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Capecitabine

Web Resources: Capecitabine
Recent Research Publications

Web Resources: Capecitabine (6 links)


Recent Research Publications

Aitelhaj M, Lkhoyaali S, Rais G, et al.
First line chemotherapy plus trastuzumab in metastatic breast cancer HER2 positive - Observational institutional study.
Pan Afr Med J. 2016; 24:324 [PubMed] Free Access to Full Article Related Publications
Breast cancer is the most common malignant disease and among the most frequent causes of cancer mortality in females worldwide. Metastatic breast cancer (MBC) is conventionally considered to be incurable. In first-line treatment of HER-2 positive MBC, randomized trials have demonstrated that trastuzumab when combined with chemotherapy significantly improves progression free survival and overall survival. To evaluate survival and toxicity of chemotherapy with Trastuzumab as first line therapy of human epithermal growth factor receptor 2 positive metastatic breast cancer, in Moroccan population. It is a phase IV observational institutional monocentric study. Including patients with metastatic breast cancer HER2 positive, as first-line chemotherapy combined with Trastuzumab from March 2009 until March 2010. Primary end point: progression free survival, secondary end point response rate and overall survival. A total of 20 patients were enrolled between March 2009 and March 2010. The lung was the first metastatic site in 60% of the cases, followed by bone, liver, nodes, skin and brain. All patients received chemotherapy with Trastuzumab: 9 of them with Docetaxel, 8 with vinorelbine, and 3 with capecitabine. The progression free survival was estimated by the Kaplan-Meier method, from the date of first cycle to the date of progression or at the last consultation, and the median was 12.8 months. Trastuzumab based chemotherapy was generally well tolerated; 5 patients (25%) presented cardiotoxicity. The results of this study join the literature and show the benefit of Trastuzumab to chemotherapy in first line metastatic breast cancer HER-2 positive.

Lee HS, Chung MJ, Park JY, et al.
A randomized, multicenter, phase III study of gemcitabine combined with capecitabine versus gemcitabine alone as first-line chemotherapy for advanced pancreatic cancer in South Korea.
Medicine (Baltimore). 2017; 96(1):e5702 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: This phase III trial compared the efficacy and safety of gemcitabine plus capecitabine (GemCap) versus single-agent gemcitabine (Gem) in advanced pancreatic cancer as first-line chemotherapy.
METHODS: A total of 214 advanced pancreatic cancer patients were enrolled from 16 hospitals in South Korea between 2007 and 2011. Patients were randomly assigned to receive GemCap (oral capecitabine 1660 mg/m plus Gem 1000 mg/m by 30-minute intravenous infusion weekly for 3 weeks followed by a 1-week break every 4 weeks) or Gem (by 30-minute intravenous infusion weekly for 3 weeks every 4 weeks).
RESULTS: Median overall survival (OS) time, the primary end point, was 10.3 and 7.5 months in the GemCap and Gem arms, respectively (P = 0.06). Progression-free survival was 6.2 and 5.3 months in the GemCap and Gem arms, respectively (P = 0.08). GemCap significantly improved overall response rate compared with Gem alone (43.7% vs 17.6%; P = 0.001). Overall frequency of grade 3 or 4 toxicities was similar in each group. Neutropenia was the most frequent grade 3 or 4 toxicity in both groups.
CONCLUSION: GemCap failed to improve OS at a statistically significant level compared to Gem treatment. This study showed a trend toward improved OS compared to Gem alone. GemCap and Gem both exhibited similar safety profiles.

Roberto M, Romiti A, Botticelli A, et al.
Evaluation of 5-fluorouracil degradation rate and Pharmacogenetic profiling to predict toxicity following adjuvant Capecitabine.
Eur J Clin Pharmacol. 2017; 73(2):157-164 [PubMed] Related Publications
BACKGROUND: On account of the lack of predictive biomarkers of toxicity, we investigated whether polymorphisms of genes involved in fluoropyrimidine metabolism and 5-fluorouracil (5-FU) degradation rate were associated with outcomes of adjuvant capecitabine in patients with early stage gastrointestinal cancers.
METHODS: Genotyping of DPYD GIVS14A, MTHFR C677T and A1298C SNPs were performed by pyro-sequencing technology. PCR analysis was used for genotyping TYMS-TSER. We also evaluated the 5-FU degradation rate, which determines the amount of drug consumed by PBMC in a time unit. Association of these variables with clinical outcome was evaluated using multivariate logistic regression analysis.
RESULTS: One hundred forty-two patients with early stage colon (39%), rectal (28%), stomach (20%) and pancreatic (13%) cancer, treated with adjuvant capecitabine, were included in this retrospective analysis. Seventy and 20% of the patients suffered from at least one G1-4 and G3-4 adverse events, respectively. According to the 5-FU degradation rate, three and 13 patients were assigned as poor (<0.86 ng/mL/10(6) cells/min) and ultra-rapid (>2.1 ng/mL/10(6) cells/min) metabolizers, respectively. At a multivariate logistic regression analysis, an altered 5-FU degradation rate (values <0.86 or >2.10 ng/mL/10(6) cells/min) was associated with grade 3-4 adverse events (OR = 2.09, 95% CI: 1.14-3.82, P = 0.01). No correlation was reported between toxicity and gene polymorphisms except for hand-foot syndrome that was more frequent in the MTHFR 1298CC homozygous variant genotype (OR = 2.03, 95% CI 1.04-3.96, P = 0.03).
CONCLUSIONS: 5-FU degradation rate may be regarded as possible predictive biomarker of capecitabine toxicity in early stage gastrointestinal cancer.

