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The Role of Capecitabine in Locally Advanced Rectal Cancer Treatment

An Update

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Abstract

Preoperative infusional 5-fluorouracil (5-FU) and concurrent radiation therapy (RT) followed by total mesorectal surgery is the current standard of care for locally advanced rectal cancer (LAR). When compared with postoperative 5-FU-based chemoradiation, this strategy is associated with significantly lower rates of local relapse, lower toxicity and better compliance. Capecitabine is a rationally designed oral prodrug that is converted into 5-FU by intracellular thymidine phosphorylase. Substitution of infusional 5-FU with capecitabine is an attractive option that provides a more convenient administration schedule and, possibly, increased efficacy. Indeed, incorporation of capecitabine in combined modality neoadjuvant therapy for LAR has been under intense investigation during the last 10 years. Phase I and II clinical trials showed that a regimen consisting of capecitabine 825mg/m2 twice daily for 7 days/week continuous oral administration in combination with RT is an active and well tolerated regimen, thereby being the preferred concurrent regimen. The definitive demonstration that efficacy of capecitabine/RT is similar to 5-FU/RT has been provided by the NSABP-R-04 and the German Margit trials. One approach to improve outcomes in rectal cancer is to deliver a second RT-sensitizing drug with effective systemic activity. Oxaliplatin and irinotecan are therefore good candidates. However, two phase III trials demonstrated that incorporation of oxaliplatin to capecitabine with RT did not improve early outcomes and, by contrast, increased toxicity. Capecitabine has also been combined with irinotecan. This regimen showed encouraging results in phase I and II clinical trials, which led to an ongoing phase III clinical trial.

New strategies with induction chemotherapy with or without chemo-radiation prior to surgery are currently under investigation. Whether or not capecitabine has a role in this setting is being investigated in ongoing trials. Incorporation of agents directed towards new targets, such as anti-epidermal growth factor receptor (EGFR) antibodies or antiangiogenic agents, in combination preoperative regimens, is being hampered by results of early trials in which efficacy outcomes with cetuximab were poor and an excessive rate of surgical complications with bevacizumab was observed. The lack of improvements in efficacy with the addition of cetuximab or bevacizumab in the adjuvant treatment of colon cancer led to concerns about further devel-opment of these agents in rectal cancer. The role of capecitabine in the postoperative adjuvant setting is the aim of the ongoing Dutch SCRIPT trial. The prediction of response associated with capecitabine has been based on expression of thymidylate synthase and dihydropyrimidine dehydrogenase, as well as on gene expression arrays. All these procedures require further validation and should be considered as investigational. In conclusion, capecitabine can safely and effectively replace intravenous continuous infusion of 5-FU in the preoperative chemoradiation setting for rectal cancer management. The addition of other new antineoplastic agents to a fluoropy-rimidine-based regimen remains investigational.

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Acknowledgements

This study was supported in part by a grant from ROCHE España. The sponsors had no role in the design and conduct of the study; in the collection, analysis, and interpretation of data; or in the preparation, review, or approval of the manuscript. The authors’ work was independent of the funders. The authors would like to acknowledge the editorial assistance provided by TFS (Trial Form Support) Spain.

The authors have no conflicts of interest that are directly relevant to the content of this review. All authors participated in the elaboration of the manuscript. They all made a significant contribution to the manuscript, review of the literature and critically reviewed the manuscript. In addition, all authors read and approved the final version of the manuscript.

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Authors and Affiliations

  1. Servicio de Oncología Médica, Fundación Instituto Valenciano de Oncología, Calle Gregorio Gea, 31, 46009, Valencia, Spain

    Carlos Fernández-Martos MD

  2. Servicio de Oncología Médica, Hospital de Granollers, Barcelona, Spain

    Miquel Nogué

  3. Servicio de Oncología Médica, Hospital Universitario La Paz (IdiPAZ), Madrid, Spain

    Paloma Cejas, Víctor Moreno-García & Jaime Feliu

  4. Drug Development Unit, Royal Marsden Hospital, Surrey, UK

    Víctor Moreno-García

  5. Servicio de Oncología Radioterapia, ERESA-Hospital General Universitario, Valencia, Spain

    Ana Hernández Machancoses

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  1. Carlos Fernández-Martos MD
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  2. Miquel Nogué
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  3. Paloma Cejas
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  5. Ana Hernández Machancoses
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  6. Jaime Feliu
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Correspondence to Carlos Fernández-Martos MD.

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Fernández-Martos, C., Nogué, M., Cejas, P. et al. The Role of Capecitabine in Locally Advanced Rectal Cancer Treatment. Drugs 72, 1057–1073 (2012). https://doi.org/10.2165/11633870-000000000-00000

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