Pharmacogenetics-Guided Phase I Study of Capecitabine on an Intermittent Schedule in Patients with Advanced or Metastatic Solid Tumours.

The FDA-approved starting dosage of capecitabine is 1,250 mg/m(2), and market research indicates that U.S. physicians routinely prescribe 1,000 mg/m(2). Retrospective analyses however report reduced toxicity and efficacy in a subset of patients with the 3R/3R genotype of the thymidylate synthase gene enhancer region (TSER). This study sought to develop TSER genotype-specific guidelines for capecitabine dosing. Capecitabine was dose-escalated in advanced and/or metastatic cancer patients with TSER 3R/3R (Group A; N = 18) or 2R/2R + 2R/3R (Group B; N = 5) from 1,250 to 1,625 mg/m(2) b.i.d., every 2 weeks on/1 week off for up to 8 cycles. Parent and metabolites pharmacokinetics, adverse events, and tumour response were assessed. The maximum tolerated and recommended doses in 3R/3R patients are 1,625 mg/m(2) and 1,500 mg/m(2). At 1,500 mg/m(2), one in nine 3R/3R patients experienced a dose-limiting toxicity. Dosing guidelines for 2R/2R + 2R/3R remain undetermined due to poor accrual. The results indicate that 3R/3R patients may be amenable to 1,500 mg/m(2) b.i.d. on an intermittent schedule, and is the first to prospectively validate the utility of TSER pharmacogenetic-testing before capecitabine treatment.

Dose modifications in Asian cancer patients with hepatic dysfunction receiving weekly docetaxel: A prospective pharmacokinetic and safety study.

Hepatic dysfunction may modify the safety profile and pharmacokinetics of docetaxel in cancer patients, but no validated guideline exists to guide dose modification necessitated by this uncommon comorbidity. We carried out the first prospective study of a personalized dosage regimen for cancer patients with liver dysfunction treated with docetaxel. Weekly dosages were stratified by hepatic dysfunction classification as such: Category 1, normal; Category 2, mild--alkaline phosphatase, aspartate aminotransferase, and/or alanine aminotransferase ≤5× upper limit of normal (ULN), and total bilirubin within normal range; and Category 3, moderate--any alkaline phosphatase, and aspartate aminotransferase or alanine aminotransferase ≤5-10× ULN, and/or total bilirubin ≤1-1.5× ULN. Category 1, 2 and 3 patients received starting dosages of 40, 30, and 20 mg/m(2) docetaxel, respectively. Pharmacokinetics were evaluated on day 1 and 8 of the first treatment cycle, and entered into a multilevel model to delineate interindividual and interoccasion variability. Adverse event evaluation was carried out weekly for two treatment cycles. We found that docetaxel clearance was significantly different between patient categories (P < 0.001). Median clearance was 22.8, 16.4, and 11.3 L/h/m(2) in Categories 1, 2, and 3, respectively, representing 28% and 50% reduced clearance in mild and moderate liver dysfunction patients, respectively. However, docetaxel exposure (area under the concentration-time curve) and docetaxel-induced neutropenia (nadir and the maximum percentage decrease in neutrophil count) were not significantly different between categories. Median area under the concentration-time curve was 1.74, 1.83, and 1.77 mg·h/L in Categories 1, 2, and 3, respectively. The most common Grade 3/4 toxicity was neutropenia (30.0%). An unplanned comparison with the Child-Pugh and National Cancer Institute Organ Dysfunction Working Group grouping systems suggests that the proposed classification system appears to more effectively discriminate patients by docetaxel clearance and dose requirements. (ClinicalTrials.gov registration no. NCT00703378).

Screening based on risk for colorectal cancer is the most cost-effective approach.