Tan Q, Qin Q, Yang W, et al.
Combination of 125I brachytherapy and chemotherapy for unresectable recurrent breast cancer: A retrospective control study.
Medicine (Baltimore). 2016; 95(44):e5302 [PubMed] Related Publications
Recurrent breast cancer remains an incurable malignancy and cannot be removed by surgery in the majority of cases. This study aimed to explore the feasibility and efficacy of the combination of I brachytherapy and chemotherapy for the treatment of unresectable recurrent breast cancer. Patients with unresectable recurrent breast cancer treated between January 2011 and December 2014 with a combination of I brachytherapy and capecitabine or gemcitabine were evaluated and outcomes were compared with those of women treated with capecitabine or gemcitabine in conventional dose as a monotherapy. Of 61 patients evaluated, 28 received the combination treatment and 33 received capecitabine or gemcitabine monotherapy. The combination of I brachytherapy and chemotherapy resulted in a significant improvement in progression-free survival versus capecitabine or gemcitabine monotherapy (median, 17.8 vs 11.4 months; hazard ratio [HR], 0.44; 95% confidence interval [CI], 0.23-0.84; P = 0.013). The objective response rate (ORR) was significantly higher with the combination (82.1%) than with monotherapy (54.5%; P = 0.022), and the rate of pain relief was higher in the combination arm (100% vs 73.6%; P = 0.038). There was no significant improvement for overall survival (median, 30.1 vs 27.2 months; HR, 0.82; 95% CI, 0.47-1.44; P = 0.496). There were no serious complications detected during the follow-up period, any grade toxicities were comparable between treatment arms. In conclusion, the combination of I brachytherapy and second-line chemotherapy is superior to chemotherapy alone and is an effective and safe therapy for unresectable recurrent breast cancer. However, further investigation and much larger scale randomized controlled trials with long-term follow-up are needed.

Crespo G, Jiménez-Fonseca P, Custodio A, et al.
Capecitabine and temozolomide in grade 1/2 neuroendocrine tumors: a Spanish multicenter experience.
Future Oncol. 2017; 13(7):615-624 [PubMed] Related Publications
BACKGROUND & METHODS: Capecitabine and temozolomide chemotherapy was used in 65 patients with grade 1/2 neuroendocrine tumors (NETs). 46 patients (70.8%) had pancreatic NETs (pNETs).
RESULTS: Response rate was 47.7%, with two complete responses (3.1%), 29 partial responses (44.6%) and 27 patients (41.5%) achieved stable disease. Median progression-free survival was 16.1 months (95% CI: 10.7-21.6) and overall survival was 38.3 months (95% CI: 24.6-51.9). Differences in progression-free survival and overall survival between pNETs and non-pNETs were not found. Nine (13.8%) patients experienced grade 3/4 toxicities, mainly thrombocytopenia (10.8%) and neutropenia (7.7%).
CONCLUSION: This is the largest reported series of NETs treated with capecitabine and temozolomide in daily practice and shows that this combination is a promising treatment option for both grade 1/2 pNETs and non-pNETs.

Chien CR, Chen WT, Wang HM, et al.
A Comparative Effectiveness Study of Two Oral Chemotherapy Drugs (UFT vs. Capecitabine) in Neoadjuvant Concurrent Chemoradiotherapy for Patients with Locally Advanced Rectal Cancer.
Anticancer Res. 2016; 36(11):6155-6160 [PubMed] Related Publications
BACKGROUND/AIM: Capecitabine is the current standard oral chemotherapy used in neoadjuvant concurrent chemoradiotherapy (NCCRT) for locally advanced rectal cancer (LARC) in North America. We compared the effectiveness of another oral chemotherapy agent, UFT (an oral combination of uracil and tegafur), to that of capecitabine.
MATERIALS AND METHODS: We identified LARC patients diagnosed from 2007 to 2011 using a population-based registry in Taiwan (Health and Welfare Data Science Center, HWDC) and constructed a propensity score matched cohort to balance observable potential confounders. We compared the hazard ratio (HR) of death between the UFT and capecitabine groups. We performed supplementary analysis (SA) to evaluate the robustness of our finding regarding potential unobserved confounders (SA-1) and the robustness of the result in a subgroup when an additional potential confounder was taken into account (SA-2).
RESULTS: Our study population comprised of 200 patients balanced with respect to observed co-variables. UFT lowered the hazard of death significantly more than capecitabine (HR=0.58, 95% confidence interval (CI)=0.35-0.95, p=0.03). Our result was moderately sensitive in SA-1 but not significant in SA-2.
CONCLUSION: The effectiveness of UFT in NCCRT for LARC is probably non-inferior to that of capecitabine.

Cazzaniga ME, Torri V, Riva F, et al.
Efficacy and safety of vinorelbine-capecitabine oral metronomic combination in elderly metastatic breast cancer patients: VICTOR-1 study.
Tumori. 2017; 103(1):e4-e8 [PubMed] Related Publications
PURPOSE: Elderly patients with metastatic breast cancer are expected to derive similar benefits from chemotherapy as younger patients, but are more likely to experience therapy-related toxicity. Data from the VICTOR-1 study showed that metronomic therapy with vinorelbine and capecitabine was effective and well tolerated in patients with metastatic breast cancer. This analysis determined the efficacy and safety of the metronomic combination of oral vinorelbine and capecitabine in a subgroup of VICTOR-1 study patients aged ≥70 years.
METHODS: Eighteen of the 32 patients enrolled in VICTOR-1 were aged ≥70 years. Objective response and clinical benefit rates were calculated and toxicity was determined using the NCI-CTCAE criteria.
RESULTS: All patients had at least 1 comorbidity (4 had 2 comorbidities), and 77.7% were taking concomitant medication. Eight patients (44%) had received ≥1 chemotherapy regimens for metastatic disease and most (78%) had ≥2 metastatic sites. Grade 1-2 adverse events occurred in 45.8% of cycles, whereas the incidence of grade 3 and grade 4 events was very low (1.5% and 0.7%, respectively). Median time to progression was 10.5 months (range 1-40). The objective response rate was 33% and the clinical benefit rate was 67%.
CONCLUSIONS: The all-oral metronomic combination of vinorelbine and capecitabine had an acceptable efficacy profile and appears to be better tolerated than standard treatment schedules in elderly metastatic breast cancer patients (age ≥70 years).

