Weekly bolus 5-fluorouracil and bevacizumab in the palliative treatment of metastatic colorectal cancer.

736 Background: Patients with metastatic colorectal cancer (mCRC) are often elderly with multiple co-morbidities making them poor candidates for combination chemotherapy. Evidence suggests significant benefit from the addition of Bevacizumab (Bev) to single agent fluoropyrimidine chemotherapy in the palliative treatment of mCRC. There is no current trial data to support use of weekly bolus 5-fluorouracil (5-FU) chemotherapy combined with Bev. We present details of our experience with this treatment regimen. Methods: Patients with mCRC treated with weekly bolus 5-FU 370 mg/m2and Bev 5mg/kg every 2 weeks (Weekly-5FU-Bev) as a new line of palliative treatment were reviewed. All were deemed unsuitable for Capecitabine. Data were collected retrospectively from patient records. Survival statistics were calculated from date of treatment initiation using Kaplan-Meier methods. Results: From 2012-2015, 21 patients were treated with Weekly-5FU-Bev. Median age was 80 years (range 56-90 years), 57.1% were performance status (PS) 0, 19% PS 1 and 23.8% PS 2. 61.9% patients were Ras wild-type. Median treatment duration to date is 20 weeks (range 4-117 weeks). Treatment was stopped in 8 due to progressive disease, 1 due to toxicity and 4 for other reasons. Treatment was generally well tolerated with significant fatigue the most commonly reported side effect in 24%. 3 patients experienced venous thrombo-embolic events, 1 developed uncontrolled hypertension and 1 suffered a non-fatal tumour perforation. There were no treatment related deaths. Clinical benefit rate determined by best response to treatment was impressive at 66.7% with 1 complete response, 1 partial response, 1 biochemical response (non-measurable disease) and 12 patients with stable disease. Median progression free survival was 9.3 months (95% CI 2.8-15.8 months). Median overall survival has not been reached with 15 patients still alive. Conclusions: Acknowledging the limitations of this retrospective analysis of a carefully selected patient group, Weekly-5FU-Bev appears to be well tolerated and efficacious in the treatment of elderly patients with mCRC and can be considered an option in patients unsuitable for or intolerant of Capecitabine.

Microsatellite Instability Predicts Improved Response to Adjuvant Therapy With Irinotecan, Fluorouracil, and Leucovorin in Stage III Colon Cancer: Cancer and Leukemia Group B Protocol 89803

Purpose Colon cancers exhibiting DNA mismatch repair (MMR) defects demonstrate distinct clinical and pathologic features, including better prognosis and reduced response to fluorouracil (FU) –based chemotherapy. This prospective study investigated adjuvant chemotherapy containing FU and irinotecan in patients with MMR deficient (MMR-D) colon cancers. Patients and Methods Cancer and Leukemia Group B 89803 randomly assigned 1,264 patients with stage III colon cancer to postoperative weekly bolus FU/leucovorin (LV) or weekly bolus irinotecan, FU, and LV (IFL). The primary end point was overall survival; disease-free survival (DFS) was a secondary end point. Tumor expression of the MMR proteins, MLH1 and MSH2, was determined by immunohistochemistry (IHC). DNA microsatellite instability was also assessed using a panel of mono- and dinucleotide markers. Tumors with MMR defects were those demonstrating loss of MMR protein expression (MMR-D) and/or microsatellite instability high (MSI-H) genotype. Results Of 723 tumor cases examined by genotyping and IHC, 96 (13.3%) were MMR-D/MSI-H. Genotyping results were consistent with IHC in 702 cases (97.1%). IFL-treated patients with MMR-D/MSI-H tumors showed improved 5-year DFS as compared with those with mismatch repair intact tumors (0.76; 95% CI, 0.64 to 0.88 v 0.59; 95% CI, 0.53 to 0.64; P = .03). This relationship was not observed among patients treated with FU/LV. A trend toward longer DFS was observed in IFL-treated patients with MMR-D/MSI-H tumors as compared with those receiving FU/LV (0.57; 95% CI, 0.42 to 0.71 v 0.76; 95% CI, 0.64 to 0.88; P = .07; hazard ratio interaction between tumor status and treatment, 0.51; likelihood ratio P = .117). Conclusion Loss of tumor MMR function may predict improved outcome in patients treated with the IFL regimen as compared with those receiving FU/LV.

Irinotecan Fluorouracil Plus Leucovorin Is Not Superior to Fluorouracil Plus Leucovorin Alone As Adjuvant Treatment for Stage III Colon Cancer: Results of CALGB 89803

Purpose Randomized studies have shown that irinotecan (CPT-11) extends survival in metastatic colorectal cancer patients when administered in second-line and when added to fluorouracil (FU) plus leucovorin (LV) in first-line therapy of metastatic colorectal cancer. When this study was initiated, FU plus LV was standard adjuvant treatment for stage III colon cancer. We evaluated the efficacy and safety of weekly bolus CPT-11 plus FU plus LV in the treatment of patients with completely resected stage III colon cancer. Methods A total of 1,264 patients were randomly assigned to receive either standard weekly bolus FU plus LV regimen or weekly bolus CPT-11 plus FU plus LV. The primary end points of the study were overall survival (OS) and disease-free survival (DFS). Results Treatment arms were well-balanced for patient characteristics and prognostic variables. There were no differences in either DFS or OS between the two treatment arms. Toxicity, including lethal toxicity, was significantly higher on the CPT-11 plus FU plus LV arm. Conclusion The addition of CPT-11 to weekly bolus FU plus LV did not result in improvement in DFS or OS in stage III disease, but did increase both lethal and nonlethal toxicity. This trial demonstrates that advances in the treatment of metastatic disease do not necessarily translate into advances in adjuvant treatment, and it reinforces the need for randomized controlled adjuvant studies.