Bevacizumab Added to Moderate-dose Chemotherapy for Refractory Uterine Cancer

Abstract

Background/Aim: Bevacizumab (bev), when added to a moderate dose combination of previously failed cytotoxins, as a third- and fourth-line therapy for refractory gastric, cholangiocarcinoma, and ovarian cancers, produced high-quality responses. The regimen was based on preclinical models designed in order to simultaneously partner both bev and each of the cytotoxins with 4-5 synergistic drugs. Patients and Methods: Eligible patients (n=9) had high-grade endometrial tumors and had failed standard chemotherapy. Bev (10 mg/kg every 2 weeks) and cyclophosphamide (150-250 mg/m²), were added to a combination of gemcitabine, fluorouracil, leucovorin, irinotecan and a platinum analogue –first without and then with docetaxel– each at approximately 1/2 to 1/3 of their standard dosage. Dose modification aimed at a repeated absolute neutrophil count (ANC) of 750-1,500 μl or platelets of 125,000-75,000 μl. Safety measures included stop-go use (intermittent, as needed, brief withholding of bev with resumption when again tolerated), of bev, and both prospective and ongoing dose modification in order to protect the bowels. Results: Induction treatment was free of life-threatening complications. Nine consecutive patients, 3 under second- and 6 under multi-line treatment, had 9 objective responses and 8 produced long clinical benefits, 2 of which were complete responses. Seven responses created opportunities for personalized added treatment and research. Absolute median survival was 21.5 months for the 8 patients with platinum-resistant tumors. One patient was unable to tolerate a first standard adjuvant dose of paclitaxel. After rapid peritoneal progression of disease, treatment has produced 52+ months of unmaintained complete remission. Conclusion: Bev, in the combination that was used in this study, meets response, survival, and toxicity criteria for further testing against second- or multi-line chemotherapy-resistant tumors and also when a standard treatment is not safe.