Dose-intense capecitabine, oxaliplatin and bevacizumab as first line treatment for metastatic, unresectable colorectal cancer: a multi-centre phase II study.

BACKGROUND: Dose intense chemotherapy may improve efficacy with acceptable toxicity. A phase II study was conducted to determine the feasibility of a dose-intense two weekly schedule of capecitabine, oxaliplatin, and bevacizumab in metastatic colorectal cancer (mCRC). METHODS: 49 patients with previously untreated mCRC were recruited. Nineteen received capecitabine (1750 mg/m(2) oral BD days 1-7)oxaliplatin (85 mg/m(2)i.v. day 1) and bevacizumab (5 mg/kg i.v. day 1) using a 14-day cycle (C1750). Following toxicity concerns capecitabine was reduced to 1500 mg/m2oral BD (C1500) and 30 further patients recruited. RESULTS: Over 80% of patients received at least 75% of planned chemotherapy doses over the first two cycles. At C1750 Grade 3 or higher toxicity occurred in 74% (95% CI 49% to 91%) and on C1500 in 70% (95% CI 51% to 85%). The median progression-free survival was 6.9 months (95% CI 4.7 to 8.7) for C1750 dose and 8.9 months (95% CI 4.1 to 12.4) for C1500. 3 treatment-related deaths occurred. CONCLUSIONS: Dose intense capecitabine and oxaliplatin with bevacizumab does not show additional efficacy and has potentially significant toxicity. Its use outside of clinical trials is not recommended. TRIAL REGISTRATION: ISRCTN41540878.

T1-2 anal carcinoma requires elective inguinal radiation treatment--the results of Trans Tasman Radiation Oncology Group study TROG 99.02.

BACKGROUND AND PURPOSE: Elective inguinal irradiation increases morbidity. We describe outcomes of moderate intensity chemoradiation treating anal canal and adjacent pelvic nodes only. MATERIAL AND METHODS: Forty patients with T1-2, N0 anal carcinoma were enrolled between March 1999 and March 2003. Inguinal nodes were NOT electively irradiated. The anal canal and regional pelvic nodes received 36 Gy/20# over 4 weeks, and 2 weeks later the anal canal was boosted with 14.4 Gy/8#. Chemotherapy was 5 fluorouracil 800 mg/m(2)/day on days 1-4 and 36-39, and Mitomycin C 10mg/m(2) on day 1. RESULTS: Median follow-up was 44 months. Complete response was 95%. Four year results were; overall survival 71%, local control 82%, and colostomy-free survival (including salvage) 85%. Inguinal failure occurred in 22.5% but was isolated in only 12.5%. Treatment was well tolerated acutely with no toxic deaths. Severe late toxicity occurred in 7.5%. CONCLUSIONS: This moderate dose 'non inguinal' chemoradiation regimen resulted in modest acute toxicity, minimal long term morbidity and local control in line with other series. However staging failed to identify 12.5% of patients whose isolated inguinal failure might have been prevented by elective irradiation. Without more effective staging, all patients should receive elective inguinal irradiation.

Transient retinal effects of 5,6-dimethylxanthenone-4-acetic acid (DMXAA, ASA404), an antitumor vascular-disrupting agent in phase I clinical trials.

PURPOSE: 5,6-Dimethylxanthenone-4-acetic acid (DMXAA), an anticancer vascular-disrupting agent, has induced transient visual symptoms in some patients. Exploratory investigations were undertaken to characterize the visual disturbances in two consecutive phase I trials. METHODS: Assessments were made in 21 patients before and immediately after a 20-minute IV infusion of DMXAA, including visual acuity, funduscopy, color discrimination, pattern electroretinography (PERG), pattern visual-evoked potentials (VEP), and full-field electroretinography (ERG). Evaluation of late effects was undertaken subsequently in 12 patients before and after 6 weeks of IV DMXAA at one dose per week. RESULTS: Frequency and intensity of transient visual disturbance increased with DMXAA dose, occurring in two thirds of patients at 3000 mg x m(-2). Symptoms included blurring, flickering, fragmentation, alteration of colors, and contrast and mild photosensitivity, starting during the infusion and resolving completely, usually within 60 minutes. Visual acuity was unchanged but color discrimination was perturbed. Dose-dependent increases in PERG P50 implicit time by up to 23 ms returned toward baseline values within 90 minutes. Prominent transient changes on ERG included prolonged scotopic rod and 30-Hz flicker implicit times and reduced 30-Hz flicker amplitude. In the second trial, no clinically significant sustained effects were detected, although an increase in bright flash a-wave implicit time (P = 0.022) was seen on whole-group analysis. In vitro studies showed nonspecific phosphodiesterase inhibition by DMXAA. CONCLUSIONS: DMXAA induced acute, transient disturbance of retinal activity consistent with phosphodiesterase inhibition. No clinically significant cumulative effects were noted and most effects occurred at doses higher than those used in ongoing clinical trials (ClinicalTrials.gov numbers, NCT00856336, NCT00863733, and NCT00003697).

Acute coronary syndrome induced by capecitabine therapy.

Capecitabine, a new member of the fluoropyrimidine family, is an orally administered drug that delivers fluorouracil (5-FU) selectively to the tumour. Although the cardiotoxicity of 5-FU is well documented, there is little published data about cardiovascular adverse effects of Capecitabine. This case highlights the possible development of acute coronary syndrome as a side effect of Capecitabine therapy.

Serum insulin-like growth factor-I and insulin-like growth factor binding protein-3 following chemotherapy for advanced breast cancer.

BACKGROUND: Insulin-like growth factor-I (IGF-I) and IGF binding protein-3 (IGFBP-3) appear to influence the growth of breast cancer cells in vitro, and epidemiological studies suggest higher serum IGF-I levels increase the risk of breast cancer. IGF-I and IGFBP-3 have therefore been measured in women with advanced breast cancer to determine if changes in serum levels predict the response to treatment by chemotherapy. METHODS: Serum IGF-I and IGFBP-3 levels were measured in 14 patients before and after 1 week of chemotherapy. Changes in serum levels were compared with duration of survival. RESULTS: Mean basal serum levels of IGF-I and IGFBP-3 were not significantly different between patients with advanced breast cancer and controls or women with early breast cancer. Serum IGFBP-3 fell significantly 1 week after initiation of chemotherapy. Patient survival was not significantly related to baseline IGF-I or IGFBP-3 levels, but when the fall in serum levels 1 week after starting treatment was expressed either as absolute change or as a percentage of baseline, those individuals with a decrease in IGFBP-3 greater than the median had significantly poorer survival (median survival 5.5 months vs 18 months). These results were independent of other prognostic variables such as previous disease-free survival, and were also unaffected by the change in serum albumin with treatment. The fall in IGF-I and IGFBP-3 with chemotherapy mainly occurred in those with hepatic metastases, but prediction of survival was explained solely by the extent of the fall in IGFBP-3. CONCLUSIONS: This preliminary study has shown that serum IGFBP-3 falls significantly following initiation of chemotherapy and the extent of reduction significantly predicts the response to treatment.