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.

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.

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-specific antigen kinetics and biochemical control following stereotactic body radiation therapy, high dose rate brachytherapy, and low dose rate brachytherapy: A multi-institutional analysis of 3502 patients.

BACKGROUND AND PURPOSE: Stereotactic body radiation therapy (SBRT), low dose rate brachytherapy (LDR-BT) and high dose rate brachytherapy (HDR-BT) are ablative-intent radiotherapy options for prostate cancer (PCa). These vary considerably in dose delivery, which may impact post-treatment prostate-specific antigen (PSA) patterns and biochemical control. We compared PSA kinetics between SBRT, HDR-BT, and LDR-BT, and assessed their relationships to biochemical recurrence-free survival (BCRFS). METHODS AND MATERIALS: Retrospective PSA data were analyzed for 3502 men with low-risk (n = 2223; 63.5%), favorable intermediate-risk (n = 869; 24.8%), and unfavorable intermediate-risk (n = 410; 11.7%) PCa treated with SBRT (n = 1716; 49.0%), HDR-BT (n = 512; 14.6%), or LDR-BT (n = 1274; 36.4%) without upfront androgen deprivation therapy at 10 institutions from 1990 to 2017. We compared nadir PSA (nPSA), time to nPSA, achievement of nPSA <0.2 ng/mL and <0.5 ng/mL, rates of nPSA <0.4 ng/mL at 4 years, and BCRFS. RESULTS: Median follow-up was 72 months. Median nPSA and nPSA <0.2 ng/mL were stratified by risk group (interaction p ≤ 0.001). Median nPSA and time to nPSA were 0.2 ng/mL at 44 months after SBRT, 0.1-0.2 ng/mL at 37 months after HDR-BT, and 0.01-0.2 ng/mL at 51 months after LDR-BT (mean log nPSA p ≤ 0.009 for LDR-BT vs. SBRT or HDR-BT for low/favorable intermediate-risk). There were no differences in nPSA <0.4 ng/mL at 4 years (p ≥ 0.51). BCRFS was similar for all three modalities (p ≥ 0.27). Continued PSA decay beyond 4 years was predictive of durable biochemical control. CONCLUSION: LDR-BT led to lower nPSAs with longer continued decay compared to SBRT and HDR-BT, but no differences in BCRFS.

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.

Stereotactic body radiotherapy for localized prostate cancer: disease control and quality of life at 6 years.

BACKGROUND: Stereotactic body radiotherapy (SBRT) may yield disease control for prostate cancer in a brief, hypofractionated treatment regimen without increasing treatment toxicity. Our report presents a 6-year update from 304 low- (n = 211), intermediate- (n = 81), and high-risk (n = 12) prostate cancer patients who received CyberKnife SBRT. METHODS: The median PSA at presentation was 5.8 ng/ml. Fifty-seven patients received neoadjuvant hormonal therapy for up to one year. The first 50 patients received a total dose of 35 Gy in 5 fractions of 7 Gy. The subsequent 254 patients received a total dose of 36.25 Gy in 5 fractions of 7.25 Gy. Toxicity was assessed with the Expanded Prostate Cancer Index Composite questionnaire and the Radiation Therapy Oncology Group urinary and rectal toxicity scale. Biochemical failure was assessed using the nadir + 2 definition. RESULTS: No patients experienced Grade III or IV acute complications. Fewer than 5% of patients experienced any acute Grade II urinary or rectal toxicities. Late urinary Grade II complications were observed in 4% of patients treated to 35 Gy and 9% of patients treated to 36.25 Gy. Five (2%) late Grade III urinary toxicities occurred in patients who were treated with 36.25 Gy. Late Grade II rectal complications were observed in 2% of patients treated to 35 Gy and 5% of patients treated to 36.25 Gy. Bowel and urinary quality of life (QOL) scores initially decreased, but later returned to baseline values. An overall decrease of 20% in the sexual QOL score was observed. QOL in each domain was not differentially affected by dose. For patients that were potent prior to treatment, 75% stated that they remained sexually potent. Actuarial 5-year biochemical recurrence-free survival was 97% for low-risk, 90.7% for intermediate-risk, and 74.1% for high-risk patients. PSA fell to a median of 0.12 ng/ml at 5 years; dose did not influence median PSA levels. CONCLUSIONS: In this large series with long-term follow-up, we found excellent biochemical control rates and low and acceptable toxicity, outcomes consistent with those reported for from high dose rate brachytherapy (HDR BT). Provided that measures are taken to account for prostate motion, SBRT's distinct advantages over HDR BT include its noninvasiveness and delivery to patients without anesthesia or hospitalization.

