The efficacy of therapeutic regimens incorporating weekly or every-3-weeks
paclitaxel (PTX) for
ovarian cancer is debated. We investigated the addition of
bevacizumab in regimens of
chemotherapy with different PTX doses and schedules in preclinical models. Treatments were
cisplatin (DDP) with weekly PTX (conventional), or dose-dense-equi (every other day to the conventional cumulative dose), or dose-dense-high (total dose 1.5 times higher), with or without
bevacizumab. Treatment efficacy was evaluated analyzing
tumor growth in different time-windows in two patient-derived
ovarian cancer xenografts with different sensitivity to
cisplatin.
Tumor progression,
metastasis and survival were studied in
ovarian cancer models growing orthotopically and disseminating in the mouse peritoneal cavity. Short-term effects on cell cycle,
tumor cell proliferation/apoptosis and vasculature were evaluated by flow cytometry and immunohistochemistry. PTX dose-dense (with/without DDP) was superior to the conventional scheme in a dose-dependent manner; the high efficacy was confirmed by the lower ratio of
tumor to normal cells. All schemes benefited from
bevacizumab, which reduced
tumor vessels. However, DDP/PTX dose-dense-high (only
chemotherapy) was at least as active as DDP/PTX conventional plus
bevacizumab. DDP/PTX dose-dense-high plus
bevacizumab was the most effective in delaying
tumor progression, though it did not prolong mouse survival and the continuous treatment with
bevacizumab was associated with a malignant disease. These findings indicate that the effect of
bevacizumab in combination with
chemotherapy may depend on the schedule-dose of the treatment and help to explain the unclear benefits after
bevacizumab.