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Published: Wednesday, Jun 09, 2010
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Sorafenib Plus Dacarbazine Improves Progression-Free Survival in Patients With Advanced Melanoma, and Is Well Tolerated

There is currently no standard of care for patients with advanced melanoma. Dacarbazine is perhaps the most commonly used cytotoxic agent. Dacarbazine has a moderate toxicity profile. Treatment typically yields a low objective response rate (5% to 20%), a median progression-free survival (PFS) of 1.5 to 1.6 months, and no improvement in overall survival (OS).

David F. McDermott, MD, Beth Israel Deaconess Medical Center, Boston and colleagues performed a multicenter, randomized, double- blind, placebo-controlled phase II study evaluating the efficacy and safety of sorafenib (Nexavar) combined with dacarbazine in patients with advanced melanoma. Results were published in the May 1, 2008 issue of Journal of Clinical Oncology.

Study enrollees (N = 101) were chemotherapynaïve patients with stage III (unresectable) or IV melanoma. Patients were randomized to receive either sorafenib plus dacarbazine (N = 51) or placebo plus dacarbazine (N = 50). On day 1 of a 21-day cycle, patients received intravenous dacarbazine 1000 mg/m2, for a maximum of 16 cycles. Sorafenib 400 mg or placebo was administered orally twice a day, continuously. The primary end point of the trial was PFS by independent assessment. Additional end points included OS, time to progression (TTP), objective response rate, PFS rates at months 6 and 9, duration of response, and change from baseline in ECOG performance status.

Median PFS in the combination therapy arm was 21.1 weeks, compared with 11.7 weeks in the dacarbazine monotherapy arm (hazard ratio [HR], 0.665; P = 0.068). PFS was greater in the combination therapy arm at six months (41.0% vs. 19.5%) and nine months (22.2% vs. 12.2%). Median TTP was 21.1 weeks in the combination therapy arm, compared with 11.7 weeks in the dacarbazine monotherapy arm, resulting in an estimated HR of 0.619 (sorafenib plus dacarbazine/placebo plus dacarbazine; P = 0.039). Median OS in the two arms was similar (45.6 wk vs 51.3 wk in the combination therapy and dacarbazine monotherapy arms, respectively; P > 0.05). There was no significant difference in change from baseline in ECOG performance status.

The median duration of sorafenib treatment was 19.1 weeks, compared with 12.1 weeks for placebo. The median number of cycles of dacarbazine cycles in the combination therapy arm was five, compared with four in the dacarbazine monotherapy arm. The combination regimen was well tolerated and had a manageable toxicity profile.

The authors concluded that the combination of sorafenib and dacarbazine was well-tolerated and yielded an encouraging improvement in PFS in patients with advanced melanoma, and recommended further study of this combination.





Bevacizumab Can Be Added to Chemotherapy for Head and Neck Cancer

Tanguy Siewert, MD, University of Chicago Cancer Research Center at the University of Chicago, in Illinois, and colleagues conducted a phase I doseescalation study to determine the maximum-tolerated dose (MTD) and dose-limiting toxicity (DLT) of bevacizumab (Avastin), when added to the standard FHX (fluorouracil, hydroxyurea, radiation therapy) chemoradiotherapy in patients with poor-prognosis head and neck cancer. Results were reported in the May 1, 2008 issue of Journal of Clinical Oncology.

Patients 18 years of age or older were eligible for the trial if they had histologically proven head and neck cancer. Enrollees could have either (1) recurrent, previously radiated disease without distant spread, or low-volume distant disease requiring locoregional palliation; or (2) no history pf previous treatment, with an estimated two-year survival < 10% with radiation. Prior radiotherapy had to be completed at least four months and/or chemotherapy at least one month before initiating treatment, and patients had to have recovered from adverse effects. Bevacizumab was escalated 2.5 to 10 mg/kg, fluorouracil 600 to 800 mg/m2 (120-hour continuous infusion), and hydroxyurea from 500 to 1000 mg (twice daily for 5 days), starting day 1. Treatment was repeated every 14 days for seven cycles. At the MTD, the cohort was expanded.

Forty-three patients were treated. Median overall survival was 10.7 months. One- and two-year survival rates were 49% and 28%, respectively. Median for patients not previously radiated (40.1 mo) was substantially greater than that for patients with prior radiotherapy (9.2 mo; P = 0.0046). Distant metastases were present in some patients in both groups. Further subgroup analysis was performed for patients with recurrent, nonmetastatic head and neck cancer who underwent re-irradiation (N = 29). Median survival in this group was 10.3 months, with one- and two-year survival rates of 41.4% and 17.2%, respectively (N = 29); the two-year cumulative incidence of death resulting from disease was 51.7%.


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