Cyberknife radiosurgery in treating trigeminal neuralgia.

PURPOSE: To assess the short term efficacy of Cyberknife stereotactic radiosurgical treatment of trigeminal neuralgia (TN). METHODS: 17 consecutive patients with medically or surgically refractory unilateral TN were treated with Cyberknife radiosurgery. Using superimposed CT cisternogram and MR images, the target segment of the trigeminal nerve was consistently defined as a 6 mm length of nerve approximately 2-3 mm distal to the dorsal root entry zone of the brainstem. A radiosurgical rhizotomy was performed with the Cyberknife utilizing a single collimator to deliver an average maximum dose of 73.06 Gy (range 72.91-73.73) to the target. RESULTS: Follow-up data were available for 16 of the 17 patients post-treatment (range 1-27 months, average 11.8 months). Overall, 14 of 16 (88%) patients responded favorably with either partial or complete relief of symptomatology. 11 of these patients were successfully free of all pain at some point in their post-treatment course, with seven patients pain free to the last follow-up visit (average 5.0 months, range 1-13 months). Symptoms recurred in four patients, taking place at 3, 7.75, 9 and 18 months after Cyberknife therapy. Only two patients reported side effects. One patient developed a bothersome feathery dysesthesia while the second patient reported a non-bothersome mild jaw hypoesthesia. There were no substantial complications related to stereotactic radiosurgery. CONCLUSION: Cyberknife radiosurgery is a viable treatment alternative in patients with TN with competitive efficacy demonstrated in our group of patients while minimizing adverse effects.

Stereotactic Body Radiation Therapy for Low- and Low-Intermediate-Risk Prostate Cancer: Is there a Dose Effect?

This study examines the efficacy and toxicity of two stereotactic body radiation therapy (SBRT) dose regimens for treatment of early prostate cancer. Forty-one patients treated with 35 Gy were matched with 41 patients treated with 36.25 Gy. Both patient groups received SBRT in five fractions over five consecutive days using the CyberKnife. Each group had 37 low-risk patients and 4 intermediate-risk patients. No statistically significant differences were present for age, prostate volume, PSA, Gleason score, stage, or risk between the groups. The dose was prescribed to the 83-87% isodose line to cover the prostate and a 5-mm margin all around, except 3 mm posteriorly. The overall median follow-up is 51 months (range, 45-58 months) with a median 54 and 48 months follow-up for the 35 and 36.25-Gy dose groups, respectively. One biochemical failure occurred in each group yielding a 97.5% freedom from biochemical failure. The PSA response has been favorable for all patients with a mean PSA of 0.1 ng/ml at 4-years. Overall toxicity has been mild with 5% late grade 2 rectal toxicity in both dose groups. Late grade 1 urinary toxicity was equivalent between groups; grade 2 urinary toxicity was 5% (2/41 patients) and 10% (4/41 patients) in the 35-Gy and 36.25-Gy dose groups (p = 0.6969), respectively. Overall, the highly favorable PSA response, limited biochemical failures, limited toxicity, and limited impact on quality of life in these low- to low-intermediate-risk patients are supportive of excellent long-term results for CyberKnife delivered SBRT.

Stereotactic body radiotherapy as boost for organ-confined prostate cancer.

