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      Chemotherapy-Induced Constipation and Diarrhea: Pathophysiology, Current and Emerging Treatments

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          Abstract

          Gastrointestinal (GI) side-effects of chemotherapy are a debilitating and often overlooked clinical hurdle in cancer management. Chemotherapy-induced constipation (CIC) and Diarrhea (CID) present a constant challenge in the efficient and tolerable treatment of cancer and are amongst the primary contributors to dose reductions, delays and cessation of treatment. Although prevalence of CIC is hard to estimate, it is believed to affect approximately 16% of cancer patients, whilst incidence of CID has been estimated to be as high as 80%. Despite this, the underlying mechanisms of both CID and CIC remain unclear, but are believed to result from a combination of intersecting mechanisms including inflammation, secretory dysfunctions, GI dysmotility and alterations in GI innervation. Current treatments for CIC and CID aim to reduce the severity of symptoms rather than combating the pathophysiological mechanisms of dysfunction, and often result in worsening of already chronic GI symptoms or trigger the onset of a plethora of other side-effects including respiratory depression, uneven heartbeat, seizures, and neurotoxicity. Emerging treatments including those targeting the enteric nervous system present promising avenues to alleviate CID and CIC. Identification of potential targets for novel therapies to alleviate chemotherapy-induced toxicity is essential to improve clinical outcomes and quality of life amongst cancer sufferers.

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          Randomized, phase III trial of panitumumab with infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as first-line treatment in patients with previously untreated metastatic colorectal cancer: the PRIME study.

          Panitumumab, a fully human anti-epidermal growth factor receptor (EGFR) monoclonal antibody that improves progression-free survival (PFS), is approved as monotherapy for patients with chemotherapy-refractory metastatic colorectal cancer (mCRC). The Panitumumab Randomized Trial in Combination With Chemotherapy for Metastatic Colorectal Cancer to Determine Efficacy (PRIME) was designed to evaluate the efficacy and safety of panitumumab plus infusional fluorouracil, leucovorin, and oxaliplatin (FOLFOX4) versus FOLFOX4 alone as initial treatment for mCRC. In this multicenter, phase III trial, patients with no prior chemotherapy for mCRC, Eastern Cooperative Oncology Group performance status of 0 to 2, and available tissue for biomarker testing were randomly assigned 1:1 to receive panitumumab-FOLFOX4 versus FOLFOX4. The primary end point was PFS; overall survival (OS) was a secondary end point. Results were prospectively analyzed on an intent-to-treat basis by tumor KRAS status. KRAS results were available for 93% of the 1,183 patients randomly assigned. In the wild-type (WT) KRAS stratum, panitumumab-FOLFOX4 significantly improved PFS compared with FOLFOX4 (median PFS, 9.6 v 8.0 months, respectively; hazard ratio [HR], 0.80; 95% CI, 0.66 to 0.97; P = .02). A nonsignificant increase in OS was also observed for panitumumab-FOLFOX4 versus FOLFOX4 (median OS, 23.9 v 19.7 months, respectively; HR, 0.83; 95% CI, 0.67 to 1.02; P = .072). In the mutant KRAS stratum, PFS was significantly reduced in the panitumumab-FOLFOX4 arm versus the FOLFOX4 arm (HR, 1.29; 95% CI, 1.04 to 1.62; P = .02), and median OS was 15.5 months versus 19.3 months, respectively (HR, 1.24; 95% CI, 0.98 to 1.57; P = .068). Adverse event rates were generally comparable across arms with the exception of toxicities known to be associated with anti-EGFR therapy. This study demonstrated that panitumumab-FOLFOX4 was well tolerated and significantly improved PFS in patients with WT KRAS tumors and underscores the importance of KRAS testing for patients with mCRC.
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            Chemotherapy in advanced gastric cancer: a systematic review and meta-analysis based on aggregate data.

