Clinical Investigation
Stereotactic Body Radiation Therapy for Localized Prostate Cancer: A Systematic Review and Meta-Analysis of Over 6,000 Patients Treated On Prospective Studies

https://doi.org/10.1016/j.ijrobp.2019.03.051Get rights and content

Purpose

Utilization of stereotactic body radiation therapy (SBRT) for treatment of localized prostate cancer is increasing. Guidelines and payers variably support the use of prostate SBRT. We therefore sought to systematically analyze biochemical recurrence-free survival (bRFS), physician-reported toxicity, and patient-reported outcomes after prostate SBRT.

Methods and Materials

A systematic search leveraging Medline via PubMed and EMBASE for original articles published between January 1990 and January 2018 was performed. This was supplemented by abstracts with sufficient extractable data from January 2013 to March 2018. All prospective series assessing curative-intent prostate SBRT for localized prostate cancer reporting bRFS, physician-reported toxicity, and patient-reported quality of life with a minimum of 1-year follow-up were included. The study was performed according to the Preferred Reporting Items for Systematic Reviews and Meta-Analyses statement. Meta-analyses were performed with random-effect modeling. Extent of heterogeneity between studies was determined by the I2 and Cochran's Q tests. Meta-regression was performed using Hartung–Knapp methods.

Results

Thirty-eight unique prospective series were identified comprising 6116 patients. Median follow-up was 39 months across all patients (range, 12-115 months). Ninety-two percent, 78%, and 38% of studies included low, intermediate, and high-risk patients. Overall, 5- and 7-year bRFS rates were 95.3% (95% confidence interval [CI], 91.3%-97.5%) and 93.7% (95% CI, 91.4%-95.5%), respectively. Estimated late grade ≥3 genitourinary and gastrointestinal toxicity rates were 2.0% (95% CI, 1.4%-2.8%) and 1.1% (95% CI, 0.6%-2.0%), respectively. By 2 years post-SBRT, Expanded Prostate Cancer Index Composite urinary and bowel domain scores returned to baseline. Increasing dose of SBRT was associated with improved biochemical control (P = .018) but worse late grade ≥3 GU toxicity (P = .014).

Conclusions

Prostate SBRT has substantial prospective evidence supporting its use, with favorable tumor control, patient-reported quality of life, and levels of toxicity demonstrated. SBRT has sufficient evidence to be supported as a standard treatment option for localized prostate cancer while ongoing trials assess its potential superiority.

Introduction

Prostate cancer is the most common cancer diagnosed in men in the United States, and as such, it contributes greatly to the national health care expenditure on cancer care.1, 2 External beam radiation therapy is an effective curative treatment option for men with localized prostate cancer and has traditionally been delivered with small daily doses of radiation therapy over 8 to 9 weeks. A fundamental reason that radiation therapy was historically delivered in small doses over many fractions was the inability to spatially spare normal tissues adjacent to the high-dose target volume. Normal tissues generally are better able to tolerate smaller doses of radiation delivered over many weeks, and thus conventional fractionation results in a therapeutic window whereby toxicity to normal tissue is acceptable while still providing tumor control. A serious drawback to this treatment approach is that the high number of fractions increases health care costs compared with shorter treatment durations and also creates burdens and logistical challenges for patients.3

Prostate cancer is also radiobiologically unique in that it has a low alpha-to-beta ratio, which suggests that the therapeutic ratio should favor hypofractionation (larger doses per fraction with fewer total fractions).4 Fortunately, imaging and treatment technologies have markedly improved over the past 3 decades and now allow the ability to substantially reduce doses delivered to the rectum and bladder when treating prostate cancer. This has provided the opportunity to study varying degrees of hypofractionated treatment regimens and has inspired numerous clinical trials assessing the optimal dose per fraction when treating prostate cancer with radiation therapy.5, 6, 7, 8, 9, 10, 11, 12 These trials have demonstrated that moderate hypofractionation (eg, 20 treatments) has comparable efficacy and toxicity data to the conventional ≥37 treatments of radiation therapy.5, 6, 7, 8, 9, 10, 11, 12 Stereotactic body radiation therapy (SBRT) represents an extreme form of hypofractionation in which treatment is usually delivered in 4-7 fractions. Development and optimization of this ultrahypofractionation technique over the last 20 years has resulted in incorporation of SBRT into routine clinical practice, and SBRT is now a standard-of-care treatment option for many tumors of the lung, brain, spine, liver, and pancreas.

