Capecitabine In Colorectal Cancer Research Articles

The effect of TJ-28 (Eppikajutsuto) on the prevention of hand-foot syndrome using Capecitabine for colorectal cancer: The Yokohama Clinical Oncology Group Study (YCOG1102)

Eppikajututo (TJ-28, a Kampo medicine) is effective against rheumatoid arthritis and eczema. We conducted a randomized comparative trial to assess the efficacy of TJ-28 for preventing hand-foot syndrome (HFS) as a complication of adjuvant chemotherapy using capecitabine. The present study was a multi-institutional randomized-controlled trial (UMIN000005899). Colorectal cancer patients scheduled to receive capecitabine chemotherapy as adjuvant therapy were randomly assigned to receive TJ-28 (7500mg/day) or oral pyridoxine (60mg/day). Patients were monitored for the development of grade ≥ 2 HFS according to the National Cancer Institute Common Toxicity Criteria until chemotherapy completion. Twenty-two patients were enrolled in this study. The relative dose intensity of capecitabine was 76.2% in the TJ-28 group and 68.2% in the pyridoxine group. Grade ≥ 2 HFS developed in 6 (50.0%) of 12 TJ-28 patients and in 4 (40.0%) of 10 pyridoxine patients. Chemotherapy treatment failure was observed in seven patients, mainly due to HFS, liver dysfunction, diarrhea, and neutropenia. Chemotherapy treatment failure due to HFS occurred in none of the TJ-28 group and 2 patients (20.0%) in the pyridoxine group (p = 0.114). Capecitabine-associated HFS was not markedly prevented by TJ-28 compared with pyridoxine. However, TJ-28 might support the continuation of chemotherapy with capecitabine. Further studies are warranted to clarify the benefits of TJ-28.

Dihydropyrimidine Dehydrogenase Levels in Colorectal Cancer Cells Treated with a Combination of Heat Shock Protein 90 Inhibitor and Oxaliplatin or Capecitabine.

Purpose: Dihydropyrimidine dehydrogenase (DPD) is the principal enzyme in the catabolism of fluoropyrimidine drugs including capecitabine. A recent report has suggested that oxaliplatin chemotherapy is associated with elevated DPD levels and chemoresistance pattern. As a newly developed chemotherapeutic agent, 17-allyloamino-17-demethoxy-geldanamycin (17-AAG) can be effective in combination therapy with oxaliplatin and capecitabine in colorectal cancer (CRC). DPD expression level can be a predictive factor in oxaliplatin and capecitabine-based chemotherapy. We evaluated DPD in mRNA and protein levels with new treatments: 17-AAG in combination with oxaliplatin and capecitabine in HT-29 and HCT-116 cell lines. Methods: Drug sensitivity was determined by the water-soluble tetrazolium-1 assay in a previous survey. Then, we evaluated the expression levels of DPD and its relationship with the chemotherapy response in capecitabine, oxaliplatin, and 17-AAG treated cases in single and combination cases in two panels of CRC cell lines. DPD gene and protein expression levels were determined by real-time polymerase chain reaction and western blotting assay, respectively. Results: DPD gene expression levels insignificantly increased in single-treated cases versus untreated controls in both cell lines versus controls. Then, the capecitabine and oxaliplatin were added in double combinations, where DPD gene and protein expression increased in combination cases compared to pre-chemotherapy and single drug treatments. Conclusion: The elevated levels of cytotoxicity in more effective combinations could be related to a different mechanism apart from DPD mediating effects or high DPD level in the remaining resistance cells (drug-insensitive cells), which should be investigated in subsequent studies.

Single nucleotide polymorphisms of ENOSF1 are predictors of therapeutic safety of capecitabine in colorectal cancer

Single nucleotide polymorphisms of <i>ENOSF1</i> are predictors of therapeutic safety of capecitabine in colorectal cancer

A polymorphism in ABCC4 is related to efficacy of 5-FU/capecitabine-based chemotherapy in colorectal cancer patients

