' knowledge, this is the first score systematically integrating both chemotherapy and patient risk for older patients and has a potential for future clinical application.