High Dose "HDR-Like" Prostate SBRT: PSA 10-Year Results From a Mature, Multi-Institutional Clinical Trial.

Purpose/Objectives: Although ample intermediate-term prostate stereotactic body radiotherapy (SBRT) outcomes have been reported, 10-year results remain relatively sparse. Materials/Methods: Eighteen institutions enrolled 259 low- and intermediate-risk patients. Median follow-up is 5.5 years, with 66 patients followed ≥ 10 years. This SBRT regimen specifically emulated an existing HDR brachytherapy dose schedule and isodose morphology, prescribed to 38 Gy/4 fractions, delivered daily by robotic SBRT, mandating > 150% dose escalation in the peripheral zone. Androgen deprivation therapy was not allowed, and a hydrogel spacer was not available at that time. Results: Median pre-SBRT PSA 5.12 ng/mL decreased to 0.1 ng/mL by 3.5 years, with further decrease to a nadir of < 0.1 ng/mL by 7 years, maintained through 10 years. Ten-year freedom from biochemical recurrence measured 100% for low-risk, 84.3% for favorable intermediate risk (FIR), and 68.4% for unfavorable intermediate (UIR) cases. Multivariable analysis revealed that the UIR group bifurcated into two distinct prognostic subgroups. Those so classified by having Gleason score 4 + 3 and/or clinical stage T2 (versus T1b/T1c) had a significantly poorer 10 year freedom from biochemical recurrence rate, 54.8% if either or both factors were present, while UIR patients without these specific factors had a 94.4% 10-year freedom from biochemical recurrence rate. The cumulative incidence of grade 2 GU toxicity modestly increased over time - 16.3% at 5 years increased to 19.2% at 10 years-- while the incidence of grade 3+ GU and GI toxicity remained low and stable to 10 years - 2.6% and 0%, respectively. The grade 2 GI toxicity incidence also remained low and stable to 10 years - 4.1% with no further events after year 5. Conclusion: This HDR-like SBRT regimen prescribing 38 Gy/4 fractions but delivering much higher intraprostatic doses on a daily basis is safe and effective. This treatment achieves a median PSA nadir of <0.1 ng/mL and provides high long-term disease control rates without ADT except for a subgroup of unfavorable intermediate-risk patients.

Refining the definition of biochemical failure in the era of stereotactic body radiation therapy for prostate cancer: The Phoenix definition and beyond.

BACKGROUND AND PURPOSE: The Phoenix definition for biochemical failure (BCF) after radiotherapy uses nadir PSA (nPSA) + 2 ng/mL to classify a BCF and was derived from conventionally fractionated radiotherapy, which produces significantly higher nPSAs than stereotactic body radiotherapy (SBRT). We investigated whether an alternative nPSA-based threshold could be used to define post-SBRT BCFs. MATERIALS AND METHODS: PSA kinetics data on 2038 patients from 9 institutions were retrospectively analyzed for low- and intermediate-risk PCa patients treated with SBRT without ADT. We evaluated the performance of various nPSA-based definitions. We also investigated the relationship of relative PSA decline (rPSA, PSA18month/PSA6month) and timing of reaching nPSA + 2 with BCF. RESULTS: Median follow-up was 71.9 months. BCF occurred in 6.9% of patients. Median nPSA was 0.16 ng/mL. False positivity of nPSA + 2 was 30.2%, compared to 40.9%, 57.8%, and 71.0% for nPSA + 1.5, nPSA + 1.0, and nPSA + 0.5, respectively. Among patients with BCF, the median lead time gained from an earlier nPSA + threshold definition over the Phoenix definition was minimal. Patients with BCF had significantly lower rates of early PSA decline (mean rPSA 1.19 vs. 0.39, p < 0.0001) and were significantly more likely to reach nPSA + 2 ≥ 18 months (83.3% vs. 21.1%, p < 0.0001). The proposed criterion (rPSA ≥ 2.6 or nPSA + 2 ≥ 18 months) had a sensitivity and specificity of 92.4% and 81.5%, respectively, for predicting BCF in patients meeting the Phoenix definition and decreased its false positivity to 6.4%. CONCLUSION: The Phoenix definition remains an excellent definition for BCF post-SBRT. Its high false positivity can be mitigated by applying additional criteria (rPSA ≥ 2.6 or time to nPSA + 2 ≥ 18 months).

Toxicity After Stereotactic Body Radiation Therapy for Prostate Cancer in Patients With Inflammatory Bowel Disease: A Multi-institutional Matched Case-Control Series.