            This systematic review and meta-analysis were performed to assess the efficacy and tolerability of chemotherapy in patients with advanced gastric cancer. Randomized phase II and III clinical trials on first-line chemotherapy in advanced gastric cancer were identified by electronic searches of Medline, Embase, the Cochrane Controlled Trials Register, and Cancerlit; hand searches of relevant abstract books and reference lists; and contact to experts. Meta-analysis was performed using the fixed-effect model. Overall survival, reported as hazard ratio (HR) with 95% CI, was the primary outcome measure. Analysis of chemotherapy versus best supportive care (HR = 0.39; 95% CI, 0.28 to 0.52) and combination versus single agent, mainly fluorouracil (FU) -based chemotherapy (HR = 0.83; 95% CI = 0.74 to 0.93) showed significant overall survival benefits in favor of chemotherapy and combination chemotherapy, respectively. In addition, comparisons of FU/cisplatin-containing regimens with versus without anthracyclines (HR = 0.77; 95% CI, 0.62 to 0.95) and FU/anthracycline-containing combinations with versus without cisplatin (HR = 0.83; 95% CI, 0.76 to 0.91) both demonstrated a significant survival benefit for the three-drug combination. Comparing irinotecan-containing versus nonirinotecan-containing combinations (mainly FU/cisplatin) resulted in a nonsignificant survival benefit in favor of the irinotecan-containing regimens (HR = 0.88; 95% CI, 0.73 to 1.06), but they have never been compared against a three-drug combination. Best survival results are achieved with three-drug regimens containing FU, an anthracycline, and cisplatin. Among these, regimens including FU as bolus exhibit a higher rate of toxic deaths than regimens using a continuous infusion of FU, such as epirubicin, cisplatin, and continuous-infusion FU.
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              Capecitabine: a review.

              Fluorouracil (FU) is an antimetabolite with activity against numerous types of neoplasms, including those of the breast, esophagus, larynx, and gastrointestinal and genitourinary tracts. Systemic toxicity, including neutropenia, stomatitis, and diarrhea, often occur due to cytotoxic nonselectivity. Capecitabine was developed as a prodrug of FU, with the goal of improving tolerability and intratumor drug concentrations through tumor-specific conversion to the active drug. The purpose of this article is to review the available information on capecitabine with respect to clinical pharmacology, mechanism of action, pharmacokinetic and pharmacodynamic properties, clinical efficacy for breast and colorectal cancer adverse-effect profile, documented drug interactions, dosage and administration, and future directions of ongoing research. Relevant English-language literature was identified through searches of PubMed (1966 to August 2004), International Pharmaceutical Abstracts (1977 to August 2004), and the Proceedings of the American Society of Clinical Oncology (January 1995 to August 2004). Search terms included capecitabine, Xeloda, breast cancer, and colorectal cancer. The references of the identified articles were reviewed for additional sources. In addition, product information was obtained from Roche Pharmaceuticals. Studies from the identified literature that addressed this article's objectives were selected for review, with preference given to Phase II/III trials. Capecitabine is an oral prodrug that is converted to its only active metabolite, FU, by thymidine phosphorylase. Higher levels of this enzyme are found in several tumors and the liver, compared with normal healthy tissue. In adults, capecitabine has a bioavailability of approximately 100% with a Cmax of 3.9 mg/L, Tmax of 1.5 to 2 hr, and AUC of 5.96 mg.h/L. The predominant route of elimination is renal, and dosage reduction of 75% is recommended in patients with creatinine clearance (CrCl) of 30 to 50 mL/min. The drug is contraindicated if CrCl is < 30 mL/min. Capecitabine has shown varying degrees of efficacy with acceptable tolerability in numerous cancers including prostate, renal cell, ovarian, and pancreatic, with the largest amount of evidence in metastatic breast and colorectal cancer. Single-agent capecitabine was compared with IV FU/leucovorin (LV) using the bolus Mayo Clinic regimen in 2 Phase III trials as first-line treatment for patients with metastatic colorectal cancer. Overall response rate (RR) favored the capecitabine arm (26% vs 17%, P < 0.001); however, this did not translate into a difference in time to progression (TTP) (4.6 months vs 4.7 months) or overall survival (OS) (12.9 months vs 12.8 months). In Phase II noncomparative trials, combinations of capecitabine with oxaliplatin or irinotecan have produced results similar to regimens combining FU/LV with the same agents in patients with colorectal cancer. In metastatic breast cancer patients who had received prior treatment with an anthracycline-based regimen, a Phase III trial comparing the combination of capecitabine with docetaxel versus docetaxel alone demonstrated superior objective tumor RR (42% vs 30%, P = 0.006), median TTP (6.1 months vs 4.2 months, P < 0.001), and median OS (14.5 months vs 11.5 months, P = 0.013) with the combination treatment. Noncomparative Phase II studies have also supported efficacy in patients with metastatic breast cancer pretreated with both anthracyclines and taxanes, yielding an overall RR of 15% to 29% and median OS of 9.4 to 15.2 months. The most common dose-limiting adverse effects associated with capecitabine monotherapy are hyperbilirubinemia, diarrhea, and hand-foot syndrome. Myelosuppression, fatigue and weakness, abdominal pain, and nausea have also been reported. Compared with bolus FU/LV, capecitabine was associated with more hand-foot syndrome but less stomatitis, alopecia, neutropenia requiring medical management, diarrhea, and nausea. Capecitabine has been reported to increase serum phenytoin levels and the international normalized ratio in patients receiving concomitant phenytoin and warfarin, respectively. The dose of capecitabine approved by the US Food and Drug Administration (FDA) for both metastatic colorectal and breast cancer is 1250 Mg/M2 given orally twice per day, usually separated by 12 hours for the first 2 weeks of every 3-week cycle. Capecitabine is currently approved by the FDA for use as first-line therapy in patients with metastatic colorectal cancer when single-agent fluoropyrimidine therapy is preferred. The drug is also approved for use as (1) a single agent in metastatic breast cancer patients who are resistant to both anthracycline- and paclitaxel-based regimens or in whom further anthracycline treatment is contra indicated and (2) in combination with docetaxel after failure of prior anthracycline-based chemotherapy. Single-agent and combination regimens have also shown benefits in patients with prostate, pancreatic, renal cell, and ovarian cancers. Improved tolerability and comparable efficacy compared with IV FU/LV in addition to oral administration make capecitabine an attractive option for the treatment of several types of cancers as well as the focus of future trials.
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                Author and article information

