Gwenael Ferron

Complete Cytoreductive Surgery Plus Intraperitoneal Chemohyperthermia With Oxaliplatin for Peritoneal Carcinomatosis of Colorectal Origin

PURPOSE To compare the long-term survival of patients with isolated and resectable peritoneal carcinomatosis (PC) in comparable groups of patients treated with systemic chemotherapy containing oxaliplatin or irinotecan or by cytoreductive surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC). PATIENTS AND METHODS All patients with gross PC from colorectal adenocarcinoma who had undergone cytoreductive surgery plus HIPEC from 1998 to 2003 were evaluated. The standard group was constituted by selecting patients with colorectal PC treated with palliative chemotherapy during the same period, but who had not benefited from HIPEC because the technique was unavailable in the center at that time. RESULTS Forty-eight patients were retrospectively included in the standard group and were compared with 48 patients who had undergone HIPEC and were evaluated prospectively. All characteristics were comparable except age and tumor differentiation. There was no difference in systemic chemotherapy, with a mean of 2.3 lines per patient. Median follow-up was 95.7 months in the standard group versus 63 months in the HIPEC group. Two-year and 5-year overall survival rates were 81% and 51% for the HIPEC group, respectively, and 65% and 13% for the standard group, respectively. Median survival was 23.9 months in the standard group versus 62.7 months in the HIPEC group (P < .05, log-rank test). CONCLUSION Patients with isolated, resectable PC achieve a median survival of 24 months with modern chemotherapies, but only surgical cytoreduction plus HIPEC is able to prolong median survival to roughly 63 months, with a 5-year survival rate of 51%.

Peritoneal carcinomatosis treated with cytoreductive surgery and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) for advanced ovarian carcinoma: a French multicentre retrospective cohort study of 566 patients.

BACKGROUND Despite a high response rate to front-line therapy, prognosis of epithelial ovarian carcinoma (EOC) remains poor. Approaches that combine Cytoreductive Surgery (CRS) and Hyperthermic Intraperitoneal Chemotherapy (HIPEC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with this strategy. PATIENTS AND METHODS A retrospective cohort multicentric study from French centres was performed. All consecutive patients with advanced and recurrent EOC treated with CRS and HIPEC were included. RESULTS The study included 566 patients from 13 centres who underwent 607 procedures between 1991 and 2010. There were 92 patients with advanced EOC (first-line treatment), and 474 patients with recurrent EOC. A complete cytoreductive surgery was performed in 74.9% of patients. Mortality and grades 3 to 4 morbidity rates were 0.8% and 31.3%, respectively. The median overall survivals were 35.4 months and 45.7 months for advanced and recurrent EOC, respectively. There was no significant difference in overall survival between patients with chemosensitive and with chemoresistant recurrence. Peritoneal Cancer Index (PCI) that evaluated disease extent was the strongest independent prognostic factor for overall and disease-free survival in all groups. CONCLUSION For advanced and recurrent EOC, curative therapeutic approach combining optimal CRS and HIPEC should be considered as it may achieve long-term survival in patients with a severe prognosis disease, even in patients with chemoresistant disease. PCI should be used for patients selection.

Hyperthermic intra-peritoneal chemotherapy using Oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma. Results of a phase II prospective multicentre trial. CHIPOVAC study

INTRODUCTION The aim of the present study was to prospectively evaluate morbidity of intra-peritoneal hyperthermic chemotherapy (HIPEC) using Oxaliplatin as consolidation therapy for advanced epithelial ovarian carcinoma and, secondly, to study peritoneal recurrence. METHODS Between 2004 and 2007, 31 patients from 18 to 65 years with FIGO stage IIIC epithelial ovarian carcinoma were treated by surgery and a total of 6 cycles of platinum based chemotherapy. Those patients were eligible for consolidation therapy. We performed a second look laparotomy operation with intra-peritoneal hyperthermic chemotherapy. We used Oxaliplatin 460 mg/m(2) with 2 l/m(2) of dextrose in an open medial laparotomy for a total of 30 min at a temperature of 42-44 degrees C. RESULTS The grade 3 morbidity rate was 29% (95 CI: 14-45%). Nine patients experienced a total of 13 exploratory laparotomies for intra-abdominal bleeding after HIPEC. Two-year disease free and overall survival were 27% and 67% respectively. As a result of this high level of morbidity the trial was closed. CONCLUSION Using intra-peritoneal Oxaliplatin associated with hyperthermia as consolidation therapy for advanced ovarian cancer results in a high risk of grade 3 morbidities with only a small benefit on survival.

