ABSTRACT
BACKGROUND: Adjuvant treatment for stage II colon cancer remains debated. Finding a tool to select patients at risk for disease recurrence may help the clinical decision. Circulating tumor DNA (ctDNA) has been reported recently as a potential predictive marker for disease recurrence. We thus aim to test its ability to better select stage II colon cancer patients for adjuvant therapy. METHODS: This national, phase III trial (NCT00002019-000935-15) conducted in more than 100 centers in France, plans to screen around 2640 patients in order to randomize (2:1; minimization method) 198 ctDNA positive patients. Patients aged 18 to 75 years with ECOG performance status ≤1 with R0 surgical resection of a pT3-T4aN0 colon or high rectum adenocarcinoma will be randomized within 63 days after curative-intent surgery, to adjuvant mFOLFOX6 (oxaliplatin 85 mg/m², leucovorin 400 mg/m², and 5-FU bolus 400 mg/m2 then 5FU Continuous infusion 2.4 g/m²) every two weeks for 12 cycles or observation. Patients will be followed for maximum 7 years. A gain of 17.5% in 3-yr disease free survival (DFS) is expected (42.5% in the experimental arm vs. 25% in the control arm; HR:0.62; α, 5% [two-sided log-rank test]; 1-ß, 80%). Secondary endpoints include 2-yr DFS, overall survival, and toxicity. Recruitement began End of January 2020.
Subject(s)
Biomarkers, Tumor/genetics , Chemotherapy, Adjuvant/methods , Circulating Tumor DNA/blood , Colonic Neoplasms/drug therapy , Adolescent , Adult , Aged , Biomarkers, Tumor/blood , Colonic Neoplasms/genetics , Colonic Neoplasms/mortality , Colonic Neoplasms/pathology , Disease-Free Survival , Female , Fluorouracil/administration & dosage , France , Humans , Leucovorin/administration & dosage , Male , Middle Aged , Neoplasm Staging , Oxaliplatin/administration & dosage , Treatment Outcome , Young AdultABSTRACT
PURPOSE: We examined the prognostic impact of specific KRAS mutations in patients with stage III colon adenocarcinoma receiving adjuvant FOLFOX alone or combined with cetuximab in a phase III trial (N0147). Analysis was restricted to BRAF-wild-type tumors, because BRAF mutation was associated with poor prognosis, and BRAF and KRAS mutations are mutually exclusive. EXPERIMENTAL DESIGN: The seven most common KRAS mutations in codon 12 and codon 13 were examined in 2,478 BRAF-wild-type tumors. Because KRAS mutations in codon 12 (n = 779) or 13 (n = 220) were not predictive of adjuvant cetuximab benefit, study arms were pooled for analysis. Disease-free survival (DFS) was evaluated by HRs using Cox models. RESULTS: KRAS mutations in codon 12 (multivariate HR, 1.52; 95% confidence interval, CI, 1.28-1.80; P < 0.0001) or codon 13 (multivariate HR, 1.36; 95% CI, 1.04-1.77; P = 0.0248) were significantly associated with shorter DFS compared with patients with wild-type KRAS/BRAF tumors, independent of covariates. KRAS codon 12 mutations were independently associated with proficient mismatch repair (P < 0.0001), proximal tumor site (P < 0.0001), low grade, age, and sex, whereas codon 13 mutations were associated with proximal site (P < 0.0001). CONCLUSION: KRAS mutations in either codon 12 or 13 are associated with inferior survival in patients with resected stage III colon cancer. These data highlight the importance of accurate molecular characterization and the significant role of KRAS mutations in both codons in the progression of this malignancy in the adjuvant setting. Clin Cancer Res; 20(11); 3033-43. ©2014 AACR.