PURPOSE: To evaluate the safety of stereotactic body radiation therapy (SBRT) for prostate cancer in men with inflammatory bowel disease (IBD). METHODS AND MATERIALS: We queried a consortium database for patients with IBD receiving SBRT for prostate cancer between 2006 and 2012. Identified patients were matched with patients without a history of IBD in a 3:1 fashion based on dose, fractionation, use of androgen deprivation therapy, and age distribution. Logistic regression was used to evaluate the association between having IBD and experiencing acute and late gastrointestinal (GI) and genitourinary (GU) toxicities as scored on the Common Terminology Criteria for Adverse Events scale. Time to late toxicity was evaluated using proportional hazard Cox models. Our study was limited by absence of data on prostate size, baseline International Prostate Symptom Score, and rectal dose-volume histogram parameters. RESULTS: Thirty-nine patients with flare-free IBD at time of treatment (median follow-up 83.9 months) and 117 matched controls (median follow-up 88.7 months) were identified. A diagnosis of IBD was associated with increased odds of developing any late grade GI toxicity (odds ratio [OR] 6.11, P <.001) and GU toxicity (odds ratio 6.14, P < .001), but not odds of developing late grade ≥2 GI (P = .08) or GU toxicity (P = .069). Acute GI and GU toxicity, both overall and for grade ≥2 toxicities, were more frequent in men with IBD (P < .05). Time to late GI and GU toxicity of any grade was significantly shorter in patients with IBD (P < .001). Time to late grade ≥2 GU, but not grade ≥2 GI toxicity, was also shorter in patients with IBD (P = .044 for GU and P = .144 for GI). CONCLUSIONS: Patients with IBD who received SBRT for PCa had a higher likelihood of developing acute GI and GU toxicity, in addition to experiencing lower grade late toxicities that occurred earlier. However, patients with IBD did not have a higher likelihood for late grade ≥2 GI or GU toxicity after SBRT compared with the control cohort. Interpretation of this data are limited by the small sample size. Thus, men with IBD in remission should be properly counseled about these risks when considering SBRT.

Salvage stereotactic body radiotherapy (SBRT) for intraprostatic relapse after prostate cancer radiotherapy: An ESTRO ACROP Delphi consensus.

BACKGROUND AND PURPOSE: Between 30% and 47% of patients treated with definitive radiotherapy (RT) for prostate cancer are at risk of intraprostatic recurrence during follow-up. Re-irradiation with stereotactic body RT (SBRT) is emerging as a feasible and safe therapeutic option. However, no consensus or guidelines exist on this topic. The purpose of this ESTRO ACROP project is to investigate expert opinion on salvage SBRT for intraprostatic relapse after RT. MATERIALS AND METHODS: A 40-item questionnaire on salvage SBRT was prepared by an internal committee and reviewed by a panel of leading radiation oncologists plus a urologist expert in prostate cancer. Following the procedure of a Delphi consensus, 3 rounds of questionnaires were sent to selected experts on prostate re-irradiation. RESULTS: Among the 33 contacted experts, 18 (54.5%) agreed to participate. At the end of the final round, participants were able to find consensus on 14 out of 40 questions (35% overall) and major agreement on 13 questions (32.5% overall). Specifically, the consensus was reached regarding some selection criteria (no age limit, ECOG 0-1, satisfactory urinary flow), diagnostic procedures (exclusion of metastatic disease, SBRT target defined on the MRI) and therapeutic approach (no need for concomitant ADT, consideration of the first RT dose, validity of Phoenix criteria for salvage SBRT failure). CONCLUSION: While awaiting the results of ongoing studies, our ESTRO ACROP Delphi consensus may serve as a practical guidance for salvage SBRT. Future research should address the existing disagreements on this promising approach.

Stereotactic Body Radiotherapy for High-Risk Localized Carcinoma of the Prostate (SHARP) Consortium: Analysis of 344 Prospectively Treated Patients.

PURPOSE: To explore the efficacy and toxicity of stereotactic body radiation therapy (SBRT) in high-risk prostate cancer (HRPCa) in a consortium of 7 institutional phase 2 trials and prospective registries. METHODS AND MATERIALS: Individual patient data were pooled for 344 patients with a minimum follow-up of 24 months. Biochemical recurrence-free survival (BCRFS) and distant metastasis-free survival (DMFS) were estimated using a Kaplan-Meier framework. Fine and Gray competing risk and Cox proportional hazards regression models were developed to assess the association between time to BCR and time to distant metastasis and prespecified variables of interest. Logistic regression models were developed to evaluate associations between acute and late grade ≥2 genitourinary and gastrointestinal and the following a priori-specified variables: age, dose per fraction, ADT use, and nodal radiation therapy. RESULTS: Median follow-up was 49.5 months. Seventy-two percent of patients received ADT, with a median duration of 9 months, and 19% received elective nodal radiation therapy. Estimated 4-year BCRFS and DMFS rates were 81.7% (95% CI, 77.2%-86.5%) and 89.1% (95% CI, 85.3%-93.1%). The crude incidences of late grade ≥3 genitourinary and gastrointestinal toxicity were 2.3% and 0.9%. CONCLUSIONS: These data support a favorable toxicity and efficacy profile for SBRT for HRPCa. Further prospective studies are needed to evaluate the optimal dose and target volume in the context of SBRT for HRPCa.

