Luigi Frigerio

324 - Hyperthermic intraperitoneal chemotherapy with cisplatin and paclitaxel in advanced ovarian cancer: a multicenter prospective observational study

J Gynecol Oncol. 2015 Jan;26(1):54-61. English. Published online Jan 08, 2015. Copyright © 2015. Asian Society of Gynecologic Oncology, Korean Society of Gynecologic Oncology
Federico Coccolini, Luca Campanati, Fausto Catena, Valentina Ceni, Marco Ceresoli, Jorge Jimenez Cruz, Marco Lotti, Stefano Magnone, Josephine Napoli, Diego Rossetti, Pierandrea De Iaco, Luigi Frigerio, Antonio Pinna,Ingo Runnebaum,Luca Ansaloni

abstract: Epithelial ovarian cancer (EOC) is the fifth most frequent cancer among females and approximately two thirds of the patients present with advanced disease (International Federation of Gynecology and Obstetrics [FIGO] stage III or IV) at diagnosis [1]. The current standard treatment for these patients consists in maximum cytoreductive surgery (CRS) and platinum-based chemotherapy [2]. Although platinum drugs are the most active agents in ovarian cancer, taxanes have emerged as an important group of drugs, particularly when given in conjunction with platinum. Though the response rate for first line carboplatin and paclitaxel (PTX) is 70% to 80%, this approach still yields poor results and overall 5-year survival rate is less than 30%. Several studies have sought to improve survival by addition of a third agent (topotecan, gemcitabine, doxorubicin) without any survival advantage. Currently the 3rd International Gynecologic Cancer Intergroup Ovarian Cancer Consensus Conference (Baden-Baden, Germany, 2004) proposed carboplatin and PTX as standard of care and as the favored standard treatment protocol for comparison in clinical trials [3]. In ovarian cancer, the peritoneal cavity is the main site of disease diffusion and the administration of chemotherapy into the peritoneal cavity increases the drug’s dose delivered to the tumor site without compromising plasma drugs levels. Based on this idea, three studies [4, 5, 6] compared intravenous versus intraperitoneal (IP) administration of cisplatin (CDDP) and PTX and showed an increase of median survival in the IP treatment group. Based on these results, the US National Cancer Institute prompted a clinical announcement in 2006 stating that IP chemotherapy should be considered for optimally debulked patients. Despite the advantage of this approach, IP chemotherapy has not become routine practice because of major toxicity, lack of experience in placing and managing indwelling catheters, and the difficulty to diffuse the drugs in all peritoneal cavity due to adhesions and anatomic niches. In recent years, maximum cytoreductive effort combined with hyperthermic intraperitoneal chemotherapy (HIPEC) has been a promising treatment for non-ovarian carcinomatosis (e.g., carcinoma of the appendix, or colon). The procedure exploits the advantages of IP therapy and the synergistic enhancement of drug cytotoxicity induced by heat. Various protocols have been described using CDDP, doxorubicin, mitomycin C, oxaliplatin, interferon α, and mitoxantrone [7]. These drugs have been chosen because of their favorable IP pharmacokinetics and their high local efficacy. Taxane have already been tested only as single drugs in HIPEC procedures [8, 9]. Our group studied the pharmacokinetics of a combination of CDDP and PTX during HIPEC after CRS in 10 patients in a previous feasibility study approved by the ethics committee (of the Papa Giovanni XXIII Hospital): the data showed that HIPEC with concomitant CDDP and PTX following CRS is associated with a highly favorable pharmacokinetic profile, despite its short treatment duration. Based on these encouraging results we decided to test the CDDP and PTX association as HIPEC drugs in advanced ovarian cancer in a larger series. The primary aim of this study was to analyze the morbidity of HIPEC using a CDDP and PTX after CRS in patients with peritoneal carcinomatosis for EOC; secondary aims were overall survival (OS) and disease-free survival (DFS). 1. Population This is an open-label, prospective, phase II study performed at the Unit of General, Emergency and Transplant Surgery at Sant’Orsola-Malpighi Hospital, University of Bologna, Italy, the Unit of General Surgery and Gynaecologic Surgery of Papa Giovanni XXIII Hospital, Bergamo and the Unit of Gynaecology of the Jena University Hospital, Germany. Patients with primary, advanced (FIGO stage IIIC to IV), or recurrent EOC were eligible for the present study to be treated with CRS+HIPEC with CDDP (100 mg/m2) and PTX (175 mg/m2). The study was approved by local Ethical Committee. Inclusion criteria: age younger than 75, Eastern Cooperative Oncology Group performance status 0 to 2 [10], resectable disease evaluated by computed tomography (CT) scan and/or positron emission tomography (PET) and diagnostic laparoscopy to identify the possibility to achieve optimal cytoreduction with residual disease less than 1 cm, no significant co-morbidities precluding the combined treatments (CRS and HIPEC), informed written consent. Exclusion criteria: other malignant pathologies, extra-abdominal metastasis, complete intestinal obstruction, active infections. The treatment plan was to perform the maximum surgical effort, aimed to remove all visible disease using peritonectomy procedures and multiorgan resection depending on the abdominal disease involvement. If residual disease <1 cm was achieved, the patients were submitted to HIPEC. Patients with residual disease larger than 1 cm were excluded from the study.
