Tumor quantification of several fluoropyrimidines resistance gene expression with a unique quantitative RT-PCR method. Implications for pretherapeutic determination of tumor resistance phenotype.

International audiencePretherapeutic determination of tumor resistance to chemotherapy is a main challenge, hindered by the low number of mechanisms characterized at the same time, the small size of the clinical specimens and the heterogeneity of the techniques or the lack of true quantification. The aim of the present study was to determine in real time quantitative RT-PCR, tumor cell expression of several transcripts involved in cancer cell resistance with a unique cDNA sample from a tumor biopsy. The technique had to be suitable in clinical practice for determination of several factors involved in resistance to a given drug family, for example, fluoropyrimidines resistance factors: thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine kinase (TK), dihydrofolate reductase (DHFR), folylpolyglutamate synthetase (FPGS). A frame-shifted artificial construct was designed specifically to work within the same conditions. We validated our technique by quantifying expressions of these 5 genes starting from tissue samples of colorectal carcinoma and the surrounding normal mucosa of 33 different patients. That real time quantitative RT-PCR technique using the frame-shifted artificial construct as a standard provided a real comparison and quantification of different resistance factors. Tumor resistance phenotype determination based on that approach will be investigated in a control study

Detection of occult liver metastases in colorectal cancer by measurement of biliary carcinoembryonic antigen concentration: a prospective study.

BACKGROUND: It has been suggested that bile CEA levels could be a sensitive index for the detection of occult liver metastases (LM) in colorectal cancer (CRC) patients. The aim of this study was to determine the potential value of biliary CEA assay in the early detection of occult LM from CRC. METHODS: From 1995 to 1999 biliary and blood CEA levels were determined in three groups of patients undergoing surgery; Group 1 (n = 35) patients with LM from CRC; Group 2 (n = 154) patients with CRC without LM; Group 3 (n = 23) was the control group. RESULTS: Biliary and serum CEA levels were significantly lower in group 3 than in group 2 (P = 0.008 and P = 0.002) and in group 2 than in group 1 (P = 0.001 and P = 0.005). With a follow-up of 36 months (group 2), 22 patients (14%) developed LM. For 59 patients, the bile CEA level during laparotomy was less than 5 ng/ml and for 95 patients this level was more than 5 ng/ml, 4 and 18 patients respectively developed metachronous LM; we found a difference (P = 0.03) between these two subgroups. When this analysis was performed with regard to the stage of the tumor, we found no difference for the node negative cancer (n = 79) subgroup (P = 0.6), but we found a significant difference for the node positive cancer (n = 75) subgroup (P = 0.01). CONCLUSIONS: Our data suggest that biliary CEA concentrations at the time of resection of the primary tumor cannot be used to identify patients with occult LM in the node-negative CCR subgroup. However, patients with node-positive CCR and bile CEA level under 5 ng/ml developed LM in only 3% of cases; it might be therefore, possible to use that as a discriminant in situations where the risk of LM is small

Prevalence of and Risk Factors for Morbidity After Elective Left Colectomy Cancer vs Noncomplicated Diverticular Disease

Hypothesis: Independent risk factors for postoperative morbidity after colectomy are most likely linked to disease characteristics. Design: Retrospective analysis. Setting: Twenty-eight centers of the French Federation for Surgical Research. Patients: In total, 1721 patients (1230 with colon cancer [CC] and 491 with diverticular disease [DD]) from a databank of 7 prospective, multisite, randomized trials on colorectal resection. Intervention: Elective left colectomy via laparotomy. Main Outcome Measures: Preoperative and intraoperative risk factors for postoperative morbidity. Results: Overall postoperative morbidity was higher in CC than in DD (32.4% vs 30.3%) but the difference was not statistically significant (P=.40). Two independent risk factors for morbidity in CC were antecedent heart failure (odds ratio [OR], 3.00; 95% confidence interval [CI], 1.42-6.32) (P=.003) and bothersome intraluminal fecal matter (2.08; 1.42-3.06) (P=.001). Three independent risk factors for morbidity in DD were at least 10% weight loss (OR, 2.06; 95% CI, 1.25-3.40) (P=.004), body mass index (calculated as weight in kilograms divided by height in meters squared) exceeding 30 (2.05; 1.15-3.66) (P=.02), and left hemicolectomy (vs left segmental colectomy) (2.01; 1.19-3.40) (P=.009). Conclusions: Patients undergoing elective left colectomy for CC or for DD constitute 2 distinct populations with completely different risk factors for morbidity, which should be addressed differently. Improving colonic cleanliness (by antiseptic enema) may reduce morbidity in CC. In DD, morbidity may be reduced by appropriate preoperative nutritive support (by immunonutrition), even in patients with obesity, and by preference of left segmental colectomy over left hemicolectomy. By decreasing morbidity, mortality should be lowered as well, especially when reoperation becomes necessary

Cytoreductive Surgery and Hyperthermic Intraperitoneal Chemotherapy for First Relapse of Ovarian Cancer.

