Cancer Treatment–Induced Arrhythmias : Focus on Chemotherapy and Targeted Therapies

The combined inhibition of BRAF and MEK is hypothesized to improve clinical outcomes in patients with melanoma by preventing or delaying the onset of resistance observed with BRAF inhibitors alone. This randomized phase 3 study evaluated the combination of the BRAF inhibitor vemurafenib and the MEK inhibitor cobimetinib. We randomly assigned 495 patients with previously untreated unresectable locally advanced or metastatic BRAF V600 mutation-positive melanoma to receive vemurafenib and cobimetinib (combination group) or vemurafenib and placebo (control group). The primary end point was investigator-assessed progression-free survival. The median progression-free survival was 9.9 months in the combination group and 6.2 months in the control group (hazard ratio for death or disease progression, 0.51; 95% confidence interval [CI], 0.39 to 0.68; P<0.001). The rate of complete or partial response in the combination group was 68%, as compared with 45% in the control group (P<0.001), including rates of complete response of 10% in the combination group and 4% in the control group. Progression-free survival as assessed by independent review was similar to investigator-assessed progression-free survival. Interim analyses of overall survival showed 9-month survival rates of 81% (95% CI, 75 to 87) in the combination group and 73% (95% CI, 65 to 80) in the control group. Vemurafenib and cobimetinib was associated with a nonsignificantly higher incidence of adverse events of grade 3 or higher, as compared with vemurafenib and placebo (65% vs. 59%), and there was no significant difference in the rate of study-drug discontinuation. The number of secondary cutaneous cancers decreased with the combination therapy. The addition of cobimetinib to vemurafenib was associated with a significant improvement in progression-free survival among patients with BRAF V600-mutated metastatic melanoma, at the cost of some increase in toxicity. (Funded by F. Hoffmann-La Roche/Genentech; coBRIM ClinicalTrials.gov number, NCT01689519.).

To determine the safety and efficacy of arsenic trioxide (ATO) in patients with relapsed acute promyelocytic leukemia (APL). Forty patients experiencing first (n = 21) or > or = second (n = 19) relapse were treated with daily infusions of ATO to a maximum of 60 doses or until all leukemic cells in bone marrow were eliminated. Patients who achieved a complete remission (CR) were offered one consolidation course of ATO that began 3 to 4 weeks later. Patients who remained in CR were eligible to receive further cycles of ATO therapy on a maintenance study. Thirty-four patients (85%) achieved a CR. Thirty-one patients (91%) with CRs had posttreatment cytogenetic tests negative for t(15;17). Eighty-six percent of the patients who were assessable by reverse transcriptase polymerase chain reaction converted from positive to negative for the promyelocytic leukemia/retinoic acid receptor-alpha transcript by the completion of their consolidation therapy. Thirty-two patients received consolidation therapy, and 18 received additional ATO as maintenance. Eleven patients underwent allogeneic (n = 8) or autologous (n = 3) transplant after ATO treatment. The 18-month overall and relapse-free survival (RFS) estimates were 66% and 56%, respectively. Twenty patients (50%) had leukocytosis (> 10,000 WBC/microL) during induction therapy. Ten patients developed signs or symptoms suggestive of the APL syndrome and were effectively treated with dexamethasone. Electrocardiographic QT prolongation was common (63%). One patient had an absolute QT interval of > 500 msec and had an asymptomatic 7-beat run of torsades de pointe. Two patients died during induction, neither from drug-related causes. This study establishes ATO as a highly effective therapy for patients with relapsed APL.

To assess the activity of taxol in patients with advanced, progressive, and drug-refractory ovarian cancer and to delineate more clearly the toxicity of taxol in this patient population. Nonrandomized, prospective phase II trial. Forty-seven patients with drug-refractory epithelial ovarian cancer who had one or more lesions measurable in perpendicular diameters. Of these patients, 45 were evaluable for toxicity and 40 were evaluable for response. PATIENTS were treated every 22 days with varying doses of taxol (110 to 250 mg/m2 body surface) given as a 24-hour infusion with subsequent doses based on adverse effects. A premedication regimen was used to avoid acute hypersensitivity reactions. Twelve patients (30%; CI, 16% to 44%) responded to taxol for periods lasting from 3 to 15 months. The dose-limiting toxicity was myelosuppression with leukocytes affected more severely and commonly than thrombocytes or reticulocytes. Leukopenia was usually brief in duration but was associated with sepsis in 3 cases (2 fatal). Other adverse effects included myalgias, arthralgias, alopecia, diarrhea, nausea, vomiting, mucositis, and peripheral neuropathy. Rare cases of cardiac and central neurotoxicity were also noted. Taxol is an active agent in drug-refractory ovarian cancer and deserves further study in combination with other active drugs in previously untreated patients with advanced ovarian cancer.