Eddy Cotte

Intraperitoneal Chemohyperthermia Using a Closed Abdominal Procedure and Cytoreductive Surgery for the Treatment of Peritoneal Carcinomatosis: Morbidity and Mortality Analysis of 216 Consecutive Procedures

Background: Peritoneal carcinomatosis has been regarded as a lethal clinical entity. Recently, aggressive treatments combining intraperitoneal chemohyperthermia (IPCH) with cytoreductive surgery have resulted in long-term survival in selected patients. The aim of this trial was to analyze the mortality and morbidity of 216 consecutive treatments of peritoneal carcinomatosis by IPCH by using a closed abdominal procedure combined with cytoreductive surgery.Methods: Between February 1989 and August 2001, 207 patients who underwent 216 IPCH procedures using a closed abdominal procedure with mitomycin C, cisplatin, or both were prospectively studied.Results: The postoperative mortality and morbidity rates were 3.2% and 24.5%, respectively. The most frequent complications were digestive fistula (6.5%) and hematological toxicity (4.6%). Morbidity was statistically linked with the carcinomatosis stage (P = .016), the duration of surgery (P = .005), and the number of resections and peritonectomy procedures (P = .042). Duration of surgery and carcinomatosis stage were the most common predictors of morbidity.Conclusions: The frequency of complications after IPCH and cytoreductive surgery was mainly associated with the carcinomatosis stage and the extent of the surgical procedure. The IPCH closed abdominal procedure has shown an acceptable frequency of adverse events.

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.

Hyperthermic intraperitoneal chemotherapy: Nomenclature and modalities of perfusion

Following international consensus, HIPEC should be the acronym used in the scientific literature to refer to the hyperthermic intraperitoneal chemotherapy. Several modalities of perfusion are used to deliver HIPEC: open abdominal technique (Coliseum), closed abdominal technique, peritoneal cavity expander, semi‐opened abdominal technique. There is no sufficient evidence in literature confirming the superiority of one technique over the others in terms of outcome, morbidity and safety to the personnel of the operating theatre. Each option has its own operational advantages and disadvantages and future prospective studies must be conducted to establish which one is the best alternative. Today, the best technique is the one which is routinely used and improved into each specialized institution involved in the management of peritoneal surface malignancy. J. Surg. Oncol. 2008;98:242–246.

Effect of Interval (7 or 11 weeks) Between Neoadjuvant Radiochemotherapy and Surgery on Complete Pathologic Response in Rectal Cancer: A Multicenter, Randomized, Controlled Trial (GRECCAR-6)

Purpose A pathologic complete response (pCR; ypT0N0) of a rectal tumor after neoadjuvant radiochemotherapy (RCT) is associated with an excellent prognosis. Several retrospective studies have investigated the effect of increasing the delay after RCT. The aim of this study was to evaluate the effect of increasing the interval between the end of RCT and surgery on the pCR rate. Methods GRECCAR6 was a phase III, multicenter, randomized, open-label, parallel-group controlled trial. Patients with cT3/T4 or Tx N+ tumors of the mid or lower rectum who had received RCT (45 to 50 Gy with fluorouracil or capecitabine) were included. Patients were randomly included in the 7-week or the 11-week (11w) group. Primary end point was the pCR rate defined as a ypT0N0 specimen (NCT01648894). Results A total of 265 patients from 24 centers were enrolled between October 2012 and February 2015. The majority of the tumors were cT3 (82%). After RCT, surgery was not performed in nine patients (3.4%) because of the occurrence of distant metastasis (n = 5) or other reasons. Two patients underwent local resection of the tumor scar. A total of 47 (18.6%) specimens were classified as ypT0 (four had invaded lymph nodes [8.5%]). The primary end point (ypT0N0) was not different (7 weeks: 20 of 133, 15.0% v 11w: 23 of 132, 17.4%; P = .5983). Morbidity was significantly increased in the 11w group (44.5% v 32%; P = .0404) as a result of increased medical complications (32.8% v 19.2%; P = .0137). The 11w group had a worse quality of mesorectal resection (complete mesorectum [I] 78.7% v 90%; P = .0156). Conclusion Waiting 11 weeks after RCT did not increase the rate of pCR after surgical resection. A longer waiting period may be associated with higher morbidity and more difficult surgical resection.