In prostate cancer, there have been multiple phase 1, 2, and even phase 3 trials assessing SBRT, and these demonstrate a similar toxicity profile and noninferior disease control compared with conventionally fractionated radiation therapy.13, 14, 15, 16, 17, 18, 19, 20, 21, 22, 23, 24, 25, 26, 27, 28, 29, 30, 31, 32, 33, 34, 35, 36, 37, 38, 39, 40, 41, 42, 43, 44, 45, 46, 47 Despite this recent surge of data to support SBRT, select organizations have yet to update their guidelines to support the adoption of SBRT in the treatment of prostate cancer. For example, the American Society for Radiation Oncology, American Urological Association, and American Society of Clinical Oncology released their guidelines for the treatment of prostate cancer with hypofractionated radiation therapy and stated there is “low” quality of evidence for SBRT for intermediate and high-risk prostate cancer based on what they determined to be a paucity of prospective data,48 although they do acknowledge that SBRT may be offered for men with intermediate risk disease, with a preference for treatment as part of a clinical trial or multi-institutional registry. This inspired our group to conduct an independent systematic review and meta-analysis of all prospective studies performed and published or presented to date to comprehensively assess outcomes after prostate cancer SBRT including tumor control, toxicity, and patient-reported quality of life (QOL).

Section snippets

Search strategy and study selection

This systematic review and meta-analysis was performed in accordance with the Preferred Reporting Items for Systematic Review and Meta-Analyses guidelines.49 A systematic literature search was performed using the MEDLINE (via PubMed) and EMBASE electronic databases and supplemented with review of national meeting abstracts. Prostate SBRT was defined as treatment delivered over less than 10 treatments with greater than or equal to 5 Gy per fraction. Search terms included “prostate” and “cancer”

Results

A total of 2265 unique studies were identified using our search strategy. After screening, 158 full-text articles and abstracts were reviewed for eligibility. Thirty-eight studies met eligibility criteria for quantitative analysis, composed of 6116 patients (Table 1, Fig. E1, Table E1, available at https://doi.org/10.1016/j.ijrobp.2019.03.051). Twenty-two studies were clinical trials, of which 17 were phase 2 or 3 trials composed of 2174 patients. All but 2 studies had at least 1 associated

Discussion

We herein demonstrate that there is considerable evidence that prostate SBRT is an effective treatment for localized prostate cancer, with a very favorable toxicity profile that has minimal impact on long-term urinary and bowel QOL. Moreover, to date, no randomized study has demonstrated that altering radiotherapeutic dose, fractionation, or target volume affects prostate cancer–specific or overall survival. Thus, toxicity, QOL, patient convenience, and cost become increasingly important when

Conclusions

Prostate SBRT has substantial evidence to support its use for treatment of localized prostate cancer, particularly in men with intermediate-risk disease. Phase 1 to 3 trials consistently report excellent tumor control and patient-reported QOL with very low acute and late toxicity. Our findings support that SBRT could be considered a standard radiotherapeutic strategy for localized prostate cancer while ongoing trials assess its potential superiority to other treatment methods.

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    Note—An online CME test for this article can be taken at https://academy.astro.org.

    The authors thank the Prostate Cancer Foundation (D.E.S.) and the Prostate Cancer National Institutes of Health Specialized Programs of Research Excellence (D.E.S., P50CA186786) for their support. This research was partially supported by National Institutes of Health grant CA 083654 (H.E.H.).

    Disclosures: Varian Medical Systems, Inc (A.U.K.); Myriad Genetics research funding and consulting and GenomeDx research funding (T.M.M.); consultation for Ferring, Astellas consulting and research funding, Janssen consulting and research funding, Nanobiotix consulting, Dendreon consulting, Blue Earth consulting, GenomeDX consulting, Bayer consulting, and equity from Augmenix, Inc (P.L.N.); Augmenix, Inc research funding (N.D.); F.Y.F. is the cofounder of Bayer, Sanofi, Clovis, and PFS Genomics, Inc; and Z.S.Z. is on the external advisory board for Scripps Proton Therapy Center and is a paid consultant for EMD Serono.

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