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Selumetinib is a potent, selective MEK inhibitor with efficacy in several tumor models. This study compared selumetinib with capecitabine in patients with advanced or metastatic pancreatic cancer who had been pretreated with a gemcitabine-based regimen. In this randomized, multicenter phase II study (NCT00372944), patients received either 100 mg oral selumetinib twice daily or 1,250 mg/m(2) oral capecitabine twice daily for 2 weeks followed by a 1-week break, given in 3-weekly cycles. The primary endpoint was overall survival. In all 70 patients were randomized. The median survival was 5.4 months in the selumetinib group and 5.0 months in the capecitabine group (hazard ratio 1.03; two-sided 80% confidence interval = 0.68,1.57; P = 0.92). Disease progression events occurred in 84% and 88% of patients in the selumetinib and capecitabine treatment groups, respectively. Gastrointestinal adverse events (nausea, vomiting and diarrhea) were commonly observed in both treatment groups. Other frequently reported adverse events were acneiform dermatitis and peripheral edema with selumetinib, and palmar-plantar erythrodysaesthesia with capecitabine. There was no statistically significant difference in overall survival between selumetinib and capecitabine as second-line treatment in patients with advanced pancreatic cancer. Selumetinib was well tolerated with a manageable safety profile.

Background: Vandetanib (ZACTIMA) is a once-daily oral inhibitor of vascular endothelial growth factor, epidermal growth factor and RET receptor tyrosine kinases. The safety and tolerability of vandetanib plus mFOLFOX6 was investigated in patients with advanced colorectal cancer (CRC)., Methods: Patients eligible for first- or second-line chemotherapy received once-daily oral doses of vandetanib (100 or 300 mg) plus 14-day treatment cycles of mFOLFOX6., Results: Seventeen patients received vandetanib 100 mg (n = 9) or 300 mg (n = 8) plus mFOLFOX6. The protocol definition of a tolerable dose (vandetanib-related dose-limiting toxicity [DLT] in less than two patients) was met in both dose cohorts, with one DLT of diarrhoea reported in each. Overall, the most common adverse events were diarrhoea, nausea and lethargy (all n = 11). There was no pharmacokinetic interaction between vandetanib and mFOLFOX6. Preliminary efficacy results included one complete response and three confirmed partial responses., Conclusions: In patients with advanced CRC, once-daily vandetanib (100 or 300 mg) with mFOLFOX6 was generally well tolerated.

Randomised trials have established the importance of oxaliplatin (O) and irinotecan (I) in advanced colorectal cancer (CRC). However, patients enrolled in clinical studies represent a restricted population and little is known about the use of O and I in the general population and the subsequent outcomes outside clinical studies. We used the Australian Health Insurance Commission (HIC) database to describe prescribing patterns of O and I and their impact on survival in all patients with 5-fluorouracil (5-FU) refractory CRC in Australia in 2002 and 2003. In 2999 patients, there was a marked increase in initial treatment with O rather than I; 48% of patients received O first in 2002 vs 66% in 2003 (P<0.001). Overall 40-45% of patients received both O and I; however, younger patients were more likely to receive both drugs (P<0.001). After 5-FU failure and treatment with O or I, the proportion of patients surviving 6 or 12 months was estimated to be 0.67 (95% CI, 0.66-0.69) and 0.42 (95% CI, 0.40-0.44), respectively. Survival was superior for patients who received both O and I; however, the sequence of agents had no impact. Older patients (> or =70 years) had inferior survival no matter which drug was used as initial treatment. Analysis of the Australian HIC database provides a valuable means of assessing patterns of use and outcomes of new therapies.

Protracted venous infusion 5-fluorouracil (5FU) combined with mitomycin C (MMC) has demonstrated significant activity against metastatic colorectal cancer. Owing to potential synergy based upon upregulation of thymidine phosphorylase by MMC, the combination of capecitabine and MMC may improve outcomes in irinotecan-refractory disease. Eligible patients with progressive disease during or within 6 months of second-line chemotherapy were treated with capecitabine (1250 mg m(-2) twice daily) days 1-14 every 3 weeks and MMC (7 mg m(-2) IV bolus) once every 6 weeks. A total of 36 patients were recruited, with a median age of 64 years (range 40-77), and 23 patients (78%) were performance status 0-1. The objective response rate was 15.2%. In all, 48.5% of patients had stable disease. Median failure-free survival was 5.4 months (95% CI 4.6-6.2). Median overall survival was 9.3 months (95% CI: 6.9-11.7). Grade 3 toxicities were palmar-plantar erythema 16.7%, vomiting 8.3%, diarrhoea 2.8%, anaemia 8.3%, and neutropenia 2.8%. No patients developed haemolytic uraemic syndrome. Symptomatic improvement occurred for pain, bowel symptoms, and dyspnoea. Capecitabine in combination with MMC is an effective regimen for metastatic colorectal cancer resistant to 5FU and irinotecan with an acceptable toxicity profile and a convenient administration schedule.