Prostate Stereotactic Body Radiation Therapy: An Overview of Toxicity and Dose Response.

PURPOSE: Ultrahypofractionationed radiation therapy for prostate cancer is increasingly studied and adopted. The American Association of Physicists in Medicine Working Group on Biological Effects of Hypofractionated Radiotherapy therefore aimed to review studies examining toxicity and quality of life after stereotactic body radiation therapy (SBRT) for prostate cancer and model its effect. METHODS AND MATERIALS: We performed a systematic PubMed search of prostate SBRT studies published between 2001 and 2018. Those that analyzed factors associated with late urinary, bowel, or sexual toxicity and/or quality of life were included and reviewed. Normal tissue complication probability modelling was performed on studies that contained detailed dose/volume and outcome data. RESULTS: We found 13 studies that examined urinary effects, 6 that examined bowel effects, and 4 that examined sexual effects. Most studies included patients with low-intermediate risk prostate cancer treated to 35-40 Gy. Most patients were treated with 5 fractions, with several centers using 4 fractions. Endpoints were heterogeneous and included both physician-scored toxicity and patient-reported quality of life. Most toxicities were mild-moderate (eg, grade 1-2) with a very low overall incidence of severe toxicity (eg, grade 3 or higher, usually <3%). Side effects were associated with both dosimetric and non-dosimetric factors. CONCLUSIONS: Prostate SBRT appears to be overall well tolerated, with determinants of toxicity that include dosimetric factors and patient factors. Suggested dose constraints include bladder V(Rx Dose)Gy <5-10 cc, urethra Dmax <38-42 Gy, and rectum Dmax <35-38 Gy, though current data do not offer firm guidance on tolerance doses. Several areas for future research are suggested.

Tumor Control Probability Modeling and Systematic Review of the Literature of Stereotactic Body Radiation Therapy for Prostate Cancer.

PURPOSE: Dose escalation improves localized prostate cancer disease control, and moderately hypofractionated external beam radiation is noninferior to conventional fractionation. The evolving treatment approach of ultrahypofractionation with stereotactic body radiation therapy (SBRT) allows possible further biological dose escalation (biologically equivalent dose [BED]) and shortened treatment time. METHODS AND MATERIALS: The American Association of Physicists in Medicine Working Group on Biological Effects of Hypofractionated Radiation Therapy/SBRT included a subgroup to study the prostate tumor control probability (TCP) with SBRT. We performed a systematic review of the available literature and created a dose-response TCP model for the endpoint of freedom from biochemical relapse. Results were stratified by prostate cancer risk group. RESULTS: Twenty-five published cohorts were identified for inclusion, with a total of 4821 patients (2235 with low-risk, 1894 with intermediate-risk, and 446 with high-risk disease, when reported) treated with a variety of dose/fractionation schemes, permitting dose-response modeling. Five studies had a median follow-up of more than 5 years. Dosing regimens ranged from 32 to 50 Gy in 4 to 5 fractions, with total BED (α/ß = 1.5 Gy) between 183.1 and 383.3 Gy. At 5 years, we found that in patients with low-intermediate risk disease, an equivalent doses of 2 Gy per fraction (EQD2) of 71 Gy (31.7 Gy in 5 fractions) achieved a TCP of 90% and an EQD2 of 90 Gy (36.1 Gy in 5 fractions) achieved a TCP of 95%. In patients with high-risk disease, an EQD2 of 97 Gy (37.6 Gy in 5 fractions) can achieve a TCP of 90% and an EQD2 of 102 Gy (38.7 Gy in 5 fractions) can achieve a TCP of 95%. CONCLUSIONS: We found significant variation in the published literature on target delineation, margins used, dose/fractionation, and treatment schedule. Despite this variation, TCP was excellent. Most prescription doses range from 35 to 40 Gy, delivered in 4 to 5 fractions. The literature did not provide detailed dose-volume data, and our dosimetric analysis was constrained to prescription doses. There are many areas in need of continued research as SBRT continues to evolve as a treatment modality for prostate cancer, including the durability of local control with longer follow-up across risk groups, the efficacy and safety of SBRT as a boost to intensity modulated radiation therapy (IMRT), and the impact of incorporating novel imaging techniques into treatment planning.

Dose-response with stereotactic body radiotherapy for prostate cancer: A multi-institutional analysis of prostate-specific antigen kinetics and biochemical control.

