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.

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.

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.

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.

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.

[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).

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.