Rectal Cancer at the Crossroads: The Dilemma of Clinically Staged T3, N0, M0 Disease

Imagine that tomorrow you develop some minor rectal bleeding. Your primary care physician refers you to a gastroenterologist who performs a colonoscopy finds a 3-cm moderately differentiated adenocarcinoma beginning at 8 cm from the anal verge. Staging computed tomography scans show no evidence of distant metastases. Pelvic magnetic resonance imaging (MRI) confirms a 3-cm mass, and a small part of the smooth black line of the muscularis propria is violated by the tumor on two contiguous MRI slices. There is no perirectal lymphadenopathy. Is preoperative chemoradiotherapy the right initial treatment for your clinical stage of disease? Our current uncertainty regarding the optimal adjuvant therapy for all clinically staged T3, N0, M0 rectal cancers was not always the case. More than two decades ago, the results of two randomized North American trials (the Gastrointestinal Tumor Study Group Protocol 7175 and the Mayo/North Central Cancer Treatment Group Protocol 79-47-51) demonstrated an increase in local control, disease-free survival, and overall survival when long-course radiation was administered concurrently with fluorouracil (FU) -based chemotherapy after surgical resection for patients with stage II and III rectal cancer. The National Surgical Adjuvant Breast and Bowel Project R01 trial then established that adjuvant FU chemotherapy after a rectal cancer resection was associated with improved survival compared with surgery alone or surgery with postoperative radiation. After the publication of these studies, it became standard of care for all patients with completely resected stage II or III rectal cancer to be treated in the postoperative setting with both FU-based chemoradiotherapy and FU chemotherapy for the best possible chance of achieving local control and overall survival. More recently, before preoperative chemoradiotherapy and total mesorectal excision (TME) emerged as a new standard of care, investigators evaluated whether there was a select group of patients in which adjuvant chemoradiotherapy could be safely omitted. Retrospective data from the non-TME era suggest that there may be a favorable subset of patients with pathologic T3, N0 disease (well to moderately differentiated histology, extending 2 mm or less into the perirectal fat, without lymphatic or vascular invasion, upper rectal location, and adequate node dissection) who may not benefit from adjuvant treatment. Furthermore, subset analyses of the largest postoperative trials evaluating adjuvant chemoradiotherapy demonstrate significantly improved local control and survival outcomes for patients with T3, N0 or T1/2, N1 disease. It is reasonable to expect even better results in the TME era. The landmark German Rectal Cancer Study, which directly compared preoperative versus postoperative chemoradiotherapy in the setting of modern clinical staging with endorectal ultrasound (ERUS) and modern surgical resection with TME, transformed our postoperative treatment standard and challenged our growing consensus that not all pathologically staged T3, N0 cancers require adjuvant therapy. This large randomized trial demonstrated that local control, rate of any grade 3 or 4 acute or late toxicity, and treatment compliance were significantly improved when chemoradiotherapy was administered preoperatively. Although preoperative chemoradiotherapy was the clear winner, new concerns emerged. First, 18% of the patients on the postoperative treatment arm who were clinically staged by ERUS as having T3 or N cancer, were found at resection to have T1-2, N0 disease and did not need adjuvant therapy. Second, due to preoperative chemoradiotherapy downstaging, we lost accuracy in predicting which patients may not benefit from adjuvant therapy, such as those with good-risk pathologic T3, N0 tumors. It is important to note that administering chemoradiotherapy and additional chemotherapy comes with a price: increased treatment-related deaths, and enhanced morbidity including radiation enteritis, diarrhea, ileus, bowel obstruction, and hematologic toxicities. In addition, functional anorectal outcome such as number of bowel movements per day, fecal continence, and sexual function have been demonstrated to be worse in patients receiving radiation. Guillem et al, in this issue of the Journal of Clinical Oncology, admirably address the question regarding the necessity of adjuvant therapy for all patients with T3, N0 rectal cancer in this new era of preoperative therapy. Although we are now aware of the potential overstaging risk from the German study, how often do we miss more advanced disease for patients with ERUSor MRI-staged T3, N0 rectal cancer? In this large multicenter review, 22% of the patients believed to have clinically node-negative T3 disease were identified after chemoradiotherapy at the time of resection to have positive mesorectal lymph nodes. Although this analysis may be criticized for its retrospective nature, heterogeneity in the treatment techniques among institutions, as well as for the lack of central staging and pathology review, it still strongly emphasizes the significant degree of understaging that can occur with modern ERUS and MRI practice at some of the best JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 26 NUMBER 3 JANUARY 2