Chemotherapy for Well-Differentiated Pancreatic Neuroendocrine Tumours with a Ki-67 Index ≥10%: Is There a More Effective Antitumour Regimen? A Retrospective Multicentre Study of the French Group of Endocrine Tumours (GTE)

BACKGROUND: The best chemotherapy regimen for well- differentiated pancreatic neuroendocrine tumours (pNETs) with a Ki-67 index ≥10% is still debated. We evaluated the antitumour efficacy of various first-line chemotherapy regimens (streptozocin based, platinum based, or dacarbazine/temozolomide based) in this situation. METHODS: In this retrospective multicentre study of the French Group of Endocrine Tumours (GTE), we recruited consecutive patients with advanced well-differentiated pNETs and a Ki-67 index ≥10% receiving chemotherapy between 2000 and 2012. The primary endpoint was progression-free survival (PFS) according to RECIST. RESULTS: Seventy-four patients (42 men, median age 55.5 years) were enrolled from 10 centres. Fifty-one patients (69%) had grade 2 NET and 61 (82%) were stage IV. Median overall survival was 36.3 months. Forty-four patients (59%) received streptozocin-based, 18 (24%) platinum-based, and 12 (16%) dacarbazine/temozolomide-based chemotherapy regimens. These 3 groups were similar regarding age, functioning tumours, grade, the number of metastatic sites, and surgery for primary tumours, but not regarding surgery for metastases and time since diagnosis. Grade 3 NET (HR 2.15, 95% CI: 1.18-3.92, p = 0.012) and age above 55 years (HR 1.84, 95% CI: 1.06-3.18, p = 0.030) were associated with shorter median PFS in the multivariate analyses. Compared to streptozocin-based chemotherapy, no difference was found in terms of PFS for the platinum-based or for the dacarbazine/temozolomide-based chemotherapy regimen: median PFS was 7.2, 7.5, and 7.2 months, respectively (p = 0.51). CONCLUSIONS: Patients with intermediate or highly proliferative well-differentiated pNETs may benefit from 1 of the 3 chemotherapy regimens. Increased age and grade 3 were associated with shorter median PFS. Randomised studies searching for response predictors and the best efficacy-tolerance ratio are required to personalise the strategy

La limite Campanien-Maastrichtien dans le Limbourg belgo-néerlandais

The chalks of the Halembaye quarry and the Beutenaken pit have been investigated to define their macro-and micropalaeonto-logical content and especially to bring data on the vertical distribution of the main index fossils with regard to the Campanian-Maastrichtian boundary in the area of the type Maastrichtian. The Maastrichtian stage is here considered in its large sense, with its base defined by the first appearance of Belemnella lanceolata.Les craies de la carrière d'Halembaye et de l'affleurement de Beutenaken ont été soumises à une investigation macro-et micro-paléontologique en vue de disposer d'informations coordonnées sur l'extension des principaux fossiles marqueurs, ceci par rapport à la limite Campanien-Maastrichtien telle qu'elle se présente dans la région du Maastrichtien-type. L'étage Maastrichtien est considéré ici dans son sens large, c'est-à-dire avec sa base définie par la première apparition de Belemnella lanceolataFelder P. J., Foucher Jean-Claude, Legoux O., Manivit Hélène, Meessen J.M.P Th., Van Der Tuuk L.A, Robaszynski Francis, Bless Martinus Johannes Maria. La limite Campanien-Maastrichtien dans le Limbourg belgo-néerlandais. In: Géologie Méditerranéenne. Tome 10, numéro 3-4, 1983. Colloque sur les étages coniaciens à Maastrichtien. Marseille, 26-28 septembre 1983. pp. 59-72

Perioperative FOLFOX 4 Versus FOLFOX 4 Plus Cetuximab Versus Immediate Surgery for High-Risk Stage II and III Colon Cancers

International audiencePerioperative 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

Neoadjuvant FOLFOX 4 versus FOLFOX 4 plus cetuximab versus immediate surgery for high-risk stage II and III colon cancers: A phase II multicentre randomised controlled trial (PRODIGE 22)

IF 11.855International audienc

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

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

International audienceBACKGROUND: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