Subject(s)
Adenocarcinoma/drug therapy , Adenocarcinoma/genetics , Colonic Neoplasms/drug therapy , Colonic Neoplasms/genetics , Mutation , Proto-Oncogene Proteins/genetics , ras Proteins/genetics , Adenocarcinoma/mortality , Adult , Aged , Aged, 80 and over , Antibodies, Monoclonal, Humanized/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/administration & dosage , Antineoplastic Combined Chemotherapy Protocols/therapeutic use , Cetuximab , Chemotherapy, Adjuvant , Codon , Colonic Neoplasms/mortality , DNA Mutational Analysis , Disease-Free Survival , Female , Fluorouracil/administration & dosage , Humans , Kaplan-Meier Estimate , Leucovorin/administration & dosage , Male , Middle Aged , Multiplex Polymerase Chain Reaction , Neoplasm Staging , Organoplatinum Compounds/administration & dosage , Proportional Hazards Models , Proto-Oncogene Proteins B-raf/genetics , Proto-Oncogene Proteins p21(ras) , Young AdultABSTRACT
BACKGROUND: The risks of chemoradiotherapy in elderly patients with rectal cancer have not yet been well-characterised. METHODS: We retrospectively reviewed the charts of patients with rectal cancer over 70 years old who were treated with chemoradiotherapy in two French university hospitals. RESULTS: A total of 125 patients were evaluated. Mean age was 75.1 ± 4.1 years and ranged from 70 to 90 years. Adverse effects ≥ grade 2 were observed in 32% of the patients and adverse effects ≥ grade 3 in 15%. Dose reduction for toxicity was performed in 18% of the patients and chemoradiotherapy discontinuation was necessary in 9%. Postoperative morbidity was 16% with two treatment-related deaths. Two-year survival rate was 84%. No variables had any influence on treatment-related adverse events. CONCLUSIONS: In selected elderly patients, chemoradiotherapy is well-tolerated, without any significant increase in adverse events, and the results are similar to those recorded in younger patients.
Subject(s)
Antineoplastic Agents/therapeutic use , Chemoradiotherapy, Adjuvant/adverse effects , Rectal Neoplasms/pathology , Rectal Neoplasms/therapy , Aged , Aged, 80 and over , Capecitabine , Deoxycytidine/analogs & derivatives , Deoxycytidine/therapeutic use , Disease-Free Survival , Female , Fluorouracil/analogs & derivatives , Fluorouracil/therapeutic use , France , Humans , Kaplan-Meier Estimate , Leucovorin/therapeutic use , Male , Neoplasm Metastasis , Neoplasm Staging , Organoplatinum Compounds/therapeutic use , Oxaliplatin , Retrospective Studies , Tegafur/therapeutic use , Vitamin B Complex/therapeutic useSubject(s)
Antineoplastic Agents/adverse effects , Benzenesulfonates/adverse effects , Breast Diseases/chemically induced , Eczema/chemically induced , Pyridines/adverse effects , Carcinoma, Hepatocellular/drug therapy , Humans , Liver Neoplasms/drug therapy , Male , Middle Aged , Niacinamide/analogs & derivatives , Nipples , Phenylurea Compounds , SorafenibABSTRACT
UNLABELLED: Perianal fistulizing Crohn's disease (PFCD) treatment is based on fistula drainage, antibiotics, immunosuppressant (IS) drugs, and infliximab. Our aim was to study the effectiveness of combination therapy on PFCD and to search for clinical or imaging features associated with the initial complete clinical response and its stability overtime. PATIENTS AND METHODS: All patients with PFCD treated in our tertiary center between 2000 and 2005 by infliximab in combination with seton placement and/or IS and evaluated by MRI before treatment were included in the study. Basal clinical and MRI characteristics were recorded. Response to treatment was evaluated after the infliximab induction regiment and at the end of the follow-up. RESULTS: Twenty-six patients were included and followed-up for an average 4.9 years. A complex fistula was present in 69% (18/26 patients) of cases and eight (8/26 patients) had an ano-vaginal fistula. After infliximab induction therapy, 13 patients (50%) achieved a complete clinical response. The initial clinical response was significantly associated with the absence of both, active intestinal disease (54% vs. 8%, P = 0.03) and active proctitis (77% vs. 23%, P = 0.01). No initial MRI characteristics were linked to the initial response. In multivariate analysis, only the presence of active proctitis was associated with the lack of response (P = 0.047). At the end of the follow-up, 42% of the patients remained in clinical remission. No clinical characteristics were associated to sustained response when among long-standing responders two exhibited a normal post-treatment MRI. CONCLUSION: An initial complete response of PFCD was observed in half of the patients after combined therapy including infliximab that decreased to 42% later on. Complete healing of fistulas on MRI was possible but unusual. The initial response seemed related to the absence of active intestinal disease, especially in the rectum, when the long-term response could not be predicted by the basal characteristics of patients.