**4. Neoadjuvant chemotherapy**

Neoadjuvant chemotherapy (NAC) followed by interval debulking surgery (IDS) has been proposed in the management of advanced Epithelial ovarian cancer in order to increase the rate of complete optimal surgery with less surgical morbidity [11–13]. Reserved initially for unresectable disease or for patients in bad and poor general condition, the use of NAC and IDS has increased over the past two decades and frequently the first debulking is now realized only after several cycles of chemotherapy [11, 13]. Vergote et al. [11] in a large phase III randomized trial including patients with advanced stages IIIc-IV reported the non-inferiority of interval surgery after 3 cycles of NAC compared to upfront surgery [11] s The hazard ratio for death (intentionto-treat analysis) in the group assigned to neoadjuvant chemotherapy followed by interval debulking was 0.98 (90% confidence interval [CI], 0.84–1.13; P = 0.01 for non-inferiority) [11].

The median progression-free survival was 10.3 months in the control group, 11.2 in the beva-

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

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

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

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 com-

The rational for giving chemotherapy directly into the peritoneal cavity is supported by preclinical, pharmacodynamics and pharmacocinetic data [21]. Compared with intravenous (IV) treatment, intraperitoneal (IP) administration allows an increase in drug concentration inside

In the majority of patients, epithelial ovarian cancer is confined to the peritoneal cavity at initial diagnosis and in recurrence [22]. As a result ovarian cancer is a good target for intra-

The hypothesis of improved effectiveness is explained by the increasing concentration of the cytotoxic agent in the tumor microenvironment. Analysis of intratumoral drug concentrations demonstrates that higher drug exposure is observed for lesions 2–3 mm or smaller

pared to the control group 17.9 vs. 12.3 months, HR 0,77, P = 0.0021) [18].

The peritoneal cavity is the most common route of ovarian cancer spread.

) every 3 weeks for 6 cycles, or to

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Chemotherapy for Primary and Recurrent Epithelial Ovarian Cancer

cizumab-initiation group, and 14.1 in the bevacizumab-throughout group [18].

patients with advanced epithelial ovarian cancer [18].

survival of 36.6 and 28.8 months, respectively [19].

**6. Intraperitoneal chemotherapy**

the abdominal cavity.

peritoneal therapy.

randomly assigned to carboplatin and paclitaxel (175 mg/m2

However, in clinical practice, optimal surgical timing and selection criteria for neoadjuvant chemotherapy and interval surgery remain controversial. Retrospective studies and metaanalyses observed a large survival advantage for patients receiving initial and complete removal of all macroscopic tumors prior to chemotherapy [14]. Moreover, the quality of surgery was heterogeneous in the EORTC trial among participating centres with variations in surgical aggressiveness and rates of complete resection, residual tumor of 1 cm or less was achieved in 42% of patients in the primary cytoreduction arm and in 81% of patients in the NACT arm. In the intent to treat analysis, the NACT arm was non inferior to the primary surgery arm with respect to the primary outcome of overall survival [14]. This argument explains the comparatively low survival observed for those treated with upfront surgery in this study. Furthermore, retrospective data have also suggested that NAC and IDS compared to primary surgery may increase the risk of developing platinum-resistant disease and less sensitive recurrent disease [15]. A minimum of 6 cycles of treatment is recommended including at least 3 cycles of adjuvant therapy after interval debulking surgery [16].
