Improving local control in rectal cancer: radiation sensitizers or radiation dose?

One of the primary research objectives in radiation therapy over the past two decades has been the development of agents and approaches that will enhance effectiveness. A major focus of this effort has been the concurrent use of drugs as radiosensitizers that will improve the therapeutic ratio of radiotherapy. This approach— chemoradiotherapy—is now the standard of treatment in many cancers, including rectal, anal, cervical, esophageal, gastric, head and neck, and lung. Rectal cancer is an area where radiation sensitization has been extensively addressed, primarily to improve local control and the major morbidities associated with local pelvic failure after combinedmodality therapy. Although total mesorectal excision combined with pelvic radiation therapy and a fluoropyrimidine as a radiation sensitizer has produced major improvements in local control, local failure still occurs far too commonly in more locally advanced disease. Such failures are associated with major symptomatology and with adverse effects on quality of life. In addition, there is a glimmer of hope that improved primary radiation therapy could eliminate the need for abdominal-perineal resection and permanent colostomy, as in anal cancer. There are essentially two approaches to improve local control with radiation therapy—either use a higher radiation dose or use more effective radiation sensitization. In some anatomic situations, improved dose localization techniques associated with improved technology have enabled increases of radiation dose. This approach is most effective when the target is the gross tumor mass. In neoadjuvant rectal cancer therapy, the real target is not the clinically apparent tumor mass, but rather the microscopic extensions of tumor that may be missed by the surgeon. This microscopic disease is the root of local failure and the resulting pain and morbidity. In rectal cancer, issues such as maintenance of anal sphincter function and avoidance of small bowel or bladder injury become of major importance in high-dose therapy limiting the total radiation dose. The other approach that has enormous appeal involves the use of radiation sensitizers. If a drug selectively sensitizes the tumor, one could have a selective escalation of the effective biologic dose to the tumor, and therefore improve local control without increasing morbidity. Reflecting this view, a number of studies have been done to develop such sensitizers for rectal cancer. These studies have emphasized drugs that appear to have benefit when used as chemotherapy for metastatic disease, and have included both biologic and cytotoxic agents. At present, only the fluoropyrimidines (eg, fluorouracil) have proven to be of value in phase III clinical trials, although a number of other agents have demonstrated intriguing potential. Fluorouracil has been used for the past four decades as a radiation sensitizer for multiple disease sites, but most heavily in the GI tract, where it continues to be used in the definitive therapy of diseases extending anatomically from the esophagus to the anal canal. Cisplatin has been the other major success story, with the combination of radiation therapy and cisplatin improving both local control and survival in GI cancers, such as esophageal cancer, as well as other malignancies, such as head and neck and cervical cancers. Improved results with cetuximab in head and neck cancers and temozolomide in gliomas suggest that there are multiple opportunities to develop other agents as radiation sensitizers. In rectal cancer, the combination of bevacizumab and fluorouracil for radiosensitization has produced encouraging results in a phase II clinical trial. With all these exciting data, intensive research has focused on identifying other biologics and cytotoxics that can function as clinically effective radiosensitizers. While we continue to study established agents to improve radiosensitization, a new class of agents may be well suited for this application. Nanoparticle-based therapeutics are poised to make major impacts on cancer therapy. While many remain in preclinical development, others have been studied in clinical trials and several are US Food and Drug Administration approved. Data from approved nanoparticle therapeutics (such as protein-bound paclitaxel) have shown higher therapeutic efficacy and lower toxicity. Nanoparticles preferentially accumulate in tumors due to leaky tumor vasculature and, because they are macromolecules, are less likely to affect normal tissues near the tumor. These are characteristics that are very favorable for a radiosensitizer. Oxaliplatin is a drug with good potential as a radiosensitizer in rectal cancer. It has proven efficacy against metastatic colorectal cancer and has been routinely used in the adjuvant setting. There are preclinical data that suggest that oxaliplatin is a good radiation sensitizer, and early phase studies have been performed. In the present study by Gerard et al (the Prodige 2-ACCORD 12/0405 trial) in this issue of Journal of Clinical Oncology, there was a nonstatistically significant improvement in the pathologic complete response rate in the experimental arm, although the percent improvement was substantial (risk ratio, 0.72). Another report, by Aschele et al, was also a negative study, with no proven benefit for the addition of oxaliplatin during JOURNAL OF CLINICAL ONCOLOGY E D I T O R I A L VOLUME 28 NUMBER 10 APRIL 1 2010