**6. Intraperitoneal chemotherapy**

**4. Neoadjuvant chemotherapy**

300 Ovarian Cancer - From Pathogenesis to Treatment

**5. Targeted therapy**

every 3 weeks.

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]. 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 includ-

ing at least 3 cycles of adjuvant therapy after interval debulking surgery [16].

**1.** Cycles 1–6: carboplatin, AUC 6 Paclitaxel, 175 mg/m2

**2.** Cycles 1–6: carboplatin, AUC 6 Paclitaxel, 175 mg/m2

**3.** Cycles 1–6: carboplatin, AUC 6 Paclitaxel, 175 mg/m2

wk. Cycles 7–22: placebo every 3 weeks.

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:

cycle 2) every 3 weeks the Cycles from 7 to 22 patients received Placebo every 3 weeks.

cycle 2) every 3 weeks the Cycles from 7 to 22 patients received Bevacizumab at 15 mg/kg

Placebo (starting in cycle 2) every 3

Bevacizumab, 15 mg/kg (starting in

Bevacizumab, 15 mg/kg (starting in

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

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 the abdominal cavity.

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 intraperitoneal therapy.

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 when intraperitoneal administration is performed compared with intravenous infusion [23]. Moreover, avascular tumors are more exposed to higher drug concentrations with intraperitoneal rather than intravenous administration [24].

earlier in the patients who had regular CA 125 monitoring. Quality of life was lower in the

Chemotherapy for Primary and Recurrent Epithelial Ovarian Cancer

http://dx.doi.org/10.5772/intechopen.80890

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The choice of chemotherapy agents in recurrent disease is based on the response to first line treatment, the current symptoms; the time elapsed from last chemotherapy and the side

The prognosis and the response to second-line therapy and subsequent lines depends in great part on the progression-free interval after the last dose of the preceding line of chemotherapy.

• Platinum-refractory disease when the progression occurs during treatment or within

• Platinum-resistant disease as a progression within 6 months of platinum-based therapy;

• Partially platinum-sensitive disease when the progression occurs between 6 and 12 months; • Platinum-sensitive patients progressing with an interval of more than 12 months (GCIG

• For patients with platinum-sensitive recurrent ovarian cancer: carboplatin-doublet should

A meta-analysis including four randomized trials confirmed an improvement in PFS with a HR of 0, 68 (95% CI 0.57–0.81) and OS with a HR of 0.8 (95% CI 0.64–1.0) [29].The phase III Calypso [30] trial compared two doublets, taxol and carboplatin vs. carboplatin with pegylated lipososmal doxorubicin (PLD). The PFS with the second regimen (11.3 months) was not inferior to the taxane-carboplatin (9.4 months, P < 0.001, HR = 0.82) [3]. However the PLD regimen was better tolerated because of the minimal incidence of neuropathy, alopecia,

Again, the selection between the different options of platinum-based doublets should be

Bevacizumab (Avastin) has also been studied as a treatment option in patients with recurrent ovarian cancer. The phase III OCEANS [31], study performed in women with platinum-sensitive recurrent ovarian cancer compared gemcitabine plus carboplatin with or without bevacizumab for 10 cycles followed by bevacizumab alone until disease progression or toxicity as compared to placebo. Chemotherapy with bevacizumab improved PFS, 12 months with bevacizumab vs.

Regimens based on non-platinum combinations are another option for patients with platinum-sensitive disease. In a phase III randomized trial OVA 301 [32], PLD alone was compared with PLD combined with the Mariane-derived alkaloid trabectidin (Yondelis), this combination regimen improved the PFS [32], Median PFS was 7.3 months with trabectedin/PLD v 5.8 months with PLD (hazard ratio, 0.79; 95% CI, 0.65–0.96; P = 0.0190). Overall response rate

8 months in the placebo group, as well as the response rate (79 vs. 57%, P < 0.001) [31].

(ORR) was 27.6% for trabectedin/PLD vs. 18.8% for PLD (P = 0.0080) [32].

based on the previous toxicity profile and convenience of administration [16].

early treatment group [27].

We define:

effects of previous drugs administered.

4 weeks after the last dose.

be the treatment of choice [16].

and arthralgia and with less hypersensitivity reactions [3].

Consensus) [28].

A meta-analysis of five clinical trials confirmed a benefit in OS for intraperitoneal chemotherapy [25]. This led to a National Cancer Institute alert in 1996 recommending that intraperitoneal chemotherapy should be considered in patients with small volume (<1 cm) or no residual disease after surgery [16]. However, this has not been adopted as a standard care of in the majority of institutions and countries due to its great toxicity [16].
