Paclitaxel i.v. Plus Cisplatin i.p for NACT in Patients With Advanced Ovarian Cancer

Phase III Clinical Trial of Intravenous Paclitaxel Plus Intraperitoneal Cisplatin for Neo-adjuvant Chemotherapy in Patients With Advanced Ovarian Cancer

To test the effect of intravenous paclitaxel plus intraperitoneal cisplatin for neo-adjuvant chemotherapy in patients with advanced ovarian cancer, the investigators conducted a phase III single arm clinical trial. Included patients will receive interval debulking surgery after 2-6 cycles neoadjuvant chemotherapy based on the clinical judgment of the gynecologic oncologist. Six cycles of chemotherapy will conducted after surgery. And the neoadjuvant chemotherapy is as follows: paclitaxel 135 mg/m2 i.v. and cisplatin 75 mg/m2 i.p. on day 1. The primary end point is optimal debulking rates. the investigators also will evaluate effect on parameters of volume of ascites, tumor size, duration of surgery, hemorrhage, hospitalizations and postoperative complication etc. After comparing with data published online, the investigators will try to find out if paclitaxel i.v. plus cisplatin i.p. is a superior neoadjuvant chemotherapy for advanced ovarian carcinoma.

BACKGROUND AND INTRODUCTION Epithelial ovarian cancer (EOC) is the leading cause of death from gynecologic malignancy in the developed world with the majority of women presenting with stage III/IV disease. Most patients with advanced-stage cancer will eventually experience recurrence and die as a result of the disease. Therefore, more effective therapies are needed in the treatment of this aggressive cancer. After the results of the Gynecologic Oncology Group trial (GOG-152) (NCT00002568) the investigatorsre published, interval debulking surgery was no longer recommended for patients in whom optimal cytoreduction was not achieved despite a maximal effort at primary debulking surgery[1]. The use of neoadjuvant chemotherapy (NACT) before a definitive debulking attempt is increasingly used in advanced EOC based on two RCTs (EORTC55971 and CHORUS) which demonstrated non-inferiority and lothe investigatorsr perioperative morbidity compared with primary surgery follothe investigatorsd by chemotherapy[2, 3]. But what is the preferred chemotherapy regimen for women who will receive NACT is still a question[4]. Evidence from the peritoneal dialysis literature suggests that the peritoneal permeability of a number of hydrophilic anticancer drugs may be considerably less than plasma clearance. Pharmacokinetic calculations indicate that such drugs administered i.p.(intraperitoneal chemotherapy,i.p.) in large volumes are expected to maintain a significantly greater concentration in the peritoneal space than in the plasma. Prior studies have reported on the pharmacologic advantage of delivering cisplatin i.p., with a 20-fold higher concentration in the i.p. space compared with that measured in plasma after i.v. administration[5]. This concentration difference offers a potentially exploitable biochemical advantage in the treatment of patients with presumed microscopic residual ovarian cancer confined to the peritoneal cavity[6]. In addition, i.p. therapy allows for continuous and prolonged exposure of high drug concentrations with lothe investigatorsr peak plasma levels over time[7]. Three randomized clinical trials (RCTs) and a meta-analysis had demonstrated improved survival for women with stage III EOC who received a combination of i.v. and i.p. chemotherapy following optimal, primary debulking surgery[8-10]. GOG 172 confirmed a continued benefit for women who had received the experimental arm[11]. OV21/PETROC proved in women with stage IIIC or IVA EOC treated with NACT and optimal debulking surgery, i.p. carboplatin-based chemotherapy is the investigatorsll tolerated and associated with an improved PD9 (9-month progressive disease rate) compared with i.v. carboplatin-based chemotherapy. But there is no RCT focused on the role of i.p. in NACT[12]. From the retrospective data in our institution (not published yet), compared with intravenous paclitaxel plus carboplatin, intravenous paclitaxel plus i.p. cisplatin shothe investigatorsd more effective in NACT, and side effects like nausea and vomiting are acceptable and manageable, moreover, with lothe investigatorsr bone marrow suppression rate. To determine the role of i.p. cisplatin in NACT the investigators desiged a RCT to compare optimal debulking rates and progression-free survival (PFS) in women with stage IIIc or IV epithelial ovarian carcinoma after treated with NACT using intravenous paclitaxel plus carboplatin and intravenous paclitaxel plus i.p. cisplatin. OBJECTIVES OF THE TRIAL To test effect of intravenous paclitaxel plus intraperitoneal cisplatin for neo-adjuvant chemotherapy in patients with advanced ovarian cancer TRIAL DESIGN. Treatment: paclitaxel 135 mg/m2 i.v. and cisplatin 75 mg/m2 i.p. on day 1 Principal surgeon: Only senior surgeons will be allothe investigatorsd to have the responsibility for the surgery. Each senior surgeon will follow carefully the guideline for surgery. Cycle of chemotherapy: Surgery may be performed after 2-6 cycles based on the clinical judgment of the gynecologic oncologist. Six cycles of chemotherapy will conducted after surgery. THERAPEUTIC REGIMENS Interval debulking surgery should be performed within 6 the investigatorseks after course 2-6 in all patients with response or stable disease. If this time limit is not met the patient has to be excluded from this protocol. Follothe investigatorsd by 6 courses of chemotherapy within 3 the investigatorseks after surgery. Regimens: paclitaxel 135 mg/m2 i.v. and cisplatin 75 mg/m2 i.p. on day 1 ENDPOINT OF THIS STUDY First stage Primary end point: Optimal debulking rates Optimal cytoreduction was defined as largest residual tumor nodule not greater than 1 cm in maximal diameter at the completion of the primary operation. Secondary end points: Volume of ascites Tumor size Duration of surgery, hemorrhage, hospitalizations Postoperative complication (infection, venous complications, hospitalization etc.) AEs of chemotherapy *Upper abdomen surgical procedures the investigatorsre defined as splenectomy, pancreatectomy, gallbladder resection, liver resection, diaphragmatic resection. Second stage Primary end point Progression free survival (PFS) Secondary end points Overall survival (OS)

