Radiation Therapy for Rectal Cancer: Current Status and Future Directions

From Cancer Control: Journal of the Moffitt Cancer Center
Sarah E. Hoffe, MD; Ravi Shridhar, MD, PhD; Matthew C. Biagioli, MD

Abstract
Background: Treatment for rectal cancer has evolved over the past 70 years from surgery alone to the selective use of trimodality therapy for high-risk patients. Radiotherapy (RT) has improved the potential for tumor downstaging, thus enhancing sphincter preservation and local control.

Methods: This article reviews the evolution of strategies that incorporate pelvic RT, intraoperative RT, and high-dose-rate endorectal brachytherapy (HDRBT). By tracing the arc of the pendulum that has swung from postoperative RT to preoperative RT, we address the current standard of care and explore the potential of novel radiation techniques and radiosensitizing agents to improve outcomes.

Results: With randomized trial data confirming that preoperative RT in addition to chemotherapy improves local control and decreases acute and late morbidity, neoadjuvant programs have now demonstrated the prognostic significance of downstaging as well. Patients with tumors that have a good response to preoperative treatment have superior survival.

Conclusions: Future studies will determine the optimal regimen to enhance the pathologic complete or near complete response rates for locally advanced disease. Advances in radiation technology are being investigated to determine whether efficacy can be increased and toxicity decreased so that more aggressive chemotherapeutic agents can be combined. With the growing improvements in combined modality therapy, a future of better rectal cancer outcomes looms brighter than ever before.

Introduction

Colorectal cancer is the third most common malignancy in the United States.[1]
Each year, over 40,000 patients are diagnosed with rectal cancer, a malignancy defined by the National Cancer Institute panel of experts as occurring in the distal large bowel 12 cm or less from the anal verge by rigid proctoscopy.[2]
This consensus definition has been adopted based on the fact that it is measurable and reproducible. However, considerable differences in terminology exist, with some authors reporting that the most useful landmark to discriminate sigmoid colon from rectum is the loss of taenia coli, the appendices epiploicae, and the surgical mesocolon at approximately the level of the third sacral vertebra.[3]

By 1940, pathologic analysis of rectal cancer resection specimens had identified penetration of the primary tumor through the bowel wall and involved lymph nodes as factors associated with worse outcomes.[4,5] In 1954, Astler and Coller[6] confirmed the prognostic significance of direct cancer extension outside the bowel wall. In the 1970s, areas of failure found at reoperation following an initially curative resection for rectal adenocarcinoma were investigated, with results showing that survival and disease relapse rates are indeed related to the degree of bowel wall penetration and the extent of nodal disease.[7] This early work paved the way for the identification of those patients with high-risk disease, described in the modern TNM staging system as T3/T4 and/or node-positive. This review traces the evolution of pelvic radiation therapy (RT) and brachytherapy into the treatment arsenal for these patients, with emphasis on our current and future practice.

In the era before the adoption of total mesorectal excision (TME), surgery alone for transmural or node-positive rectal adenocarcinoma was associated with local failure rates of up to 50%.[8–10] This setting provided the foundation for exploration of strategies to improve outcomes following resection. The first trial was conducted by the Gastrointestinal Tumor Study Group (GITSG 7175), which randomized patients to surgery alone vs semustine and 5-fluorouracil (5-FU) vs pelvic RT alone vs chemoradiation.[11]
The arm that combined chemo therapy and RT showed a significant improvement in local control and survival.[12] Following this trial, investigators at the Mayo Clinic/North Central Cancer Treatment Group (Mayo/NCCTG) explored the question of postoperative RT alone vs postoperative chemoradiation with semustine and 5-FU on protocol NCCTG 794751.[13] With over 7 years of median follow-up, there was a 34% reduction in tumor recurrence (P = .002) and a 36% reduction in cancer-related death (P = .007) in favor of the chemoradiation arm. These two positive trials set a new standard for the postoperative management of highrisk rectal cancer. In 1990, the NCI issued a consensus conference statement declaring that combined-modality therapy is the new standard of care in this setting.

http://www.medscape.com/viewarticle/715159?src=mp&spon=17&uac=71630FV