Stereotactic body radiotherapy (SBRT) boost following external beam radiation therapy (EBRT) for advanced localized prostate cancer may reduce toxicity while escalating the dose. We present preliminary biochemical control and urinary, rectal and sexual toxicities for 73 patients treated with SBRT as a boost to EBRT. Forty-one intermediate- and 32 high-risk localized prostate cancer patients received 45 Gy EBRT with SBRT boost. Twenty-eight patients (38.3%) received a total SBRT boost dose of 18 Gy (3 fractions of 6 Gy), 28 patients (38.3%) received 19.5 Gy (3 fractions of 6.5 Gy), and 17 patients (23.2%) received 21 Gy (3 fractions of 7 Gy). Toxicity was assessed using the Radiation Therapy Oncology Group urinary and rectal toxicity scale. Biochemical failure was assessed using the Phoenix definition. The median follow-up was 33 months (range, 22 - 43 months). Less than 7% Grade II and no higher grade acute toxicities occurred. To date, one Grade III and no Grade IV late toxicities occurred. For the 97% of patients with 24 months minimum follow-up, 71.8% achieved a PSA nadir threshold of 0.5 ng/mL. Three intermediate-risk and seven high-risk biochemical failures occurred; one high-risk patient died of his cancer. Three-year actuarial biochemical control rates were 89.5% and 77.7% for intermediate- and high-risk patients, respectively. SBRT boost for prostate cancer treatment is safe and feasible with minimal acute toxicity. At 33 months late toxicity and biochemical control are promising. Long-term durability of these findings remains to be established.

CyberKnife radiosurgery for prostate cancer.

Treatment of prostate cancer with SBRT is an area of significant controversy for many in the radiation oncology community despite radiobiologic data that strongly suggest the prostate would be an excellent SBRT target. Recently, new data have emerged that show promising outcomes with minimal toxicity for CyberKnife SBRT of prostate cancer. In the following we present the motivating factors for prostate cancer SBRT followed by a critical evaluation of the current literature and discussion of the future of prostate cancer treatment with SBRT.

Stereotactic body radiotherapy for organ-confined prostate cancer.

BACKGROUND: Improved understanding of prostate cancer radiobiology combined with advances in delivery of radiation to the moving prostate offer the potential to reduce treatment-related morbidity and maintain quality of life (QOL) following prostate cancer treatment. We present preliminary results following stereotactic body radiotherapy (SBRT) treatment for organ-confined prostate cancer. METHODS: SBRT was performed on 304 patients with clinically localized prostate cancer: 50 received 5 fractions of 7 Gy (total dose 35 Gy) and 254 received 5 fractions of 7.25 Gy (total dose 36.25 Gy). Acute and late toxicity was assessed using the Radiation Therapy Oncology Group scale. The Expanded Prostate Cancer Index Composite questionnaire was used to assess QOL. Prostate-specific antigen response was monitored. RESULTS: At a median 30-month (26 - 37 month, range) follow-up there were no biochemical failures for the 35-Gy dose level. Acute Grade II urinary and rectal toxicities occurred in 4% of patients with no higher Grade acute toxicities. One Grade II late urinary toxicity occurred with no other Grade II or higher late toxicities. At a median 17-month (8 - 27 month, range) follow-up the 36.25 Gy dose level had 2 low- and 2 high-risk patients fail biochemically (biopsy showed 2 low- and 1 high-risk patients were disease-free in the gland). Acute Grade II urinary and rectal toxicities occurred in 4.7% (12/253) and 3.6% (9/253) of patients, respectively. For those patients with a minimum of 12 months follow-up, 5.8% (12/206) had late Grade II urinary toxicity and 2.9% (6/206) had late Grade II rectal toxicities. One late Grade III urinary toxicity occurred; no Grade IV toxicities occurred. For both dose levels at 17 months, bowel and urinary QOL returned to baseline values; sexual QOL decreased by 10%. CONCLUSIONS: The low toxicity and maintained QOL are highly encouraging. Additional follow-up is needed to determine long-term biochemical control and maintenance of low toxicity and QOL.