Maximal cytoreduction in patients with FIGO stage IIIC to stage IV ovarian, fallopian, and peritoneal cancer in day-to-day practice: a Retrospective French Multicentric Study

Objectives To evaluate the outcome of maximal cytoreductive surgery in patients with stage IIIC to stage IV ovarian, tubal, and peritoneal cancer regarding overall survival (OS) and disease-free survival (DFS). Materials and Methods Five hundred twenty-seven patients with stage IIIC (peritoneal) and stage IV (pleural) ovarian, fallopian tube, and peritoneal carcinoma underwent surgery between January 2003 and December 2007 in 7 gynecologic oncology centers in France. Patients undergoing primary and interval debulking surgery were included, whichever the number of chemotherapy cycles. The extent of disease, type of surgical procedure, and amount of residual disease were recorded. A multivariate analysis of the outcome was performed, taking into account the stage, grade, and timing of surgery. Results Median DFS was 17.9 months, but median OS was not reached at the time of analysis. Complete cytoreductive surgery, without evident residual tumor at the end of the procedure, was obtained in 71% of all patients (primary surgery, 33%). After neoadjuvant therapy, the rate of complete debulking surgery was higher (74%) compared to primary cytoreductive surgery (65%). Twenty-three percent of patients needed “ultra radical surgery” to achieve this goal. The most significant predictive factor for DFS and OS was complete cytoreductive surgery compared to any amount, even minimal (1–10 mm), of residual disease. In the group of patients with complete cytoreductive surgery, the patients undergoing surgery before chemotherapy showed better DFS than those having first chemotherapy. Conclusion The findings confirm that complete cytoreduction is the criterion standard of surgery in the management of advanced ovarian, peritoneal, and fallopian tube cancer, whatever the timing of surgery. With experienced teams, surgery was completed, without evident residual tumor in 71% of the cases.

Oxaliplatin-based hyperthermic intraperitoneal chemotherapy in primary or recurrent epithelial ovarian cancer: A pilot study of 31 patients.

The feasibility and safety of oxaliplatin‐based hyperthermic intraperitoneal chemotherapy (HIPEC) associated with cytoreductive surgery (CRS) was assessed in patients with peritoneal carcinomatosis resulting from primary advanced or relapsing epithelial ovarian cancer (EOC).

Multi-Center Evaluation of Post-Operative Morbidity and Mortality after Optimal Cytoreductive Surgery for Advanced Ovarian Cancer

Purpose While optimal cytoreduction is the standard of care for advanced ovarian cancer, the related post-operative morbidity has not been clearly documented outside pioneering centers. Indeed most of the studies are monocentric with inclusions over several years inducing heterogeneity in techniques and goals of surgery. We assessed the morbidity of optimal cytoreduction surgery for advanced ovarian cancer within a short inclusion period in 6 referral centers dedicated to achieve complete cytoreduction. Patients and Methods The 30 last optimal debulking surgeries of 6 cancer centers were included. Inclusion criteria included: stage IIIc- IV ovarian cancer and optimal surgery performed at the site of inclusion. All post-operative complications within 30 days of surgery were recorded and graded using the Memorial secondary events grading system. Student-t, Chi2 and non-parametric statistical tests were performed. Results 180 patients were included. There was no demographic differences between the centers. 63 patients underwent surgery including intestinal resections (58 recto-sigmoid resection), 24 diaphragmatic resections, 17 splenectomies. 61 patients presented complications; One patient died post-operatively. Major (grade 3–5) complications requiring subsequent surgeries occurred in 21 patients (11.5%). 76% of patients with a major complication had undergone an ultraradical surgery (P = 0.004). Conclusion While ultraradical surgery may result in complete resection of peritoneal disease in advanced ovarian cancer, the associated complication rate is not negligible. Patients should be carefully evaluated and the timing of their surgery optimized in order to avoid major complications.

Microparticles mediated cross-talk between tumoral and endothelial cells promote the constitution of a pro-metastatic vascular niche through Arf6 up regulation

The tumor stroma plays an essential role in tumor growth, resistance to therapy and occurrence of metastatic phenotype. Tumor vessels have been considered as passive conducts for nutrients but several studies have demonstrated secretion of pro-tumoral factors by endothelial cells. The failure of anti-angiogenic therapies to meet expectations raised by pre-clinical studies prompt us to better study the cross-talk between endothelial and cancer cells. Here, we hypothesized that tumor cells and the endothelium secrete bio-active microparticles (MPs) participating to a functional cross-talk. We characterized the cancer cells MPs, using breast and ovarian cancer cell lines (MCF7, MDA-MB231, SKOV3, OVCAR3 and a primary cell lines, APOCC). Our data show that MPs from mesenchymal-like cell lines (MDA-MB231, SKOV3 and APOCC) were able to promote an activation of endothelial cells through Akt phosphorylation, compared to MPs from epithelial-like cell lines (OVCAR3 and MCF7). The MPs from mesenchymal-like cells contained increased angiogenic molecules including PDGF, IL8 and angiogenin. The endothelial activation was associated to increased Arf6 expression and MPs secretion. Endothelial activation functionalized an MP dependent pro-tumoral vascular niche promoting cancer cells proliferation, invasiveness, stem cell phenotype and chemoresistance. MPs from cancer and endothelial cells displayed phenotypic heterogeneity, and participated to a functional cross-talk where endothelial activation by cancer MPs resulted in increased secretion of EC-MPs sustaining tumor cells. Such cross-talk may play a role in perfusion independent role of the endothelium.

