**5. Targeted therapy**

The addition of bevacizumab (a humanized monoclonal antibody to VEGF) to first-line chemotherapy based on platinum-taxane in advanced ovarian cancer demonstrated a significant improvement of PFS. This was evaluated in GOG-218 [17] a phase 3 trial in which they randomly assigned patients with newly diagnosed stage III (incompletely resectable) or stage IV epithelial ovarian cancer who had debulking surgery to receive one of these three treatments:


The median progression-free survival was 10.3 months in the control group, 11.2 in the bevacizumab-initiation group, and 14.1 in the bevacizumab-throughout group [18].

The administration of bevacizumab during and up to 10 months after paclitaxel and carboplatin chemotherapy prolongs the median progression-free survival by about 4 months in patients with advanced epithelial ovarian cancer [18].

Similar results were obtained in the ICON-7 trial [19] where a total of 1528 women from 11 countries were studied, 70% had stage IIIC or IV ovarian cancer. In this study patients were randomly assigned to carboplatin and paclitaxel (175 mg/m2 ) every 3 weeks for 6 cycles, or to this regimen plus bevacizumab (7.5 mg/Kg), given every 3 weeks for 5 or 6 cycles and continued for 12 more cycles or until disease progression. The PFS at 36 months was 20.3 months with chemotherapy alone, as compared with 21.8 months with chemotherapy plus bevacizumab. In the updated analyses, PFS at 42 months was 22.4 months without bevacizumab versus 24.1 months with bevacizumab (P = 0.04); in patients at high risk for disease progression, the benefit was greater with bevacizumab than without it, with PFS at 42 months of 18.1 months with bevacizumab, versus 14.5 months with standard chemotherapy, with median overall survival of 36.6 and 28.8 months, respectively [19].

These observations suggest that effectiveness of anti-angiogenic therapy may be greater in more advanced disease. However this was not supported by other studies testing the impact of different anti-angiogenesis factors added to chemotherapy in advanced ovarian cancer [18]. Both pazopanib [20] and nindetanib [18] showed a significant increase in PFS in patients with small tumors. The PFS benefit of the addition of nindetanib to first-line chemotherapy resulted in a more pronounced effect in the non-high-risk subgroup (stage II or stage III and residual ≤1 c m) with 27.1 vs. 20.8 months. In contrast, there was no significant benefit noted for high risk patients (FIGO IV or stage III with residual tumors). Pazopanib as maintenance therapy after first line chemotherapy showed a significant advantage with respect to PFS compared to the control group 17.9 vs. 12.3 months, HR 0,77, P = 0.0021) [18].
