PREMIUM: A French prospective multicenter observational study of factors impacting on efficacy and compliance to cetuximab treatment in first-line KRAS wild-type metastatic colorectal cancer.

BACKGROUND: Cetuximab improves progression-free survival (PFS) and overall survival (OS) in patients with KRAS wild type (wt) metastatic colorectal cancer (mCRC). Few data are available on factors impacting both efficacy and compliance to cetuximab treatment, which is, in combination with chemotherapy, a standard-of-care first-line treatment regimen for patients with KRAS wt mCRC. PATIENTS AND METHODS: PREMIUM is a prospective, French multicenter, observational study that recruited patients with KRAS wt mCRC scheduled to receive cetuximab, with or without first-line chemotherapy, as part of routine clinical practice, between October 28, 2009 and April 5, 2012 (ClinicalTrials.gov Identifier: NCT01756625). The main endpoints were the factors impacting on efficacy and compliance to cetuximab treatment. Predefined efficacy endpoints were PFS and safety. RESULTS: A total of 493 patients were recruited by 94 physicians. Median follow-up was 12.9 months. Median progression-free survival was 11 months [9.6-12]. In univariate analyses, ECOG performance status (PS), smoking status, primary tumor location, number of metastatic organs, metastasis resectability, surgery, folliculitis, xerosis and paronychia maximum grade, and acne preventive treatment were statistically significant. In multivariate analysis (Hazard Ratios of multivariate stepwise Cox models), ECOG PS, surgery, xerosis and folliculitis were positive prognostics factors for longer PFS. Among all patients, 69 (14%) were non-compliant. In multivariate analysis, no variables were statistically significant. The safety profile of cetuximab was consistent with previous studies. CONCLUSIONS: ECOG PS <2, surgical treatment performed, and maximum grade xerosis or folliculitis developed were predictive factors of cetuximab efficacy on KRAS wt mCRC patients. Unfortunately, we failed in identifying predictive factors for compliance in these patients.

Prognostic factors in patients treated with second-line chemotherapy for advanced gastric cancer: results from the randomized prospective phase III FFCD-0307 trial.

AIM: The aim of this study was to determine prognostic factors in patients treated with second-line therapy (L2) for locally advanced or metastatic gastric and gastro-esophageal junction (GEJ) adenocarcinoma in a randomized phase III study with predefined L2. METHODS: In the FFCD-0307 study, patients were randomly assigned to receive in L1 either epirubicin, cisplatin, and capecitabine (ECX arm) or fluorouracil, leucovorin, and irinotecan (FOLFIRI arm). L2 treatment was predefined (FOLFIRI for the ECX arm and ECX for the FOLFIRI arm). Chi square tests were used to compare the characteristics of patients treated in L2 with those of patients who did not receive L2. Prognostic factors in L2 for progression-free survival (PFS) and overall survival (OS) were analyzed using a Cox model. RESULTS: Among 416 patients included, 101/209 (48.3%) patients in the ECX arm received FOLFIRI in L2, and 81/207 (39.1%) patients in the FOLFIRI arm received ECX in L2. Patients treated in L2, compared with those who only received L1 had : a better ECOG score (0-1: 90.4% versus 79.7%; p = 0.0002), more frequent GEJ localization (40.8% versus 27.6%; p = 0.005), and lower platelet count (median: 298000 versus 335000/mm3; p = 0.02). In multivariate analyses, age < 60 years at diagnosis (HR 1.49, 95% CI 1.09-2.03, p = 0.013) and ECOG score 2 before L2 (HR 2.62, 95% CI 1.41-4.84, p = 0.005) were the only significant poor prognostic factors for OS. CONCLUSION: Age ≥ 60 years at diagnosis and ECOG score 0/1 before L2 were the only favorable prognostic factors for OS.

Azathioprine dose reduction in inflammatory bowel disease patients on combination therapy: an open-label, prospective and randomised clinical trial.