Liu KT, Wan JF, Zhu J, et al.
Role of pelvic radiotherapy for locally advanced rectal cancer and synchronous unresectable distant metastases.
Cancer Radiother. 2016; 20(8):805-810 [PubMed] Related Publications
PURPOSE: To evaluate the efficacy and safety of pelvic irradiation combined systematic chemotherapy in patients with locally advanced (cT3-T4 and/or cN+) rectal cancer and synchronous unresectable distant metastases.
PATIENTS AND METHODS: A total of 76 eligible patients who received pelvic radiotherapy and concurrent capecitabine-based chemotherapy were retrospectively reviewed. Patients survival curves were constructed using the Kaplan-Meier method, and a multivariate analysis was performed to identify independent prognostic factors.
RESULTS: Most of the adverse events were mild during the period of combined chemoradiotherapy. Twenty-two patients experienced resection of primary tumour and 16 patients underwent radical surgery of all lesions. Only five patients had pelvic progression during the follow-up period. The median progression-free survival and median overall survival were 13 and 30 months, respectively. Radical surgery of all lesions following chemoradiotherapy was found to be an independent prognostic factor according to multivariate analysis.
CONCLUSIONS: Pelvic irradiation combined with systematic chemotherapy in patients with locally advanced rectal cancer and synchronous unresectable distant metastases is effective and tolerable, both for pelvic and distant control. A curative resection following chemoradiotherapy was associated with prolonged survival.

Park K, Kim KP, Park S, Chang HM
Comparison of gemcitabine plus cisplatin versus capecitabine plus cisplatin as first-line chemotherapy for advanced biliary tract cancer.
Asia Pac J Clin Oncol. 2017; 13(1):13-20 [PubMed] Related Publications
AIM: It remains unclear whether capecitabine combined with cisplatin would show similar effects compared with standard therapy using gemcitabine and cisplatin in advanced biliary tract cancer (BTC).
METHODS: Patients with advanced BTC who were treated with first-line chemotherapy at Asan Medical Center were retrospectively analyzed. All patients received either cisplatin followed by gemcitabine on days 1 and 8 every 3 weeks (GP group), or capecitabine on days 1-14 with cisplatin on day 1 every 3 weeks (XP group).
RESULTS: Of the 134 patients who met the inclusion criteria, 78 received XP and 56 were treated with GP. After a median follow-up of 26.2 months, the progression-free survival was 5.7 months for XP versus 4.1 months for GP (hazard ratio [HR] = 0.81, P = 0.31). The overall survival (OS) was 11.0 months for XP versus 9.8 months for GP (HR = 0.84, P = 0.36). In the multivariate analysis, there were no significant differences in PFS and OS between the two groups.
CONCLUSION: XP seems to be as effective as GP in patients with advanced BTC. The XP regimen is feasible and might offer increased convenience regarding the schedule of drug administration.

McHugh CI, Lawhorn-Crews JM, Modi D, et al.
Effects of capecitabine treatment on the uptake of thymidine analogs using exploratory PET imaging agents: (18)F-FAU, (18)F-FMAU, and (18)F-FLT.
Cancer Imaging. 2016; 16(1):34 [PubMed] Free Access to Full Article Related Publications
BACKGROUND: A principal goal for the use of positron emission tomography (PET) in oncology is for real-time evaluation of tumor response to chemotherapy. Given that many contemporary anti-neoplastic agents function by impairing cellular proliferation, it is of interest to develop imaging modalities to monitor these pathways. Here we examined the effect of capecitabine on the uptake of thymidine analogs used with PET: 3'-deoxy-3'-[(18)F]fluorothymidine ((18)F-FLT), 1-(2'-deoxy-2'-[(18)F]fluoro-β-D-arabinofuranosyl) thymidine ((18)F-FMAU), and 1-(2'-deoxy-2'-[(18)F]fluoro-β-D-arabinofuranosyl) uracil ((18)F-FAU) in patients with advanced cancer.
METHODS: Fifteen patients were imaged, five with each imaging agent. Patients had been previously diagnosed with breast, colorectal, gastric, and esophageal cancers and had not received therapy for at least 4 weeks prior to the first scan, and had not been treated with any prior fluoropyrimidines. Subjects were imaged within a week before the start of capecitabine and on the second day of treatment, after the third dose of capecitabine. Tracer uptake was quantified by mean standard uptake value (SUVmean) and using kinetic analysis.
RESULTS: Patients imaged with (18)F-FLT showed variable changes in retention and two patients exhibited an increase in SUVmean of 172.3 and 89.9 %, while the other patients had changes ranging from +19.4 to -25.4 %. The average change in (18)F-FMAU retention was 0.2 % (range -24.4 to 23.1) and (18)F-FAU was -10.2 % (range -40.3 to 19.2). Observed changes correlated strongly with SUVmax but not kinetic measurements.
CONCLUSIONS: This pilot study demonstrates that patients treated with capecitabine can produce a marked increase in (18)F-FLT retention in some patients, which will require further study to determine if this flare is predictive of therapeutic response. (18)F-FAU and (18)F-FMAU showed little change, on average, after treatment.

Rödel C, Hofheinz R, Fokas E
Rectal cancer: Neoadjuvant chemoradiotherapy.
Best Pract Res Clin Gastroenterol. 2016; 30(4):629-39 [PubMed] Related Publications
The monolithic approach to apply the same schedule of preoperative 5-fluorouracil (5-FU)- or capecitabine-based chemoradiotherapy (CRT) to all patients with clinically staged TNM stage II/III rectal cancer need to be questioned. Five randomized trials have been completed to determine if the addition of oxaliplatin to preoperative 5-FU/capecitabine-based CRT offers an advantage compared with single-agent CRT. In contrast to the German CAO/ARO/AIO-04 trial, results from the ACCORD 12, STAR-01, PETACC-6 and NSAPB R-04 trials failed to demonstrate a significant improvement of early or late efficacy endpoints with the addition of oxaliplatin. Most of the phase II trials incorporating cetuximab into CRT reported disappointingly low rates of pCR; the combination of CRT with VEGF inhibition showed encouraging pCR rates but at the cost of increased surgical complications. Novel clinical trials currently address (1) the role of induction and consolidation chemotherapy before or after CRT, (2) minimal or omitted surgery following complete response to CRT, or (3) the omission of radiotherapy for selected patients with response to neoadjuvant chemotherapy. The notion of different multimodal treatment concepts according to tumor stage, location, mesorectal fascia margin status, molecular profiles, tumor response, and patients' preferences becomes increasingly popular and will render the multimodal treatment approach of rectal cancer more risk-adapted.