BACKGROUND AND PURPOSE: The optimal dose for prostate stereotactic body radiotherapy (SBRT) is still unknown. This study evaluated the dose-response relationships for prostate-specific antigen (PSA) decay and biochemical recurrence (BCR) among 4 SBRT dose regimens. MATERIALS AND METHODS: In 1908 men with low-risk (50.0%), favorable intermediate-risk (30.9%), and unfavorable intermediate-risk (19.1%) prostate cancer treated with prostate SBRT across 8 institutions from 2003 to 2018, we examined 4 regimens (35 Gy/5 fractions [35/5, n = 265, 13.4%], 36.25 Gy/5 fractions [36.25/5, n = 711, 37.3%], 40 Gy/5 fractions [40/5, n = 684, 35.8%], and 38 Gy/4 fractions [38/4, n = 257, 13.5%]). Between dose groups, we compared PSA decay slope, nadir PSA (nPSA), achievement of nPSA ≤0.2 and ≤0.5 ng/mL, and BCR-free survival (BCRFS). RESULTS: Median follow-up was 72.3 months. Median nPSA was 0.01 ng/mL for 38/4, and 0.17-0.20 ng/mL for 5-fraction regimens (p < 0.0001). The 38/4 cohort demonstrated the steepest PSA decay slope and greater odds of nPSA ≤0.2 ng/mL (both p < 0.0001 vs. all other regimens). BCR occurred in 6.25%, 6.75%, 3.95%, and 8.95% of men treated with 35/5, 36.25/5, 40/5, and 38/4, respectively (p = 0.12), with the highest BCRFS after 40/5 (vs. 35/5 hazard ratio [HR] 0.49, p = 0.026; vs. 36.25/5 HR 0.42, p = 0.0005; vs. 38/4 HR 0.55, p = 0.037) including the entirety of follow-up, but not for 5-year BCRFS (≥93% for all regimens, p ≥ 0.21). CONCLUSION: Dose-escalation was associated with greater prostate ablation and PSA decay. Dose-escalation to 40/5, but not beyond, was associated with improved BCRFS. Biochemical control remains excellent, and prospective studies will provide clarity on the benefit of dose-escalation.

Prostate SBRT: Comparison the Efficacy and Toxicity of Two Different Dose Fractionation Schedules.

Background: CyberKnife SBRT is capable of producing dosimetry comparable to that created by HDR brachytherapy. Our original CyberKnife prostate SBRT schedule of 3,800 cGy/4 fractions ("high dose") was based upon favorable published prostate HDR brachytherapy experience. Subsequently, our trial was modified to allow a lower dose of 3,400 cGy/5 fractions ("moderate dose") in selected cases. Methods: Two hundred eighty-nine low and intermediate-risk patients were treated to either high dose (178 pts) or moderate dose (111 pts). The dose selection was individualized; high dose more commonly used in younger, intermediate-risk patients, and moderate dose more commonly used in older, low-risk patients. Results: Median PSA reached 5-year nadir levels of 0.034 ng/mL in the high dose, vs. 0.1 ng/mL in the moderate dose groups, respectively (p = 0.044 by year 4), with 62 vs. 44% reaching an ablation PSA nadir (<0.1 ng/mL) by year 5, respectively. Five year biochemical relapse free survival rates measured 98.3% for moderate dose and 94.3% for high dose groups, respectively (p = 0.1946). Five-year actuarial grade 2 genitourinary (GU) toxicity rates measured 11.6 vs. 8.7% for high dose vs. moderate dose groups, respectively, with a far lower incidence of grade ≥3 GU and grade ≥2 GI toxicity rates in both groups. Conclusions: Both regimens are efficacious in their respective, selected groups. Both arms have low grade ≥3 GU toxicity and ≥grade 2 GI toxicity. In favor of the original high dose regimen, it has longer follow-up, produces a lower PSA nadir value and is more likely to eventually produce an ablation PSA nadir (<0.1 ng/mL). In favor of the lower dose regimen, it also produces a low PSA nadir, and does so with a slightly lower grade 2 GU toxicity rate. As a lower PSA nadir could be the initial predictor a lower clinical relapse rate far beyond 5 years, even if no difference is apparent within that time frame, a practical strategy could be to more strongly consider the high dose regimen in those with the greatest potential longevity, while for those with a more limited longevity, particularly if they have minimal negative prognostic factors, the moderate dose regimen could be more attractive.

Retreatment for Local Recurrence of Prostatic Carcinoma After Prior Therapeutic Irradiation: Efficacy and Toxicity of HDR-Like SBRT.

