Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus Immediate Surgery for High-Risk Stage II and III Colon Cancers: A Phase II Multicenter Randomized Controlled Trial (PRODIGE 22).

BACKGROUND: Perioperative chemotherapy has proven valuable in several tumors, but not in colon cancer (CC). OBJECTIVE: The aim of this study was to evaluate the efficacy and safety of perioperative chemotherapy in patients with locally advanced nonmetastatic CC. METHODS: This is a French multicenter randomized phase II trial in patients with resectable high-risk T3, T4, and/or N2 CC on baseline computed tomography (CT) scan. Patients were randomized to receive either 6 months of adjuvant FOLFOX after colectomy (control) or perioperative FOLFOX for 4 cycles before surgery and 8 cycles after (FOLFOX peri-op). In RAS wild-type patients, a third arm testing perioperative FOLFOX-cetuximab was added. Tumor Regression Grade (TRG1) of Ryan et al was the primary endpoint. Secondary endpoints were toxicity, perioperative morbidity, and quality of surgery. RESULTS: A total of 120 patients were enrolled. At interim analysis, the FOLFOX-cetuximab arm was stopped (lack of efficacy). The remaining 104 patients (control, n = 52; FOLFOX preop n = 52) represented our intention-to-treat population. In the FOLFOX perioperative group, 96% received the scheduled 4 cycles before surgery. R0 resection and complete mesocolic excision rate were 94% and 93%, respectively. Overall mortality and morbidity rates were similar in both groups. Perioperative FOLFOX chemotherapy did not improve major pathological response rate (TRG1 = 8%) but was associated with a significant pathological regression (TRG1-2 = 44% vs 8%, P < 0.001) and a trend to tumor downstaging as compared to the control group. CT scan criteria were associated with a 33% rate of overstaging in control group. CONCLUSIONS: Perioperative FOLFOX for locally advanced resectable CC is feasible with an acceptable tolerability but is not associated with an increased major pathological response rate as expected. However, perioperative FOLFOX induces pathological regression and downstaging. Better preoperative staging tools are needed to decrease the risk of overtreating patients.

Randomized phase III trial in elderly patients comparing LV5FU2 with or without irinotecan for first-line treatment of metastatic colorectal cancer (FFCD 2001-02).

BACKGROUND: Metastatic colorectal cancer (mCRC) frequently occurs in elderly patients. However, data from a geriatric tailored randomized trial about tolerance to and the efficacy of doublet chemotherapy (CT) with irinotecan in the elderly are lacking. The benefit of first-line CT intensification remains an issue in elderly patients. PATIENTS AND METHODS: Elderly patients (75+) with previously untreated mCRC were randomly assigned in a 2 × 2 factorial design (four arms) to receive 5-FU (5-fluorouracil)-based CT, either alone (FU: LV5FU2 or simplified LV5FU2) or in combination with irinotecan [IRI: LV5FU2-irinotecan or simplified LV5FU2-irinotecan (FOLFIRI)]. The CLASSIC arm was defined as LV5FU2 or LV5FU2-irinotecan and the SIMPLIFIED arm as simplified LV5FU2 or FOLFIRI. The primary end point was progression-free survival (PFS). Secondary end points were overall survival (OS), safety and objective response rate (ORR). RESULTS: From June 2003 to May 2010, 71 patients were randomly assigned to LV5FU2, 71 to simplified LV5FU2, 70 to LV5FU2-irinotecan and 70 to FOLFIRI. The median age was 80 years (range 75-92 years). No significant difference was observed for the median PFS: FU 5.2 months versus IRI 7.3 months, hazard ratio (HR) = 0.84 (0.66-1.07), P = 0.15 and CLASSIC 6.5 months versus SIMPLIFIED 6.0 months, HR = 0.85 (0.67-1.09), P = 0.19. The ORR was superior in IRI (P = 0.0003): FU 21.1% versus IRI 41.7% and in CLASSIC (P = 0.04): CLASSIC 37.1% versus SIMPLIFIED 25.6%. Median OS was 14.2 months in FU versus 13.3 months in IRI, HR = 0.96 (0.75-1.24) and 15.2 months in CLASSIC versus 11.4 months in SIMPLIFIED, HR = 0.71 (0.55-0.92). More patients presented grade 3-4 toxicities in IRI (52.2% versus 76.3%). CONCLUSION: In this elderly population, adding irinotecan to an infusional 5-FU-based CT did not significantly increase either PFS or OS. Classic LV5FU2 was associated with an improved OS compared with simplified LV5FU2. CLINICALTRIALSGOV: NCT00303771.

