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Rectal Cancer Multi-modality Therapy for Rectal Cancer— Past, Present, and Future Lindsay C Overton, 1 Charles R Thomas Jr, 2 Dan O Herzig 3 and Charles D Lopez 1 1. Division of Hematology and Medical Oncology, Department of Medicine and the Knight Cancer Institute; 2. Department of Radiation Medicine and the Knight Cancer Institute; 3. Department of Surgery and the Knight Cancer Institute, Oregon Health and Science University, Portland, OR, US. Abstract The treatment of rectal cancer currently involves coordinated efforts for combined modality therapy with pre-operative chemoradiation followed by surgical management and additional adjuvant chemotherapy. The landscape of rectal cancer has shifted significantly over the past 30 years. This review aims to track this changing landscape, with a particular focus on current research and future endeavors. Keywords Rectal cancer, pre-operative chemoradiation therapy, multi-modality therapy, pathologic complete response, organ preservation Disclosure: The authors have no conflicts of interest to declare. Received: February 26, 2013 Accepted: March 27, 2013 Citation: Oncology & Hematology Review, 2013;9(1):26–30. Correspondence: Charles D Lopez, MD, PhD, Associate Professor of Medicine, Division of Hematology and Medical Oncology, Mail Code: L586, Department of Medicine and the Knight Cancer Institute, 3181 SW Sam Jackson Park Road, Oregon Health and Science University, Portland, Oregon, USA 97239. E: lopezc@ohsu.edu Over the past three decades, the treatment of rectal adenocarcinoma has evolved from a predominantly surgical disease to one involving combined triple-modality therapy with chemotherapy, radiation therapy, and surgery. Optimizing combined modality therapy for rectal cancer has been the subject of many trials involving radiotherapy techniques, chemotherapy regimens, and surgical approaches—and the optimal timing of all modalities. Current research continues to investigate optimization of these modalities for improved reduction in recurrent disease, decrease in morbidity, and increase in overall survival. Past Treatment Prior to the 1980s, patients with rectal cancer were predominantly treated with resection. The surgical technique was not standardized, resulting in inconsistent circumferential and distal margins, and technical difficulty of a low pelvic anastomosis frequently led to the need for a permanent colostomy in many instances. Prior to the understanding of the importance of total mesorectal excision (TME), surgical resection led to significant local failure rates, generally about 30–40 %, and up to 67 % in some series with advanced staged disease. 1–3 To reduce local failure rates, radiation was added postoperatively with a subsequent decrease in recurrence rates to around 20 %. 4–11 Meta-analyses published in 2000 and 2001 further supported the benefit of the addition of radiotherapy over surgery alone. 12,13 The Colorectal Cancer Collaborative Group published a meta-analysis in 2001 that evaluated 22 randomized trials comparing radiotherapy either before or after surgery to surgery alone. There was a trend toward an improvement in survival in the patients that received radiotherapy compared with surgery alone and support for the use of radiotherapy to reduce isolated local recurrences from 22 to 12.5 %. 12 With increasing agreement regarding the benefit of radiotherapy, it achieved widespread use by early 2000. The role of chemotherapy, while clear for 26 colon cancer, was not as clear for rectal cancer. However, three large studies supported the addition of 5-FU-based chemotherapy to radiation and surgery for the treatment of rectal cancer. 14–16 The GITSG-7175 trial examined patients with Dukes Stage B2, C1 or C2 (corresponding to stage II or III) disease randomized to surgery alone, postoperative radiotherapy, postoperative chemotherapy with 5-FU/methyl-CCNU, or combined chemoradiotherapy (CRT) with radiation and 5-FU/methyl-CCNU. Overall, this study showed that recurrence rates were highest in the group that received surgery alone and lowest in the group that received adjuvant radiation plus chemotherapy. 14 The NSABP R-01 trial further supported the use of systemic therapy. Patients with resected stage II or III disease were randomized to observation, adjuvant chemotherapy with methyl-CCNU/ vincristine/5-FU (MOF) or postoperative radiation therapy. Although there was no combined modality treatment arm, there was an improvement in disease-free survival in patients receiving postoperative chemotherapy compared with surgery alone or postoperative RT alone. 15 The Mayo Clinic/North Central Cancer Treatment Group (NCCTG) further confirmed the role of CRT. Patients with stage II or III rectal cancer were assigned to postoperative RT alone or postoperative RT plus bolus 5-FU (in addition to a cycle of bolus 5-FU/methyl-CCNU before and after CRT). Postoperative CRT resulted in a 47 % reduction in the risk of relapse and a 36 % reduction in the risk of cancer-related death. 16 Although use of methyl-CCNU is no longer used, the National Institutes of Health consensus conference endorsed the use of postoperative 5-FU based CRT for patients with stage II or III rectal cancer. 17 Present Treatment Although the addition of postoperative CRT improved outcomes, the rate of local pelvic recurrences remained high, leading to significant morbidity. Improvements in surgical methods, with TME, were an important advance © Touch ME dical ME dia 2013