François Noël Gilly

Peritoneal Colorectal Carcinomatosis Treated With Surgery and Perioperative Intraperitoneal Chemotherapy: Retrospective Analysis of 523 Patients From a Multicentric French Study

PURPOSE Peritoneal carcinomatosis (PC) from colorectal cancer traditionally is considered a terminal condition. Approaches that combine cytoreductive surgery (CRS) and perioperative intraperitoneal chemotherapy (PIC) have been developed recently. The purpose of this study was to assess early and long-term survival in patients treated with that strategy. PATIENTS AND METHODS A retrospective-cohort, multicentric study from French-speaking countries was performed. All consecutive patients with PC from colorectal cancer who were treated with CRS and PIC (with or without hyperthermia) were included. Patients with PC of appendiceal origin were excluded. Results The study included 523 patients from 23 centers in four French-speaking countries who underwent operation between 1990 and 2007. The median follow-up was 45 months. Mortality and grades 3 to 4 morbidity at 30 days were 3% and 31%, respectively. Overall median survival was 30.1 months. Five-year overall survival was 27%, and five-year disease-free survival was 10%. Complete CRS was performed in 84% of the patients, and median survival was 33 months. Positive independent prognostic factors identified in the multivariate analysis were complete CRS, PC that was limited in extent, no invaded lymph nodes, and the use of adjuvant chemotherapy. Neither the grade of disease nor the presence of liver metastases had a significant prognostic impact. CONCLUSION This combined treatment approach against PC achieved low postoperative morbidity and mortality, and it provided good long-term survival in patients with peritoneal scores lower than 20. These results should improve in the future, because the different teams involved will gain experience. This approach, when feasible, is now considered the gold standard in the French guidelines.

Early- and Long-Term Outcome Data of Patients With Pseudomyxoma Peritonei From Appendiceal Origin Treated by a Strategy of Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy

PURPOSE Pseudomyxoma peritonei (PMP) originating from an appendiceal mucinous neoplasm remains a biologically heterogeneous disease. The purpose of our study was to evaluate outcome and long-term survival after cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC) consolidated through an international registry study. PATIENTS AND METHODS A retrospective multi-institutional registry was established through collaborative efforts of participating units affiliated with the Peritoneal Surface Oncology Group International. RESULTS Two thousand two hundred ninety-eight patients from 16 specialized units underwent CRS for PMP. Treatment-related mortality was 2% and major operative complications occurred in 24% of patients. The median survival rate was 196 months (16.3 years) and the median progression-free survival rate was 98 months (8.2 years), with 10- and 15-year survival rates of 63% and 59%, respectively. Multivariate analysis identified prior chemotherapy treatment (P < .001), peritoneal mucinous carcinomatosis (PMCA) histopathologic subtype (P < .001), major postoperative complications (P = .008), high peritoneal cancer index (P = .013), debulking surgery (completeness of cytoreduction [CCR], 2 or 3; P < .001), and not using HIPEC (P = .030) as independent predictors for a poorer progression-free survival. Older age (P = .006), major postoperative complications (P < .001), debulking surgery (CCR 2 or 3; P < .001), prior chemotherapy treatment (P = .001), and PMCA histopathologic subtype (P < .001) were independent predictors of a poorer overall survival. CONCLUSION The combined modality strategy for PMP may be performed safely with acceptable morbidity and mortality in a specialized unit setting with 63% of patients surviving beyond 10 years. Minimizing nondefinitive operative and systemic chemotherapy treatments before definitive cytoreduction may facilitate the feasibility and improve the outcome of this therapy to achieve long-term survival. Optimal cytoreduction achieves the best outcomes.

