Côme Lepage

Epidemiology and Management of Liver Metastases From Colorectal Cancer

Objective/Background:Little is known about the epidemiology and the management of liver metastases from colorectal cancer at a population level. The aim of this population-based study was to report on the incidence, treatment, and prognosis of synchronous and metachronous liver metastases. Methods:Data were obtained from the population-based cancer registry of Burgundy (France). Results:The proportion of patients with synchronous liver metastases was 14.5%. Age-standardized incidence rates were 7.6 per 100,000 in males, 3.7 per 100,000 in females. The 5-year cumulative metachronous liver metastasis rate was 14.5%. It was 3.7% for TNM stage I tumors, 13.3% for stage II, and 30.4% for stage III (P < 0.001). The risk of liver metastasis was also associated to gross features. Resection for cure was performed in 6.3% of synchronous liver metastases and 16.9% of metachronous liver metastases. Age, presence of another site of recurrence, and period of diagnosis were independent factors associated with the performance of a resection for cure. The 1- and 5-year survival rates were 34.8% and 3.3% for synchronous liver metastases. Their corresponding rates were, respectively, 37.6% and 6.1% for metachronous liver metastases. Conclusion:Liver metastases from colorectal cancer remain a substantial problem. More effective treatments and mass screening represent promising approaches to decrease this problem.

Incidence and patterns of recurrence after resection for cure of colonic cancer in a well defined population.

The aim of this study was to determine the incidence and patterns of failure following potentially curative surgery of colonic cancer.

Incidence and management of malignant digestive endocrine tumours in a well defined French population

Background and aims: Little is known about the epidemiology of malignant digestive endocrine tumours. The aim of this study was to report on their incidence and management in a well defined population. Methods: Data were obtained from the population based Digestive Cancer Registry of Burgundy (France) over a 24 year period. Incidence rates were calculated by sex, age groups, and period of diagnosis. Treatment and stage at diagnosis were also investigated. Prognosis was determined using crude and relative survival rates. A multivariate relative survival analysis was performed. Results: Between 1976 and 1999, 229 cases were recorded. Age standardised incidence rates were 0.76/100 000 for men and 0.50/100 000 for women. They increased over time in both sexes. The resectability rate was 74.1%. Among recorded cases, 26.6% did not extend beyond the organ, 20% had lymph node metastases, and 53.3% had visceral metastases or were unresectable. There was no improvement in the resection rate or in the stage at diagnosis over the study period. The overall relative survival rate was 66.9% at one year, 50.4% at five years, and 40.6% at 10 years. Stage at diagnosis, age at diagnosis, and subsite were independent significant prognostic factors. Conclusions: Although their incidence is increasing, malignant digestive endocrine tumours remain a rare cancer, representing 1% of digestive cancers. Stage at diagnosis and prognosis at a population level are worse than those reported in hospital series. In the short term, new therapeutic possibilities represent the best way to improve their prognosis.

Oxaliplatin, fluorouracil, and leucovorin with or without cetuximab in patients with resected stage III colon cancer (PETACC-8): an open-label, randomised phase 3 trial

BACKGROUND Since the 1990s, fluorouracil-based adjuvant chemotherapy has significantly reduced the risk of tumour recurrence in patients with stage III colon cancer. We aimed to assess whether the addition of cetuximab to standard adjuvant oxaliplatin, fluorouracil, and leucovorin chemotherapy (FOLFOX4) in patients with stage III colon cancer improved disease-free survival (DFS). METHODS For this open-label, randomised phase 3 study done in nine European countries, we enrolled patients through an interactive voice response system to the central randomisation centre, with a central stratified permuted block randomisation procedure. We randomly assigned patients with resected (R0) stage III disease (1:1) to receive 12 cycles of FOLFOX4 twice a week with or without cetuximab. Patients were stratified by N-status (N1 vs N2), T-status (T1-3 vs T4), and obstruction or perforation status (no obstruction and no perforation vs obstruction or perforation or both). A protocol amendment (applied in June, 2008, after 2096 patients had been randomly assigned to treatment-restricted enrolment to patients with tumours wild-type at codons 12 and 13 in exon 2 of the KRAS gene (KRAS exon 2 wild-type). The primary endpoint was DFS. Analysis was intention to treat in all patients with KRAS exon 2 wild-type tumours. The study is registered at EudraCT, number 2005-003463-23. FINDINGS Between Dec 22, 2005, and Nov 5, 2009, 2559 patients from 340 sites in Europe were randomly assigned. Of these patients, 1602 had KRAS exon 2 wild-type tumours (intention-to-treat population), 791 in the FOLFOX4 plus cetuximab group and 811 in the FOLFOX4 group. Median follow-up was 3·3 years (IQR 3·2-3·4). In the experimental and control groups, DFS was similar in the intention-to-treat population (hazard ratio [HR] 1·05; 95% CI 0·85-1·29; p=0·66), and in patients with KRAS exon 2/BRAF wild-type (n=984, HR 0·99; 95% CI 0·76-1·28) or KRAS exon 2-mutated tumours (n=742, HR 1·06; 95% CI 0·82-1·37). We noted heterogeneous responses to the addition of cetuximab in preplanned subgroup analyses. Grade 3 or 4 acne-like rash (in 209 of 785 patients [27%] vs four of 805 [<1%]), diarrhoea (113 [14%] vs 70 [9%]), mucositis (63 [8%] vs 10 [1%]), and infusion-related reactions (55 [7%] vs 30 [4%]) were more frequent in patients treated with FOLFOX4 plus cetuximab than in those patients who received FOLFOX4 alone. INTERPRETATION The addition of cetuximab to FOLFOX4 did not improve DFS compared with FOLFOX4 alone in patients with KRAS exon 2 wild-type resected stage III colon cancer. This trial cannot conclude on the benefit of cetuximab in the studied population, but the heterogeneity of response suggests that further investigation of the role of FOLFOX4 plus cetuximab in specific patient subgroups is warranted. FUNDING Fédération Francophone de Cancérologie Digestive (FFCD), Merck KGaA, and Sanofi-Aventis.

