Neoadjuvant short- or long-term radio(chemo)therapy for rectal cancer: how and who should be treated?

There are two general approaches to preoperative radiotherapy (RT) in rectal cancer: short-course (25 Gy in 5 fractions) radiation with immediate surgery and long-course 5-fluorouracil (5-FU)-based chemoradiotherapy (CRT; 50.4 Gy in 28 fractions) with surgery scheduled 6-8 weeks thereafter. While it is clear that downsizing and downstaging effects are more pronounced with long-course CRT and delayed surgery, a Polish randomized trial and, more recently, an Australian phase III trial demonstrated no significant differences in long-term oncologic outcomes and late toxicity rates between either preoperative concept. Ongoing studies currently address short-course preoperative RT with a longer interval to surgery (Stockholm III trial), and short-course RT with sequential combination chemotherapy in patients with synchronous distant metastasis. With respect to the long-course CRT approach, newer-generation chemotherapeutics as well as molecularly targeted agents have been tested within phase I-III studies, both as induction/adjuvant chemotherapy as well as during concomitant CRT. Evidently, the monolithic approaches to either apply the same schedule of preoperative 5-FU-based CRT to all patients with TNM stage II/III rectal cancer or to give preoperative short-course RT for all patients with resectable rectal cancer irrespective of tumor stage and location need to be questioned. The inclusion of different multimodal treatments into the surgical oncological concept, adapted to tumor location, stage, and individual patient risk factors and preferences is upcoming. Clearly, future developments will aim at identifying and selecting patients for ideal treatment alternatives.