FOLFOX4 versus sequential dose-dense FOLFOX7 followed by FOLFIRI in patients with resectable metastatic colorectal cancer (MIROX): a pragmatic approach to chemotherapy timing with perioperative or postoperative chemotherapy from an open-label, randomized phase III trial.

BACKGROUND: Perioperative FOLFOX4 (oxaliplatin plus 5-fluorouracil/leucovorin) chemotherapy is the current standard in patients with resectable metastases from colorectal cancer (CRC). We aimed to determine whether a sequential chemotherapy with dose-dense oxaliplatin (FOLFOX7) and irinotecan (FOLFIRI; irinotecan plus 5-fluorouracil/leucovorin) is superior to FOLFOX4. The chemotherapy timing was not imposed, and was perioperative or postoperative. PATIENTS AND METHODS: In this open-label, phase III trial, patients with resectable or resected metastases were randomly assigned either to 12 cycles of FOLFOX4 (oxaliplatin 85 mg/m(2)) or 6 cycles of FOLFOX7 (oxaliplatin 130 mg/m(2)) followed by 6 cycles of FOLFIRI (irinotecan 180 mg/m(2)). Randomization was done centrally, with stratification by chemotherapy timing, type of local treatment (surgery versus radiofrequency ablation with/without surgery), and Fong's prognostic score. The primary end point was 2-year disease-free survival (DFS). RESULTS: A total of 284 patients were randomized, 142 in each treatment group. Chemotherapy was perioperative in 168 (59.2%) patients and postoperative in 116 (40.8%) patients. Perioperative chemotherapy was preferentially proposed for synchronous metastases, whereas postoperative chemotherapy was more frequently used for metachronous metastases. Two-year DFS was 48.5% in the FOLFOX4 group and 50.0% in the FOLFOX7-FOLFIRI group. In the multivariable analysis, more than one metastasis [hazard ratio (HR) = 2.15] and synchronous metastases (HR = 1.63) were independent prognostic factors for shorter DFS. Five-year overall survival (OS) rate was 69.5% with FOLFOX4 versus 66.6% with FOLFOX7-FOLFIRI. CONCLUSIONS: FOLFOX7-FOLFIRI is not superior to FOLFOX4 in patients with resectable metastatic CRC. Five-year OS rates observed in both groups are the highest ever reported in this setting, possibly reflecting the pragmatic approach to chemotherapy timing. CLINICAL TRIALS NUMBER: NCT00268398.

Long-term follow-up after biliary stent placement for postcholecystectomy bile duct strictures: a multicenter study.

BACKGROUND AND STUDY AIMS: Endoscopic stenting is a recognized treatment of postcholecystectomy biliary strictures. Large multicenter reports of its long-term efficacy are lacking. Our aim was to analyze the long-term outcomes after stenting in this patient population, based on a large experience from several centers in France. METHODS: Members of the French Society of Digestive Endoscopy were asked to identify patients treated for a common bile duct postcholecystectomy stricture. Patients with successful stenting and follow-up after removal of stent(s) were subsequently included and analyzed. Main outcome measures were long-term success of endoscopic stenting and related predictors for recurrence (after one stenting period) or failure (at the end of follow-up). RESULTS: A total of 96 patients were eligible for inclusion. The mean number of stents inserted at the same time was 1.9±0.89 (range 1-4). Stent-related morbidity was 22.9% (n=22). The median duration of stenting was 12 months (range 2-96 months). After a mean follow-up of 6.4±3.8 years (range 0-20.3 years) the overall success rate was 66.7% (n=64) after one period of stenting and 82.3% (n=79) after additional treatments. The mean time to recurrence was 19.7±36.6 months. The most significant independent predictor of both recurrence and failure was a pathological cholangiography at the time of stent removal. CONCLUSION: Endoscopic stenting helps to avoid surgery in more than 80% of patients bearing postcholecystectomy common bile duct strictures. However, a persistent anomaly on cholangiography at the time of stent removal is a strong predictor of recurrence and may lead to consideration of surgery.