Optimal cytoreduction was defined as largest residual tumor nodule not greater than 1 cm in maximal diameter at the completion of the primary operation.

Progression free survival (PFS) will be measured from the date enrollment to the first documented date of progression, or death, whichever occurs first, assessed up to 36 months.

Overall survival (OS) will be measured from the date of enrollment to the date of death, whatever the cause, assessed up to 36 months.

Inclusion Criteria: Preferentially biopsy proven Stage IIIc or IV epithelial ovarian carcinoma, or peritoneal or fallopian tube carcinoma (the presence of metastases outside the pelvis measuring at least 2 cm in diameter (as noted during diagnostic laparoscopy or laparotomy or on computed tomography [CT]),with a low likelihood of achieving cytoreduction to, 1 cm (ideally to no visible disease). Or women who have a high perioperative risk profile. Fine needle aspiration (FNA) showing an adenocarcinoma and cytopathology from ascites or pleural effusion is acceptable under the following conditions: the patient has a pelvic (ovarian) mass, AND omental cake or other metastasis larger than 2 cm in the upper abdomen and/or regional lymphnode metastasis irrespective of size or stage IV AND serum CA125/CEA ratio > 25. If the serum CA125/CEA ratio is < 25, a barium enema (or colonoscopy) and gastroscopy (or radiological examination of the stomach) should be negative for the presence of a primary tumor (< 6 weeks before randomization), and normal mammography (< 6 weeks). WHO performance status of 0, 1, or 2. No other serious disabling diseases contraindicating for cytoreductive surgery or platin based chemotherapy. No other prior primary malignancies, except for carcinoma in situ of the cervix and basal carcinoma of the skin. No clinical evidence of brain or leptomeningeal metastases. Adequate hematological, renal and hepatic function to permit platin-paclitaxel based chemotherapy: WBC > 3.0 x 109/L, N >1.5 x 109/L, platelets > 100 x 109/L, serum creatinine < 1.25 x upper normal range, serum bilirubin < 1.25 x upper normal range. Absence of any psychological, familial, sociological or geographical condition potentially preventing compliance with the study protocol and follow-up schedule; those conditions should be assessed with the patient before registration in the trial. Before patient registration/randomization, informed consent must be obtained and documented according to national and local regulatory requirements and the local rules followed in the institution. Exclusion Criteria: serious disabling diseases that would contraindicate primary cytoreductive surgery or platinumbased chemotherapy mucinous or borderline histology, extensive intra-abdominal adhesions, bowel obstruction or unresolved>grade 2 peripheral neuropathy.

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