BACKGROUND & AIMS: Performing single endoscopic examinations or selective screening based on risk might be more practical than recommended screening strategies for colorectal cancer (CRC). We investigated the cost effectiveness of these strategies, under real-life conditions of suboptimal compliance, and the societal cost perspective. METHODS: We used Markov modeling to analyze data from 787,000 individuals in Singapore, aged 50 to 75 years, with an age-standardized rate of CRC of 30 to 40/100,000 in 2009. Potential outcomes, incremental cost-effectiveness ratio, and net health benefit were compared between single sigmoidoscopy or colonoscopy and current recommended screening strategies, and also with a strategy of selective screening based on risk of CRC. RESULTS: Performing single sigmoidoscopies on individuals when they are 60 years old was the cheapest screening strategy; it would reduce CRC incidence by 19% and mortality by 16%, compared with no screening. A single colonoscopy is less cost effective than a single sigmoidoscopy, unless the proportion of right-sided lesions exceeds 65%. The fecal occult blood test (iFOBT) had the lowest incremental cost-effectiveness ratio when all strategies were compared with no screening; iFOBT and colonoscopic examinations every 10 years each had extended dominance over other strategies. Screening subjects 50 to 60 years old by iFOBT and subjects 60 to 72 years old with colonoscopies every 10 years was the most cost-effective strategy (US$25,000/quality-adjusted life-years). Risk for CRC, adherence, and cost of colonoscopy were the main determinants of cost effectiveness, based on sensitivity analysis. CONCLUSIONS: Markov modeling analysis indicates that selectively screening individuals for CRC based on risk is the most cost-effective approach; it limits the cost and number of colonoscopies needed and significantly reduces CRC mortality.

Impact of UDP-gluconoryltransferase 2B17 genotype on vorinostat metabolism and clinical outcomes in Asian women with breast cancer.

OBJECTIVES: Vorinostat, a histone deacetylase inhibitor being actively evaluated in solid tumors, is metabolized by UGT2B17. UGT2B17 null genotype (UGT2B17*2) has been shown in vitro to reduce UGT2B17 activity. This variant is common in Asians but rare in Caucasians, and we studied its impact on vorinostat pharmacokinetics and pharmacodynamics in a clinical study in Asian patients with metastatic breast cancer. METHODS: Eligible patients received 400 mg of vorinostat monotherapy daily in a lead-in phase I followed by a phase II study. Patients were genotyped for UGT2B17*2, which was correlated with vorinostat pharmacokinetics and clinical outcomes. RESULTS: Twenty-six patients were treated with no complete response, one partial response, six stable disease lasting for 12 weeks or more, and 19 progressive disease. Sixteen patients (62%) were UGT2B17*2 homozygotes and had significantly lower mean area under the curve ratio of vorinostat-O-glucuronide/vorinostat (1.84 vs. 2.51 on day 1, P=0.02; 1.63 vs. 2.38 on day 15, P=0.028), and trended toward having higher vorinostat area under the curve (399.02 vs. 318.40, P=0.188), more serious adverse events (31 vs. 0%, P=0.121), higher clinical benefit rate (40 vs. 10%, P=0.179), and longer median progression-free survival (3.0 vs. 1.5 months, P=0.087) than patients with at least one wild-type allele. CONCLUSION: UGT2B17*2 genotype reduces vorinostat glucuronidation and may increase vorinostat efficacy and toxicity. These observations are important in the development of vorinostat, and may have clinical implications on other cancer and noncancer drugs that are UGT2B17 substrates such as exemestane and ibuprofen.

Exon sequencing and association analysis of EPHX1 genetic variants with maintenance warfarin dose in a multiethnic Asian population.

