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Gastrointestinal Cancer Conventional Pre-operative Chemoradiotherapy and Post-operative Adjuvant Chemotherapy with Induction Chemotherapy Followed by Chemoradiotherapy and Surgery in Locally Advanced Rectal Cancer Carlos Fernández-Martos, MD, 1 Rafael Estevan, MD 2 and Joan Maurel, MD, PhD 3 1. Head, Gastrointestinal Oncology Unit, Medical Oncology Department, Valencia Oncology Institute; 2. Head, Surgery Department, Valencia Oncology Institute; 3. Head, Gastrointestinal Oncology Service, Medical Oncology Department, Hospital Clinic, Barcelona Abstract In locally advanced rectal cancer, pre-operative combined-modality treatment with 5-fluorouracil and radiation has become standard, as it improves locoregional control. However, to date, no improvement has been demonstrated in terms of survival outcomes. Phase III trials published in the past decade included clinically staged populations of heterogeneous risk, and one recurring finding was that there was poor adherence to the adjuvant chemotherapy treatment after surgery. No randomized studies have been able to show that the administration of adjuvant chemotherapy in patients undergoing pre-operative radiochemotherapy improves outcomes, compared to observation. One strategy to address this is to give upfront chemotherapy prior to pre-operative chemoradiotherapy. Compared with post-operative chemotherapy, the upfront strategy does not appear to improve pathological complete response, but it has been found to have a better toxicity profile, improve compliance with treatment, and provide greater exposure to systemic treatment. This can be important for patients at higher risk of distant disease relapse. Introducing a systemically active combination chemotherapy prior to chemoradiotherapy and surgery in an appropriately selected high-risk population may well be the next step in phase III testing in order to improve disease-free survival. Keywords Neoadjuvant therapy, locally advanced rectal cancer, induction chemotherapy Disclosure: The authors have no conflicts of interest to declare. Received: January 9, 2012 Accepted: January 20, 2012 Citation: Oncology & Hematology Review, 2012;8(1):48–54 Correspondence: Carlos Fernández-Martos, MD, Fundación Instituto Valenciano de Oncología, C/ Beltrán Báguena, 8 46009 Valencia, Spain. E: cfmartos@fivo.org In North America and in many European countries, pre-operative 5-fluorouracil (5-FU) and radiation followed by total mesorectal excision (TME) and post-operative adjuvant 5-FU is one of the standard treatments for locally advanced rectal cancer (LARC) stage II and III. This approach has resulted in a five-year cumulative local relapse rate of less than 10 % and an incidence of distant metastases of about 35 %. 1,2 Phase III trials published in the past decade have included patients with stage I, II, and III and with clinically staged II and III rectal cancer. 1–3 The most significant conclusions are that pre-operative combined-modality treatment with chemotherapy and long-term chemoradiotherapy has a major impact on local control. However, there has been no impact on disease-free survival (DFS) or overall survival (OS). Since survival is mainly determined by distant metastases, efforts should be directed toward preventing systemic disease. Recent landmark trials have compared DFS rates following adjuvant therapy in patients with stage II and III colon cancer versus patients with stage II and III rectal cancer, and the results indicate less favorable outcomes in the latter group (see Figure 1). Although the reasons for this are not yet fully understood, the difference may be explained, in part, by 48 the higher incidence of local relapse, the heterogeneous risk population, and the limited and poor efficacy of adjuvant post-operative chemotherapy in patients undergoing pre-operative chemoradiotherapy. In this article, we will review the main achievements and shortcomings of the standard pre-operative combined-modality treatment followed by surgery and adjuvant chemotherapy, as well as recent data from trials that explored the newer strategy of induction chemotherapy followed by chemoradiation and surgery. Pre-operative Combined-Modality Treatment, Surgery, and Adjuvant Chemotherapy in Stage II and III Rectal Cancer The following first section of the article looks at the achievements and shortcomings of standard pre-operative combined-modality treatment. Landmark Trials Two critical questions have definitively been answered during the past decade: the question of the timing of chemoradiotherapy (before or after surgical resection) and whether or not pre-operative chemoradiotherapy is better than radiotherapy alone. © TOUCH BRIEFINGS 2012