Incidence and Management of Primary Malignant Small Bowel Cancers: A Well-defined French Population Study

BACKGROUND AND AIM:Few data are available from population-based statistics on small bowel cancers. The aim of this study was to report on their incidence and management.METHODS:Data were obtained from the population-based Digestive Cancer Registry of Burgundy over a 26-yr period. Incidence rates were calculated by gender, age group, histological type, and 5-yr period. Treatment and stage at diagnosis were investigated. Prognosis was determined using crude and relative survival rates. A multivariate relative survival analysis was performed.RESULTS:Age-standardized incidence rates were 1.2/100,000 inhabitants for men and 0.8/100,000 inhabitants for women. The mean 5-yr variation in incidence were, respectively, +46.7% (P < 0.01) and + 53.2% (P < 0.05). There were four main histological types: adenocarcinoma (40.4%), malignant endocrine tumors (30.5%), lymphoma (20.1%), and sarcoma (9.0%). Resection for cure was performed in 56.6% of the cases. Cancer was not extending beyond the organ in 33.2% of the cases, was associated with lymph node metastasis in 32.1%, and with distant metastasis or unresectability in 34.7%. The 5-yr relative survival rate was 37.4%. It varied between 56.8% for endocrine tumors and 17.8% for sarcoma. In the multivariate analysis, age, histology, and stage at diagnosis significantly influenced the prognosis.CONCLUSIONS:Small bowel cancers represent a heterogeneous group of rare tumors. Prognosis at a population level is worse than in hospital series. In the short term, new therapeutic possibilities represent the best way to improve prognosis.

Transcatheter Arterial Embolization of Splenic Artery Aneurysms and Pseudoaneurysms: Short- and Long-Term Results

We evaluated outcomes of endovascular treatment of splenic artery aneurysms and pseudoaneurysms. From April 2002 to May 2007, 17 patients (mean age 55.2 years, range 17-82) with splenic artery aneurysms (n = 7) or pseudoaneurysms (n = 10) underwent endovascular treatment. Six patients were asymptomatic, three had symptomatic nonruptured aneurysms, and eight had ruptured aneurysms. Lesions were in the proximal splenic artery (n = 5), intermediate splenic artery (n = 3), splenic hilum (n = 6), or parenchyma (n = 3). Embolization was with microcoils by sac packing (n = 8), sandwich occlusion of the main splenic artery (n = 4), or cyanoacrylate glue into the feeding artery (n = 4). Computed angiotomography was done within the first month and magnetic resonance angiography after 6 and 12 months, then yearly. Mean follow-up was 29 months (range 1-62). Exclusion of the aneurysm was achieved in 16 (94.1%) patients. One patient with an intraparenchymal pseudoaneurysm underwent splenectomy after failed distal catheterization. No major complications occurred. Postembolization syndrome developed in four patients, who had radiographic evidence of splenic microinfarcts. Transcatheter embolization of splenic artery aneurysms/pseudoaneurysms is safe and effective and may induce less morbidity than open surgery, in particular by preserving the spleen. Coil artifacts may make magnetic resonance angiography preferable over computed tomography for follow-up.

Refractory bleeding from gastroduodenal ulcers: arterial embolization in high-operative-risk patients.