To investigate the association of microRNA (miRNA) binding-site polymorphisms in the drug transporter genes with the efficacy of 5-Fluorouracil (5-FU)/capecitabine-based chemotherapy in colorectal cancer (CRC), 6 polymorphisms were determined in 432 CRC patients by using DNA sequencing method. The impacts of the polymorphisms on the miRNA-mediated regulation of gene expression were evaluated by using the methods including quantitative real-time PCR, western blotting, and luciferase reporter assays. The effects of miRNA on the intracellular concentration and cytotoxicity of 5-FU in CRC cells were measured by high performance liquid chromatography conjected tandem mass spectrometry (HPLC-MS/MS) and MTT methods, respectively. Statistical analysis showed that a polymorphism rs3742106 in the 3′-UTR of ATP-binding cassette subfamily C member 4 (ABCC4) gene was significantly associated with the efficacy of 5-FU/capecitabine-based chemotherapy in CRC. The patients with T/T genotype had significantly higher response rate than those with G/G and G/T genotypes. The expression of ABCC4 was inhibited by miR-3190-5p through binding to the 3′-UTR of the ABCC4 gene. This regulatory role of miR-3190-5p was disrupted by rs3742106. Furthermore, we found that the intracellular concentration of 5-FU was elevated by miR-3190-5p, and consequently the sensitivity of CRC cells to 5-FU was also enhanced. Rs3742106 might be regarded as a genetic biomarker for individualized use of 5-FU and capecitabine in CRC.

Factors Impacting Treatment Choice in the First-Line Treatment of Colorectal Cancer.

IntroductionTo investigate the factors that affect the choice of 5-fluorouracil (5-FU) or its oral alternative, capecitabine, as first-line treatment in patients with colorectal cancer (CRC).MethodsPatients treated with 5-FU or capecitabine for CRC between January 1, 2011 and December 31, 2013 in a teaching hospital in the Sydney metropolitan area, Australia were identified using the hospital’s database MOSAIQ®. The electronic medical record of each patient was manually reviewed to extract factors potentially affecting treatment choice. Logistic regression was used to assess which patient and/or treatment factors could explain the choice between 5-FU or capecitabine. Where it was available in the medical correspondence, the explicit reason for the choice made was extracted.Results170 CRC patients were included; 119 on 5-FU, and 51 on capecitabine. The odds of receiving capecitabine as a first-line treatment were positively associated with giving patients a choice in the decision (OR = 17.51, 95% CI: 5.37–57.08). Qualitative data suggest treatment choices were motivated by convenience (oral administration) and tolerability. Time from diagnosis to treatment commencement (OR = 1.02 per month, 95% CI 1.00–1.04) was also found to be positively associated with the choice of capecitabine. The odds of being treated with capecitabine were lower for patients who lived further from the treating hospital (OR = 0.22, 95% CI 0.05–0.94).ConclusionThis study suggests that patient choice, favoring oral capecitabine over i.v. 5-FU, was a key factor influencing first-line treatment for CRC in this cohort. To respect their autonomy, patients should be involved in the clinical decision making process.Electronic supplementary materialThe online version of this article (doi:10.1007/s40487-016-0020-4) contains supplementary material, which is available to authorized users.

2171 Effect of degradation rate of 5-FU and genetic polymorphisms of DPYD, TSER and MTHFR on toxicity of capecitabine in colorectal cancer

2171 Effect of degradation rate of 5-FU and genetic polymorphisms of DPYD, TSER and MTHFR on toxicity of capecitabine in colorectal cancer

Use of capecitabine in management of early colon cancer

Capecitabine (Xeloda®, Roche, Basel, Switzerland) is a pro-drug of 5-fluorouracil (5-FU), and it is converted to 5-FU in the cancer cell by enzymatic degradation. The role of capecitabine in colorectal cancer has evolved in the last 15 years. In early trials in the metastatic setting, capecitabine has shown superior response rates compared with those achieved with 5-FU (Mayo Clinic regimen) (26% vs 17%), with equivalent progression-free survival and overall survival. In the adjuvant setting, the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial demonstrated that capecitabine as a single agent led to improvement in relapse-free survival (hazard ratio: 0.86, 95% confidence interval: 0.74–0.99, P = 0.04) and was associated with significantly fewer adverse events than 5-FU plus leucovorin (LV, folinic acid). On the basis of the X-ACT trial, capecitabine was approved by the United States Food and Drug Administration, the National Institute for Clinical Excellence, and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer. The next step was to incorporate capecitabine into combination therapy. The XELOXA trial studied the combination of capecitabine and oxaliplatin (XELOX) vs 5-FU/LV and demonstrated 5-year disease-free survival of 66% for XELOX, compared with 60% for 5-FU/LV. The toxicity profile was also quite comparable in the two arms. So both the single agent use of capecitabine as well as in combination with oxaliplatin can be considered as part of the standard of care in management of early colon cancer in appropriately selected patient groups.