BACKGROUND AND OBJECTIVES: Warfarin inhibits vitamin K epoxide reductase, of which microsomal epoxide hydrolase is a putative member. Several studies have found signals of association with warfarin maintenance dose in the EPHX1 gene. The aim of this study was to determine the effects of EPHX1 variants on warfarin maintenance dose in a multiethnic Asian population. METHODS: We sequenced the exons of EPHX1 using PCR and direct sequencing in 279 patients consisting of three major ethnic groups receiving maintenance warfarin with a stable international normalized ratio. The effects of EPHX1 variants were assessed using multiple linear regression. RESULTS: An association between an intronic SNP rs1877724 and warfarin maintenance dose was found, with homozygous variant carriers requiring approximately 0.5 mg/day lower than wild type and heterozygotes after adjustment for covariates. However, its contribution is small, explaining only an additional 0.8% of the dose variability. Rare variants were pooled but there was no association between their presence and warfarin maintenance dose. However, the presence of noncoding rare SNPs was significantly associated with warfarin maintenance dose. CONCLUSION: Despite a significant finding in rs1877724, which concurs with an earlier study, overall, genetic variants in EPHX1 do not have a clinically significant impact on warfarin dose requirements in our population.

Comparison of the pharmacokinetics and pharmacodynamics of S-1 between Caucasian and East Asian patients.

S-1 is an oral fluoropyrimidine anti-neoplastic agent that is converted by CYP2A6 to 5-fluorouracil (5FU). We prospectively studied the pharmacokinetics and pharmacodynamics of S-1 in two groups of East Asian and Caucasian patients with solid malignancy refractory to standard chemotherapy, or for which 5FU was indicated, to elucidate differences in relation to CYP2A6 genotype and phenotype. S-1 was given orally at 30 mg/m(2) b.i.d. for 14 days every 21 days. Dose normalized AUC(0-48 h) for tegafur (P = 0.05) and gimeracil (P = 0.036) were higher in East Asians; conversely, AUC(0-48 h) of fluoro-ß-alanine was higher in Caucasians (P = 0.044). Exposure to 5FU was similar in both groups (P = 0.967). Mean cotinine:nicotine ratio was 54% higher in the Caucasian group (P = 0.03), and correlated with oral clearance of tegafur (r = 0.59; P = 0.002). Grade 3/4 gastrointestinal toxicities were more common in Caucasians than Asians (21%vs 0%). Treatment with S-1 yields no significant difference in 5FU exposure between Caucasians and East Asians.

The need for a system of prognostication in skeletal metastasis to decide best end-of-life care - a call to arms.

INTRODUCTION: The near terminal patient with skeletal metastasis may suitably be palliated with an intramedullary nail whereas another patient with good survival potential may benefit from a more extensive resection and reconstructive procedure. In a previous study by the senior author (Nathan et al, 2005), life expectancy in patients operated on for bone metastases correlated with clinical and haematological parameters in a normogram. We performed a cross-cultural comparison to validate this normogram. MATERIALS AND METHODS: We randomly selected 73 patients who had undergone surgery for metastatic bone disease between 28 December 2000 and 11 March 2009. The time to deaths was recorded from hospital records and telephone interviews. Multiple parameters including clinical, radiological and haematological were evaluated for significant prognostic value using Kaplan-Meier survivorship analysis. Statistically significant parameters were entered into a Cox regression model for statistically independent significance. A multi-tier prediction of survival was performed by workers from various levels of seniority. RESULTS: At the time of analysis, there were 40 deaths (55%). Median survival was 15.8 (95% CI, 7.9 to 23.7) months. Kaplan-Meier analysis showed that low haemoglobin (P = 0.0000005), presence of lymph node metastases (P = 0.00008), multiple bone metastases (P = 0.003), presence of visceral metastases, (P = 0.007), low lymphocyte count (P = 0.02) and low serum albumin (P = 0.02) were significantly associated with poor survival. By Cox regression analysis, presence of visceral metastases (P = 0.002), presence of lymph node metastases (P = 0.0002) and low haemoglobin (P = 0.01) were shown to be independent factors in the prediction of survival. Survivorship readings were superimposed onto the previous normogram and found to be similar. Independent blinded use of the normogram allowed good prediction of survival. There was a tendency to underestimate survival when patients survived beyond 1 year of skeletal metastasis. CONCLUSION: Our findings are similar to that of the previous study in showing a relationship between the above-mentioned parameters and survival. This is despite differences in patient demographic characteristics and management protocols. Use of the tools may allow better siting of most appropriate surgery in metastatic bony disease.