Goals and Background We evaluated the efficacy and medium-term outcomes of transcatheter embolization to control massive bleeding from gastroduodenal ulcers after failed endoscopic treatment in high-operative-risk patients. Study Retrospective study of 35 consecutive emergency embolization procedures in hemodynamically unstable patients (24 men, 11 women, mean age 71±11.6 y) referred from 1999 to 2006 for selective angiography after failed endoscopic treatment. Mean follow-up was 27 months. Results Endovascular treatment was feasible in 33 patients and consistently stopped the bleeding. “Sandwich” coiling of the gastroduodenal artery was performed in 11 patients and superselective occlusion of the terminal feeding artery with glue, coils, or gelatine particles in 22 patients. Early rebleeding occurred in 6 patients and was managed successfully using endoscopy (n=2), reembolization (n=1), or surgery (n=3). No major complications related to catheterization occurred. Seven patients died within 30 days of embolization and 3 died later during the follow-up, but none of the deaths were due to rebleeding. No late bleeding recurrences were reported. Conclusions Selective angiographic embolization is safe and effective for controlling life-threatening bleeding from gastroduodenal ulcers, usually obviating the need for emergency surgery in critically ill patients, whose immediate survival depends on their underlying conditions.

Trends in the management and survival of digestive tract cancers among patients aged over 80 years

Background:  Advances have occurred in the management of digestive tract cancers, but it is not known how much they have benefited the elderly.

The lifelong risk of metachronous colorectal cancer justifies long-term colonoscopic follow-up.

BACKGROUND The aim of this study was to calculate the risk of metachronous colorectal cancers, to specify their characteristics and potential risk factors in a well-defined French population over a 27-year period. PATIENTS AND METHODS The 10,801 patients who had colorectal cancers totalled 61,879 person-years of follow-up. The actuarial method was used to obtain crude metachronous colorectal cancer rates. Standardised incidence ratios (SIRs) were calculated. RESULTS The cumulative rate of metachronous colorectal cancer was 1.8% at 5 years, 3.4% at 10 years and 7.2% at 20 years. The incidence of metachronous colorectal cancer following a first colorectal cancer was higher than expected (SIR: 1.5 [1.3-1.7] p<0.001). It remained greater throughout the study period, significantly only between the first and the fifth years following diagnosis (SIR: 1.9 [1.6-2.3] p<0.010). As compared to solitary cancers, metachronous cancers were diagnosed at earlier stages (23.5% versus 40.9% were stage I, p<0.001). None of the personal and tumour characteristics were predicting factors for the development of metachronous colorectal cancer. CONCLUSION Patients with colorectal cancer are at greater risk of developing a metachronous colorectal cancer. Among them, no predicting factors for the development of metachronous tumours were found. Thus lifelong colonoscopic surveillance is needed.

Prognostic value of KRAS mutations in stage III colon cancer: post-hoc analysis of the PETACC8 phase III trial dataset

BACKGROUND The prognostic value of KRAS mutations in colon adenocarcinoma is controversial. We examined this question as an ancillary study of the PETACC8 phase III trial. PATIENTS AND METHODS We analyzed the prognostic impact of KRAS exon 2 mutations in stage III colon cancer patients (n = 1657) receiving adjuvant FOLFOX ± cetuximab therapy included in the PETACC8 trial. Patients with BRAF-mutated cancers were excluded and, as no difference was found for time to recurrence (TTR) and disease-free survival (DFS) between treatment arms, both were pooled for analysis. Associations with TTR and DFS were analyzed using a Cox proportional hazards model. RESULTS KRAS mutations were found in 638 of 1657 tumors and linked to shorter TTR (P < 0.001). However, when specific mutations were compared with wild-type, codon 12 mutations [hazard ratio (HR) 1.67, 95% confidence interval (CI) 1.35-2.04; P < 0.001] but not codon 13 (HR 1.23, 95% CI 0.85-1.79; P = 0.26) were significantly associated with shorter TTR, independently of other covariates. The interaction test showed that, regarding tumor location (distal versus proximal), KRAS genotype affects differently on recurrence (P = 0.02) and DFS (P = 0.042). Subgroup analysis showed that KRAS only affected TTR and DFS in distal tumors (n = 1043; 692 wild type; 351 mutated), with an increased risk of relapse (HR 1.96, 95% CI 1.51-2.56; P < 0.0001) for KRAS codon 12 mutations and a borderline significance for codon 13 mutations (HR 1.59, 95% CI 1.00-2.56; P = 0.051). CONCLUSION KRAS exon 2 mutations are independent predictors of shorter TTR in patients with resected stage III distal colon cancers receiving adjuvant therapy. Future clinical trials in the adjuvant setting should consider both the tumor location and KRAS mutations as important stratification factors. CLINICAL TRIAL NUMBER This is an ancillary study of the PETACC8 trial: EUDRACT 2005-003463-23.