Stereotactic body radiotherapy for primary management of early-stage, low- to intermediate-risk prostate cancer: report of the American Society for Therapeutic Radiology and Oncology Emerging Technology Committee.

s Korean Institute of Radiological and Medical Sciences. Forty-four patients received 32–36 Gy in 4 fractions, with the exception of 1 patient who received 24 Gy in 3 fractions (49, 50). There were 10 low-risk (PSA <10 ng/mL, Gleason score <6, Stage T1b-T2a), 9 intermediate-risk (PSA 10–20 ng/mL, Gleason score 7), and 25 high-risk patients (PSA $20 ng/mL or Gleason score $8). With a median followup of 13 months, overall survival at 3 years was 100%, with a 3-year FFBF rate of 78%. Fourteen patients experienced Grade 1 or 2 acute rectal toxicity, and 17 patients experienced Grade 1 or 2 bladder toxicity. There were no Grade 3 or greater acute toxicities. Late toxicity was not reported. Radiation Medical Group of San Diego. Ten patients received 38 Gy in 4 fractions (51). Very preliminary results were reported; the median pretreatment PSA level was 6.9 ng/mL, and at 4 months after treatment it had decreased to 0.7 ng/mL in the first 8 patients. Toxicity was not detailed. 21st Century Oncology (Fort Myers, FL). Twenty-two patients received 36.25 Gy in 5 fractions (52). The Common Toxicity Criteria for Adverse Effects, version 3.0, were used to assess toxicity at intervals from 1 to 12 months after treatment. Twenty-two patients were reported, of whom 18 had been followed for at least 1 month. During treatment, 3 patients reported dysuria and 5 urinary hesitancy, all Grade 1 toxicities. At 1 month, 1 patient reported continued dysuria and hesitancy, and 4 patients reported frequency and urgency. During treatment, 5 patients reported diarrhea, and 2 reported proctitis. At 1 month, 1 patient reported continued proctitis, Grade 1. Patients followed for more than 3 months returned to baseline urinary and rectal function. No reporting of clinical outcomes was made. CLINICAL DATA OVERVIEW Preliminary results, primarily available only in abstract form and consisting of reports of clinical experiences from single institutions, show that SBRT for the prostate is technically feasible, with little reported acute morbidity. Very early results, of limited statistical power, suggest that treatment will induce an initial PSA response of a magnitude equivalent to that seen with conventionally fractionated radiotherapy. Data are not available regarding long-term disease control, survival, and chronic toxicity. In the absence of randomized trials and mature, long-term follow-up data, a conservative estimation of consequences of non-use of SBRT would be a continuation of treatment following standard, accepted 1302 I. J. Radiation Oncology d Biology d Physics Volume 76, Number 5, 2010 fractionation schemes, with realization of the associated tumor control and normal tissue complication probabilities. FUTURE POTENTIAL BASED ON CLINICAL DEVELOPMENT Assuming favorable outcomes from the maturation of long-term data from the aforementioned randomized studies, one can envision a significant change in the landscape of external-beam prostate radiotherapy. If it is found that SBRT of the prostate results in improved cell killing or an improved therapeutic ratio, it is likely that this technique will gain favor in the radiotherapy community. Prediction of social implications Prostate cancer is the leading cancer in men, with 186,320 new cases (25% of all cancer in men) estimated in 2008 by the American Cancer Society. Currently there are several standard local treatment options that include radical prostatectomy, prostate brachytherapy (seed implantation or high-dose-rate interstitial regimens), external-beam prostate irradiation alone (from a variety of radiation sources), and combinations of external-beam radiation and brachytherapy as a boost. Prostate SBRT may provide an alternative that significantly reduces the overall cost of treatment and greatly reduces overall treatment time, which is favored by patients. Shorter treatment regimens may have significant impact on patients’ ability to continue working, with minimal impact on productivity and resources, as long as acute toxicities and recovery times are not extended. Preliminary data suggest this is not the case, but additional studies are required to verify these preliminary observations. Longer follow-up is required to confirm clinical outcomes and quality-of-life measures. As various SBRT regimens evolve, it is important to document via adequately powered clinical trials their relative efficacy and toxicity. This is particularly important in the setting of a shift in paradigm based on biologic modeling, to ensure that outcomes are at least equivalent to the longestablished conventional fractionation regimens. Currently, evidence does not exist to establish that the hypofractionated techniques, especially with accelerated SBRT regimens, are equivalent to standard-fractionation radiation treatments. Prostate SBRT regimens are largely unverified in any venue other than relatively small single-institution trials with generally short follow-up. Analysis of potential clinical issues The American Society for Therapeutic Radiology and Oncology maintains the position that new technologies and modifications of existing technologies representing significant paradigmatic shifts in treatment approach should be implemented into clinical practice in such a manner as to ensure safety, efficacy and, ideally, cost-effectiveness. Current conventionally fractionated courses of radiotherapy for prostate cancer at escalated doses are among the longest treatment courses for any disease, creating a major impetus to find effective shortened regimens. The potential biologic advantages of hypofractionation in general are based on modeling of the linear-quadratic formula for the a/b ratio for prostate cancer cells and normal tissues, such as bladder and rectum. This model may not adequately address the complexities of tumor and normal tissue response, and therefore may not accurately be able to predict the dose per fraction that may be safely administered. If the linear-quadratic equation is appropriate, the a/b ratio for prostate cancer may not be as low as some studies have suggested, when hypoxia and other factors are considered. Furthermore, it may not be the case that all risk groups will benefit equally; in fact, the intermediate-risk group has shown the most benefit from dose escalation in randomized trials, with less benefit to highor low-risk groups. If biologic differences account for such variable outcomes, the same may be true for hypofractionation. Androgen deprivation therapy has also been suggested to influence the a/b estimate, and the interactions between androgen ablation and hypofractionation have also not been adequately addressed. To date, a variety of hypofractionation regimens have been used, and the optimal schema remains undefined. Rectal toxicity is a major concern regarding prostate SBRT. Central to the success of dose escalation for prostate cancer with 3D conformal radiotherapy and IMRT has been the use of dose–volume constraints derived from thousands of patients treated with conventionally fractionated radiotherapy. Rectal dose constraints are not defined for fractions sizes used with SBRT. The late effects of even small volumes of rectum treated to doses in the range of 3–10 Gy are not known. A smaller, tighter margin on the prostate provides rectal sparing, but optimization of immobilization and precise daily real-time organ localization is required. A smaller margin also has the potential to result in poorer tumor control. Parameters for optimal dose per fraction, normal tissue dose constraints, PTV definitions, and dose distribution standards remain to be established for SBRT. Technologic advances such as SBRT combined with optimum immobilization and organ localization may allow refinements in dose delivery precision to achieve the goal of minimal margins around the target structure while permitting dose acceleration. Clinical implementation of this technique will require a consistent investment in new technologies capable of achieving this precision, or poorer local control rates will probably result. These techniques are typically more time-consuming for the radiation oncologist and staff, involving the need for extensive contouring and closer oversight on treatment by the physician, as well as daily localization procedures on the part of the therapists. This increased time commitment should be offset by the fewer number of fractions used. The authors of this report believe further clinical trials addressing the uncertainties in the clinical implementation of this new approach to prostate cancer treatment should be conducted. The technique holds sufficient promise to warrant further investigation. If proven efficacious and safe, conventional and/or accelerated hypofractionation may provide social and economic benefits to prostate cancer patients as well. SBRT to prostate: ETC report d M. K. BUYYOUNOUSKI et al. 1303