Effects of polymorphisms in the MTHFR gene on 5-FU hematological toxicity and efficacy in Thai colorectal cancer patients.

Background: The two common methylenetetrahydrofolate reductase (MTHFR) polymorphisms 677G>A and 1298A>C may have been affecting 5-FU toxicity in cancer patients for decades. Drug efficacy has also been shown by previous studies to be affected. In this study, we investigated the effects of these polymorphisms on 5-FU hematological toxicity and treatment efficacy, to provide enhanced pharmacological treatment for cancer patients. Methods: This is a retrospective study involving 52 Thai colorectal cancer patients who were treated with 5-FU based therapy, using TaqMAN real-time PCR to genotype the MTHFR polymorphisms (677G>A and 1298A>C). The toxicity and response rate were assessed using standardized measures. Results: Neutropenia was significantly more likely to be experienced (P=0.049, OR=7.286, 95% CI=0.697-76.181) by patients with the MTHFR 677G>A polymorphism, in the same way as leukopenia (P =0.036, OR=3.333, 95%CI=2.183-5.090) and thrombocytopenia (P<0.001, OR=3.917, 95%CI=2.404-6.382). The MTHFR 1298A>C polymorphism had no statistical association with hematological toxicity in 5-FU treatment. The response rate to 5-FU was not significantly affected by these two polymorphisms. Conclusion: The MTHFR polymorphism 677G>A is a significant risk factor for developing leukopenia, neutropenia and thrombocytopenia as toxic effects of 5-FU therapy in cancer patients. Therefore, patients receiving 5-FU-based therapy should be aware of their polymorphisms as one risk factor for experiencing severe toxicity.

Evaluation of adverse events and health-related quality of life in patients with colorectal cancer receiving ambulatory home-based chemotherapy in Thailand.

AIMS: To compare adverse events and health-related quality of life in ambulatory home-based chemotherapy with those in inpatient. DESIGN: Prospective non-randomized observational study. METHODS: Participants were divided into two groups according to patients' preference receiving chemotherapy. RESULTS: Sixty-four participants were enrolled in the inpatient, and 111 were in an ambulatory home-based chemotherapy. The frequency of anaemia, neutropenia and thrombocytopenia was significantly higher in inpatient group than in ambulatory home-based chemotherapy group (p < .001, <.001 and .002, respectively). Nausea, mucositis, and fatigue were more common in ambulatory home-based chemotherapy group than in inpatient group (p < .001, .022, and .005, respectively). Patients in the ambulatory home-based chemotherapy group showed higher social well-being (SWB) scores than inpatient group (coefficient 1.92, 95% confidence interval [CI] 0.65 to 3.19, p .003).

Home-based chemotherapy for stage III colon cancer patients in Thailand: Cost-utility and budget impact analyses.

Home-based chemotherapy (HC) is a new treatment alternative to hospital-based chemotherapy treatment (IP) and is administered via portable intravenous pumps at the patient's home. HC reduces the demand for inpatient bed capacity in hospitals and reduces the cost of an infusion. This study takes a societal perspective while conducting the cost-utility and budget impact analyses (BIA) of HC and IP with an mFOLFOX6 regimen on patients with stage III colon cancer. We conducted a cost-utility analysis with a 6-month time horizon. The parameter inputs for the model were gathered from a retrospective cohort study on patients diagnosed with stage III colon cancer at Ramathibodi Hospital, Bangkok. The resource usage of HC and IP was determined based on medical records. The per-unit direct medical, home health service, and adverse events (AE) management costs were gathered from the standard cost list. The health outcome of treatment was measured in terms of quality-adjusted life years. Disutility related to AE was calculated. We conducted a sensitivity analysis for the uncertainty results and performed BIA based on the societal perspective on a 1-year time horizon. HC provided a cost-saving of $1,513.37 per patient for the period of treatment. Thus, assuming 526 patients per year, the use of HC could achieve a cumulative annual cost-saving of $828,436. HC is a cost-saving strategy compared to IP for stage III colon cancer treatment. We recommend that the service reimbursement should include national standardization in chemotherapy regimens as well as practice guidelines and protocols to prevent serious AEs.

Effect of drug metabolizing enzymes and transporters in Thai colorectal cancer patients treated with irinotecan-based chemotherapy.