Mahlberg R, Lorenzen S, Thuss-Patience P, et al.
New Perspectives in the Treatment of Advanced Gastric Cancer: S-1 as a Novel Oral 5-FU Therapy in Combination with Cisplatin.
Chemotherapy. 2017; 62(1):62-70 [PubMed] Related Publications
Oral fluoropyrimidines have been available for more than 10 years. Capecitabine is well established in treating solid tumors in Europe. S-1 (Teysuno®), an oral formulation containing the 5-fluorouracil (5-FU) prodrug tegafur and the two enzyme modulators gimeracil and oteracil, has not been available in non-Asia countries until recently. In Japan, S-1 in combination with cisplatin is the recommended first-line treatment in patients with gastric cancer. In Europe, the first trials with S-1 were disappointing due to high unacceptable incidences of adverse events. Pharmacokinetic studies showed differences in Asian and Caucasian patients; therefore, a new non-Asian study program was initiated, which led to the pivotal phase 3 trial First-Line Advanced Gastric Cancer Study (FLAGS). In FLAGS, 1,053 patients with advanced gastric cancer from 24 non-Asian countries were enrolled. S-1 plus cisplatin showed no overall survival (OS) benefit when compared to 5-FU plus cisplatin. The primary endpoint superior OS was not met but better tolerability was shown. A post hoc noninferiority OS and safety analysis showed that S-1 plus cisplatin has the same efficacy as 5-FU plus cisplatin but a more favorable safety profile. This led to the approval of S-1 in combination with cisplatin in gastric cancer in Europe in 2011. This article reviews the mode of action of S-1, pivotal study results from an EU point of view, and future perspectives.

Rachar V, Czejka M, Kitzmueller M, et al.
Assessment of Pharmacokinetic Interaction Between Capecitabine and Cetuximab in Metastatic Colorectal Cancer Patients.
Anticancer Res. 2016; 36(9):4715-23 [PubMed] Related Publications
AIM: This study focuses on the plasma disposition and metabolic activation of capecitabine (CCB) when administered alone or when combined with cetuximab (CTX).
PATIENTS AND METHODS: Twenty-four chemo-naïve patients with KRAS wild-type colorectal cancer were randomized into two arms and received either CCB alone (1,000 mg/m(2) bid p.o.), followed by CCB plus CTX (loading dose (LD)=400 mg/m(2) followed by 250 mg/m(2) weekly i.v. maintenance dose) (Arm A; n=12 patients (patients)) or CCB plus CTX followed by CCB alone (Arm B; n=12 patients). Plasma samples were collected from the cubital vein and CCB, 5'-desoxy-5-fluorocytidine (5'-DFCR) and 5'-desoxy-5 fluorouridine (5'-DFUR) were quantified by a sensitive, selective reversed phase high-performance liquid chromatography (HPLC) assay. Non-compartment pharmacokinetic parameters have been calculated by Phoenix WinNonlin.
RESULTS: No clinically relevant impact of CTX on CCB pharmacokinetic parameters and metabolic conversion could be detected in both arms after statistical evaluation (ANOVA).
CONCLUSION: From the pharmacokinetic point of view, co-administration of CTX to CCB seems to be safe.

Forgacz K, Agrawal AK, Sawicki T, Marek GW
Second-Line Chemotherapy of Advanced Colorectal Cancer: Predictive and Prognostic Factors.
Adv Clin Exp Med. 2016 Jul-Aug; 25(4):725-32 [PubMed] Related Publications
BACKGROUND: Colorectal cancer progression presents a significant clinical problem. After its dissemination, the foundation of its treatment comprises of palliative chemotherapy.
OBJECTIVES: The aim of this study was to assess the predictive and prognostic value of clinical response to second line treatment (with capecitabine or with a two-drug regimen including irinotecan) and to analyze its relation to selected clinical and pathological variables with respect to time to disease progression.
MATERIAL AND METHODS: The retrospective analysis of 164 patients with advanced colorectal cancer treated in 2001- -2008 included chosen clinical, pathological and follow-up data.
RESULTS: Response to second-line chemotherapy was observed in 34 out of 164 patients: In 18/82 in the irinotecan group (22%) and in 16/82 in the capecitabine group (19.5%). The mean survival time to progression following the second line of treatment amounted to 5.85 and 6.2 months respectively. Statistically, a higher number of patients in good condition of 0 to 1 was documented in the group responding to treatment. Significant correlation was documented between primary stage of the disease and time to progression in patients treated with capecitabine (p = 0.0258). The recurrence of the disease was observed in 44/45 patients following operation with radical intention but with an insufficient number of excised lymph nodes. A significantly longer time to progression was observed in women treated with capecitabine. In logistic regression, lack of treatment response was found to be an independent factor affecting the time to disease progression. Patients who did not respond to the second line of treatment demonstrated a significantly shorter time to disease progression than patients who responded to it and they showed a significantly higher number of patients with leucopenia during treatment.
CONCLUSIONS: Clinical response to treatment in both treated groups is of significant importance for the probability of local recurrence of the disease, preservation of a good patient's condition and the higher level of leukocytes during treatment.