This study used a prospectively managed clinical database in order to identify 1470 patients with gastrointestinal cancers receiving protracted venous infusion (PVI) fluorouracil (5FU). It aimed to determine the time course of toxicity due to PVI 5FU and to analyse factors predicting toxicity. The initial development of stomatitis occurred more rapidly than diarrhoea or palmar plantar erythema (PPE). The percentage of patients with National Cancer Institute Common Toxicity Criteria (CTC) grade 2 or worse PPE peaked at 9% between weeks 8 and 17, whereas this peak occurred earlier for stomatitis and diarrhoea. The development of CTC grade 1 toxicity in the first 28 days after commencement of chemotherapy was classified as early grade 1 toxicity. Multivariate Cox regression analysis showed that female sex, better performance status, elevated bilirubin, early grade 1 PPE and early grade 1 diarrhoea were independent prognostic factors for the development of CTC grade 2 or worse PPE (P<0.01). Female sex, increased age, elevated alanine transaminase and urea and early grade 1 PPE were significant independent prognostic factors for the development of CTC grade 2 or worse stomatitis (P<0.01). Early CTC grade 1 diarrhoea predicted CTC grade 2 or worse diarrhoea (P<0.01). Older, female patients with good performance status and impaired liver and renal function who develop early grade 1 PPE alone or in combination with diarrhoea are at highest risk of subsequently developing grade 2 or worse PPE or stomatitis during treatment with PVI 5FU. Reduction of infused 5FU dose should be considered for these patients. Such an approach could both reduce severe toxicity owing to chemotherapy and minimise treatment delays, and should be evaluated prospectively.

Background: This randomised study compared protracted venous infusion (PVI) fluorouracil (5-FU) with PVI 5-FU plus mitomycin C (MMC) in patients with advanced oesophago-gastric cancer., Patients and Methods: Two hundred and fifty-four patients with adenocarcinoma, squamous cell carcinoma or undifferentiated carcinoma involving the oesophagus, oesophago-gastric junction or the stomach were randomised. The major end points were tumour response, survival, toxicity and quality of life., Results: The median age of patients treated was 72 years and the two arms were well-balanced for baseline demographic factors. The overall response rate was 16.1% [95% confidence interval (CI) 9.5% to 22.7%] in patients treated with PVI 5-FU alone compared with 19.1% (95% CI 12.0% to 26.0%) for those treated with PVI 5-FU plus MMC (P = 0.555). Median time to treatment failure was 3.9 months for PVI 5-FU and 3.8 months for PVI 5-FU plus MMC (P = 0.195). Median survival was 6.3 months for PVI 5-FU and 5.3 months for PVI 5-FU plus MMC (P = 1.0). Toxicity was mild for both treatments. Symptomatic benefit measured by improvement in pain control, weight loss, dysphagia and oesophageal reflux was observed in over 64% of patients in each arm. Quality of life scores were comparable in each arm., Conclusions: PVI 5-FU is a safe, effective form of palliation for patients with advanced oesophago-gastric cancer although the addition of MMC adds little extra benefit.

Background: Dihydropyrimidine dehydrogenase (DPD) tumour expression may provide added value to human equilibrative nucleoside transporter-1 (hENT1) tumour expression in predicting survival following pyrimidine-based adjuvant chemotherapy.Methods: DPD and hENT1 immunohistochemistry and scoring was completed on tumour cores from 238 patients with pancreatic cancer in the ESPAC-3(v2) trial, randomised to either postoperative gemcitabine or 5-fluorouracil/folinic acid (5FU/FA).Results: DPD tumour expression was associated with reduced overall survival (hazard ratio, HR = 1.73 [95% confidence interval, CI = 1.21-2.49], p = 0.003). This was significant in the 5FU/FA arm (HR = 2.07 [95% CI = 1.22-3.53], p = 0.007), but not in the gemcitabine arm (HR = 1.47 [0.91-3.37], p = 0.119). High hENT1 tumour expression was associated with increased survival in gemcitabine treated (HR = 0.56 [0.38-0.82], p = 0.003) but not in 5FU/FA treated patients (HR = 1.19 [0.80-1.78], p = 0.390). In patients with low hENT1 tumour expression, high DPD tumour expression was associated with a worse median [95% CI] survival in the 5FU/FA arm (9.7 [5.3-30.4] vs 29.2 [19.5-41.9] months, p = 0.002) but not in the gemcitabine arm (14.0 [9.1-15.7] vs. 18.0 [7.6-15.3] months, p = 1.000). The interaction of treatment arm and DPD expression was not significant (p = 0.303), but the interaction of treatment arm and hENT1 expression was (p = 0.009).Conclusion: DPD tumour expression was a negative prognostic biomarker. Together with tumour expression of hENT1, DPD tumour expression defined patient subgroups that might benefit from either postoperative 5FU/FA or gemcitabine. [ABSTRACT FROM AUTHOR]