Use of capecitabine in management of early colon cancer

Use of capecitabine in management of early colon cancer H Hameed, J CassidyBeatson West of Scotland Cancer Centre, Glasgow, Scotland, UKAbstract: Capecitabine (Xeloda®, Roche, Basel, Switzerland) is a pro-drug of 5-fluorouracil (5-FU), and it is converted to 5-FU in the cancer cell by enzymatic degradation. The role of capecitabine in colorectal cancer has evolved in the last 15 years. In early trials in the metastatic setting, capecitabine has shown superior response rates compared with those achieved with 5-FU (Mayo Clinic regimen) (26% vs 17%), with equivalent progression-free survival and overall survival. In the adjuvant setting, the Xeloda in Adjuvant Colon Cancer Therapy (X-ACT) trial demonstrated that capecitabine as a single agent led to improvement in relapse-free survival (hazard ratio: 0.86, 95% confidence interval: 0.74–0.99, P = 0.04) and was associated with significantly fewer adverse events than 5-FU plus leucovorin (LV, folinic acid). On the basis of the X-ACT trial, capecitabine was approved by the United States Food and Drug Administration, the National Institute for Clinical Excellence, and the Scottish Medicines Consortium as monotherapy for the adjuvant treatment of stage III colon cancer. The next step was to incorporate capecitabine into combination therapy. The XELOXA trial studied the combination of capecitabine and oxaliplatin (XELOX) vs 5-FU/LV and demonstrated 5-year disease-free survival of 66% for XELOX, compared with 60% for 5-FU/LV. The toxicity profile was also quite comparable in the two arms. So both the single agent use of capecitabine as well as in combination with oxaliplatin can be considered as part of the standard of care in management of early colon cancer in appropriately selected patient groups.Keywords: 5-fluorouracil, 5-FU, leucovorin, folinic acid, LV, XELOX, oxaliplatin, FOLFOX

Abstract P2-09-24: Relationship of Capecitabine Response to Thymidine Phosphorylase Expression and Overall Survival in Advanced Breast Cancer

Abstract Background: Capecitabine is an oral fluoropyrimidine carbamate that is metabolised to FU through three enzymatic steps. Thymidine phosphorylase (TP) is involved in the final step of the conversion from 5'-deoxy-5-fluorouridine (5'-DFUR) to 5-FU. TP is highly expressed in cancer cells compared to normal tissue. By exploiting this difference in TP activity, capecitabine is activated and preferentially converted into 5-FU within tumours. Besides this, TP is identical to platelet-derived endothelial cell growth factor (PD-ECGF), a known angiogenic factor. While TP expression is predictive of benefit from capecitabine in colorectal cancer (CRC), initial studies in advanced breast cancer (ABC) examining the predictive value of TP and related enzymes have produced mixed results. Furthermore, whether response to capecitabine is associated with any overall survival (OS) benefit has not been studied. Materials and Methods: This retrospective study analysed 92 ABC patients who received at least one cycle of capecitabine for locally advanced or metastatic disease with intention to treat. Best responses to capecitabine (assessed clinically or by imaging) whilst patients were on capecitabine were included for analysis. TP expression was analysed by immunohistochemistry in primary excised samples. Composite TP scoring (including cytoplasm and stroma) was used to define TP status. Chi-squared tests were carried out to find associations between TP and clinical factors. Kaplan Meier survival curves were produced for relapse free survival and OS. The logrank statistic was calculated to test independence of the survival curves by category. Results: On multivariate analysis, when the TP composite factor was added to a Cox regression model for OS using age, ER, grade, nodal status and size, it appeared to act as an independent prognostic factor for OS after first primary (hazard ratio: 0.45, p=0.01). Overall, responses included partial response (PR) in 38% and stable disease (SD) for 3 months or longer in 25% patients. There was no statistically significant correlation for capecitabine response and TP status. Also there was no significant difference in time to first relapse or from first relapse to start of capecitabine stratified by response, showing that response was not intrinsically related to better prognosis or slower growing cancers. However, there was a significantly prolonged OS equivalent for both SD and PR to capecitabine (logrank, p=0.02). Discussion: Most studies in ABC have not found high TP expression alone to predict better response to capecitabine. The results of our study, the largest to date, confirm these findings. A combined approach studying plasma levels of 5'-DFUR along with intra-tumoral TP should be investigated further. Interestingly, the finding of high TP as an independent prognostic factor could be due to deprivation of thymidine needed for proliferation, but this also needs further investigation. By analysing the long term course of breast cancer based on ultimate pattern of response, this study suggests a substantial benefit of capecitabine even though second or third line. It also suggests that if patients achieve SD therapy should continue. Citation Information: Cancer Res 2010;70(24 Suppl):Abstract nr P2-09-24.