PURPOSE: We evaluated the use of high dose-rate-like stereotactic body radiation therapy (SBRT) retreatment for biopsy-proven local persistence in prostate postradiation therapy, evaluating efficacy and toxicity. METHODS AND MATERIALS: From 2009 to 2018, 50 patients with biopsy-proven recurrent prostate cancer >2 years after prior treatment were retreated with a high dose-rate-like dose of 3400 cGy over 5 fractions. Previous radiation therapy dose measured 75.6 Gy (64.8-81.0) and median salvage interval was 8.1 years (32-241 mo.). Eighty-three percent of patients had Gleason score 7 or higher disease at retreatment. Those with preexisting toxicity >grade 1 from their prior course were excluded. The planning target volume was comprised of the clinical target volume (prostate + any contiguous extension only) with no additional expansion. Toxicity assessment used CTCAE v.3.0 criteria. RESULTS: Median follow-up was 44 months (3-110). Median pre-SBRT salvage baseline prostate specific antigen (PSA) of 3.97 ng/mL decreased to 0.6 ng/mL and 0.16 ng/mL at 1 and 5 years in nonrelapsed patients, respectively. Actuarial 5-year biochemical disease-free survival (DFS) measured 60%, with corresponding 5-year actuarial local, distant, and salvage androgen deprivation therapy free rates of 94%, 89%, and 69%, respectively. Actuarial 5-year biochemical DFS measured 78% if PSA at salvage was <6.92 ng/mL versus 12% with ≥6.92 ng/mL (P = .0001). Toxicity was primarily in the GU domain, with an 8% 5-year actuarial rate of grade 3+, 3% when limited to salvage of "conventional external beam only" local relapse. No gastrointestinal (GI) toxicity >grade 1 occurred. Of the 30% sexually potent at the time of salvage, 82% subsequently lost potency. CONCLUSIONS: SBRT salvage of local prostate recurrence in previously irradiated patients appears clinically feasible in this challenging group. It demonstrates favorable PSA and DFS response, typically deferring the need for salvage androgen deprivation therapy or other treatment by over 5 years, with low GU and GI toxicity.

Testosterone Levels and Sexual Quality of Life After Stereotactic Body Radiation Therapy for Prostate Cancer: A Multi-Institutional Analysis of Prospective Trials.

PURPOSE: The impact of higher scatter doses per fraction on testicular function and quality of life after prostate stereotactic body radiation therapy (SBRT) is poorly studied. METHODS AND MATERIALS: Six hundred thirty-six patients treated with SBRT for low- to intermediate-risk prostate cancer from 2009 to 2014 were included. Changes in testosterone and in sexual and hormonal domain scores on the Expanded Prostate Cancer Index Composite-26 (EPIC) questionnaire over a 24-month period were evaluated via a 1-sided t test. EPIC score changes were evaluated in comparison with a distribution-based minimal clinically important difference threshold, wherein changes of greater than one half or greater than one third of the standard deviation in each domain were considered as medium-sized or small-sized effects, respectively. RESULTS: Median and mean percent changes in testosterone at the 3- to 6-month, 7- to 12-month, 13- to 18-month, and 19- to 24-month time periods were -13.41% and -4.49% (P = .02); -12.23% and -2.77% (P = .13); -11.20% and -0.29% (P = .47); -5.00% and + 1.20% (P = .65). When analyzed after dividing the cohort into 3 groups based on baseline testosterone values using tertiles, testosterone tended to increase in patients in the first group and decrease in patients in the third group. Overall, the decline in EPIC hormonal domain scores never exceeded the threshold for a small-sized effect, though the decline in EPIC sexual domain scores did pass this threshold at the 19- to 24-month time period (mean 10.90 point decline). This decline was not present when groups were examined individually. CONCLUSIONS: In this large cohort of prospectively followed patients, there was a transient decline in testosterone shortly after SBRT that normalized by 24 months posttreatment. There was no significant change in EPIC hormonal domain scores. A significant decline in EPIC sexual domain scores, consistent with a small-sized clinically detectable difference, manifested between 19 and 24 months of follow-up. These results are consistent with testosterone decline patterns and sexual function changes seen after other forms of photon-based radiation therapy.

Long-term Outcomes of Stereotactic Body Radiotherapy for Low-Risk and Intermediate-Risk Prostate Cancer.