Tampellini M, Gned D, Baratelli C, et al.
Changes in hepatic perfusion assessed by dynamic contrast enhanced MRI, associated with morphologic evaluation, in patients with liver metastases from colorectal cancer treated with first-line chemotherapy.
Radiol Med. 2016; 121(12):950-957 [PubMed] Related Publications
INTRODUCTION: Blood perfusion of liver metastases can be non-invasively assessed by dynamic contrast enhanced magnetic resonance imaging (DCE-MRI). The aim of this study was to explore whether the ratio of hepatic arterial to total liver blood flow (Hepatic Perfusion Index-HPI) and the area under the enhancement curve (AUC) of selected liver areas in patients with hepatic metastases from colorectal cancer treated with first-line chemotherapy could predict response and/or be a prognostic variable.
PATIENTS AND METHODS: Sequential liver DCE-MRI studies with morphological imaging reconstruction were performed in 43 consecutive patients at baseline and every 3 months during oxaliplatin-based first-line chemotherapy. Data about HPI of the whole liver, and AUC of metastatic and healthy areas were calculated at each time-point and compared both at baseline and sequentially during the treatment.
RESULTS: Baseline HPI and AUC values did not discriminate patients responsive to chemotherapy, nor those with better survival outcomes. HPI and AUC values at 3 months decreased significantly more in responders than non-responders. AUCs calculated from areas of the liver with or without neoplastic lesions varied consistently, being increased in progressing patients and decreased in responding patients.
DISCUSSION: Our results did not support the hypothesis of a predictive or prognostic role of HPI and AUCs calculated by DCE-MRI in liver metastatic CRC patients, thus the primary endpoint of the study was not reached. However, reduced arterial blood flow in metastatic liver can be obtained by chemotherapy alone, without any anti-angiogenic agent; interestingly, HPI and AUC data suggest a possible relationship between tumor metabolism and entire liver perfusion.

Meulendijks D, Cats A, Beijnen JH, Schellens JH
Improving safety of fluoropyrimidine chemotherapy by individualizing treatment based on dihydropyrimidine dehydrogenase activity - Ready for clinical practice?
Cancer Treat Rev. 2016; 50:23-34 [PubMed] Related Publications
Fluoropyrimidines remain the cornerstone of treatment for different types of cancer, and are used by an estimated two million patients annually. The toxicity associated with fluoropyrimidine therapy is substantial, however, and affects around 30% of the patients, with 0.5-1% suffering fatal toxicity. Activity of the main 5-fluorouracil (5-FU) metabolic enzyme, dihydropyrimidine dehydrogenase (DPD), is the key determinant of 5-FU pharmacology, and accounts for around 80% of 5-FU catabolism. There is a consistent relationship between DPD activity and 5-FU exposure on the one hand, and risk of severe and potentially lethal fluoropyrimidine-associated toxicity on the other hand. Therefore, there is a sound rationale for individualizing treatment with fluoropyrimidines based on DPD status in order to improve patient safety. The field of individualized treatment with fluoropyrimidines is now rapidly developing. The main strategies that are available, are based on genotyping of the gene encoding DPD (DPYD) and measuring of pretreatment DPD phenotype. Clinical validity of additional approaches, including genotyping of MIR27A has also recently been demonstrated. Here, we critically review the evidence on clinical validity and utility of strategies available to clinicians to identify patients at risk of developing severe and potentially fatal toxicity as a result of DPD deficiency. We evaluate the advantages and limitations of these methods when used in clinical practice, and discuss for which strategies clinical implementation is currently justified based on the available evidence and, in addition, which additional data will be required before implementing other, as yet less developed strategies.

Handa S, Kuroiwa R, Miyano M, et al.
Assessment of Injection Site Reactions for Peripheral Intravenous Oxaliplatin Infusion and Potential Remedies.
Gan To Kagaku Ryoho. 2016; 43(8):985-8 [PubMed] Related Publications
We investigated the medical and nursing records of 19 patients with unresectable advanced recurrent colorectal cancers treated using oxaliplatin and capecitabine(CapeOX)with or without bevacizumab at the outpatient tumor center of Showa UniversityHospital between November 1, 2009 and November 30, 2011, to clarifydifferences in the incidence of injection site reactions according to the use or non-use of an intravenous infusion solution warming device. Vascular pain and other injection site reactions occurred in 13 patients(68.4%). Injection site reactions occurred in 33 of the total of 77 chemotherapytreatments (42.9%). No difference in incidence of injection site reactions was seen according to whether the intravenous infusion solution warmer was used. The most common time to onset of injection site reactions after commencing oxaliplatin administration was 60-90 min, and symptoms were seen to decrease when non-steroidal anti-inflammatorydrugs were coadministered. We intend to leverage these studyfindings to demonstrate the mechanism of onset for injection site reactions and to propose measures for handling adverse drug reactions.

Supaadirek C, Pesee M, Thamronganantasakul K, et al.
Outcomes of Preoperative Chemoradiotherapy and Combined Chemotherapy with Radiotherapy Without Surgery for Locally Advanced Rectal Cancer.
Asian Pac J Cancer Prev. 2016; 17(7):3511-4 [PubMed] Related Publications
PURPOSE: To evaluate the treatment outcomes of patients with locally advanced rectal cancer treated with preoperative concurrent chemoradiotherapy (CCRT) or combined chemotherapy together with radiotherapy (CMTRT) without surgery.
MATERIALS AND METHODS: A total of 84 patients with locally advanced rectal adenocarcinoma (stage II or III) between January 1st, 2003 and December 31st, 2013 were enrolled, 48 treated with preoperative CCRT (Gr.I) and 36 with combined chemotherapy and radiotherapy (CMTRT) without surgery (Gr.II). The chemotherapeutic agents used concurrent with radiotherapy were either 5fluorouracil short infusion plus leucovorin and/or capecitabine or 5fluorouracil infusion alone. All patients received pelvic irradiation.
RESULTS: There were 5 patients (10.4%) with a complete pathological response. The 3 yearoverall survival rates were 83.2% in Gr.I and 24.8 % in Gr.II (p<0.01). The respective 5 yearoverall survival rates were 70.3% and 0% (p<0.01). The 5 yearoverall survival rates in Gr.I for patients who received surgery within 56 days after complete CCRT as compared to more than 56 days were 69.5% and 65.1% (p=0.91). Preoperative CCRT used for 12 of 30 patients in Gr.I (40%) with lower rectal cancer demonstrated that in preoperative CCRT a sphincter sparing procedure can be performed.
CONCLUSIONS: The results of treatment with preoperative CCRT for locally advanced rectal cancer showed comparable rates of overall survival and sphincter sparing procedures as compared to previous studies.

