Capecitabine is an active drug in the treatment of paclitaxel-refractory metastatic breast cancer. It has a favorable toxicity profile with the added advantage of being an oral drug administered at home.

BackgroundOver 37 000 new colorectal cancers are diagnosed in the UK each year. Most present symptomatically to primary care. AimTo conduct a systematic review of the diagnostic value of symptoms associated with colorectal cancer. DesignSystematic review. MethodMEDLINE, Embase, Cochrane Library, and CINAHL were searched to February 2010, for diagnostic studies of symptomatic adult patients in primary care. Studies of asymptomatic patients, screening, referred populations, or patients with colorectal cancer recurrences, or with fewer than 100 participants were excluded. The target condition was colorectal cancer. Data were extracted to estimate the diagnostic performance of each symptom or pair of symptoms. Data were pooled in a meta-analysis. The quality of studies was assessed with the QUADAS tool. ResultsTwenty-three studies were included. Positive predictive values (PPVs) for rectal bleeding from 13 papers ranged from 2.2% to 16%, with a pooled estimate of 8.1% (95% confidence interval [CI] = 6.0% to 11%) in those aged ≥50 years. Pooled PPV estimates for other symptoms were: abdominal pain (three studies) 3.3% (95% CI = 0.7% to 16%); and anaemia (four studies) 9.7% (95% CI = 3.5% to 27%). For rectal bleeding accompanied by weight loss or change in bowel habit, pooled positive likelihood ratios (PLRs) were 1.9 (95% CI = 1.3 to 2.8) and 1.8 (95% CI = 1.3 to 2.5) respectively, suggesting higher risk when both symptoms were present. Conversely, the PLR was one or less for abdominal pain, diarrhoea, or constipation accompanying rectal bleeding. ConclusionThe findings suggest that investigation of rectal bleeding or anaemia in primary care patients is warranted, irrespective of whether other symptoms are present. The risks from other single symptoms are lower, though multiple symptoms also warrant investigation.

Capecitabine is a tolerable oral outpatient therapy that shows promising clinical activity in a variety of cancers. The recommended phase II dose is 2,510 mg/m2 daily administered by this intermittent schedule.

Purpose: The purpose of this study was to determine the maximum tolerated dose, toxicity, and pharmacokinetics of BMS-247550 administered as a 1-h i.v. infusion every 3 weeks.Experimental Design: Patients with advanced solid malignancies were premedicated and treated with escalating doses of BMS-247550. Blood sampling was performed to characterize the pharmacodynamics and pharmacokinetics of BMS-247550.Results: Twenty-five patients were treated at six dose levels ranging from 7.4 to 59.2 mg/m 2 . At 50 mg/m 2 , 4 of 9 patients (44.4%) had dose-limiting toxicity (neutropenia, abdominal pain/nausea). At 40 mg/m 2 (the recommended Phase II dose), 2 of 12 patients (16.7%) had dose-limiting neutropenia. Overall, the most common nonhematological toxicity was fatigue/generalized weakness (grade 3-4 seen in 9.0% of patients), followed by neurosensory deficits manifested as peripheral neuropathy and by gastrointestinal discomfort. At 40 mg/m 2 , the incidence of grade 3 fatigue, abdominal pain, diarrhea, and neuropathy was 7.7%. Grade 1-2 neuropathy was observed in all patients enrolled and treated at 40 mg/m 2 . Two patients with paclitaxel-refractory ovarian cancer, one patient with taxane-naïve breast cancer, and another patient with docetaxel-refractory breast cancer had objective partial responses (lasting 6.0, 5.3, 3.0, and 4.5 months, respectively)

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Summary Ixabepilone (BMS-247550) is a semi-synthetic, microtubule stabilizing epothilone B analogue which is more potent than taxanes and has displayed activity in taxane-resistant patients. The human plasma pharmacokinetics of ixabepilone have been described. However, the excretory pathways and contribution of metabolism to ixabepilone elimination have not been determined. To investigate the elimination pathways of ixabepilone we initiated a mass balance study in cancer patients. Due to autoradiolysis, ixabepilone proved to be very unstable when labeled with conventional [ 14 C]-levels (100 μCi in a typical human radio-tracer study). This necessitated the use of much lower levels of [ 14 C]-labeling and an ultrasensitive detection method, Accelerator Mass Spectrometry (AMS). Eight patients with advanced cancer (3 males, 5 females; median age 54.5 y; performance status 0-2) received an intravenous dose of 70 mg, 80 nCi of [ 14 C] ixabepilone over 3 h. Plasma, urine and faeces were collected up to 7 days after administration and total radioactivity (TRA) was determined using AMS. Ixabepilone in plasma and urine was quantitated using a validated LC-MS/MS method. Mean recovery of ixabepilone-derived radioactivity was 77.3% of dose. Fecal excretion was 52.2% and urinary excretion was 25.1%. Only a minor part of TRA is accounted for by unchanged ixabepilone in both plasma and urine, which indicates that metabolism is a major elimination mechanism for this drug. Future studies should focus on structural elucidation of ixabepilone metabolites and characterization of their activities.

Recommended combination doses of continuous capecitabine and paclitaxel are capecitabine 1,331 mg/m(2)/d and paclitaxel 175 mg/m(2)/d IV every 3 weeks. Favorable preclinical mechanistic interactions between capecitabine and paclitaxel, as well as an acceptable toxicity profile without clinically relevant pharmacokinetic interactions, support the performance of disease-directed evaluations of this combination.

Recommended combination doses of capecitabine on an intermittent schedule and paclitaxel are capecitabine 1650 mg/m2/d orally for 14 days and paclitaxel 175 mg/m2 i.v. every 3 weeks. The favorable preclinical interactions between capecitabine and paclitaxel, as well as the acceptable toxicity profile and antitumor activity in patients with metastatic breast cancer, support further clinical evaluations to determine an optimal role for the combination of capecitabine and paclitaxel in breast cancer and other relevant malignancies.