Bevacizumab Added to Moderate-dose Chemotherapy for Refractory Uterine Cancer

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.

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.

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.

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.