Purpose: To compare the survival benefit obtained with cisplatin plus gemcitabine, a cisplatin-based triplet, and nonplatinum sequential doublets in advanced non–small-cell lung cancer (NSCLC). Patients and Methods: Stage IIIB to IV NSCLC patients were randomly assigned to receive cisplatin 100 mg/m² day 1 plus gemcitabine 1,250 mg/m² days 1 and 8, every 3 weeks for six cycles (CG); cisplatin 100 mg/m² day 1 plus gemcitabine 1,000 mg/m² and vinorelbine 25 mg/m² days 1 and 8, every 3 weeks for six cycles (CGV); or gemcitabine 1,000 mg/m² plus vinorelbine 30 mg/m² days 1 and 8, every 3 weeks for three cycles, followed by vinorelbine 30 mg/m² days 1 and 8 plus ifosfamide 3 g/m² day 1, every 3 weeks for three cycles (GV–VI). Results: Five hundred fifty-seven patients were assigned to treatment (182 CG, 188 CGV, 187 GV–VI). Response rates were significantly inferior for the nonplatinum sequential doublet (CG, 42%; CGV, 41%; GV–VI, 27%; CG v GV–VI, P = .003). No differences in median survival or time to progression were observed. Toxicity was higher for the triplet: grade 3 to 4 neutropenia (GC, 32%; CGV, 57%; GV–VI, 27%; P < .05); neutropenic fever (CG, 4%; CGV, 19%; GV–VI, 5%; P < .0001); grade 3 to 4 thrombocytopenia (CG, 19%; CGV, 23%; GV–VI, 3%; P = .0001); and grade 3 to 4 emesis (GC, 22%; GCV, 32%; GV–VI, 6%; P < .0001). Conclusion: On the basis of these results, CG remains a standard regimen for first-line treatment of advanced NSCLC.

Background.: Concomitant chemoradiotherapy followed by total mesorectal excision is standard treatment for locally advanced rectal cancer. This approach, however, focuses on local disease control and delays systemic treatment. Induction chemotherapy has the advantage of earlier administration of systemic therapy and may improve distant control. The objective of the current study was to assess the efficacy and toxicity of adding bevacizumab to induction chemotherapy followed by preoperative bevacizumab-based chemoradiotherapy in patients with locally advanced rectal cancer. Patients and Methods.: Eligible patients had high-risk rectal adenocarcinoma defined by magnetic resonance imaging criteria. Treatment consisted of four 21-day cycles of bevacizumab (7.5 mg/kg) and XELOX (capecitabine plus oxaliplatin), followed by concomitant radiotherapy (50.4 Gy) plus bevacizumab (5 mg/kg every 2 weeks) and capecitabine (825 mg/m2 twice daily on days 1–15). Surgery was scheduled for 6–8 weeks after chemoradiotherapy. The primary endpoint was pathologic complete response (pCR). Results.: Between July 2007 and July 2008, 47 patients were recruited. Among 45 patients who underwent surgery, pCR was achieved in 16 patients (36%; 95% confidence interval: 22.29%–51.27%), and an additional 17 patients (38%) had Dworak tumor regression grade 3. R0 resection was performed in 44 patients (98%). Most grade 3/4 adverse events occurred during the induction phase and included diarrhea (11%), asthenia (4%), neutropenia (6%), and thrombocytopenia (4%). Eleven patients (24%) required surgical reintervention. Conclusions.: Addition of bevacizumab to induction chemotherapy and chemoradiotherapy is feasible, with impressive activity and manageable toxicity. However, caution is recommended regarding surgical complications.

ML18147 evaluated continued bevacizumab with second-line chemotherapy for patients with metastatic colorectal cancer (mCRC) progressing after the standard first-line bevacizumab-containing therapy. Evaluating outcomes according to tumor Kirsten rat sarcoma virus oncogene (KRAS) status was an exploratory analysis. KRAS data were collected from local laboratories (using their established methods) and/or from a central laboratory (mutation-specific Scorpion amplification-refractory mutation system). No adjustment was made for multiplicity; analyses were not powered to detect statistically significant differences. Of 820 patients, 616 (75%) had unambiguous KRAS data; 316 (51%) had KRAS wild-type tumors and 300 (49%) had mutant KRAS tumors. The median progression-free survival (PFS) was 6.4 months for bevacizumab plus chemotherapy and 4.5 months for chemotherapy [P < 0.0001; HR = 0.61; 95% confidence interval (CI): 0.49–0.77] for wild-type KRAS and 5.5 and 4.1 months, respectively (P = 0.0027; HR = 0.70; 95% CI: 0.56–0.89) for mutant KRAS. The median overall survival (OS) was 15.4 and 11.1 months, respectively (P = 0.0052; HR = 0.69; 95% CI: 0.53–0.90) for wild-type KRAS and 10.4 versus 10.0 months, respectively (P = 0.4969; HR = 0.92; 95% CI: 0.71–1.18) for mutant KRAS. In both analyses, no treatment interaction by KRAS status was observed (PFS, P = 0.4436; OS, P = 0.1266). Bevacizumab beyond first progression represents an option for patients with mCRC treated with bevacizumab plus standard first-line chemotherapy, independent of KRAS status.

BACKGROUND: Recurrent osteosarcoma is a drug‐resistant disease with a dismal prognosis. The objective of this Phase II study was to evaluate the activity of ecteinascidin 743 (ET‐743) as a salvage therapy in these patients.METHODS: Patients with recurrent osteosarcoma who had received standard chemotherapeutic agents were eligible. ET‐743 was administered at a dose of 1500 μg/m² as a 24‐hour infusion every 3 weeks. Pharmacokinetic studies were performed during the first cycle.RESULTS: Twenty‐five patients were enrolled, 23 of whom were assessable for response (median age of 18 years; range, 12–67 years). The median number of previous chemotherapeutic agents was five (range, three to eight previous agents). Sixty‐one cycles were administered (median number of cycles per patient was 2; range, 1–9 cycles per patient). Three patients (12%) achieved minor responses (49% 36% and 25%, respectively). Fifteen patients (60%) developed a transient elevation of hepatic transaminases (Grade 3 or 4 [according to the National Cancer Institute Common Toxicity Criteria]), which was not cumulative. Grade 3 or 4 neutropenia and thrombocytopenia were observed in 12 patients (48%) and 6 patients (24%), respectively. The mean area under the curve (AUC) in 4 patients experiencing Grade 4 toxicity (76.4 ± 29.3 ng × hr/mL) was significantly greater (P = 0.034) than that in those for whom the most severe toxicity was Grade 3 (39.5 ± 17.2 ng × hr/mL [n = 12]) or Grade 1‐2 (52.6 ± 15.6 ng × hr/mL [n = 5]). There were no other significant correlations found between pharmacokinetic variables and patient characteristics, toxicity, or therapeutic response.CONCLUSIONS: ET‐743 was found to be well tolerated in heavily pretreated osteosarcoma patients but had limited antitumor activity as a single agent. The combination of ET‐743 with cisplatin or doxorubicin should be considered. Cancer 2003;98:832–40. © 2003 American Cancer Society.DOI 10.1002/cncr.11563