Chronic brainstem ischemia in subclavian steal syndrome.

Subclavian steal syndrome is usually an incidental finding and rarely causes vertebrobasilar ischemia. We present a 58-year-old man who, over six months, experienced progressive slowing in both talking and walking. Cervical duplex sonography revealed severe stenosis of the right subclavian artery; fixed retrograde flow was noted in the right vertebral artery on transcranial Doppler. The hyperemia-ischemia cuff test resulted in considerable reduction in flow velocities in both posterior cerebral arteries. We attributed his slowness to chronic vertebrobasilar ischemia and surgical revascularization was performed. His symptoms subsided immediately after surgery. The improved perfusion in the posterior circulation was demonstrated on technetium-99 hexamethylpropyleneamine oxime single photon-emission CT. Early diagnosis and prompt treatment resulted in an improved quality of life.

Small cell gallbladder carcinoma complicated by paraneoplastic hyponatremia: a case report and literature review.

INTRODUCTION: Gallbladder carcinoma has been associated with various paraneoplastic syndromes. These may be the presenting manifestations that lead the clinician to a diagnosis. CASE REPORT: We report a case of small cell gallbladder carcinoma complicated by paraneoplastic hyponatremia. The hyponatremia was further exacerbated by platinum-based chemotherapy. DISCUSSION: There have previously been no reports of paraneoplastic hyponatremia in gallbladder carcinoma. We discuss the management of this problem and also provide a short literature review on the other paraneoplastic syndromes associated with gallbladder carcinoma. CONCLUSION: Symptoms and signs of gallbladder cancer may be insidious. Thorough workup is needed if the patient presents with symptoms and signs of a paraneoplastic syndrome.

Phase II study of gemcitabine and carboplatin in metastatic breast cancers with prior exposure to anthracyclines and taxanes.

BACKGROUND: Patients with metastatic breast cancer (MBC) are usually exposed to both anthracyclines and taxanes during neoadjuvant or adjuvant treatment of primary breast cancer or during initial therapy of MBC. We investigate the combination of gemcitabine and carboplatin in MBC with prior exposure to both anthracyclines and taxanes. PATIENTS AND METHODS: MBC patients previously treated with anthracyclines and taxanes were enrolled in a single tertiary center phase II study. Treatment consisted of gemcitabine (1,000 mg/m(2) I.V on days 1 and 8) and carboplatin (AUC 5 I.V on day 1) administered every 3 weeks. Results 41 patients were recruited. Objective response rate was 39% including 1 complete response (2%) and 15 partial responses (37%). Twelve patients (29%) had stable disease. Median time to progression was 4.6 months (95% CI 3.3-5.9 months) and median overall survival 10.5 months (95% CI 7.6-13.4 months). Grade 3 & 4 hematological toxicities included neutropenia (58%), febrile neutropenia (15%), anemia (12%) and thrombocytopenia (49%), including 7% who required platelet transfusions. Non-hematological toxicity was rarely severe. 56% of patients required at least one dose reduction; the mean relative dose intensity for gemcitabine and carboplatin were 0.82 (range 0.5-1.0) and 0.95 (range 0.75-1.00) respectively, with no difference in dose intensity between responders and non-responders. CONCLUSION: Gemcitabine combined with carboplatin has promising efficacy in MBC with prior treatment with anthracyclines and taxanes but has significant haematological toxicities requiring dose modifications. The regimen may be modified to gemcitabine 800 mg/m(2) days 1 and 8 to improve tolerability.

Post-treatment tumor gene expression signatures are more predictive of treatment outcomes than baseline signatures in breast cancer.