Selection of patients and staging of peritoneal surface malignancies

Peritoneal carcinomatosis (PC) is a common evolution of cancer of the gastrointestinal tract, and has been traditionally regarded as a terminal disease with short median survival. During the last 20 years, thanks to its favourable oncologic results, a new loco-regional therapeutic approach, combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy (HIPEC), has an important development. Due to its significant, but acceptable, morbidity and mortality, and high cost, this comprehensive management plan requires knowledgeable patient selection. Quantitative prognostic indicators are required to assess a patients eligibility. Large multicenter studies have identified several prognostic factors, which can be used for a better selection of patients who would benefit from the combination of cytoreductive surgery with HIPEC. Indications for treatment of PC with cytoreduction and HIPEC are now validated for several diseases: peritoneal mesothelioma, pseudomyxoma peritonei, PC from the appendix, and colorectal cancer. Indications are still under discussion for gastric and ovarian carcinomatosis. Computed tomography is the best radiological for staging the disease. The extent of peritoneal carcinomatosis is, however, difficult to evaluate preoperatively, and precise evaluation is most often performed during surgical exploration. Cytoreductive surgery associated with HIPEC for the treatment of peritoneal carcinomatosis should be performed for young patients with limited and resectable carcinomatosis, in specialized institutions involved in the management of peritoneal surface malignancies.

Neopterin is a novel reliable fecal marker as accurate as calprotectin for predicting endoscopic disease activity in patients with inflammatory bowel diseases.

Background:Fecal biomarkers have emerged as an important tool for assessing and monitoring disease activity in patients with inflammatory bowel diseases (IBDs). We performed a prospective head-to-head comparison of the diagnostic accuracy of both fecal calprotectin (fCal) and neopterin (fNeo), and serum C-reactive protein in predicting endoscopic disease severity in patients with IBD. Methods:A total of 133 consecutive patients with IBD (78 Crohns disease [CD] and 55 ulcerative colitis [UC]) undergoing a colonoscopy provided fecal samples for the measurement of fCal and fNeo concentrations and a blood sample for the serum C-reactive protein measurement. Endoscopic disease activities were scored independently according to the Simple Endoscopic Score for CD in patients with CD and to the Rachmilewitz Index in patients with UC. The respective performances of the fecal markers with respect to endoscopic disease severity were assessed by computing correlations, sensitivities, specificities, and overall accuracies at adjusted cutoffs and also test operating characteristics. Results:The fCal and fNeo concentrations differed significantly in clinically and endoscopically active IBD when compared with those in patients with inactive disease. Both fCal and fNeo concentrations correlated closer with endoscopic scores in UC (r = 0.75 and r = 0.72, respectively; P < 0.0001 for both) than in CD (r = 0.53 and r = 0.47, respectively; P < 0.0001 for both). Using cutoffs of 250 &mgr;g/g for fCal and 200 pmol/g for fNeo, both fecal markers had similar overall accuracies to predict endoscopic activity in patients with CD (74%) and also a higher and similar accuracies (88% and 90%, respectively) in patients with UC, whereas accuracies of C-reactive protein were slightly lower in patients with CD and UC. Conclusions:The fNeo is a novel reliable surrogate biomarker with the potential to identify patients with IBD with active mucosal lesions and represents an alternative marker as accurate as fCal to predict and monitor the severity of mucosal damages in patients with IBD.