Thirteen-month registration of patients with gastroenteropancreatic endocrine tumours in France.

The prevalence, clinical profiles and management of gastroenteropancreatic endocrine tumours (GEP) in France are not known. From August 1, 2001 to September 1, 2002, standardized records on patients with GEP were prospectively completed in 87 participating centres. The total group amounted to 668 patients (median age: 56 years, range: 12-89). WHO performance status was 0/1 for 80.2% of patients. The primary sites were the small bowel and colon (288), pancreas (211), unknown (77), stomach (33), non-digestive primary sites (24), appendix (20), rectum-anus (12), and oesophagus or cardia (3). GEP were functional in 260 patients (39%). Most pancreatic tumours were non-functional (72%). Metastatic disease was observed in 73.4% of cases. Most tumours (85.8%) were well or moderately differentiated. Somatostatin receptor scintigraphy was performed in only 55% of patients. The following treatment modalities were employed: resection of primary tumour: 66%; systemic chemotherapy: 41%; somatostatin analogues: 44 and 26% for GEP of small intestine and pancreas, respectively; interferon: 12%, and intra-arterial hepatic (chemo)embolization in 23 and 15% of GEP arising from the midgut and pancreas, respectively. Despite their low prevalence, well-differentiated GEP represent a significant and heterogeneous clinical group, which warrants improved medical education, referral to expert centres at an early stage, and the design of prospective therapeutic trials.

Structural enhancement and video endoscopy: results of a large prospective comparative study.

INTRODUCTION: The structural-enhancement (SE) function electronically improves the video-endoscopic signal of Olympus processors (EXERA CV-160 or greater), enabling an increase in relief that may help in the detection of flat or ulcerated and raised lesions, especially those of small size. We assessed the diagnostic impact of this technique in the screening of lesions during basic video colonoscopy. METHODS: Maximum-level SE was programmed into processors on alternate weeks, and endoscopy dates were planned by an assistant unaware of the SE schedule, thus ensuring randomization. The endoscopists-senior practitioners with 3-29 years of digestive endoscopy practice-were informed of the experiment >3 weeks before it began and were not told about it again either before or during the study. This was to ensure that endoscopy examinations were performed without over-awareness of the technical conditions. GIF-100 to -160 Olympus endoscopes were used. RESULTS: During the study, 606 patients underwent upper digestive video-endoscopy, 305 with and 301 without the use of the SE function. Of 645 patients who underwent video colonoscopy, 593 were included in the study and 52 were excluded due to poor cleansing (8%); of those included, 330 were analyzed with and 263 without the SE function. We observed no differences in the detection of lesions (small or large) by either upper digestive endoscopy or video colonoscopy. CONCLUSION: This is the first study comparing video-endoscopy diagnosis with or without SE during upper digestive endoscopy and colonoscopy. The SE function available on Olympus video-endoscopy processors had no impact on the detection of lesions, not even on those of very small size.

The efficacy and safety of duodenal stenting: a prospective multicenter study.

BACKGROUND AND STUDY AIMS: Duodenal stenting has become a popular treatment in cases of malignant stenosis. However, a prospective evaluation of the efficacy and morbidity of this procedure has not been performed. A prospective multicenter study of duodenal stenting was conducted by the Société Française d'Endoscopie Digestive (SFED). PATIENTS AND METHODS: A total of 51 patients were selected (mean age 72), the majority (69%) having pancreatic adenocarcinoma. Palliative treatment was chosen because of irresectability (61.2%), inoperability (18.4%), or both (20.4 %). Enteral Wallstent prostheses were used, and the patients were followed up on day 3, after 1 month, and then every month, with weight measurement, and symptomatic and laboratory evaluation. RESULTS: One prosthesis was sufficient in 46 patients. Stent positioning and deployment were correct in 50/51 patients (98%). Twenty patients also underwent biliary stenting in addition to the duodenal stenting. On day 3, 43 patients (84%) were able to tolerate soft solids or a full diet. Six complications were attributed to stenting: three intestinal hemorrhages, two cases of peritonitis due to bowel perforation, and one case of septicemia, and these led to five deaths (mortality 9.8%). Stent dysfunction was observed in 12 cases (23.5%) after a mean delay of 75 days, comprising 11-malignant obstructions and one migration: a new stent was inserted inside the first one and was effective in eight cases; and no treatment was given in the other four patients because of their clinical state. The median survival was 71.5 days. CONCLUSIONS: Palliative endoscopic treatment of malignant duodenal stenosis using metallic prostheses is highly feasible, even with associated biliary stenting. Symptomatic improvement is fast. However, the mortality and the obstruction rate are high, suggesting that a prospective trial comparing this treatment with surgery is still required.