Introducing the United Kingdom Oncology Nursing Society's (UKONS) Position Statement on Oral Chemotherapy'

Introducing the United Kingdom Oncology Nursing Society's (UKONS) Position Statement on Oral Chemotherapy'

Association of survival outcomes with dose intensity of adjuvant therapy (AT) with capecitabine for colorectal cancer (CRC).

3624 Background: The incidence of capecitabine-associated dose-limiting toxicities (DLT) is higher in clinical practice than reported in trials (ASCO 2008, abstr 4101). This often results in a reduced relative dose intensity (RDI). We examined the pattern and impact of DLT and RDI on relapse-free (RFS) and overall survival (OS) in patients (pts) receiving adjuvant capecitabine for CRC. Methods: A chart review was conducted on pts treated at the BC Cancer Agency with ≥1 cycle of single-agent capecitabine for stage II/III CRC. The reference capecitabine regimen was based on 8 cycles dosed at 1,250 mg/m2 BID. RFS and OS were analyzed by the Kaplan-Meier method and multivariate Cox proportional-hazards models. Results: 179 pts (median age 69y, 56% male, 90% colon, 73% stage III) were included. 85% of pts experienced at least one episode of DLT, with the most common causes being HFS (54%) and diarrhea (19%). Median RDI was 70% with 69% of pts having an RDI of <80%. Receiving less than the median RDI was associated with performance status ≥2 (17% vs. 3%, p=0.0016) and having ≥1 DLT (78% vs. 59%, p=0.010). On univariate analysis, pts receiving greater than the median RDI had significantly better RFS (3y 69% vs. 32%, p=0.03) and OS (3y 62% vs. 22%, p=0.01). On multivariate analysis, RDI remained an independent predictor for RFS (HR 0.35, 0.14-0.88) and OS (HR 0.37, 0.17-0.82) when controlled for age, nodal status and gender (see Table). Conclusions: In clinical practice, DLTs from adjuvant capecitabine monotherapy are not uncommon and can lead to reduced RDI. In our retrospective study, achieving an RDI of >70% was independently associated with RFS and OS. However, this was achieved in only 50% of the cohort. Strategies to optimize toxicity management while maintaining dose intensity should be considered for patients on AT with oral capecitabine. Multivariate model for OS Variable HR 95% CI P value RDI (>70%) 0.35 0.14-0.88 0.026 Node status (+ve vs. –ve) 4.47 1.01-19.71 0.048 Sex (M vs. F) 2.85 1.13-7.16 0.026 Age (per year) 0.96 0.92-0.99 0.022 Multivariate model for RFS Variable HR 95% CI P value RDI (>70%) 0.37 0.17-0.82 0.014 Nodal status (+ve vs –ve) 3.3502 1.10-10.20 0.033 Age (per year) 0.95 0.91-0.99 0.032 No significant financial relationships to disclose.

Capecitabine in colorectal cancer

Capecitabine is an oral pro-drug that is converted, via a three-step enzymatic pathway, into the cytotoxic drug 5-fluorouracil. 5-fluorouracil has an established role in the management of patients with colorectal cancer in the adjuvant and advanced disease settings. In this article we review the available clinical data for the use of capecitabine as a single agent or in combination with other cytotoxic drugs (e.g., irinotecan or oxaliplatin), or targeted anticancer treatment (e.g., anti-EGF receptor or VEGF therapy), in patients with early-stage or advanced colorectal cancer.

Update on Capecitabine in Colorectal Cancer

In combination chemotherapy for metastatic colorectal cancer, i.v. 5-fluorouracil (5-FU) can be replaced by oral 5-FU (in the form of capecitabine or another orally available analogue) without negatively affecting overall toxicity and without remarkably reducing the efficacy of treatment in terms of response rate or overall survival. Preclinical evidence of synergy has led to promising early and successfully completed studies combining capecitabine plus oxaliplatin with bevacizumab, cetuximab, and epidermal growth factor receptor tyrosine kinase inhibitors. The use of preoperative capecitabine plus radiation is achieving good rates of pathological complete response in rectal cancer. While capecitabine is generally well tolerated, its potential toxicities need careful management and may require individual dose adaption.

Spotlight on Capecitabine in Colorectal Cancer*

Capecitabine is an orally administered fluoropyrimidine which is selectively activated in tumor tissue to the active moiety fluorouracil and is cytotoxic through inhibition of DNA synthesis.