BACKGROUND: Infliximab (IFX) combined with azathioprine (AZA) is more effective than IFX monotherapy in inflammatory bowel disease (IBD). AIM: To identify the AZA optimal dose that is required for efficacy when receiving combination therapy. METHODS: Patients with IBD in durable remission on combination therapy were enrolled in a 1-year, open-label, prospective trial after randomisation into three groups: AZA steady (2-2.5 mg/kg/day, n=28) vs AZA down (dose was halved 1-1.25 mg/kg/day, n=27) vs AZA stopped (n=26). Primary endpoint was failure defined as occurrence of a clinical relapse and/or any change in IBD therapy. RESULTS: Eighty-one patients were included. Five (17.9%), 3 (11.1%), and 8 (30.8%) patients experienced failure at 1 year in groups AZA steady, AZA down and AZA stopped, respectively (P=.1 across the groups). The median trough levels of IFX at inclusion were close to those measured at the end of follow-up in group AZA steady (3.65 vs 3.45 µg/mL, P=.9) and in group AZA down (3.95 vs 3.60 µg/mL, P=.5), whereas these levels dropped from 4.25 to 2.15 µg/mL (P=.02) in group AZA stopped. Four (14.3%), four (14.8%) and 11 (42.3%) patients experienced an unfavourable evolution of IFX pharmacokinetics in groups AZA steady, AZA down and AZA stopped, respectively. A threshold of 6-TGN <105 pmoles/8.108 RBC was associated with an unfavourable evolution of IFX pharmacokinetics. CONCLUSIONS: Under combination therapy, AZA dose reduction, but not withdrawal, appears to be as effective as continuation of AZA at full dose.

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.

Combination of C-reactive protein, infliximab trough levels, and stable but not transient antibodies to infliximab are associated with loss of response to infliximab in inflammatory bowel disease.

BACKGROUND: Antibodies to infliximab [ATI] and trough levels to infliximab [TRI] are associated with loss of response in inflammatory bowel diseases [IBD]. The best way to predict loss of response [LOR] to infliximab [IFX] is unknown. METHODS: We conducted a prospective observational cohort study enrolling all IBD patients who were in clinical remission at Week 14 after IFX treatment initiation. TRI, ATI and C-reactive protein [CRP] level were measured at Week 22 [T1] and thereafter at every other IFX infusion. Loss of clinical response was defined by a flare requiring therapeutic change [IFX dose intensification, initiation of another drug class, and/or surgery]. RESULTS: A total of 93 patients [59 Crohn's disease, mean duration of follow-up 17.2 months] were included; 32 patients [34.4%] lost clinical response during follow-up. Cumulative probability of LOR was 50% at 20 months. Mean TRI at T1 was significantly lower in IBD patients with stable ATI as compared with those with transient ATI or without ATI [0.052, 3.34 ,and 4.29 µg/ml, respectively; p = 0.001 between no ATI vs stable ATI, and p = 0.005 between stable and transient ATI] [p = 0.0001]. Three independent factors were predictive of LOR after Cox proportional hazards modelling: TRI > 5.5 µg/ml (hazard ratio [HR]: 0.21; 95% confidence interval [CI]: 0.05-0.89;p = 0.034) at T1, CRP > 5mg/l [HR: 2.5; 95% CI: 1.16-5.26; p = 0.019] at T1, and stable ATI defined by two consecutive ATI > 20ng/ml [HR: 3.77; 95% CI: 1.45-10.0; p = 0.007]. Transient ATI did not influence LOR. CONCLUSIONS: LOR can be predicted based on a combination of CRP, TRI and stable ATI with a high degree of accuracy.

Association of Anti-glycan Antibodies and Inflammatory Bowel Disease Course.

BACKGROUND AND AIMS: The usefulness of anti-glycan antibodies alone or combined with anti-Saccharomyces cerevisiae [ASCA] or perinuclear antineutrophil cytoplasmic [pANCA] antibodies for diagnosis of inflammatory bowel disease [IBD], differentiation between Crohn's disease [CD] and ulcerative colitis [UC], disease stratification including IBD phenotype, and also for determination of the course of the disease, remain unclear. METHODS: A large panel of serological anti-glycan carbohydrate antibodies, including anti-mannobioside IgG antibodies [AMCA], anti-chitobioside IgA [ACCA], anti-laminaribioside IgG antibodies [ALCA], anti-laminarin [anti-L] and anti-chitine [anti-C] were measured in the serum from a cohort of 195 patients with IBD] [107 CD and 88 UC]. The respective accuracy of isolated or combined markers for diagnosis, disease differentiation, stratification disease phenotype, and severity of the disease course, defined by a wide panel of criteria obtained from the past medical history, was assessed. RESULTS: The positivity of at least one anti-glycan antibody was detected in a significant higher proportion of CD and UC compared with healthy controls [p < 0.0001 and p < 0.0007, respectively]. Whereas ASCA and ANCA antibody status had the highest efficacy to be associated with CD in comparison with UC (area under receiver operating characteristic curve [AUROC] = 0.70 for each], the adjunction of anti-laminarin antibody substantially improved the differentiation between CD and UC [AUROC = 0.77]. Titres of ACCA [> 51U/ml] and anti-laminarin [> 31U/ml] were significantly linked with a higher association with steroid dependency (odds ratio [OR] =2.0 [1.0-4.0], p = 0.03 and OR = 2.4 [1.1-5.2], p = 0.02, respectively]. We further defined the respective performance of anti-glycan antibodies to discriminate between patients with severe or not severe CD and UC course and determined the associated optimal cut-off values: severe CD course was significantly more likely in case of AMCA > 77U/ml [OR = 4.3; p = 0.002], ASCA > 63U/ml [OR = 3.5; p < 0.009] and at a lesser degree ACCA > 50U/ml [OR = 2.8; p < 0.02] and severe UC course was significantly associated with AMCA > 52U/ml [OR = 3.4; p = 0.04] and ACCA > 25U/ml [OR = 3.0; p < 0.04]. CONCLUSIONS: Anti-glycan antibodies are valuable serological markers, especially AMCA antibodies that may help clinicians to promptly classify patients into high risk for severe disease.