Levels of Fecal Calprotectin Are Associated With the Severity of Postoperative Endoscopic Recurrence in Asymptomatic Patients With Crohn’s Disease

Objectives:Fecal calprotectin (fCal) is widely used as marker of gut inflammation and is strongly associated with the severity of endoscopic lesions in Crohn’s disease (CD). We analyzed the relationships between levels of fCal and high-sensitivity C-reactive protein (hsCRP) and the presence and severity of postoperative endoscopic recurrence in asymptomatic CD patients (Harvey–Bradshaw index≤3).Methods:Blood and fecal samples were collected in consecutive asymptomatic CD patients (Harvey–Bradshaw index 0.85±0.19, mean±s.e.m.) who had undergone an ileocolonic resection. hsCRP and fCal were measured and a routine ileocolonoscopy was performed within 18 months (median 7 months) from resection, to detect endoscopic recurrence according to the Rutgeerts score.Results:Eighty-six patients were included in this prospective multicenter observational cohort. fCal concentrations differed significantly in patients with endoscopic recurrence when compared with those in endoscopic remission (mean±s.e.m.: 473±78 μg/g vs. 115±18 μg/g; P<0.0001). The area under the receiver operating characteristic (ROC) curve to discriminate between patients in endoscopic remission and recurrence was 0.86 for fCal and lower for hsCRP (0.70). The best cutoff point for fCal to distinguish between endoscopic remission and recurrence was 100 μg/g as determined by the ROC curve, and its sensitivity, specificity, positive and negative predictive values (NPVs), as well as overall accuracy were 95%, 54%, 69%, 93%, and 77%, respectively.Conclusion:Measurement of fCal concentrations is a promising and useful tool for monitoring asymptomatic CD patients after ileocolonic resection. Taking into account the high NPV of fCal, a threshold below 100 μg/g could avoid systematic ileocolonoscopies in 30% of patients from this population.

Identification and verification of heat shock protein 60 as a potential serum marker for colorectal cancer

Colorectal cancer (CRC) is a major public health issue worldwide, and novel tumor markers may contribute to its efficient management by helping in early detection, prognosis or surveillance of disease. The aim of our study was to identify new serum biomarkers for CRC, and we followed a phased biomarker discovery and validation process to obtain an accurate preliminary assessment of potential clinical utility. We compared colonic tumors and matched normal tissue from 15 CRC patients, using two‐dimensional difference gel electrophoresis (2D‐DIGE), and identified 17 proteins that had significant differential expression. These results were further confirmed by western blotting for heat shock protein (HSP) 60, glutathione‐S‐transferase Pi, α‐enolase, T‐complex protein 1 subunit β, and leukocyte elastase inhibitor, and by immunohistochemistry for HSP60. Using mAbs raised against HSP60, we developed a reliable (precision of 5–15%) and sensitive (0.3 ng·mL−1) immunoassay for the detection of HSP60 in serum. Elevated levels of HSP60 were found in serum from CRC patients in two independent cohorts; the receiver‐operating characteristic curve obtained in 112 patients with CRC and 90 healthy controls had an area under the curve (AUC) of 0.70, which was identical to the AUC of carcinoembryonic antigen. Combination of serum markers improved clinical performance: the AUC of a three‐marker logistic regression model combining HSP60, carcinoembryonic antigen and carbohydrate antigen 19‐9 reached 0.77. Serum HSP60 appeared to be more specific for late‐stage CRC; therefore, future studies should evaluate its utility for determining prognosis or monitoring therapy rather than early detection.

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.

Iterative procedures combining cytoreductive surgery with hyperthermic intraperitoneal chemotherapy for peritoneal recurrence: Postoperative and long-term results†

Cytoreductive surgery (CRS) combined with hyperthermic intraperitoneal chemotherapy (HIPEC) is the best treatment of several peritoneal surface malignancies. Isolated peritoneal recurrence may be treated by iterative procedures. The aim of this study was to evaluate immediate postoperative and long‐term results after iterative CRS‐HIPEC.