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for Malignant Peritoneal Mesothelioma: Multi-Institutional Experience

PURPOSE This multi-institutional registry study evaluated cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) for diffuse malignant peritoneal mesothelioma (DMPM). PATIENTS AND METHODS A multi-institutional data registry that included 405 patients with DMPM treated by a uniform approach that used CRS and HIPEC was established. The primary end point was overall survival. The secondary end point was evaluation of prognostic variables for overall survival. RESULTS Follow-up was complete in 401 patients (99%). The median follow-up period for the patients who were alive was 33 months (range, 1 to 235 months). The mean age was 50 years (standard deviation [SD], 14 years). Three hundred eighteen patients (79%) had epithelial tumors. Twenty-five patients (6%) had positive lymph nodes. The mean peritoneal cancer index was 20. One hundred eighty-seven patients (46%) had complete or near-complete cytoreduction. Three hundred seventy-two patients (92%) received HIPEC. One hundred twenty-seven patients (31%) had grades 3 to 4 complications. Nine patients (2%) died perioperatively. The mean length of hospital stay was 22 days (SD, 15 days). The overall median survival was 53 months (1 to 235 months), and 3- and 5-year survival rates were 60% and 47%, respectively. Four prognostic factors were independently associated with improved survival in the multivariate analysis: epithelial subtype (P < .001), absence of lymph node metastasis (P < .001), completeness of cytoreduction scores of CC-0 or CC-1 (P < .001), and HIPEC (P = .002). CONCLUSION The data suggest that CRS combined with HIPEC achieved prolonged survival in selected patients with DMPM.

Peritoneal carcinomatosis from digestive tract cancer: new management by cytoreductive surgery and intraperitoneal chemohyperthermia

Peritoneal carcinomatosis is a common manifestation of digestive-tract cancer and has been regarded a terminal disease with a short median survival. Over the past decade, a new locoregional therapeutic approach combining cytoreductive surgery with intraperitoneal chemohyperthermia (IPCH) has evolved. Because of its limited benefits, high morbidity and mortality, and high cost, this comprehensive management plan requires accurate patient selection. Quantitative prognostic indicators are needed to assess a patients eligibility for combined treatment, including tumour histopathology, classification of carcinomatosis extent, assessment of completeness of cytoreduction, and determination of the extent of previous surgery. Patients with pseudomyxoma peritonei and those with peritoneal dissemination of digestive-tract cancer have shown promising survival. Complete cytoreduction with no visible disease persisting is a requirement for long-term benefit. In Japan and Korea, use of IPCH as prophylactic treatment in potentially curative gastric-cancer resection has shown improved survival and lower peritoneal recurrence rates. IPCH combined with cytoreductive surgery seems to be an effective therapeutic approach in carefully selected patients, and offers a chance for cure or palliation in this condition with few alternative treatment options.

Cytoreductive Surgery and Intraperitoneal Chemohyperthermia for Chemoresistant and Recurrent Advanced Epithelial Ovarian Cancer: Prospective Study of 81 Patients

PurposeThere is no standardized treatment for patients with chemoresistant or recurrent advanced ovarian cancer. Locoregional treatments combining cytoreductive surgery and intraperitoneal chemohyperthermia (HIPEC) may improve survival for locoregional disease.Patients and methodsA prospective single center study of 81 patients with recurrent or chemoresistant peritoneal carcinomatosis from ovarian cancer was performed. Patients were treated by maximal cytoreductive surgery combined with HIPEC (with cisplatinum at 20 mg/m²/L). A total of 47 patients were included for their third, fourth, fifth, sixth, or seventh surgical look. Altogether, 54 patients presented with extensive carcinomatosis (malignant nodules of >5 mm).ResultsComplete macroscopic resection (CCR-0) was achieved in 45 patients. Mortality and morbidity rates were 2.5% and 13.6%, respectively. With a median follow-up of 47.1 months, the overall and disease-free median survivals were 28.4 and 19.2 months, respectively. Carcinomatosis extent and completeness of cytoreduction (p = 0.02 and p <0.001, respectively) were identified as independent prognostic factors. For CCR-0 patients, overall and disease-free survivals were 54.9 and 26.9 months, respectively.ConclusionSalvage therapy combining optimal cytoreductive surgery and HIPEC may achieve long-term survival in selected patients with recurrent or chemoresistant ovarian cancer. This strategy may be most effective in patients with limited carcinomatosis or when cytoreductive surgery provides sufficient downstaging.