Development of an algorithm incorporating pharmacokinetics of adalimumab in inflammatory bowel diseases.

OBJECTIVES: Several decision algorithms based on the measurement of infliximab (IFX) trough levels and antibodies to IFX have been proposed. Whether such algorithms can be extrapolated to the pharmacokinetics of adalimumab (ADA) has yet to be determined. METHODS: A prospective study included all consecutive patients with inflammatory bowel disease (IBD) having a disease flare while being on ADA 40 mg every 2 weeks were included. All patients were primary responders to ADA therapy and were anti-tumor necrosis factor (TNF) naive. ADA trough levels and antibodies against ADA (AAA) were measured blinded to clinical data (Elisa LISA-Tracker, Theradiag). All patients were optimized with ADA 40 mg weekly. Four months later, in the absence of clinical remission (CR; Crohn's disease activity index <150 for Crohn's disease (CD), and Mayo score <2 for ulcerative colitis), patients were treated with IFX therapy. Patients were divided into three groups based on ADA trough levels and based on previous studies: group A, ADA>4.9 µg/ml; group B, ADA<4.9 µg/ml and undetectable levels of AAA (<10 ng/ml); and group C, ADA<4.9 µg/ml and AAA >10 ng/ml. RESULTS: A total of 82 patients were included (55% CD; mean age=43 years, disease duration=7.4 years, duration of ADA therapy=17 months). After optimization of ADA treatment, 29.2% of patients achieved CR in group A (N=41), 67% in group B (N=24), and 12% in group C (N=17; P<0.01 between groups A/B and B/C). C-reactive protein level at the time of relapse, disease duration, duration of ADA therapy, and IBD type was not predictive of CR after ADA optimization by univariate analysis. The response to ADA optimization was significantly more durable in group B (15 months) than in groups A and C (4 and 5 months, respectively). Fifty-two patients who failed following ADA optimization (63%) were treated with IFX, and 30.6% of them achieved CR. CR rates following IFX initiation were 6.9%, 25%, and 80% in groups A, B, and C, respectively (P<0.01 between groups C/A and between groups C/B). Duration of response to IFX was significantly higher in group C than in groups A and B (14 vs. 3 and 5 months, respectively, P<0.01). CONCLUSIONS: The presence of low ADA trough levels without AAA is strongly predictive of clinical response in 67% of cases after ADA optimization. Conversely, low ADA levels with detectable AAA are associated with ADA failure, and switching to IFX should be considered. ADA trough levels >4.9 µg/ml are associated with failure of two anti-TNF agents (ADA and IFX) in 90% of cases, and switching to another drug class should be considered.

Impact of diabetes mellitus on clinical presentation and prognosis of pancreatic cancer.

INTRODUCTION: The aim of this study was to investigate possible effects of diabetes mellitus on clinical manifestations and prognosis of pancreatic cancer (PC). PATIENTS AND METHODS: We retrospectively reviewed the clinical files of 122 patients with PC, and divided them into two groups: those with diabetes (56 patients) and those without diabetes (66 patients). The two groups were then compared for demographic profiles, clinical manifestations of PC, features of the tumor and fatal outcomes. RESULTS: Mean age, sex distribution, body mass index at cancer diagnosis, prevalence of hypertension, dyslipidemia, weight loss, abdominal pain, lumbar pain, signs of dyspepsia, and size, and histological features of the tumor were similar between the two groups. The cancer was located in the head of the pancreas in 50% of those with diabetes, and 80% of those without diabetes (P=0.04). The median survival time was similar. CONCLUSIONS: Clinical features, tumor size and prognosis of PC are similar in people with and without diabetes. Having diabetes does not seem to contribute to earlier diagnosis of PC.

