Value of microsatellite instability typing in detecting hereditary non-polyposis colorectal cancer. A prospective multicentric study by the Association Aquitaine Gastro.

AIM OF THE STUDY: To detect hereditary non-polyposis colorectal cancer (HNPCC) patients with a strategy combining clinical selection (patient age at onset of cancer less than 50 years or family history of HNPCC tumors) and microsatellite instability typing plus immunohistochemistry, leading to mismatch repair (MMR) germline mutation analysis. METHODS: Tumors were screened for microsatellite instability (MSI) and for hmlh1 and hmsh2 immunohistochemical expression. Germline mutation analysis was performed to search for MLH1 and MSH2 mutations in patients with MSI-High and MSI-Low tumors. RESULTS: 197 adenocarcinomas were studied: 164 patients were< or =50 years old, 33 were older than 50 years but had a family history of HNPCC tumors. Fifty tumors (25.4%) were MSI-High, 10 were MSI-Low (5.1%), and 130 were MS-Stable (66%). MSI typing was inconclusive in 7 (3.5%). Immunohistochemistry screening was performed on 165 tumors: sensitivity was 63.6%, specificity was 99%. Germline mutation analysis was performed in 33/60 MSI-High or Low tumors: 23 mutations were noted (70% of the tested patients). CONCLUSION: This proposed strategy of determining microsatellite instability in young colorectal cancer patients or in patients with a family history of HNPCC tumors led to an increased frequency in the detection of MMR germline mutations.

FOLFIRI® and bevacizumab in first-line treatment for colorectal cancer patients: safety, efficacy and genetic polymorphisms.

BACKGROUND: Over 50% of colorectal cancer (CRC) patients develop metastases. The aim of this study was to evaluate efficacy and tolerance of first-line FOLFIRI® + bevacizumab (B) treatment for metastatic CRC, and to assess genetic polymorphisms as potential markers. METHODS: Adult patients with histologically-proven, non-resectable metastatic CRC and ECOG ≤ 2 were included. 14-day cycles consisted of bevacizumab (5 mg/kg), irinotecan (180 mg/m2), bolus FU (400 mg/m2) and leucovorin (400 mg/m2), followed by 46-hour FU infusions (2400 mg/m2). Primary endpoint was response rate according to RECIST criteria. Secondary endpoints were overall (OS) and progression-free (PFS) survivals, response duration, and toxicity. Associations between clinical data, UGT1A1, thymidylate synthase, VEGFA polymorphisms and PFS, OS and toxicity were analyzed. RESULTS: Sixty-two patients were enrolled (median age 68y). 59/62 patients were eligible and evaluable for response at 6 months: 28 showed partial response (47.5%; 95% CI; 34.3-60.9), 20 stable disease (33.9%) and 11 progression (18.6%). Grade 3/4 toxicities were as follows: neutropenia 16.1%; diarrhea 11.3%; nausea-vomiting 1.6%. Median response duration was 9.5 months (range 2.7-20); median PFS 10.3 months (range 8.8-11.7); and median OS 25.7 months (range 20.2-29.7). 11/59 initially unresectable patients were resectable after treatment. VEGFA polymorphism (rs25648) was associated with better OS (HR: 3.61; 95% CI: 1.57-8.30). CONCLUSIONS: FOLFIRI® + bevacizumab is active with good response rate, long median OS, and a good safety profile. A VEGFA polymorphism might have a prognostic value in this malignancy. TRIAL REGISTRATION: Clinicaltrials.gov: NCT00467142 (registration date: April 25, 2007).

One-stage laparoscopic colorectal resection after placement of self-expanding metallic stents for colorectal obstruction: a prospective study.

The aim of this study was to assess the clinical outcomes of self-expandable metallic stents placing followed by laparoscopic resection and primary anastomosis for the treatment of acute colonic obstruction. From January 2003 to December 2004, 14 patients diagnosed with acute and complete colonic obstruction were treated with endoscopic colonic stenting as a bridge to an elective 1-stage laparoscopic resection. Three patients who underwent a successful stent insertion but had an inoperable tumor were excluded from the analyzed data. Ninety-three percent technical and clinical success was achieved. The stent insertion related perforation rate was 7% (1/14). The mean duration of stent insertion was approximately 1 hour and the mean time between the stent insertion and surgery was 6.2 days. Mean operating time was 132 +/- 38 minutes. No cases required conversion to laparotomy and there were no intraoperative complications. One case of anastomotic leakage was observed and treated by laparoscopic drainage and protective ileostomy. Ambulation time after operation was 1.8 +/- 0.6 days and total hospital stay length was 16.4 +/- 5.0 days. During a period of 11 +/- 7 months of follow-up, neither recurrences nor port-site metastases were observed. The management of acute colonic obstruction using endoscopic stent decompression, followed by laparoscopic resection, had good results and can be considered feasible and safe. Larger comparative studies may help to establish this approach.