Cytoreductive Surgery With Intraperitoneal Chemohyperthermia for the Treatment of Pseudomyxoma Peritonei: A Prospective Study

PURPOSEPseudomyxoma peritonei is a rare disease. Recently, cytoreductive surgery with intraperitoneal hyperthermic chemotherapy has emerged as a promising treatment for this debilitating condition. The aim of this prospective study was to evaluate this treatment strategy.METHODTwenty-seven patients with pseudomyxoma peritonei who were treated by cytoreductive surgery and intraperitoneal chemohyperthermia between 1997 and 2003 were identified from a prospective database.RESULTSClinical presentation included suspected appendicitis (33 percent), increased abdominal girth (30 percent), and a suspected ovarian mass (26 percent). Twenty-two patients underwent surgery elsewhere before referral. Seventeen complications occurred in 12 patients (44 percent). Six were considered major: three anastomotic leaks, two pleural effusions, and one intra-abdominal abscess. Histologic examination demonstrated Grade 1, 2, and 3 disease in 8 (30 percent), 10 (37 percent), and 9 patients (33 percent), respectively. Pathologic grade showed a significant influence on the complication rate (P = 0 0.008). The actuarial five-year survival was 100 percent for patients with Grade 1 disease, whereas actuarial one-, two-, three-, and five-year survival for Grades 2 and 3 were 100, 80, 64, and 32 percent, respectively (P = 0.008).CONCLUSIONSCytoreductive surgery with intraperitoneal hyperthermic chemotherapy is a feasable treatment for pseudomyxoma peritonei. It is associated with acceptable morbidity when performed by an experienced surgical team. Histologic grade is the major determinant of survival.

A comparative study of complete cytoreductive surgery plus intraperitoneal chemotherapy to treat peritoneal dissemination from colon, rectum, small bowel, and nonpseudomyxoma appendix.

Objective:To report a large number of patients with peritoneal carcinomatosis (PC) treated with complete cytoreductive (CCR-0) plus intraperitoneal chemotherapy, and to compare the results according to the origin of the primary: colon, rectum, small bowel, and appendix (excluding peritoneal pseudomyxoma). Patients and Methods:Among 615 patients treated for PC originating from these 4 types of primaries in 23 French centers, 440 were retrospectively selected as having undergone complete cytoreductive surgery and with complete data retrieval. Primary sites were: colon (n = 341), rectum (n = 27), appendix (n = 41), and small bowel (n = 31). Results:Postoperative mortality and morbidity (3.9% and 31%, respectively) did not differ according to the origin of the primary tumor. The mean follow-up was 60 months. The 5-year overall survival rates were not statistically different for the colon (29.7%), rectum (37.9%), nor the small bowel (33.8%), but was higher (P = 0.01) for appendix adenocarcinoma (63.2%). The multivariate analysis of prognostic factors singled out the extent of peritoneal seeding (P < 0.0001), positive lymph nodes (P = 0.001), and adjuvant systemic chemotherapy (P = 0.002), whereas the origin of the tumor was borderline (P = 0.06) in favor of appendix tumors. Conclusion:Cytoreductive surgery plus intraperitoneal chemotherapy yields satisfying and similar survival results in the treatment of PC from colon, rectum, and small bowel adenocarcinomas. Results were better for appendix adenocarcinoma. When feasible, this combined approach should become the gold standard treatment of PC.

