Axitinib and/or bevacizumab with modified FOLFOX-6 as first-line therapy for metastatic colorectal cancer: a randomized phase 2 study.

BACKGROUND: In this multicenter, open-label, randomized phase 2 trial, the authors evaluated the vascular endothelial growth factor receptor inhibitor axitinib, bevacizumab, or both in combination with chemotherapy as first-line treatment of metastatic colorectal cancer (mCRC). METHODS: Patients with previously untreated mCRC were randomized 1:1:1 to receive continuous axitinib 5 mg twice daily, bevacizumab 5 mg/kg every 2 weeks, or axitinib 5 mg twice daily plus bevacizumab 2 mg/kg every 2 weeks, each in combination with modified 5-fluorouracil/leucovorin/oxaliplatin (FOLFOX-6). The primary endpoint was the objective response rate (ORR). RESULTS: In all, 126 patients were enrolled from August 2007 to September 2008. The ORR was numerically inferior in the axitinib arm (n = 42) versus the bevacizumab arm (n = 43; 28.6% vs 48.8%; 1-sided P = .97). Progression-free survival (PFS) (11.0 months vs 15.9 months; 1-sided P = .57) and overall survival (OS) (18.1 months vs 21.6 months; 1-sided P = .69) also were numerically inferior in the axitinib arm. Similarly, efficacy endpoints for the axitinib/bevacizumab arm (n = 41) were numerically inferior (ORR, 39%; PFS, 12.5 months; OS, 19.7 months). The patients who received axitinib had fewer treatment cycles compared with other arms. Common all-grade adverse events across all 3 treatment arms were fatigue, diarrhea, and nausea (all ≥49%). Hypertension and headache were more frequent in the patients who received axitinib. Patients in the bevacizumab arm had the longest treatment exposures and the highest rates of peripheral neuropathy. CONCLUSIONS: Neither the addition of continuous axitinib nor the axitinib/bevacizumab combination to FOLFOX-6 improved ORR, PFS, or OS compared with bevacizumab as first-line treatment of mCRC.

Hemolytic-uremic syndrome associated with gemcitabine: a case report and review of literature.

CONTEXT: Hemolytic uremic syndrome is a rare condition compromising the clinical triad of acute renal failure, microangiopathic hemolytic anemia, and thrombocytopenia. Hemolytic uremic syndrome may be associated with a variety of etiologies, and chemotherapeutic agents have also been reported to be associated with hemolytic uremic syndrome, including mitomycin, cisplatin, bleomycin, and most recently gemcitabine. CASE REPORT: A 72-year-old Caucasian male treated with four cycles of gemcitabine at 1,000 mg/m2 developed clinical and laboratory findings compatible with hemolytic uremic syndrome. He developed microangiopathic hemolysis, rapidly declining renal function with proteinuria and hematuria, and renal biopsy revealed thrombotic microangiopathy. Hemodialysis, plasmapheresis, and corticosteroid therapy were utilized but the process ultimately was irreversible. CONCLUSION: With multiple reports of hemolytic uremic syndrome complicating gemcitabine therapy, it is imperative that clinicians heighten their awareness of this potentially lethal complication.

Peripheral neuropathy associated with capecitabine.

5-fluorouracil (5-FU)-associated peripheral neuropathy is an uncommon event. Capecitabine (CAP) is a pro-drug of 5-FU and peripheral neuropathy associated with CAP has not been reported. During analysis of 28 patients receiving CAP with concomitant radiation (XRT) for pancreatic cancer (resected or locally advanced), two patients developed signs and symptoms consistent with peripheral neuropathy. Patients received CAP 1200-1600 mg/m2 in two divided doses with XRT (total 5040-5400 Gy) x 6 weeks, followed by 4 weeks rest, then 6 cycles of CAP 2000-2500 mg/m2 in two divided doses x 14 days every (q) 3 weeks. Patients were assessed weekly during CAP-XRT and q 3 weeks during CAP alone. Patient A reported right leg weakness (foot drop) during week 4 of CAP-XRT (1600 mg/m2). Patient B developed perioral and upper extremity paresthesias during the fourth cycle of CAP alone (2500 mg/m2). Dihydropyrimidine dehydrogenase (DPD) activity was measured by radioisotopic assay using lysates of peripheral blood mononuclear cells. Neurologic examination revealed right foot drop in Patient A and was unremarkable in Patient B. Central nervous system imaging was negative. Electromyogram and nerve conduction studies showed sensorimotor peripheral neuropathy in both patients. DPD activity was normal in both patients. There was no evidence of disease progression. Neurologic symptoms resolved after stopping CAP for 4 weeks in Patient A, with no recurrence after reinitiating CAP alone at 2000 mg/m2. Patient B continued at 80% of standard dose (2000 mg/m2) and symptoms resolved without further intervention. We conclude peripheral neuropathy with 5-FU is rare. Neurotoxicity occurs most often with intermittent high dose 5-FU as bolus injection or 24- to 48-h infusions. The etiology of neurotoxicity in our two patients remains unclear; however, as CAP is rapidly metabolized to 5-FU in patients with normal liver function, it is likely that 5-FU or its active metabolites (fluoro-beta-alanine) were contributing factors. Knowledge regarding potential adverse effects of CAP is paramount and dose modification is indicated with development of neurotoxicity.