Importance: Stereotactic body radiotherapy harnesses improvements in technology to allow the completion of a course of external beam radiotherapy treatment for prostate cancer in the span of 4 to 5 treatment sessions. Although mounting short-term data support this approach, long-term outcomes have been sparsely reported. Objective: To assess long-term outcomes after stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer. Design, Setting, and Participants: This cohort study analyzed individual patient data from 2142 men enrolled in 10 single-institution phase 2 trials and 2 multi-institutional phase 2 trials of stereotactic body radiotherapy for low-risk and intermediate-risk prostate cancer between January 1, 2000, and December 31, 2012. Statistical analysis was performed based on follow-up from January 1, 2013, to May 1, 2018. Main Outcomes and Measures: The cumulative incidence of biochemical recurrence was estimated using a competing risk framework. Physician-scored genitourinary and gastrointestinal toxic event outcomes were defined per each individual study, generally by Radiation Therapy Oncology Group or Common Terminology Criteria for Adverse Events scoring systems. After central review, cumulative incidences of late grade 3 or higher toxic events were estimated using a Kaplan-Meier method. Results: A total of 2142 men (mean [SD] age, 67.9 [9.5] years) were eligible for analysis, of whom 1185 (55.3%) had low-risk disease, 692 (32.3%) had favorable intermediate-risk disease, and 265 (12.4%) had unfavorable intermediate-risk disease. The median follow-up period was 6.9 years (interquartile range, 4.9-8.1 years). Seven-year cumulative rates of biochemical recurrence were 4.5% (95% CI, 3.2%-5.8%) for low-risk disease, 8.6% (95% CI, 6.2%-11.0%) for favorable intermediate-risk disease, 14.9% (95% CI, 9.5%-20.2%) for unfavorable intermediate-risk disease, and 10.2% (95% CI, 8.0%-12.5%) for all intermediate-risk disease. The crude incidence of acute grade 3 or higher genitourinary toxic events was 0.60% (n = 13) and of gastrointestinal toxic events was 0.09% (n = 2), and the 7-year cumulative incidence of late grade 3 or higher genitourinary toxic events was 2.4% (95% CI, 1.8%-3.2%) and of late grade 3 or higher gastrointestinal toxic events was 0.4% (95% CI, 0.2%-0.8%). Conclusions and Relevance: In this study, stereotactic body radiotherapy for low-risk and intermediate-risk disease was associated with low rates of severe toxic events and high rates of biochemical control. These data suggest that stereotactic body radiotherapy is an appropriate definitive treatment modality for low-risk and intermediate-risk prostate cancer.

Patient and Dosimetric Predictors of Genitourinary and Bowel Quality of Life After Prostate SBRT: Secondary Analysis of a Multi-institutional Trial.

PURPOSE: Stereotactic body radiation therapy (SBRT) is an emerging option for localized prostate cancer. However, there are no standard dosimetric guidelines, and normal tissue tolerances for extreme hypofractionation are not well defined. We analyzed dosimetric correlations with patient-reported urinary and bowel quality of life (QOL) on a prospective trial. METHODS AND MATERIALS: Patients with low- or intermediate-risk prostate cancer from 18 institutions were enrolled on a phase 2 trial from 2007 to 2012 and treated using robotic SBRT to 38 Gy in 4 fractions on consecutive days. No androgen deprivation was used. Patients received simulation with Foley catheter for urethral delineation. The clinical target volume was prostate (low-risk patients) or prostate plus 1 cm of proximal seminal vesicles (intermediate-risk patients). Multiple dosimetric measures for urethra, bladder, and rectum were prospectively recorded. QOL using the Expanded Prostate Cancer Index Composite was assessed before and after treatment at protocol-specific time points. Linear regression was used to assess factors associated with QOL at 1 month and 2 years. RESULTS: A total of 259 patients were enrolled. QOL data were available for 98%, 96%, and 84% at baseline, 1 month, and 2 years, respectively. Median age was 69 years. Prior transurethral resection of the prostate and clinical target volume size were associated with 2-year urinary incontinence. There was a trend toward worse 2-year obstruction/irritation in older patients on multivariable analysis. Bladder and urethral doses were not associated with either 1-month or 2-year urinary QOL. In contrast, rectum maximum dose was associated with both 1-month and 2-year bowel QOL. At 2 years, the proportion with moderate or big overall bowel problems (as defined by Expanded Prostate Cancer Index Composite-26) was significantly higher in patients with rectum maximum dose greater than versus less than the median 37.4 Gy (11% vs 2%, Fisher's exact test P = .008). CONCLUSIONS: These results provide novel data that contribute to a better understanding of patient and dosimetric factors associated with adverse QOL effects from prostate SBRT.

A Pooled Analysis of Biochemical Failure in Intermediate-risk Prostate Cancer Following Definitive Stereotactic Body Radiotherapy (SBRT) or High-Dose-Rate Brachytherapy (HDR-B) Monotherapy.

