Cytoreductive surgery and HIPEC after neoadjuvant chemotherapy for advanced epithelial ovarian cancer

AIM: To reduce postoperative complications and to make possible an optimal cytoreduction, neoadjuvant chemotherapy(NACT) followed by interval debulking surgery has been applied with encouraging results. METHODS: Between December 2009 and February 2012, patients with stage ⅢC-Ⅳ epithelial ovarian cancer(EOC) underwent diagnostic laparoscopy, to assess the feasibility of optimal debulking surgery. The modifi ed Fagotti score was applied to assess the feasibility of resection with zero residual tumor. Patients who were not candidate for upfront debulking surgery were submitted to NACT, then reassessed according to the RECIST 1.1 criteria and submitted to cytoreductive surgery(CRS) and hyperthermic intraperitoneal chemotherapy(HIPEC) if they showed clinical response or stable disease. The remaining cycles of adjuvant systemic chemotherapy(ASCT) were administered postoperatively, to complete 6 cycles of systemic chemotherapy.RESULTS: Nine patients were included. Clinical response to NACT was complete in 3 patients and partial in 5 patients; one patient had stable disease. All patients underwent CRS resulting in CC0 disease prior to HIPEC. Average operative time was 510 min. Average intensive care unit stay was 2 d. Average postoperative hospital stay was 25 d. No postoperative mortality was observed. One patient experienced pelvic abscess. One patient refused ASCT. The remaining 8 patients started ASCT. Average time to chemotherapy was 36 d. All patients are alive, with an average follow up of 11 mo. Eight patients are disease-free at follow up.CONCLUSION: HIPEC after CRS for advanced EOC is feasible with acceptable morbidity and mortality. NACT may increase the chance for achieving complete cytoreduction. Phase 3 studies are needed to determine the effects of HIPEC on survival.

Criticalities in randomized controlled trials on HIPEC for ovarian cancer

Since the 1990 s, many oncological surgery groups around the world started to apply hyperthermic intraperitoneal chemotherapy(HIPEC) to the different peritoneal spread cancers. The rationale of the application of HIPEC after surgery is to complete the cytoreductive procedure. This combined treatment has now been successfully applied to many different intra-abdominal neoplasms. However, the treatment of peritoneal surface malignancies and the administration of HIPEC still lack high graded evidence data, especially in ovarian cancer. Experimental data exists about every step of the treatment of peritoneal spread ovarian cancer but unfortunately they have not yet been translated into phase Ⅲ clinical randomized trials. Moreover, treatment protocols differ between different centers. A systematic review of published randomized trial protocols was performed. HIPEC techniques are miscellaneous and not yet standardized. Well structured phase Ⅲ randomized trials among specialized centers are needed to investi-gate the effi cacy of this therapeutic approach, as well as technical details that may contribute to the standardization of the procedure and limit morbidity and mortality. In particular, new criteria are mandatory to uniformly stage the disease, to objectively evaluate the extension of cytoreduction and consequently the residual disease, to decide the best method of performing hyperthermia and to perfuse drugs. Moreover, pharmacokinetic and pharmacodynamic studies are urgently needed to assess the best type and dose of anticancer drugs.

Peritoneal carcinomatosis

Several gastrointestinal and gynecological malignancies have the potential to disseminate and grow in the peritoneal cavity.The occurrence of peritoneal carcinomatosis(PC)has been shown to significantly decrease overall survival in patients with liver and/or extraperitoneal metastases from gastrointestinal cancer.During the last three decades,the understanding of the biology and pathways of dissemination of tumors with intraperitoneal spread,and the understanding of the protective function of the peritoneal barrier against tumoral seeding,has prompted the concept that PC is a loco-regional disease:in absence of other systemic metastases,multimodal approaches combining aggressive cytoreductive surgery,intraperitoneal hyperthermic chemotherapy and systemic chemotherapy have been proposed and are actually considered promising methods to improve loco-regional control of the disease,and ultimately to increase survival.The aim of this review article is to present the evidence on treatment of PC in different tumors,in order to provide patients with a proper surgical and multidisciplinary treatment focused on optimal control of their locoregional disease.

Advanced ovarian cancer: Neoadjuvant chemotherapy plus surgery and HIPEC as up-front treatment

Epithelial ovarian cancer （EOC） is one of the most com-mon malignancies and one of the principal causes of death in gynecological neoplasms. The majority of EOC patients present with an advanced International Fed-eration of Gynecology and Obstetrics stage disease. The current standard treatment for these patients con-sists of complete cytoreduction and combined systemic chemotherapy of a platinum agent and paclitaxel. Even if the majority of patients with EOC respond to frst-line platinum based chemotherapy, almost 20% of them are resistant or refractory. According to these data, the main risk is for a certain number of patients to have undergone cytoreductive surgery （CRS） and subsequent hyperthermic intraoperative peritoneal chemotherapy （HIPEC） in a useful way. Radical surgery, especially in advanced cases, is associated with a high incidence of postoperative morbidity and mortality, which could be increased by the HIPEC. Every effort should be made for previously selected patients to improve outcome and optimize resources. Over the last decade, new options have been introduced to prolong survival. Im-proved long-term results can be achieved using CRS in combination with intraoperative HIPEC. This combina-tion has also been used in an up-front setting. Contro-versial outcomes have been reported for neoadjuvant platinum-based chemotherapy. Different papers have been published reporting discordant results. Further studies are needed.