Genetic polymorphisms in drug metabolizing enzymes and drug transporters may affect irinotecan toxicity. Although genetic polymorphisms have been shown to influence the irinotecan toxicity, data are limited in Thai population. Thus, the aim of this study was to assess the allele and genotype frequencies and the relationship between CYP3A4/5, DPYD, UGT1A1, ABCB1, and ABCC2 genetic variations and irinotecan-induced toxicity in Thai colorectal cancer patients. One hundred and thirty-two patients were genotyped, and the effect of genetic variations on irinotecan-induced toxicity was assessed in 66 patients who received irinotecan-based chemotherapy. Allele frequencies of ABCB1 c.1236C > T, ABCB1 c.3435C > T, ABCC2 c.3972C > T, ABCG2 c.421C > A, CYP3A4*1B, CYP3A4*18, CYP3A5*3, DPYD*5, UGT1A1*28, and UGT1A1*6 were 0.67, 0.43, 0.23, 0.27, 0.01, 0.02, 0.64, 0.19, 0.16, and 0.09, respectively. DPYD*2A and DPYD c.1774C > T variants were not detected in our study population. The ABCC2 c.3972C > T was significantly associated with grade 1-4 neutropenia (P < 0.012) at the first cycle. Patients carrying both UGT1A1*28 and *6 were significantly associated with severe neutropenia at the first (P < 0.001) and second (P = 0.017) cycles. In addition, patients carrying UG1A1*28 and *6 had significantly lower absolute neutrophil count (ANC) nadir at first (P < 0.001) and second (P = 0.001) cycles. This finding suggests that UGT1A1*28, *6, and ABCC2 c.3972C > T might be an important predictor for irinotecan-induced severe neutropenia.

Determination of irinotecan, SN-38 and SN-38 glucuronide using HPLC/MS/MS: Application in a clinical pharmacokinetic and personalized medicine in colorectal cancer patients.

BACKGROUND: Irinotecan (CPT-11) is chemotherapy used mainly in the metastatic colorectal cancer. The purpose of this study was to develop and validate the LC-MS/MS for the simultaneous determination of CPT-11, SN-38, and SN-38G. METHODS: A 100 µL of plasma was prepared after protein precipitation and analyzed on a C18 column using 0.1% acetic acid in water and 0.1% acetic acid in acetonitrile as mobile phases. The mass spectrometer worked with multiple reaction monitoring (MRM) in positive scan mode. The standard curves were linear on a concentration range of 5-10 000 ng/mL for CPT-11, 5-1000 ng/mL for SN-38, and 8-1000 ng/mL for SN-38G. RESULTS: In this assay, the intra and interday precision consisted of ≤9.11% and ≤11.29% for CPT-11, ≤8.70% and 8.31% for SN-38, and ≤9.90 and 9.64% for SN-38G. CONCLUSION: This method was successfully used to quantify CPT-11, SN-38, and SN-38G and applied to a pharmacokinetic study.

Quality of life in gynecologic cancer survivors compared to healthy check-up women.

OBJECTIVE: The primary objective of this study was to compare quality of life of disease-free patients after therapy for gynecologic malignancies at follow-up in comparison with healthy check-up patients. Our second objective was to assess correlation between demographic data, disease and treatment factors and quality of life scores. METHODS: Patients completed the Functional Assessment of Cancer Therapy-General (FACT-G) quality of life questionnaire at least 6 months after treatment for a gynecologic malignancy. Responses were compared to unmatched healthy women who were seen for standard gynecologic screening examinations. Statistical calculation was done using chi-squared tests, Wilcoxon rank-sum, and Kruskal-Wallis one-way analysis and Spearman rank correlations. Factors associated with FACT-G scores were evaluated using univariate and multivariate analyses. RESULTS: Eight hundred and seventy patients were recruited. The median time since therapy was 61 months (range, 6 to 173 months). The overall FACT-G scores were higher in the patient group than in the healthy group (p<0.05). The scores of each subscale measuring physical, functional, social/family and emotional well-being were also higher in the patient group (p<0.05). Multivariate analysis revealed correlation between Eastern Cooperative Oncology Group performance status, educational level, care giver, presence of economic problems and FACT-G scores. CONCLUSION: The quality of life scores were higher in gynecologic cancer patients after treatment. And the factors that associated with the higher score in the patient group are having husband as a caregiver, no financial problem, Eastern Cooperative Oncology Group score 0 or 1 and having high school or higher education.