Arredondo J, Baixauli J, Pastor C, et al.
Mid-term oncologic outcome of a novel approach for locally advanced colon cancer with neoadjuvant chemotherapy and surgery.
Clin Transl Oncol. 2017; 19(3):379-385 [PubMed] Related Publications
PURPOSE: Neoadjuvant chemotherapy is being actively tested as an emerging alternative for the treatment of locally advanced colon cancer (LACC) patients, resembling its use in other gastrointestinal tumors. This study assesses the mid-term oncologic outcome of LACC patients treated with oxaliplatin and fluoropyrimidines-based preoperative chemotherapy followed by surgery.
METHODS AND PATIENTS: Patients with radiologically resectable LACC treated with neoadjuvant therapy between 2009 and 2014 were retrospectively analyzed. Radiological, metabolic, and pathological tumor response was assessed. Both postoperative complications, relapse-free survival (RFS), and overall survival (OS) were studied.
RESULTS: Sixty-five LACC patients who received treatment were included. Planned treatment was completed by 93.8 % of patients. All patients underwent surgery without delay. The median time between the start of chemotherapy and surgery was 71 days (65-82). No progressive disease was observed during preoperative treatment. A statistically significant tumor volume reduction of 62.5 % was achieved by CT scan (39.8-79.8) (p < 0.001). It was also observed a median reduction of 40.5 % (24.2-63.7 %) (p < 0.005) of SUVmax (Standard Uptake Value) by PET-CT scan. Complete pathologic response was achieved in 4.6 % of patients. Postoperative complications were observed in 15.4 % of patients, with no cases of mortality. After a median follow-up of 40.1 months, (p 25-p 75: 27.3-57.8) 3-5 year actuarial RFS was 88.9-85.6 %, respectively. Five-year actuarial OS was 95.3 %.
CONCLUSION: Preoperative chemotherapy in LACC patients is safe and able to induce major tumor regression. Survival times are encouraging, and further research seems warranted.

Li J, Ren J, Sun W
Systematic review of ixabepilone for treating metastatic breast cancer.
Breast Cancer. 2017; 24(2):171-179 [PubMed] Related Publications
BACKGROUND: Ixabepilone is now a Food and Drug Administration-approved therapeutic option for patients with metastatic breast cancer (MBC) whose disease has progressed despite prior anthracycline and taxane therapy. We conducted a systematic review and meta-analysis to systematically evaluate the efficacy and safety of ixabepilone for treating metastatic breast cancer.
METHODS: A systematic review and meta-analysis were conducted. Randomized controlled studies applying ixabepilone for treating MBC were included. The primary outcome was Overall Survival (OS). The authors of primary articles were contacted and methodological quality was evaluated. Subgroups were drawn based on intervention measures; heterogeneity and bias were discussed.
RESULTS: Eight studies with 5247 patients were included. Compared with a weekly schedule, a triweekly schedule of ixabepilone was better at improving overall response rate (ORR), while there were no differences in improving OS and progression-free survival (PFS). Ixabepilone plus capecitabine was superior to capecitabine monotherapy in improving OS, PFS and ORR. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. There was no difference in the improvement of ORR, clinical benefit rate (CBR) and disease control rate (DCR) between ixabepilone and eribulin.
CONCLUSIONS: Current evidence suggests that a triweekly schedule of ixabepilone is more effective than weekly dosing in improving ORR. Use of ixabepilone in combination with capecitabine possesses superior clinical efficacy to the use of capecitabine alone. Paclitaxel was more effective than ixabepilone in terms of OS and PFS. The efficacy and safety between ixabepilone and eribulin were identical.

Gourmelon C, Bourien H, Augereau P, et al.
Vinflunine for the treatment of breast cancer.
Expert Opin Pharmacother. 2016; 17(13):1817-23 [PubMed] Related Publications
INTRODUCTION: Breast cancer is the most frequently diagnosed cancer and the highest cause of cancer mortality in females worldwide. The development of drugs improving overall survival in late-stage metastatic breast cancer remains a challenge. Vinflunine is the most recently developed drug in the vinca alkaloid class. Its arrival has been eagerly awaited for treatment of solid tumors, and in particular, for metastatic breast cancer.
AREAS COVERED: The pharmacological features of vinflunine are described. Its clinical development as monotherapy or in combination in metastatic breast cancer is detailed. A literature search on the topic was conducted through PubMed, clinical trials and the proceedings of the main cancer congresses.
EXPERT OPINION: The overall results from phase III studies, and in particular those that combined vinflunine with capecitabine, have been less favorable. The combination's effectiveness was at best moderate compared with other drugs which also target metastatic breast cancer, and complicated by significant hematological and gastrointestinal adverse effects. Its use in advanced metastatic breast cancer cannot currently be recommended.

Kesavan M, Turner JH
Myelotoxicity of Peptide Receptor Radionuclide Therapy of Neuroendocrine Tumors: A Decade of Experience.
Cancer Biother Radiopharm. 2016; 31(6):189-98 [PubMed] Related Publications
AIM: This review of the literature, and the authors' own decade of experience with lutetium-177-octreotate-capecitabine±temozolomide peptide receptor radionuclide therapy (PRRT)-chemotherapy of GEPNETs, analyses the risk of both short- and long-term hematotoxicity.
BACKGROUND: Myelodysplastic syndrome (MDS) and acute leukemia (AL) have been associated with PRRT in heavily pretreated patients with a history of exposure to alkylating agents. Commenced 15 years ago, PRRT is now becoming established as first- and second-line therapy for gastroentero pancreatic neuroendocrine tumors (GEPNETs), and early treatment minimizes myelotoxicity, which is the most significant potential adverse event following PRRT.
RESULTS: Sixteen key articles involving primary research were identified. A total of 2225 patients were treated (2104 treated with PRRT monotherapy and 121 with PRRT combined with chemotherapy). The average age of patients in these studies ranged from 53 to 64 years with median duration of follow-up ranging from 6 to 62 months. Short-term myelotoxicity was observed in 221 patients (10%), occurring in 213 of 2104 patients treated with PRRT monotherapy and 8 of 121 patients treated with PRRT combined with chemotherapy. Acute toxicity manifested as modest self-limited grade 3/4 toxicity (CTCAE or WHO), most often affecting platelets during the first cycle of treatment. Toxicity manifesting early was easily managed with dose modification or therapy cessation and was ameliorated by appropriate patient selection. MDS/AL was a rare stochastic event occurring in 32 (1.4%) patients. Where bone marrow biopsy was performed, cases of MDS displayed cytogenetic abnormalities, consistent with secondary MDS. Factors associated with myelotoxicity included age >70 years, impaired renal function, baseline cytopenias, prior number of therapies, prior chemotherapy (alkylating agents), and prior radiotherapy.
CONCLUSION: Early therapy with PRRT-containing regimens improves outcomes, minimizes myelotoxicity, and renders the risk of MDS and AL negligible.

