Evolving Role of Neoadjuvant Therapy in Rectal Cancer

Management of locally advanced rectal cancer is complex because curative treatment routinely involves administration of surgery, chemotherapy, and radiation. Optimal treatment delivery sequencing and timing are challenging, and moreover, there is considerable heterogeneity in risk based on rectal tumor location, extent, and nodal involvement. The goal in rectal cancer treatment is to optimize disease-free and overall survival while minimizing the risk of local recurrence and toxicity from both radiation and systemic therapy. Currently, the standard approach to management of locally advanced (T3 or T2) rectal cancer involves careful staging with a pelvic MRI and proctoscopic evaluation by a surgeon experienced in total mesorectal excision. MRI can help to distinguish between patients in low-, intermediate-, and high-risk categories. Low-risk tumors have no evidence of either extramural spread or nodal involvement and proximal location in the rectum. For such patients, R0 resection is almost always possible and immediate surgery often is reasonable. In the minority of cases where unanticipated lymph node involvement is detected at surgical pathology, postoperative radiation can be administered. Patients who opt for up-front rectal surgery need to understand that although there is a chance that radiation can be avoided, if it is necessary, it is less well tolerated when administered postoperatively. Initial surgical treatment should be reserved for low-risk patients for whom imaging indicates and multidisciplinary team members feel is able to undergo an R0 resection with low chance for regional spread of disease. For patients with high-risk disease based on distal tumor location requiring an APR, threatened radial margins, or T4 tumors, preoperative chemoradiation is essential. Indeed, this approach increases the likelihood of complete surgical resection with negative margins. For some high-risk patients, for example those with T4 or bulky nodal disease, preoperative systemic therapy followed by preoperative chemoradiation and then surgery may be optimal. The feasibility of this approach is well established based on nonrandomized trials, but it has not been evaluated in a randomized study. Preoperative administration of systemic therapy can achieve clinical downstaging, optimize rates of sphincter preservation, and establish tumor responsiveness, which may be valuable for incorporation into future treatment decisions. For patients with intermediate-risk T3 rectal cancers, for example, a cT3N1 tumor 7 cm from the anal verge with two to three regional lymph nodes in the 7-mm range, we encourage participation in the PROSPECT randomized trial, which is now open and accruing at numerous centers in North America, and shortly in Europe and South America as well. This study will determine in the era of optimal imaging, surgical technique, and better systemic chemotherapy, whether pelvic radiation remains an essential component of curative treatment. The PROSPECT study uses chemoradiation selectively rather than automatically and customizes subsequent treatment based on response to neoadjuvant FOLFOX. Clinical trials with interventions that tailor treatment to more precisely defined clinical subgroups based on both initial features and tumor responsiveness are expected to become the norm. Although this trend is likely to make clinical trial design more complex, customized treatment strategies are likely to achieve the optimal balance between under- and overtreatment and will address the heterogeneity of both tumor biology and disease presentation. For now, treatment for a patient with clinical T3N1 tumor in the mid rectum consists of the following components:Neoadjvuant chemoradiation with either 5-fluorouracil or capecitabine as sensitizing therapy. Low anterior resection with total mesorectal excision. Typically a temporary diverting ostomy is required. Postoperative administration of adjuvant systemic therapy, 8 cycles of FOLFOX is appropriate, although oxaliplatin should be omitted for early signs of peripheral neuropathy or on the basis of age/comorbidity. Although this is the current care standard, there is concern that such extensive treatment is not necessary for all patients to prevent local recurrence and to optimize cure. To determine if therapy can be streamlined, participation in PROSPECT or other clinical trials asking compelling clinical questions is a priority.