OBJECTIVES: To investigate biochemical relapse-free survival (BRFS) in men with National Comprehensive Cancer Network-defined intermediate-risk prostate cancer (PC) treated with either stereotactic body radiotherapy (SBRT) or high-dose-rate brachytherapy (HDR-B) monotherapy. MATERIALS AND METHODS: A retrospective, multi-institutional analysis of 437 patients with intermediate-risk PC treated with SBRT (N=300) or HDR-B (N=137) was performed. Men who underwent SBRT were treated to 35 to 40 Gy in 4 to 5 fractions. A total of 95.6% who underwent HDR-B were treated to 42 Gy in 6 fractions. Baseline patient characteristics were compared using a T test for continuous variables and the Mantel-Haenszel χ metric or Fisher exact test for categorical variables. Kaplan-Meier curves were generated to estimate 5-year actuarial BRFS. Multivariate analysis using a Cox proportional-hazards model was used to evaluate factors associated with biochemical failure. RESULTS: The mean age at diagnosis was 68.4 (SD±7.8) years. T-category was T1 in 63.6% and T2 in 36.4%. Mean initial prostate-specific antigen was 7.4 (SD±3.4) ng/mL. Biopsy Gleason score was ≤3+4 in 82.8% and 4+3 in 17.2%. At a median of 4.1 years of follow-up, the BRFS rate (Phoenix definition) was 96.3%, with no difference when stratifying by treatment modality or biologically equivalent dose (BED1.5). On multivariate analysis, age (hazard ratio 1.08, P=0.04) and biopsy Gleason score (hazard ratio 2.48, P=0.03) were significant predictors of BRFS. CONCLUSIONS: With a median follow-up period of 4 years, SBRT and HDR-B monotherapy provide excellent BRFS in intermediate-risk PC. Longer-term follow-up is necessary to determine the ultimate efficacy of these hypofractionated approaches, but they appear promising relative to standard fractionation outcomes.

Phase 2 Multicenter Trial of Heterogeneous-dosing Stereotactic Body Radiotherapy for Low- and Intermediate-risk Prostate Cancer: 5-year Outcomes.

BACKGROUND: Stereotactic body radiation therapy is an emerging treatment for prostate cancer (PC), with potential biological and oncologic advantages. A well-established radiation dosing schedule (38Gy in 4 fractions) has shown excellent long-term efficacy in high-dose-rate (HDR) brachytherapy. OBJECTIVE: To report 5-yr efficacy, toxicity, and quality-of-life (QOL) outcomes of a novel 4-d SBRT regimen. DESIGN, SETTING, AND PARTICIPANTS: This was a single-arm prospective phase 2 trial involving 259 patients with low- or intermediate-risk PC treated at 18 US centers from December 2007 to February 2012. The median follow-up was 5yr (interquartile range 37-85mo). INTERVENTION: SBRT with 38Gy in four fractions; radiation plans mimicked HDR brachytherapy dosimetry. OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS: We measured freedom from biochemical recurrence (BCR) and assessed toxicities using the Common Terminology Criteria for Adverse Events v3.0 and QOL using the Expanded Prostate Cancer Index Composite. RESULTS AND LIMITATIONS: The 5-yr BCR-free rates were 100% and 88.5% for patients with low- and intermediate-risk PC, respectively. The cumulative 5-yr grade 2, 3, and 4 toxicity rates were 12.4%, 1.9%, and 0.4% for urinary, and 3.4%, 0%, and 0% for gastrointestinal toxicities, respectively. The median baseline prostate-specific antigen (PSA) level of 5.12ng/ml decreased to 0.1ng/ml by ≥42mo. QOL scores decreased at 1mo but returned to baseline by 6mo, with a later decline (≥24mo) in the urinary continence domain (pad use was 2% at baseline and 10% at 5yr), and lower sexual potency over time. Comparative outcomes versus other types of radiotherapy are difficult because the trial was not randomized. CONCLUSIONS: This regimen yields a high rate of BCR-free survival, with a very low median PSA nadir suggesting prostate ablation. For properly selected patients with low- or intermediate-risk PC who choose SBRT, this treatment regimen is effective. PATIENT SUMMARY: This potent four-treatment stereotactic body radiotherapy regimen appears to be effective for patients with early prostate cancer.

High-dose-rate stereotactic body radiation therapy for postradiation therapy locally recurrent prostatic carcinoma: Preliminary prostate-specific antigen response, disease-free survival, and toxicity assessment.