International audienceBACKGROUND:To assess impact of surgery and hyperthermic intraperitoneal chemotherapy (HIPEC) in patients treated for a first relapse of ovarian cancer (FROC).PATIENTS AND METHODS:Patients with a FROC treated with second-line chemotherapy, surgery and HIPEC were retrospectively included from 13 Institutions. Studied parameters were interval free between the end of initial treatment and the first relapse, second-line chemotherapy, peritoneal cancer index and completeness of surgery, HIPEC, mortality and morbidity, pathological results and survival.RESULTS:From 2001 to 2010, 314 patients were included. The main strategy was secondary chemotherapy followed by surgery and HIPEC (269/314-85.6%). Mortality and morbidity rates were respectively 1% and 30.9%. Median follow-up was 50 months, 5-year overall survival was 38.0%, with no difference between platinum-sensitive or -resistant patients and 5-year disease-free survival was 14%.CONCLUSION:HIPEC allows encouraging survival in the treatment of FROC, better in case of complete surgery, with acceptable mortality and morbidity rates

Second-look surgery plus hyperthermic intraperitoneal chemotherapy versus surveillance in patients at high risk of developing colorectal peritoneal metastases (PROPHYLOCHIP-PRODIGE 15): a randomised, phase 3 study

International audienceBackground Diagnosis and treatment of colorectal peritoneal metastases at an early stage, before the onset of signs, could improve patient survival. We aimed to compare the survival benefit of systematic second-look surgery plus hyperthermic intraperitoneal chemotherapy (HIPEC), with surveillance, in patients at high risk of developing colorectal peritoneal metastases. Methods We did an open-label, randomised, phase 3 study in 23 hospitals in France. Eligible patients were aged 18-70 years and had a primary colorectal cancer with synchronous and localised colorectal peritoneal metastases removed during tumour resection, resected ovarian metastases, or a perforated tumour. Patients were randomly assigned (1:1) to surveillance or second-look surgery plus oxaliplatin-HIPEC (oxaliplatin 460 mg/m(2), or oxaliplatin 300 mg/m(2) plus irinotecan 200 mg/m(2), plus intravenous fluorouracil 400 mg/m(2)), or mitomycin-HIPEC (mitomycin 35 mg/m(2)) alone in case of neuropathy, after 6 months of adjuvant systemic chemotherapy with no signs of disease recurrence. Randomisation was done via a web-based system, with stratification by treatment centre, nodal status, and risk factors for colorectal peritoneal metastases. Second-look surgery consisted of a complete exploration of the abdominal cavity via xyphopubic incision, and resection of all peritoneal implants if resectable. Surveillance after resection of colorectal cancer was done according to the French Guidelines. The primary outcome was 3-year disease free survival, defined as the time from randomisation to peritoneal or distant disease recurrence, or death from any cause, whichever occurred first, analysed by intention to treat. Surgical complications were assessed in the second look surgery group only. This study was registered at ClinicalTrials.gov, NCT01226394. Findings Between June 11, 2010, and March 31, 2015, 150 patients were recruited and randomly assigned to a treatment group (75 per group). After a median follow-up of 50.8 months (IQR 47.0-54.8), 3-year disease-free survival was 53% (95% CI 41-64) in the surveillance group versus 44% (33-56) in the second-look surgery group (hazard ratio 0.97, 95% CI 0.61-1.56). No treatment-related deaths were reported. 29 (41%) of 71 patients in the second-look surgery group had grade 3-4 complications. The most common grade 3-4 complications were intra-abdominal adverse events (haemorrhage, digestive leakage) in 12 (23%) of 71 patients and haematological adverse events in 13 (18%) of 71 patients. Interpretation Systematic second-look surgery plus oxaliplatin-HIPEC did not improve disease-free survival compared with standard surveillance. Currently, essential surveillance of patients at high risk of developing colorectal peritoneal metastases appears to be adequate and effective in terms of survival outcomes. Copryright (C) 2020 Elsevier Ltd. All rights reserved