Lu M, Wang T, Wang J
Effects of paclitaxel liposome and capecitabine in the treatment of advanced gastric cancer by clinical observation.
Int J Clin Pharmacol Ther. 2016; 54(9):693-7 [PubMed] Related Publications
OBJECTIVE: To evaluate the clinical effectiveness and side effects of paclitaxel liposome and capecitabine in the treatment of 34 cases with advanced gastric cancer.
METHOD: For 64 patients with advanced gastric cancer, 30 cases were treated with docetaxel, cisplatin, and 5-fluorouracil (DCF group, control group), and 34 cases were treated with paclitaxel liposome and capecitabine (PC group, experimental group). DCF group: 75 mg/m2 of docetaxel, d1; 20 mg/m2 of cisplatin, d1-5; 350 mg/m2 of 5-fluorouracil, 4 - 6 hours of intravenous drip, d1-5, a cycle of 21 days. PC group: 135 mg/m2 of paclitaxel liposome, d1; 2,000 mg/m2.d of capecitabine, oral dose of twice per day, d1-14, a cycle of 21 days.

Turkmen E, Erdogan B, Kodaz H, et al.
Post progression survival analysis of metastatic gastric and gastroesophageal junction cancer patients after second-line treatment.
Acta Gastroenterol Belg. 2016 Apr-Jun; 79(2):211-5 [PubMed] Related Publications
PURPOSE: The aim of this study was to define the factors that -affect response and post-progression survival of metastatic gastric cancer (MGC) and gastroesophageal junction cancer (GEJ) -patients treated with second-line chemotherapy.
METHODS: We retrospectively reviewed the data of 59 patients with MGC or GEJ adenocarcinoma who received second-line treatment.
RESULTS: The median age was 54 years old (26-77). Response to second-line treatment was strongly associated with disease control with first-line treatment (p < 0.01). Median progression-free survival (PFS), overall survival (OS) and post-progression survival (PPS) were 3.2 (95% CI : 2.63-3.80), 6.5 (95% CI : 3.78-9.35) and 2.7 months (95% CI : 1.89-3.68), respectively. PFS (r = 0.55, p < 0.01) and PPS (r = 0.89, p < 0.01) were correlated with OS. Response to second-line treatment was independently related to PFS (HR : 0.12 95%CI : 0.53-0.26, p < 0.001). Having an ECOG 0 performance status (HR : 0.42 ; 95%CI : 0.21-0.86, p = 0.02) and response to second-line therapy (HR : 0.47 ; 95%CI : 0.25-0.85, p = 0.01) were independently associated with OS.
CONCLUSION: PPS and PFS were correlated with OS after second-line treatment of MGC. Response to second-line treatment prolonged OS by increasing PFS, and having an ECOG 0 PS prolonged OS by increasing PPS.

Nozawa H, Ishihara S, Kawai K, et al.
Paradoxical Reductions in Serum Anti-p53 Autoantibody Levels by Chemotherapy in Unresectable Colorectal Cancer: An Observational Study.
Oncology. 2016; 91(3):127-34 [PubMed] Related Publications
OBJECTIVE: The anti-p53 autoantibody is an emerging tumor marker that is commonly produced in response to p53 mutations. The usefulness of this antibody has been suggested in screening for and the monitoring of recurrence in colorectal cancer; however, its significance as a marker during chemotherapy remains largely unknown.
METHODS: We measured serum anti-p53 antibody levels in patients with unresectable colorectal cancer who underwent first-line systemic chemotherapy. Tumor responses were evaluated by computed tomography. We determined whether temporal changes in this antibody during therapy are associated with radiological responses.
RESULTS: Of the 83 patients in our study, 29 (35%) had elevated serum anti-p53 antibody levels before chemotherapy. Among these, antibody levels decreased in all 14 responders. In contrast, among those patients with elevated pretherapeutic serum anti-p53 antibody levels, 89% showed a paradoxical decrease in antibody levels and exhibited disease progression after chemotherapy. Moreover, serum anti-p53 antibody levels before and after chemotherapy were not associated with survival.
CONCLUSION: These results suggest that serum anti-p53 antibody levels are of limited value in the evaluation of responses to palliative chemotherapy in patients with colorectal cancer.

Matsui T, Nagata N, Hirata K, et al.
Bi-weekly Capecitabine-Oxaliplatin (XELOX) plus Bevacizumab as First-line Treatment of Metastatic Colorectal Cancer -The PHOENiX Trial.
Anticancer Res. 2016; 36(7):3437-43 [PubMed] Related Publications
AIM: This phase II study assessed the efficacy and toxicity of an intermittent weekly capecitabine regimen in combination with oxaliplatin (XELOX) plus bevacizumab as a first-line treatment of metastatic colorectal cancer (mCRC).
PATIENTS AND METHODS: Patients with measurable mCRC who were to receive first-line chemotherapy were enrolled onto this disease-oriented multicenter phase II trial. Patients with mCRC were required to have Eastern Cooperative Oncology Group performance status of 0 to 1, to be aged >20 years, and to have adequate organ function. Localization of tumor, toxicities, response rate, progression-free survival (PFS) and time to progression (TTP) were studied. Capecitabine dose was 2,500 mg/m(2)/day on days 1-7 (n=47) and was increased to 3,000 mg/m(2)/day (n=5) in combination with oxaliplatin (85 mg/m(2)) and bevacizumab (5 mg/kg), repeated every 2 weeks.
RESULTS: A total of 51 patients were enrolled from 14 institutions from December 2011 to July 2012. The median age was 66 (range=38-85) years, 29 (56.9%) had colonic cancer and 22 (43.1%) had rectal cancer in this study. Pertinent grade 3/4 toxicities were neutropenia (13.7%), peripheral neuropathy (13.7%), hypertension (13.7%), gastrointestinal perforation (3.9%), and hand-foot syndrome (5.9%). The response rate was 51% (one complete and 25 partial responses). Median PFS and TTP were 344 days and 196 days, respectively. Median overall survival has not been reached yet.
CONCLUSION: The first-line treatment of mCRC using a biweekly combination of XELOX plus bevacizumab can also be administered safely and effectively in Japan. It is suggested that this regimen is an appropriate option for the treatment of mCRC.