PURPOSE: Patients with locally recurrent adenocarcinoma of the prostate following radiation therapy (RT) present a challenging problem. We prospectively evaluated the use of "high-dose-rate-like" prostate stereotactic body RT (SBRT) salvage for this circumstance, evaluating prostate-specific antigen response, disease-free survival, and toxicity. METHODS AND MATERIALS: Between February 2009 and March 2014, 29 patients with biopsy-proven recurrent locally prostate cancer >2 years post-RT were treated. Median prior RT dose was 73.8 Gy and median interval to SBRT salvage was 88 months. Median recurrence Gleason score was 7 (79% was ≥7). Pre-existing RT toxicity >grade 1 was a reason for exclusion. Magnetic resonance imaging-defined prostate volume including any suspected extraprostatic extension, comprising the planning target volume. A total of 34 Gy/5 fractions was given, delivering a heterogeneous, high-dose-rate-like dose-escalation pattern. Toxicities were assessed using Common Terminology Criteria for Adverse Events, version 3.0, criteria. RESULTS: Twenty-nine treated patients had a median 24-month follow-up (range, 3-60 months). A median pre-SBRT salvage baseline prostate-specific antigen level of 3.1 ng/mL decreased to 0.65 ng/mL and 0.16 ng/mL at 1 and 2 years, respectively. Actuarial 2-year biochemical disease-free survival measured 82%, with no local failures. Toxicity >grade 1 was limited to the genitourinary domain, with 18% grade 2 or higher and 7% grade 3 or higher. No gastrointestinal toxicity >grade 1 occurred. CONCLUSIONS: Two-year disease-free survival is encouraging, and the prostate-specific antigen response kinetic appears comparable with that seen in de novo patients treated with SBRT, albeit still a preliminary finding. Grade ≥2 genitourinary toxicity was occasionally seen with no obvious predictive factor. Noting that our only brachytherapy case was 1 of the 2 cases with ≥grade 3 genitourinary toxicity, caution is recommended treating these patients. SBRT salvage of post-RT local recurrence appears clinically feasible, with longer term evaluation required to assess ultimate efficacy and late toxicity rates.

Virtual HDR CyberKnife SBRT for Localized Prostatic Carcinoma: 5-Year Disease-Free Survival and Toxicity Observations.

PURPOSE: Prostate stereotactic body radiotherapy (SBRT) may substantially recapitulate the dose distribution of high-dose-rate (HDR) brachytherapy, representing an externally delivered "Virtual HDR" treatment method. Herein, we present 5-year outcomes from a cohort of consecutively treated virtual HDR SBRT prostate cancer patients. METHODS: Seventy-nine patients were treated from 2006 to 2009, 40 low-risk, and 39 intermediate-risk, under IRB-approved clinical trial, to 38 Gy in four fractions. The planning target volume (PTV) included prostate plus a 2-mm volume expansion in all directions, with selective use of a 5-mm prostate-to-PTV expansion and proximal seminal vesicle coverage in intermediate-risk patients, to better cover potential extraprostatic disease; rectal PTV margin reduced to zero in all cases. The prescription dose covered >95% of the PTV (V100 ≥95%), with a minimum 150% PTV dose escalation to create "HDR-like" PTV dose distribution. RESULTS: Median pre-SBRT PSA level of 5.6 ng/mL decreased to 0.05 ng/mL 5 years out and 0.02 ng/mL 6 years out. At least one PSA bounce was seen in 55 patients (70%) but only 3 of them subsequently relapsed, biochemical-relapse-free survival was 100 and 92% for low-risk and intermediate-risk patients, respectively, by ASTRO definition (98 and 92% by Phoenix definition). Local relapse did not occur, distant metastasis-free survival was 100 and 95% by risk-group, and disease-specific survival was 100%. Acute and late grade 2 GU toxicity incidence was 10 and 9%, respectively; with 6% late grade 3 GU toxicity. Acute urinary retention did not occur. Acute and late grade 2 GI toxicity was 0 and 1%, respectively, with no grade 3 or higher toxicity. Of patient's potent pre-SBRT, 65% remained so at 5 years. CONCLUSION: Virtual HDR prostate SBRT creates a very low PSA nadir, a high rate of 5-year disease-free survival and an acceptable toxicity incidence, with results closely resembling those reported post-HDR brachytherapy.

Health-related quality of life after stereotactic body radiation therapy for localized prostate cancer: results from a multi-institutional consortium of prospective trials.

PURPOSE: To evaluate the early and late health-related quality of life (QOL) outcomes among prostate cancer patients following stereotactic body radiation therapy (SBRT). METHODS AND MATERIALS: Patient self-reported QOL was prospectively measured among 864 patients from phase 2 clinical trials of SBRT for localized prostate cancer. Data from the Expanded Prostate Cancer Index Composite (EPIC) instrument were obtained at baseline and at regular intervals up to 6 years. SBRT delivered a median dose of 36.25 Gy in 4 or 5 fractions. A short course of androgen deprivation therapy was given to 14% of patients. RESULTS: Median follow-up was 3 years and 194 patients remained evaluable at 5 years. A transient decline in the urinary and bowel domains was observed within the first 3 months after SBRT which returned to baseline status or better within 6 months and remained so beyond 5 years. The same pattern was observed among patients with good versus poor baseline function and was independent of the degree of early toxicities. Sexual QOL decline was predominantly observed within the first 9 months, a pattern not altered by the use of androgen deprivation therapy or patient age. CONCLUSION: Long-term outcome demonstrates that prostate SBRT is well tolerated and has little lasting impact on health-related QOL. A transient and modest decline in urinary and bowel QOL during the first few months after SBRT quickly recovers to baseline levels. With a large number of patients evaluable up to 5 years following SBRT, it is unlikely that unexpected late adverse effects will manifest themselves.