ABSTRACT: Prostate cancer is the second most common cause of cancer death in American men and represents a significant factor in US health care costs. Radiation therapy serves as one of the most effective treatments for prostate cancer. However, radiation is also an expensive treatment modality and is a significant contributor to the overall rise in the cost of prostate cancer care. Currently, standard external beam radiation therapy for prostate cancer consists of between 75.6 and 81.0 Gy of radiation separated into 1.8- to 2-Gy doses (or “fractions”) given daily for between 7 and 9 weeks. Recently, relatively shorter treatment schedules delivering more radiation per treatment—consisting of fractions > 2 Gy—over shorter time periods have been proposed in an effort to curtail rising health care costs and improve patient convenience. However, significant uncertainty still remains regarding outcomes from this type of more condensed treatment, known as “hypofractionated” radiation. In this article, we provide the historical background and rationale for hypofractionated prostate cancer treatment, discuss the potential benefits and risks of prostate hypofractionation, and review the clinical evidence regarding the effectiveness of hypofractionated radiation therapy for prostate cancer.
Given that prostate cancer is the most common non-cutaneous cancer among men in the Western world, its treatment is of great medical and public significance. Despite its high incidence, the relative 10-year survival following treatment is 98%. A variety of treatment modalities exist, including surgery, external beam radiotherapy, brachytherapy, proton therapy, and other novel methods of treatment.
Currently, standard external beam radiotherapy for prostate cancer consists of 75.6 to 81.0 Gy of radiation separated into 1.8- to 2-Gy doses (or “fractions”) given daily for 7 to 9 weeks. The prolonged length of this standard course of prostate radiation, coupled with advances in radiation therapy technologies, have stimulated interest in delivering more radiation per fraction for the purpose of reducing the overall length of treatment. This type of shorter treatment regimen, involving larger doses of radiation per fraction, is known as “hypofractionation” or “hypofractionated” radiotherapy. Although hypofractionation has been proposed for a variety of cancer types, such as breast and early-stage lung cancer, the utilization of hypofractionation in prostate cancer treatment remains controversial because of concerns regarding clinical efficacy and the potential for increased bowel and urinary toxicity. This potential increased toxicity represents the response of normal tissue to radiation doses and varies based on the amount of radiation delivered per fraction. Furthermore, because hypofractionated radiotherapy is an emerging technique, the National Comprehensive Cancer Network (NCCN) prostate cancer guidelines currently give no recommendations concerning hypofractionated treatment schedules.
Compared to conventional fractionation, hypofractionation allows for a smaller number of treatment visits. Depending on the reduction in the number of treatment visits, the overall cost of a treatment course is proportionally reduced. This is of particular importance in a financially constricted health care system. The challenge remains to investigate the potential benefits in terms of cost and convenience while optimizing clinical outcomes.
Prostate Hypofractionation: History and Theoretical Rationale
In radiation therapy, the alpha/beta (a/b) ratio is a theoretical measure of a tissue’s predicted response to a dose of radiation, relative to the size of the dose delivered per fraction. Conventional daily doses of radiation are normally between 1.8 and 2.0 Gy and are based on the presumed high α/β ratios of most malignant tumors. Higher α/β ratios mean that tumor response is less dependent on the amount of radiation administered with each fraction, and therefore that a lower radiation dose per treatment can typically be used. Lower tumor α/β ratios, conversely, mean that a larger dose of radiation per treatment can provide improved efficacy in terms of tumor control. Although controversial and contested, a large body of work theorizes that the α/β ratio for prostate cancer is low, implying that a hypofractionated schedule (fraction sizes greater than 2.0 Gy) could improve prostate cancer control.
Controversy concerning prostate hypofractionation stems from uncertainties not only about the radiobiology of prostate cancer, but also regarding the effect of hypofractionated treatment on the nearby tissues of the rectum and bladder. In particular, radiation toxicity that manifests in the months and years following treatment, known as “late” toxicity, is known to be especially sensitive to fraction size. Because parts of the rectum and bladder may receive the same dose of radiation as the prostate itself, the difference in the sensitivity of the rectum and bladder to variations in radiation fraction size, compared with the sensitivity of the prostate cancer itself, is what results in potential harm from hypofractionated treatment. Proponents of hypofractionated treatment argue that the rectum and bladder are less sensitive to increases in dose per fraction than prostate cancer and that therefore hypofractionation should yield negligible increases in late toxicity while providing improved cancer control. Continued study as to the balancing of toxicity and efficacy is needed.
Different Clinical Approaches to Hypofractionation
Three clinical approaches to hypofractionated radiotherapy have been proposed. The first attempts to maintain the same level of tumor control with modestly shorter treatment times while maintaining similar radiation-related toxicity compared with a conventional fractionation schedule. The second approach exploits the radiosensitivity of the prostate to increase tumor control while maintaining accepted levels of adverse effects. The third technique, known as “extreme hypofractionation,” is synonymous with stereotactic body radiotherapy (SBRT), and involves the administration of only five total fractions, with doses between 5.5 and 10 Gy per fraction. Because of the delivery of large doses per fraction, extreme hypofractionation requires the use of stereotactic techniques that minimize prostate movement and maximize accuracy of treatment. Like modestly hypofractionated treatment regimens, extreme hypofractionation remains under scrutiny due to the uncertainties surrounding its execution and effects. Fortunately, several prospective studies investigating extreme hypofractionation in prostate cancer treatment have been performed, although the number of patients and length of follow-up are modest.[7,8]