Poorly differentiated gastro-entero-pancreatic neuroendocrine carcinomas: Are they really heterogeneous? Insights from the FFCD-GTE national cohort.

BACKGROUND: Diagnosis and management of poorly differentiated gastro-entero-pancreatic (GEP) neuroendocrine carcinomas (NECs) remain challenging. Recent studies suggest prognostic heterogeneity. We designed within the French Group of Endocrine Tumours a prospective cohort to gain insight in the prognostic stratification and treatment of GEP-NEC. PATIENTS AND METHODS: All patients with a diagnosis of GEP-NEC between 1st January 2010 and 31st December 2013 could be included in this national cohort. Adenoneuroendocrine tumours were excluded. RESULTS: 253 patients from 49 centres were included. Median age was 66 years. Main primary locations were pancreas (21%), colorectal (27%), oesophagus-stomach (18%); primary location was unknown in 20%. Tumours were metastatic at diagnosis in 78% of cases. Performance status (PS) at diagnosis was 0-1 in 79% of patients. Among the 147 (58%) cases reviewed by an expert pathological network, 39% were classified as small cell NEC and 61% as large cell NEC. Median Ki67 index was 75% (range, 20-100). Median overall survival was 15.6 (13.6-17.0) months. Significant adverse prognostic factors in univariate analysis were PS > 1 (hazard ratio [HR] = 2.5), metastatic disease (HR = 1.6), NSE>2 upper limit of normal [ULN]; HR = 3.2), CgA>2 ULN (HR = 1.7) and lactate dehydrogenase >2 ULN (HR = 2.1). After first-line palliative chemotherapy (CT1) with platinum-etoposide (n = 152), objective response, progression-free survival and overall survival were 50%, 6.2 and 11.6 months; they were 24%, 2.9 and 5.9, respectively, after post-CT1 FOLFIRI regimen (n = 72). CONCLUSIONS: We report a large prospective series of GEP-NEC which show the predominance of large cell type and advanced stage at diagnosis. Prognosis was found more homogeneous than previously reported, mainly impacted by PS and tumour burden.

[Radiation protection of operators during endoscopic retrograde cholangiopancreatography]. / Radioprotection des opérateurs lors des cholangio-pancréatographies rétrogrades endoscopiques.

Radiation hazards to operators performing retrograde endoscopic cholangio-pancreatographies (RECP) have been investigated. The principles and central elements of French medical radioprotection legislation are recalled. Doses received by the operators, over a one month period representative of their usual work, were measured in two ways: by using a ionisation chamber and with thermoluminescent detectors worn by the staff. Extrapolated to 12 months, the results were inferior to the annual reglementary dose limit: whole body < 1.2 mSv (against 50 mSv), eye lens = 38.4 mSv (against 150 mSv). Further means for reducing dose levels are proposed.

[Lansoprazole versus ranitidine in the prevention of early recurrences of digestive hemorrhages from gastroduodenal ulcers. Randomized double-blind multicenter study]. / Lansoprazole versus ranitidine dans la prévention des récidives précoces des hémorragies digestives ulcéreuses gastro-duodénales. Etude multicentrique randomisée en double aveugle.