[An opinion survey about medical autopsy, Saint-Étienne University Hospital: are the French laws of bioethics to be revised?]. / Enquête d'opinion au CHU de Saint-Étienne sur la pratique des autopsies médicales: faut-il réviser la loi de 2004 relative à la bioéthique ?

PURPOSE: The aim of the medical autopsy is to define the causes of a patient's death. Although its rate has dramatically decreased, the post-mortem examination remains one of the basic tools for the assessment of medical care. The objective of this study was to identify the factors influencing the acceptance of medical autopsies. METHODS: A prospective survey was performed using questionnaire that was administered to patients and health care professionals of the Saint-Étienne university hospital. The survey consisted in several questions relating to the autopsy practice (on one's own body) and the knowledge of the procedure. RESULTS: The population surveyed consisted of 186 individuals and 112 health care professionals, including physicians, residents and nurses. The results of the study overall showed a good acceptance of autopsy. Actually, 86% of the individauls and 94.6% of health professionals would not be opposed to their own autopsy (in order to identify the cause of the death, to help relatives bereavement, to foster medical research). The main reasons of medical autopsy opposition include religion belief, body integrity, dignity and respect. Only 42.5% of patients had previously received some information about autopsies, while 33.9% of health care professionals had received a specific formation. CONCLUSION: The rate of refusal of medical autopsy was low in this survey but information relative to this procedure remains insufficient. The current law imposes to look after a nonopposition to medical autopsy of the died individual, including asking his/her relatives that markedly limit the organ donation. Modification of the French bioethical law should be beneficial to increase both medical autopsy organ donation rates.

A population-based study of adjuvant chemotherapy for stage-II and -III colon cancers.

BACKGROUND: Although clinical trials have demonstrated that adjuvant chemotherapy improves survival for stage-III colon cancer, the benefits remain controversial for stage-II lesions. The objective of the present study was to determine the extent to which adjuvant chemotherapy is used for patients with stage-II and -III colon cancers. METHODS: The study population comprised 1074 patients with stage-II and -III colon cancers diagnosed in 2000 in 12 French administrative districts and recorded in population-based cancer registries. Data were collected using a standardized procedure. RESULTS: Overall, 20.4% of patients with stage II and 61.9% with stage III received adjuvant chemotherapy. Age at diagnosis was the strongest determinant of chemotherapy. Among stage-II patients, those receiving chemotherapy decreased from 57.6% in patients aged or=85. The corresponding percentages with stage III were 93.6% and 1.4%. In multivariate analyses, other factors found to be independently and significantly associated with administration of adjuvant chemotherapy for stage II were extension of the cancer (stage IIA vs. stage IIB), clinical presentation (obstruction or perforation vs. uncomplicated cancer) and discussion of the case at a multidisciplinary case-review meeting. For stage III, apart from age, discussion of the case at a multidisciplinary meeting was the only factor independently associated with administration of chemotherapy. CONCLUSION: Adjuvant chemotherapy for stage-III colon cancer is used extensively for patients under 75 years of age. However, many elderly patients do not receive such treatment. On the other hand, a substantial percentage of stage-II colon cancer patients receive adjuvant chemotherapy despite its uncertain benefits.

Tumour necrosis factor antagonists and inflammatory bowel diseases: a national practice survey.

BACKGROUND: Although the use of tumour necrosis factor (TNF) antagonists is increasingly codified, several unresolved issues remain. AIM: To conduct a French national survey on TNF antagonists use in inflammatory bowel disease (IBD). METHODS: A postal questionnaire was sent to all French gastroenterologists among whom 450 prescribe TNF antagonists for IBD. Only anti-TNF prescribers were invited to respond. RESULTS: A total of 333 questionnaires could be analysed, which represented a rate of survey completeness of 74%. Scheduled maintenance infliximab treatment was prescribed by 92% of gastroenterologists. In Crohn's disease in remission after 1 year of TNF antagonists, 77.4% of physicians continued treatment. In luminal Crohn's disease, 97% of hospital practitioners introduced infliximab as first-line anti-TNF therapy vs. 78% of physicians with nonhospital activity (P = 0.002); only 22.5% of gastroenterologists opted for adalimumab as first-line therapy. In Crohn's disease in remission after 6 months of azathioprine in combination with infliximab, 63.8% of practitioners discontinued azathioprine. In case of pregnancy during anti-TNF treatment, 35.1% of physicians discontinued therapy at the time of conception and did not administer anti-TNF therapy during pregnancy. CONCLUSIONS: The attitudes of French gastroenterologists generally reflect the recommendations regarding the use of anti-TNF and concomitant immunosuppressive therapy in IBD.

