Will there be a future role for radiation in the neo-adjuvant therapy for rectal cancer?

Until themid-1990s, postoperative adjuvant radiation therapy was considered the standard of care in management of operable rectal cancer (1). Although several investigators had demonstrated improvements in local recurrence rates, better options for sphincter preservation, improved survival, and lower toxicities, it was impossible to undertake and complete prospective studies of preoperative (neo-adjuvant) radiationbased therapy compared with postoperative (adjuvant) in the United States within the cooperative group framework. The lack of equipoise to test the sequencing of modalities was due, in part, to bias on the part of surgeons that a preoperative approach would be superior as well as exuberance on the part of radiation and medical oncologists who were impressed with the clinical response rates from single-institution reports. Consequently, our colleagues across the pond were left to address this issue. Hence, it was only after the large European studies Swedish (2) and German (3) that preoperative radiation has found widespread acceptance in North America. Neo-adjuvant chemoradiation for locally advanced rectal cancer is now widely accepted as essential for the optimum treatment of this disease. However, from our vantage point, preoperative radiation, as part of the neo-adjuvant approach to therapy, has become fossilized. Although a variety of drugs (5-fluorouracil [5FU], Irinotecan, Oxaliplatin) and molecular targeted therapy (e.g., VEGF inhibitors, EGFR inhibitors) are being explored as single agents or in combination with cytotoxic chemotherapy, the radiation approach has standardized to the use of 5,040 cGy at 180 cGy per fraction irrespective of the stage, size, or genetic fingerprint of the cancer. We believe that this presents a window of opportunity to define, in part, a new research strategy in how we use the oldest antineoplastic ‘‘drug’’ in existence: radiation therapy. From the numerous Phase II and III studies, it is quite clear that pathologic complete response rates (pCR) to neoadjuvant therapy have basically plateaued (pCR of 10– 30%). Most multi-institutional prospective reports suggests pCR rates of less than 20%.Recent efforts have focused ondefining the appropriateness of drug doses, mode of delivery, and combinations of agents, yet radiation, which is the single most effective targeted cytotoxic agent, has received scant attention with regard to the impact of radiation dose, dose per fraction, volume effects, or interaction with drugs as a function of tumor size, stage, or the genetic modulators of radiation resistance. Is 180 cGy the only dose per fraction that works in radiation therapy? Although other disciplines constantly add to their armamentarium, we are stuck in a unidimensional treatment strategy and de facto relegating radiation therapy as a dependable bridesmaid for 27 or more novel systemic agents that are paired. Intensity-modulated radiotherapy has found great favor in practicewithout clinical trials validation, but if thiswonderful new tool delivers the sameold treatment, how longwill radiation remain relevant in an age of innovation and change? Recent studies of neo-adjuvant chemotherapy alone in rectal cancer have yielded exciting data on response to treatment. At the 2010 American Society of Clinical Oncology meeting, Schrag et al. (4) reported results of a study of 29 patients with uT2N+/T3N0-1 disease treated with six cycles of folinic acid/ fluorouracil/oxaliplatin with bevacizumab. Results indicated that 29/29 (100%) of patients underwent R0 resection and 27% had a pCR! This result is as good if not better than a lot of trials of neo-adjuvant chemo-radiation. If the addition of radiation in the neo-adjuvant setting shows no better result, will there still be a role for radiation in the future management of this disease, especially as demands for comparative effectiveness in therapeutic strategies are studied? Moreover, is there a subset of patients who are destined to experience a pCR, based on their tumor’s pretreatment molecular footprint (5), and possibly be able to forego standard radical surgery?