Strong inhibition of acid secretion could be able to decrease gastric and duodenal ulcer early rebleeding. OBJECTIVE--The aim of this double blind randomized trial was to compare early rebleeding rates of 2 groups of patients treated with ranitidine (600 mg/day) or lansoprazole (60 mg/day) per os for 6 consecutive days. METHODS--Seventy five patients with a high risk of rebleeding (clinical and endoscopical criteria) were included in this trial. These ulcers were Ia (n = 10), Ib (n = 20), IIa (n = 13), IIb (n = 32) in Forrest classification. RESULTS--Nineteen out of 75 patients rebled (25.3%): 11 out of 37 (30%) and 8 out of 38 (21%) in the ranitidine and lansoprazole groups respectively. Rates of rebleeding were 10%, 12.5%, 36% and 29% respectively in the ulcers grade Ia (previously treated with endoscopic sclerosis), Ib, IIa and IIb in the Forest classification. CONCLUSION--The rates of rebleeding were not statistically different in the 2 groups of treatment. The high rebleeding rates observed with Forrest IIa and IIb and duodenal ulcers support the need of haemostatic endoscopic therapy associated to antisecretory treatment in such patients.

[Acute thrombosis of the portal system. Treatment with alteplase and heparin or with heparin alone in 10 patients]. / Thrombose aiguë du système porte. Traitement par alteplase et héparine ou héparine seule chez 10 malades.

OBJECTIVES: We report the efficacy of alteplase (a recombinant tissue plasminogen activator) with heparin or heparin alone in the treatment of acute thrombosis of the portal venous system. METHODS: Ten consecutive patients with acute portal venous system thrombosis were studied. Five patients were treated with alteplase and heparin, and the remaining 5 patients, who were asymptomatic or had a contraindication to alteplase, were treated with heparin alone. RESULTS: In 3 of the 5 patients treated with alteplase, ultrasonography showed total resolution of the thrombus; the remaining 2 had partial resolution of the thrombus. In 4 of the 5 patients treated with heparin alone, ultrasonography showed total resolution of the thrombus, and no change in one. No bleeding occurred. CONCLUSION: Treatment with heparin can result in complete recanalisation of acute portal venous system thrombosis. These data suggest that combined therapy with systemic alteplase does not increase the efficacy of heparin.

[Obstructive intramural hematoma of the esophagus after sclerotherapy]. / Hématome intra-mural obstructif de l'oesophage post-sclérothérapie.

A case of obstructive intramural hematoma of the esophagus post variceal sclerotherapy is reported in a 44-year-old man who presented retrosternal pain and complete dysphagia. Endoscopy showed a bluish submucosal mass occupying the esophageal lumen. Diagnosis was confirmed by Computed Tomography. A favorable outcome was observed with symptomatic treatment.

[Severe mixed thrombopenia during interferon treatment for chronic viral hepatitis C]. / Thrombopénie mixte sévère au cours d'un traitement par interféron chez une femme atteinte d'une hépatite chronique virale C.

BACKGROUND: Thrombocytopenia occurred in a woman given alpha interferon for chronic hepatitis C without cirrhosis. Both central thrombocytopenia, clearly demonstrated, and peripheral thrombocytopenia, probably of autoimunne origin, were involved. CASE REPORT: A 55-year-old woman with active chronic hepatitis C (Metavir score A2, F2) was given alpha interferon. One month after treatment onset, she developed thrombocytopenia (32 G/L). A second bone marrow aspirate and osteomedullary biopsy evidenced megalokaryocytes and the platelet count responded to polyvalent immunoglobulins. Five months after discontinuing interferon, the platelet count progressively returned to normal. DISCUSSION: Central thrombocytopenia is classically described in patients given interferon and usually appears during the first weeks of treatment. In our case, the central mechanism was clearly demonstrated by the bone marrow aspirate and osteomedullary biopsy findings at a time when the platelet count was 32 G/L. A peripheral immunological participation was more difficult to prove but was strongly suggested by the persistence of thrombocytopenia despite the interruption of the interferon and the efficacy of immunoglobulins.

[Extra-hepatic manifestations of viral hepatitis]. / Manifestations extra-hépatiques des hépatites virales.

A variety of prodromal symptoms of viral hepatitis (urticaria, fever, arthralgias, headache, polyradiculonevritis) are attributed to A, B, C, D or E hepatitis only when jaundice appears, and because they disappear with it. Spectacular extrahepatic symptoms (polyarteritis nodosa, cryoglobulinemia, glomerulonephritis, marrow aplasia...) may be associated with B or C hepatitis without any liver symptom. Some of the extrahepatic symptoms observed during chronic hepatitis C therapy with interferon (thyroid dysfunctions, cutaneo-mucous lichen) may be related to the immunomodulatory effects of interferon rather than to virus C itself.