[External radiotherapy and photodynamic therapy for esophageal carcinoma: a dangerous association?]. / Radiothérapie externe et photothérapie dynamique des cancers de l'oesophage: une association dangereuse ?

A 60-year-old man presented an oesophageal transmural necrosis fistulised in the trachea following curative photodynamic therapy (PDT) for a superficial recurrence of an oesophageal carcinoma, initially treated by radiochemotherapy. Two stents, a tracheal and an oesophageal one, were placed. Eight months later the patient is in complete remission with only mild swallowing problems. This complication, although unusual, has already been described by other teams with the association of radiochemotherapy and PDT. The present case study suggests that illumination dose should be lowered in this indication.

Hyperhomocysteinaemia is associated with osteoporosis in patients with Crohn's disease.

BACKGROUND: A high prevalence of osteoporosis is observed in Crohn's disease. Recent data have shown that homocysteinaemia is an important risk factor in low-bone mineralization and fracture. AIM: To look for an association between homocysteinaemia and low-bone mineralization in Crohn's disease patients. PATIENTS AND METHODS: Ninety-two consecutive patients (sex ratio M/F 0.87; mean age: 36.6 +/- 13.2 years) were recruited between 2003 and 2005. Bone densitometry was performed on inclusion. The following parameters were analysed: age, sex, Crohn's Disease Activity Index, duration and extent of Crohn's disease, smoking status, corticosteroid treatment, immunosuppressive drugs, plasma homocysteine, folate and vitamin B12 concentration. RESULTS: The prevalence of a high homocysteine level (>15 micromol/L) was 60%. Osteoporosis and low-bone mineralization observed in 26 (28%), and 60 (65%) patients, respectively. On a multivariate analysis, associated factors for osteoporosis and low-bone mineralization were respectively: hyperhomocysteinaemia (OR: 61.4; CI: 95: 23-250; P < 0.001), and ileal Crohn's disease [OR: 13.8; CI: 95: 2.5-150; P = 0.036] for osteoporosis and hyperhomocysteinaemia [OR: 63.7; CI: 95: 8.5-250; P < 0.001] and disease duration of at least 5 years [OR: 11.4; CI: 95: 1.31-99; P = 0.039] for low-bone mineralization. Results were similar whichever site osteoporosis was detected. CONCLUSION: Hyperhomocysteinaemia was observed in 60% of our Crohn's disease patients and was strongly associated with low-bone mineralization and osteoporosis (OR: 61.4).

[Factors associated with hyperhomocysteinemia in inflammatory bowel disease: prospective study in 81 patients]. / Hyperhomocystéinémie et facteurs associés au cours des MICI: étude prospective chez 81 patients.

BACKGROUND: A high prevalence (52%) of hyperhomocysteinemia is observed in Crohn disease (CD), however it is not well documented in ulcerative colitis (UC). Furthermore, in the different works studying hyperhomocysteinemia the associated factors are different. AIM: Prospective evaluation of hyperhomocysteinemia in inflammatory bowel disease (IBD) patients, of the risk factors and the determination of a potential risk of colorectal carcinoma in case of hyperhomocysteinemia. PATIENTS AND METHODS: IBD patients followed in our department were prospectively recruited between November 2003-September 2004. To be included patients should have passed a coloscopy in the two years. Patients with kidney failure or drugs supposed, to interfere with homocystéine metabolism (folates, vitamin B12, methotrexate) were excluded from the study. The following parameters were analysed: age, sex, clinical activity indexes (CDAI for Crohn disease and CAI for ulcerative colitis), length-extent and type of the disease (CD or UC), smoking, plasma homocystein concentration, folates and vitamin B12. RESULTS: Eighty-one patients (60 CD, 21 UC, mean age 43.8 +/- 17.3) were included, 30 had an active disease at inclusion and 16 were smokers. The prevalence of high homocystein concentration was 55.6%. In univariate analysis a low rate of folates was the only risk factor for a high homocystein concentration (74 vs. 52.8%; P = 0.018). Smoking was almost an associated factor. In multivariate analysis, a low rate of folate was the only risk factor of hyperhomocysteinemia, OR = 3.59 [1.27-10.17]. Five endoscopic lesions considered as precancerous were described; these patients had all a hyperhomocysteinemia. CONCLUSION: The prevalence of hyperhomocysteinemia is high in UC and in CD. A low folate rate is the only risk factor observed in our study. There is a possible link between colorectal cancer and hyperhomocysteinemia. A high Plasma homocystein concentration must be search in inflammatory bowel disease patients and a substitutive treatment of folates and vitamin B12 is necessary in case of hyperhomocysteinemia.