Before the 1980s, rectal cancer was frequently treated with surgery alone, which resulted in high rates of local failure with significant patient morbidity and mortality. Randomized trials performed in the 1980s and 1990s demonstrated that adjuvant chemotherapy decreased rates of local failure and improved survival compared with resection alone. 1,2 These observations led to the adoption of adjuvant radiation therapy and chemotherapy as the standard treatment in the US for patients with resected stage II‐III disease. More recently, proponents of a more thorough and anatomical resection of the mesorectal tissues, i.e. the total mesorectal excision (TME) procedure, reported that local regional failure rates with this approach alone were <10%, questioning the necessity of radiation therapy. To answer this, a large randomized trial was undertaken in The Netherlands comparing neoadjuvant radiation therapy followed by TME with TME only. This trial showed that despite improved surgical techniques, radiation therapy resulted in a significant reduction in local failure (two-year local failure rate 2.4 versus 8.2%; p<0.001). 3 These findings have been supported by the preliminary results of a Medical Research Council (MRC) trial evaluating pre-operative short-course radiotherapy versus selected post-operative combined modality therapy. In this phase III study, 1,350 patients with clinically resectable rectal cancer were randomized to short-course pre-operative radiation therapy (25Gy in 5Gy fractions) and TME versus TME followed by selective post-operative chemoradiation (45Gy in 1.8Gy fractions with 5-fluorouracil (5-FU)) in patients with tumor involvement of the circumferential resection margin. In addition, patients with stage III disease received post-operative adjuvant chemotherapy. In patients undergoing pre-operative radiation therapy, local recurrence was significantly reduced compared with selective post-operative chemoradiation (4.7 and 11.1%, respectively). Furthermore, the three-year disease-free survival rate was significantly improved in patients undergoing pre-operative radiation therapy (79.5 and 74.9%, respectively). 4 These results suggest that even with TME and adjuvant chemotherapy, preoperative radiation improves outcomes over selective post-operative chemoradiation in patients with high-risk disease. Nonetheless, there may be selected stage II or III disease patients who can be treated with TME alone and, therefore, spared chemoradiation, including patients with upper rectal disease with minimal invasion beyond the rectal wall/no nodal involvement (T3N0), as well as disease confined to the rectal wall with minimal nodal involvement (T1‐2, N1). However, given the lack of prospective data supporting this approach, further investigation and validation will be required before general recommendations can be made. Another area of controversy over several decades has centered on the sequencing of radiation therapy relative to surgery. Advocates of preoperative therapy argued that this approach had many benefits, including enhanced rates of sphincter preservation, delivery of therapy to the tumor with an intact vasculature, and improved radiation tolerance. In Germany, a large randomized trial comparing pre-operative with postoperative radiation therapy and chemotherapy confirmed that a preoperative approach resulted in superior treatment compliance, less acute and late toxicity, improved rates of sphincter preservation in patients with low-lying tumors, and a significant improvement in local regional control, again simply by altering the sequence of chemotherapy in relationship to surgery.
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Oct 1, 2013
Robert Rosenheck 
Open Access
