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Rectal Cancer Future of Radiotherapy Delivery in Rectal Cancer— European and US Approaches Jordan A Torok, MD, 1 Brian G Czito, MD, 2 Christopher G Willett, MD 3 and Manisha Palta, MD 4 1. Resident; 2. Associate Professor; 3. Professor and Chair; 4. Assistant Professor, Department of Radiation Oncology, Duke University Medical Center, Durham, North Carolina, US Abstract Neoadjuvant radiation therapy is integral in the management of patients with localized rectal cancer. In parts of Europe, patients with operable rectal cancer are treated with short-course radiation therapy delivered in five daily, 5 Gy fractions to a total dose of 25 Gy, followed by surgery within 1 week. In the US, the standard for locally advanced rectal cancer is neoadjuvant chemoradiotherapy. This approach is principally based on the results of the German Rectal Cancer Study Group trial evaluating preoperative compared with postoperative chemoradiation. Surgery is typically performed at 4–8 weeks following completion of long-course chemoradiotherapy, facilitating tumor downstaging, and potential sphincter sparing surgery. No significant difference in clinical outcomes has been observed between these two approaches in two randomized clinical trials; however, further follow-up of these studies and new results from ongoing trials are anticipated to further clarify the optimal neoadjuvant treatment strategy. Keywords Rectal cancer, radiation therapy, short course, long course, chemoradiation, neoadjuvant therapy Disclosure: Jordan A Torok, MD, Brian G Czito, MD, Christopher G Willett, MD, and Manisha Palta, MD, have no conflicts of interest to disclose. No funding was received in the publication of this article. Received: July 31, 2014 Accepted: November 2, 2014 Citation: Oncology & Hematology Review, 2014;10(2):139–43 Correspondence: Manisha Palta, MD, Department of Radiation Oncology, Duke University, DUMC 3085 Durham, NC 27710, US. E: manisha.palta@dm.duke.edu Over the past several decades, two paradigms have emerged in the preoperative treatment of rectal cancer: a short course of radiation therapy (RT) often utilized in centers across Northern Europe and long- course chemoradiation (CRT) in other parts of Europe and the US. The short-course technique was validated by randomized trials comparing this technique to surgery alone. The majority of these trials included patients with resectable, nonmetastatic rectal cancer, both early and advanced stages, with surgery 1 week following treatment completion. By contrast, long-course therapy is typically offered to patients with more advanced disease (cT3-4, N+) to improve local control, R0 resection rates, and potentially increase rates of sphincter-preserving surgery. Randomized studies have compared long-course CRT followed by surgery to upfront surgery and postoperative CRT. Multiple studies have attempted to optimize the long-course CRT platform with the addition of oxaliplatin. Two randomized trials have compared short-course RT to long-course CRT; however, significant debate still exists regarding the optimal neoadjuvant approach in patients with rectal cancer. Short-course Radiotherapy In early trials of preoperative short-course RT from Sweden, patients were randomized to preoperative RT (25 Gy in five daily fractions over 5–7 days) or underwent surgery alone. The incidence of pelvic recurrence was © To u ch MEd ica l MEdia 201 4 significantly reduced with RT at the expense of increased postoperative morbidity. 1,2 A similar follow-up trial with improved RT techniques showed reduction in both locoregional and distant recurrence as well as improvement in overall survival (OS) with the short-course regimen. 3 The rate of postoperative morbidity was reduced with the improved RT technique and postoperative mortality was low in both groups. These trials set the stage for the Swedish Rectal Cancer Trial, which randomized patients to the short-course regimen followed by surgery 1 week later versus surgery alone. After a median follow-up of 13 years, RT significantly reduced local recurrence (LR) rates (9 versus 26 %; p<0.001) and improved OS (38 versus 30 %; p=0.008). 4 Subset analyses found statistically significant reductions in LR for all stage groups. However, these LR and OS benefits were not without potential toxicity. With long-term follow-up, patients treated with RT were more likely to develop small bowel obstruction. 5,6 The Swedish Rectal Cancer Trial was undertaken prior to widespread adoption of the total mesorectal excision (TME) surgical technique. Compared with the conventional surgical techniques at that time, TME significantly reduced LR rates. 7 To determine the value of preoperative RT in the TME era, investigators from The Netherlands initiated a multicenter trial randomizing 1,861 patients to preoperative short-course RT with TME compared with TME alone. The RT dose/fractionation and surgical 139