Morbidity of diaphragmatic surgery for advanced ovarian cancer: Retrospective study of 148 cases

BACKGROUND Treatment of Advanced Ovarian Cancer (AOC) includes surgery with complete cytoreduction, one of the strongest prognostic factors. To achieve complete cytoreduction, diaphragmatic surgery is often required. There is currently a lack of information in the literature regarding the morbidity and impact of this type of surgery. The aim of this study is to report specific pulmonary morbidity and overall morbidity associated with diaphragmatic surgery in patients with AOC. MATERIALS AND METHODS We conducted a multicentric (6 centres), retrospective study that included 148 patients operated on between 2004 and 2008. Patient characteristics, surgical course and postoperative complications were collected. RESULTS The complete cytoreduction rate was 84%. The surgery was categorised by timing as initial, interval or recurrence surgery in 38%, 51% and 11% of patients, respectively. In 69% of patients, one or more postoperative complications occurred: pulmonary complication (42%), digestive fistula (7%) or lymphocyst (18%). The pulmonary complications were pleural effusion (37%), pulmonary embolism (5%), pneumothorax (4%) and pulmonary infection (2%). These complications required revision surgery, pleural evacuation, or lymphocyst evacuation in 13%, 14%, and 11% of the cases, respectively. Postoperative mortality was 3%. Risk factors for pulmonary complications were the addition of extensive upper surgery to the diaphragmatic surgery (p = 0.014) and the size of the diaphragmatic resection (p = 0.012). CONCLUSIONS Diaphragmatic surgery achieved complete removal of the tumour but resulted in pulmonary complications in addition to complications of radical surgery.

Modified posterior pelvic exenteration for ovarian cancer.

Introduction: A modified posterior pelvic exenteration (MPE) might be needed to reach an optimal tumoral reduction. The issue of this study is to relate a multicentric experience of this kind of resection. Materials: Three hundred five patients who needed an MPE were analyzed from 9 French cancer centers. One hundred sixty-eight MPEs were performed during initial surgery (55.1%), 69 during interval surgery (22.6%), 36 after chemotherapy (11.8%), and 32 for recurrences (10.5%). Results: Three hundred two colorectal anastomoses were realized with a protective stoma in 59 (19.5%) of cases and a stoma closure in 76.5% (51). The rate of functional anastomosis was 96% (290/302). Complications occurred in 26.9% (82/305) of the patients, with a fistula in 25 (8.2%). The reintervention rate was 8.8% (27/305). The median length of hospitalization was 15 days. The absence of a macroscopic residual disease was obtained in 58% (173/303) of cases. A residual disease that was 1 cm or smaller was observed in 73 cases (24%) and 2 cm or smaller observed in 36 (11.9%). Postoperative chemotherapy was started with a median time of 32 days. Postoperative death occurred in 1 patient (0.33%). The survival rates were 62.7% and 27.6% at 2 and 5 years, respectively. With a multivariate analysis, the 2 significant prognostic factors were residual disease and time of surgery (P < 0.0001). Conclusions: A rectal invasion should not be an obstacle to reach the aim to obtain a macroscopic minimal residual disease or, if possible, the absence of one. An MPE is useful in those cases to reach optimal cytoreduction, with comparable results whatever the patients age is. A temporary protective stoma should be considered only exceptionally.

Fertility-preserving surgical procedures, techniques

As a result of the trend toward late childbearing, fertility preservation has become a major issue in young women with gynaecological cancer. Fertility-sparing treatments have been successfully attempted in selected cases of cervical, endometrial and ovarian cancer, and gynaecologists should be familiar with fertility-preserving options in women with gynaecological malignancies. Options to preserve fertility include shielding to reduce radiation damage, fertility preservation when undergoing cytotoxic treatments, cryopreservation, assisted reproduction techniques, and fertility-sparing surgical procedures. Radical vaginal trachelectomy with laparoscopic lymphadenectomy is an oncologically safe, fertility-preserving procedure. It has been accepted worldwide as a surgical treatment of small early stage cervical cancers. Selected cases of early stage ovarian cancer can be treated by unilateral salpingo-ophorectomy and surgical staging. Hysteroscopic resection and progesterone treatment are used in young women who have endometrial cancer to maintain fertility and avoid surgical menopause. Appropriate patient selection, and careful oncologic, psychologic, reproductive and obstetric counselling, is mandatory.