Progression Following Neoadjuvant Systemic Chemotherapy May Not Be a Contraindication to a Curative Approach for Colorectal Carcinomatosis

Objective: The objective of this retrospective study was to evaluate the influence of neoadjuvant systemic chemotherapy on patients with colorectal carcinomatosis before a curative procedure. Background: Peritoneal carcinomatosis (PC) from colorectal cancer may be treated with a curative intent by cytoreductive surgery (CRS) and hyperthermic intraperitoneal chemotherapy (HIPEC). The role of perioperative systemic chemotherapy for this particular metastatic disease remains unclear. Methods: One hundred twenty patients with PC from colorectal cancer were consecutively treated by 131 procedures combining CRS with HIPEC. The response to neoadjuvant systemic chemotherapy was assessed on data from previous explorative surgery and/or radiological imaging. Results: Ninety patients (75%) were treated with neoadjuvant systemic chemotherapy in whom 32 (36%) were considered to have responded, 19 (21%) had stable disease, and 19 (21%) developed diseases progression. Response could not be evaluated in 20 patients (22%). On univariate analysis, the use of neoadjuvant systemic chemotherapy had a significant positive prognostic influence (P = 0.042). On multivariate analysis, the completeness of CRS and the use of adjuvant systemic chemotherapy were the only significant prognostic factors (P < 0.001 and P = 0.049, respectively). Response to neoadjuvant systemic chemotherapy had no significant prognostic impact with median survival of 31.4 months in patients showing disease progression. Conclusions: In patients with PC from colorectal cancer without extraperitoneal metastases, failure of neoadjuvant systemic chemotherapy should not constitute an absolute contraindication to a curative procedure combining CRS and HIPEC.

Management of peritoneal carcinomatosis from colorectal cancer Current State of Practice

Peritoneal carcinomatosis is a common manifestation of colorectal cancer and has traditionally been regarded as a terminal disease with a short median survival. Over the 2 past decades, a new local-regional therapeutic approach combining cytoreductive surgery with intraperitoneal chemohyperthermia (hyperthermic intraperitoneal chemotherapy) has evolved. Because of its significant but acceptable morbidity and mortality and cost, careful patient selection is needed for this comprehensive management plan. Quantitative prognostic indicators are necessary as an assessment of a patient’s eligibility for combined treatment. In large phase II studies, international registries, and in one phase III study, this therapeutic strategy demonstrated promising survival results with possibility of cure. In all studies, complete cytoreduction with no visible disease remaining is a requirement for long-term benefit. Further collaboration between peritoneal surface malignancy treatment centers may help to standardize indications and techniques for hyperthermic intraperitoneal chemotherapy and peritonectomy. The development and validation of novel protocols and guidelines will allow surgeons and oncologists who discover colorectal carcinomatosis to treat these patients effectively.

Intraperitoneal Treatment With Dimethylthioampal (DIMATE) Combined With Surgical Debulking Is Effective for Experimental Peritoneal Carcinomatosis in a Rat Model

The goal was to evaluate the efficiency of intraperitoneal administration of dimethylthioampal (DIMATE), a cellular apoptosis inducer, combined, or not, with cytoreductive surgery on rats with peritoneal adenocarcinomatosis. Peritoneal carcinomatosis was induced in rats by intraperitoneal injection of adenocarcinoma cell line DHD/K12/pro B. Intraperitoneal DIMATE was given at 17.3 mg/kg. Rats were randomized into five groups of eight animals, regarding the day of treatment (2 days or 20 days after peritoneal carcinomatosis induction) and the combination with cytoreductive surgery. All rats were killed at 30 days to evaluate carcinomatosis extent (quantitative score) and ascites volume. The quantitative score of carcinomatosis and the ascites volume were significantly reduced in the groups treated with DIMATE at day 2 (P = 0.005 and P < 0.001, respectively) and when DIMATE was used with cytoreductive surgery at day 20 (P = 0.009 and P <0.001, respectively). Cytoreductive surgery or DIMATE used alone at day 20 had no significant infiuence. The intraperitoneal DIMATE administration at day 20, when not combined with surgery, had no significant infiuence on carcinomatosis extent or on ascites volume. Intraperitoneal DIMATE appeared to be an efficient drug in the prevention or treatment of peritoneal carcinomatosis when combined with cytoreductive surgery or when it was given by intraperitoneal route, before the development of macroscopic peritoneal carcinomatosis. It appears to be a promising therapeutic agent to be investigated in a human phase I trial in peritoneal carcinomatosis.