Choi JE, Choe AR, Yoon SE, et al.
Germ Cell Tumor Targeting Chemotherapy in Gastric Adenocarcinoma with an Endodermal Sinus Tumor Component: A Case Report.
Chemotherapy. 2017; 62(1):54-57 [PubMed] Related Publications
The most common sites for extragonadal germ cell tumors are the midline mediastinum, retroperitoneum and, much less frequently, the stomach. The stomach-originated primary germ cell tumor carries a poor prognosis, especially when metastasis occurs to the liver, with a mean survival time of 1 month. We describe the case of a 77-year-old male who presented with usual symptoms of gastric malignancy. Gastrectomy was performed. Histopathology of surgically resected tissue revealed a mixture of adenocarcinoma and endodermal sinus tumor components with α-fetoprotein production. After liver metastasis was identified, oxaliplatin and capecitabine were administered as palliative chemotherapy. The response was poor. For the second-line therapy, bleomycin, etoposide, and cisplatin (BEP) therapy was initiated. The overall response to these drugs was a partial response and the residual liver lesion was considered to be resectable. The patient died of pneumonia 11 months following the BEP session, representing an overall survival time of 22 months. Gastric adenocarcinoma with a germ cell tumor component is uncommon and an effective combination of chemotherapeutic agents is not yet clear. In this case, the patient received germ cell tumor-targeting chemotherapy and showed a durable response. Hence, germ cell-targeting cytotoxic agents have potential as the 'front-line regimen'.

Ursem C, Van Loon K, Venook A
Adjuvant Therapy Trials.
Cancer J. 2016 May-Jun; 22(3):196-8 [PubMed] Related Publications
In 2015, ramucirumab and TAS-102 became the 10th and 11th drugs approved by the Food and Drug administration for the treatment of patients with colorectal cancer, not counting leucovorin, and yet only 3 agents, 5-fluorouracil, capecitabine, and oxaliplatin, have proven benefit in adjuvant treatment. In fact, there have been no additions (and 1 subtraction levamisole) to our arsenal of therapies for patients with stages II and III colon cancer for more than a decade. How did we get here? Are we stuck? And how do we move forward?

Salem ME, Hartley M, Unger K, Marshall JL
Neoadjuvant Combined-Modality Therapy for Locally Advanced Rectal Cancer and Its Future Direction.
Oncology (Williston Park). 2016; 30(6):546-62 [PubMed] Related Publications
Rectal cancer treatment presents a challenge, and its optimal management requires a multidisciplinary approach involving surgical, medical, and radiation oncologists. Advances in surgical techniques, radiotherapy, and medical imaging technology have transformed the therapeutic landscape and have led to substantial improvements in both local disease control and patient survival. The currently established standard of care for patients with locally advanced rectal cancer involves preoperative (neoadjuvant) concurrent radiotherapy and infusional fluorouracil-based or oral capecitabine-based chemotherapy, also known as chemoradiotherapy (CRT), followed by surgery. Surgery is often followed by adjuvant chemotherapy. Here we discuss the evolution of standard therapy for rectal cancer patients and the use of preoperative CRT for the treatment of locally advanced disease. Treatment schemes that have attempted to broaden the horizons of standard therapy include the use of induction chemotherapy and "watch-and-wait" approaches. We examine several novel trials using these and other treatment approaches, which may eventually lead to better patient selection and the avoidance of overtreatment and unnecessary adverse effects.

Cainap C, Nagy V, Seicean A, et al.
Results of third-generation epirubicin/cisplatin/xeloda adjuvant chemotherapy in patients with radically resected gastric cancer.
J BUON. 2016 Mar-Apr; 21(2):349-59 [PubMed] Related Publications
PURPOSE: The purpose of this study was to evaluate the efficacy and toxicity of a third-generation chemotherapy regimen in the adjuvant setting to radically operated patients with gastric cancer. This proposed new adjuvant regimen was also compared with a consecutive retrospective cohort of patients treated with the classic McDonald regimen.
METHODS: Starting in 2006, a non-randomized prospective phase II study was conducted at the Institute of Oncology of Cluj-Napoca on 40 patients with stage IB-IV radically resected gastric adenocarcinoma. These patients were administered a chemotherapy regimen already considered to be standard treatment in the metastatic setting: ECX (epirubicin, cisplatin, xeloda) and were compared to a retrospective control group consisting of 54 patients, treated between 2001 and 2006 according to McDonald's trial.
RESULTS: In a previous paper, we reported toxicities and the possible predictive factors for these toxicities; in the present article, we report on the results concerning predictive factors on overall survival (OS) and disease free survival (DFS). The proposed ECX treatment was not less effective than the standard suggested by McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage was an independent prognostic factor for OS and DFS. N ratio >70% was an independent predictive factor for OS and locoregional disease control. The resection margins were independent prognostic factors for OS and DFS.
CONCLUSION: The proposed treatment is not less effective compared with the McDonald's trial. Age was an independent prognostic factor in multivariate analysis. N3 stage represented an independent prognostic factor and N ratio >70% was a predictive factor for OS and DFS. The resection margins were proven to be independent prognostic factors for OS and DFS.

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