CRS and HIPEC were performed at one of the following five different timings: T1 at the time of primary treatment if optimal cytoreduction was achieved, T2 at the time of interval debulking, T3 as a consolidation therapy following complete pathological response after initial therapy as confirmed by a second-look laparotomy, T4 at the time of first recurrence, and T5 as salvage therapy [11]. 2. Study parameters Histological type and grade were assessed according to the World Health Organization classification, and surgical stage according to the FIGO criteria [12]. Patients with recurring disease were classified according to their platinum free interval as platinum sensitive (≥6 months) or insensitive (<6 months). During the laparotomy, the extension of peritoneal carcinomatosis was recorded according to peritoneal cancer index (PCI) [13]. The number of peritonectomy procedures according to the affected anatomical area (right and left subphrenic, Glisson's capsule, right and left paracolic gutters, lesser omentectomy, pelvic) was assessed in every patient (0, no peritonectomy; 7, all peritonectomies). Completeness of cytoreduction was assessed by measuring the size of the residual peritoneal implants following surgery and assigning a complete cytoreduction (CC) score: CC0, no residual disease; CC1, residual nodules measuring less than 2.5 mm; CC2, residual nodules measuring between 2.5 mm and 2.5 cm; or CC3, residual nodules greater than 2.5 cm [14]. 3. Hyperthermic intraperitoneal chemotherapy Following surgery HIPEC was performed in patients with CC0 and CC1 as an open procedure with the Coliseum technique or as a closed technique [15] using CDDP (100 mg/m2) and PTX (175 mg/m2). IP chemotherapy was performed for 60 or 90 minutes, with a peritoneal and outflow thermal plateau of 41.5℃. Perfusate (4 to 6 L) was circulated using an extracorporeal circulation device at a flow rate of 700 mL/minute with an intra-abdominal target temperature of 42.5℃. The surgical procedure length was calculated from the induction of anesthesia to the closure of the abdominal wall. 4. Postoperative outcomes and follow-up During the immediate postoperative period, patients were assisted in an intensive care unit. To analyze postoperative morbidity, all surgical and nonsurgical complications that occurred within 30 days from the procedure were considered and all complications were classified according to the Common Terminology Criteria for Adverse Events (CTCAE) scale ver. 3.0 (August 9, 2006) [16]. After hospital discharge, patients were referred to the medical oncologic staff to plan systemic chemotherapy and were followed after chemotherapy with clinical examination and serum levels of CA-125 every 4 months for the first 2 years and every 6 months for 3 years. Every further evaluation (CT/PET) was indicated depending on the patients' clinical presentation and the increase of CA-125 levels. Recurrence and progression of disease were evaluated using the RECIST criteria [17]. The time and type of recurrence, the nature of treatment and date of death were recorded. The median follow-up was calculated from the date of HIPEC to the date of last visit or date of death. 5. Statistical analysis Patient data, including epidemiological, surgical, pathological, and survival figures, were compiled into a database (IBM SPSS ver. 20, IBM Co., Armonk, NY, USA). Survival rates were calculated using the Kaplan-Meier method, and were compared using the log-rank test (p<0.05 was considered statistically significant). Associations were calculated with the chi-square; correlations were analyzed with the binomial logistic regression method and Cox regression model, p<0.05 was considered statistically significant. Fifty-four patients were included between April 2007 and October 2013: 29 at Unit of General, Emergency and Transplant Surgery of St. Orsola-Malpighi Hospital, University of Bologna; 23 at Unit of General Surgery I of Papa Giovanni XXIII Hospital, Bergamo; and 2 at the Unit of Gynaecology of the Jena University Hospital. HIPEC was performed at T1 in one patient (1.9%), at T2 in 29 patients (56.7%), at T4 in 14 patients (25.9%), and at T5 in 10 patients (18.5%). Population and tumor characteristics are shown in Table 1. At laparotomy the mean PCI was 10.11 (range, 0 to 28), in 38 cases (70.4%) the PCI was ≤15 and in 16 cases (29.6%) the PCI was >15. CC0 was achieved for 47 patients (87%), CC1 for seven patients (13%), we did not record CC2 and CC3 patients, since suboptimal cytoreducted patients were not candidates for this study. HIPEC was performed as an open procedure with the Coliseum technique in 42 cases (77.8%) and closed technique in 12 (22.2%); the mean time of IP chemotherapy was 89.4±4.4 minutes and the peritoneal and outflow mean temperature was 41.5℃ (range, 40℃ to 42℃); the mean operation time was 8.85±1.68