                Contributors
                Journal
                Front Pharmacol
                Front Pharmacol
                Front. Pharmacol.
                Frontiers in Pharmacology
                Frontiers Media S.A.
                1663-9812
                03 November 2016
                2016
                : 7
                : 414
                Affiliations
                [1] 1Centre for Chronic Disease, College of Health and Biomedicine, Victoria University, Melbourne VIC, Australia
                [2] 2Área de Farmacología y Nutrición, Universidad Rey Juan Carlos Madrid, Spain
                [3] 3Grupo de Excelencia Investigadora URJC, Banco de Santander Grupo Multidisciplinar de Investigación y Tratamiento del Dolor, Universidad Rey Juan Carlos Madrid, Spain
                [4] 4Unidad Asociada al Instituto de Química Médica del Consejo Superior de Investigaciones Científicas Madrid, Spain
                [5] 5Unidad Asociada al Instituto de Investigación en Ciencias de la Alimentación del Consejo Superior de Investigaciones Científicas Madrid, Spain
                [6] 6Department of Physiology, University of Melbourne, Melbourne VIC, Australia
                Author notes

                Edited by: David A. Gewirtz, Virginia Commonwealth University, USA

                Reviewed by: Hamid Akbarali, Virginia Commonwealth University, USA; Liren Qian, Navy General Hospital, China; Chantal Dessy, Université Catholique de Louvain, Belgium

                *Correspondence: Kulmira Nurgali, kulmira.nurgali@ 123456vu.edu.au

                This article was submitted to Pharmacology of Anti-Cancer Drugs, a section of the journal Frontiers in Pharmacology

                Article
                10.3389/fphar.2016.00414
                5093116
                27857691
                4d14adb4-42d7-419b-a9ba-e8b66ec5fa01
                Copyright © 2016 McQuade, Stojanovska, Abalo, Bornstein and Nurgali.

                This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY). The use, distribution or reproduction in other forums is permitted, provided the original author(s) or licensor are credited and that the original publication in this journal is cited, in accordance with accepted academic practice. No use, distribution or reproduction is permitted which does not comply with these terms.

                History
                : 16 August 2016
                : 19 October 2016
                Page count
                Figures: 0, Tables: 2, Equations: 0, References: 183, Pages: 14, Words: 0
                Funding
                Funded by: Victoria University 10.13039/501100001784
                Award ID: Research Support Fund
                Categories
                Pharmacology
                Review

                Pharmacology & Pharmaceutical medicine
                chemotherapy,chemotherapy-induced constipation,chemotherapy-induced diarrhea,pathophy-siology,treatments

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