OBJECTIVE: Tumor gene expression signatures have been used to classify, prognosticate, and predict chemotherapy sensitivity in breast cancer, although almost all efforts have been focused on the unchallenged baseline tumor. Most cancer patients receive systemic therapy, and exposure to drug may modify the tumor's short-term and long-term outcomes. Drug-induced tumor gene signatures may thus be more predictive of treatment outcomes than the unperturbed tumor gene signatures. METHODS: Using a set of 47 breast cancer patients, we obtained paired prechemotherapy and postchemotherapy tumor biopsies and developed gene panels of baseline tumor (T1), postchemotherapy tumor (T2), and chemotherapy-induced relative change signatures (TDelta) to predict pathological response and progression-free survival (PFS). The signatures were validated in two independent test sets with paired prechemotherapy and postchemotherapy tumor samples, comprising of 18-20 patients each. RESULTS: T2 and TDelta were superior to T1 signatures in predicting for PFS (area under the curve of receiver operating characteristic 0.770 and 0.660 vs. 0.530) and pathological response (area under the curve of receiver operating characteristic 0.631 and 0.462 vs. 0.446) in the validation sets. In multivariate analysis for PFS with other clinical predictors, T2, but not T1, signatures remained as significant independent predictors. CONCLUSION: Postchemotherapy tumor gene signatures outperformed baseline signatures and clinical predictors in predicting for pathological response and PFS, independent of clinical and pathological response to chemotherapy. Drug-induced tumor gene signatures may be more informative than unchallenged signatures in predicting treatment outcomes. These findings challenge the current practice of relying only on the baseline tumor to predict outcome, which overlooks the contributions of therapeutic interventions.

Debulking nephrectomy followed by a "watch and wait" approach in metastatic renal cell carcinoma.

OBJECTIVE: Debulking nephrectomy has been shown to improve survival in metastatic renal cell carcinoma and is now a standard procedure. However, it remains controversial if debulking nephrectomy should routinely be followed by interferon. We report on the clinical course of metastatic renal cell carcinoma patients after debulking nephrectomy who did not receive routine systemic anticancer therapy. PATIENTS AND METHODS: Fifteen consecutive metastatic renal cell carcinoma patients were put on a "watch and wait" protocol after debulking nephrectomy. This included regular computer tomographic scans done at 6 to 8 weeks after debulking nephrectomy, and subsequently 3 to 4 monthly. Systemic treatment was instituted only after disease progression. RESULTS: At a median follow-up of 18 months, 80% of patients had progressed. However, a third of the patients had at least 6 months of progression-free interval, and 3 of 15 patients had not progressed at prolonged follow-up durations of 18, 23, and 46 months. A third of the patients remained alive and the median survival for the cohort was 25 months. Preoperative predictive factors for nonprogression after debulking nephrectomy included absence of abnormal laboratory indices, single organ system metastases, and good performance status. CONCLUSIONS: There is a subset of metastatic renal cell carcinoma patients who will have an indolent course after debulking nephrectomy. Toxic systemic therapies may be avoided in such patients for a significant period of time.

Multi-centre phase II trial of Thalidomide in the treatment of unresectable hepatocellular carcinoma.

Hepatocellular carcinoma (HCC) is a hypervascular tumour, which overexpresses vascular endothelial growth factor. Thalidomide is an antiangiogenic agent with activity in refractory multiple myeloma. The purpose of this multi-centre phase II study was to evaluate the efficacy and toxicity of thalidomide in patients with advanced HCC. From February 2000 to November 2001, 37 patients with histologically proven, bi-dimensionally measurable advanced, unresectable HCC were enrolled. The starting dose of Thalidomide was 100 mg per day and escalated weekly by 100 mg to a maximum dose of 800 mg/day according to individual patient tolerance. Radiological tumour response and treatment related toxicities were prospectively assessed. Thirty-seven patients were evaluable for toxicity and 24 patients were evaluable for response. The median Thalidomide dose was 400 mg/day. There was no complete response (CR). One patient had a radiological partial response (PR) (3%; 95% confidence interval [95% CI], 0% to 8%) and six (16%) patients had stable disease for more than 6 months. Somnolence and fatigue were the most common side effects, occurring in 84% and 73% of patients respectively. Thalidomide monotherapy is tolerable and associated with modest antitumour activity in advanced HCC.