Background: Docetaxel administered 3-weekly with cisplatin and 5-fluorouracil leads to better survival than does standard therapy in patients with oesophagogastric cancer, but leads to high rates of haematological toxicity. Weekly docetaxel is associated with less haematological toxicity. This randomised phase II study tested weekly docetaxel-based combination chemotherapy regimens, with the aim of maintaining their activity while reducing toxicity.Methods: Patients with histologically confirmed metastatic oesophageal or gastric carcinoma were randomised to receive weekly docetaxel (30 mg m(-2)) on days 1 and 8, cisplatin (60 mg m(-2)) on day 1, and 5-fluorouracil (200 mg m(-2) per day) continuously, every 3 weeks (weekly TCF, wTCF); or docetaxel (30 mg m(-2)) on days 1 and 8 and capecitabine (1600 mg m(-2) per day) on days 1-14, every 3 weeks (weekly TX, wTX).Results: A total of 106 patients were enrolled (wTCF, n=50; wTX, n=56). Response rates, the primary end point, were 47% with wTCF and 26% with wTX. Rates of febrile neutropenia were low in each arm. Median progression-free and overall survival times were 5.9 and 11.2 months for wTCF and 4.6 and 10.1 months for wTX, respectively.Conclusion: Weekly TCF and TX have encouraging activity and less haematological toxicity than TCF administered 3-weekly. Weekly docetaxel-based combination regimens warrant further evaluation in this disease. [ABSTRACT FROM AUTHOR]

The purpose of the study was to establish the optimal dose of capecitabine (X) to be used within a multicentre, randomised study evaluating the potential roles of oxaliplatin (O) and X in chemonaive patients (pts) with advanced oesophagogastric cancer. Two by two design was used, and pts were randomised to one of four regimens and stratified for extent of disease, performance status (PS) and centre. The treatment regimens are epirubicin, cisplatin, 5-fluorouracil (ECF), EOF, ECX or EOX. Doses: E 50?mg?m-2, C 60?mg?m-2 and O 130?mg?m-2 i.v. 3 weekly; F 200?mg?m-2?day-1 i.v. and X 500?mg?m-2?b.i.d.-1 (escalated to 625?mg?m-2?b.i.d.-1 after results of first interim analysis) p.o., continuously. First interim analysis was performed when 80 pts had been randomised. Dose-limiting fluoropyrimidine toxicities were stomatitis, palmar plantar erythema (PPE) and diarrhoea; 5.1%of X-treated pts experienced grade 3/4 toxicity. Protocol planned dose escalation of X to 625?mg?m-2?b.i.d.-1 was instituted and a second interim analysis has been performed; results are presented in this paper. A total of 204 pts were randomised at the time of the protocol planned 2nd interim analysis. Grade 3/4 fluoropyrimidine-related toxicity was seen in 13.7%pts receiving F, 8.4%pts receiving X 500?mg?m-2?b.i.d.-1 and 14.7%pts receiving X 625?mg?m-2?b.i.d.-1. Combined complete and partial response rates were ECF 31%(95%CI 18.7-46.3), EOF 39%(95%CI 25.9-53.1), ECX 35%(95%CI 21.4-50.3), EOX 48%(95%CI 33.3-62.8). Grade 3/4 fluoropyrimidine toxicity affected 14.7%of pts treated with X 625?mg?m-2?b.i.d.-1, which is similar to that observed with F, confirming this to be the optimal dose. The replacement of C by O and F by X does not appear to impair efficacy. The trial continues to total accrual of 1000 pts.British Journal of Cancer (2005) 92, 1976-1983. doi:10.1038/sj.bjc.6602572 www.bjcancer.com [ABSTRACT FROM AUTHOR]