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.

Nephron-Sparing Robotic Radiosurgical Therapy for Primary Renal Cell Carcinoma: Single-Institution Experience and Review of the Literature.

PURPOSE: We report our single-institution stereotactic body radiation therapy (SBRT) experience on stage I renal cancer with prospectively collected toxicity and efficacy data. METHODS AND MATERIALS: A total of 21 patients with solitary renal tumors, including 14 surgical candidates who refused surgery (66%), were treated with SBRT. Histologic confirmation was obtained on all patients before treatment; 2 had transitional cell carcinoma and 19 had renal cell carcinoma. The median age was 71 years (range, 58-88). Nearly all patients received 48 Gy in 3 fractions. RESULTS: The median follow-up was 78 months (range, 5-107). At 5 years post treatment, the local tumor control rate was 100%. Tumor size decreased by a median value of 5.3% at 1 year post treatment, 15.6% at 2 years post treatment, and 15.4% at 5 years post treatment. Glomerular filtration rate had decreased by a median value of 1.5% at 1 year post treatment, 7.0% at 2 years post treatment, and 14.2% at 5 years post treatment. Three patients experienced grade 1 toxicity; no other treatment-related adverse effects were reported. CONCLUSIONS: SBRT is a promising noninvasive treatment in the management of primary renal cell carcinoma, with evolving clinical evidence demonstrating encouraging results with respect to local control and toxicity.

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.

Stereotactic Body Radiotherapy (SBRT) for liver metastasis - clinical outcomes from the international multi-institutional RSSearch® Patient Registry.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is an emerging treatment option for liver metastases in patients unsuitable for surgery. We investigated factors associated with clinical outcomes for liver metastases treated with SBRT from a multi-center, international patient registry. METHODS: Patients with liver metastases treated with SBRT were identified in the RSSearch® Patient Registry. Patient, tumor and treatment characteristics associated with treatment outcomes were assessed. Dose fractionations were normalized to BED10. Overall survival (OS) and local control (LC) were evaluated using Kaplan Meier analysis and log-rank test. RESULTS: The study included 427 patients with 568 liver metastases from 25 academic and community-based centers. Median age was 67 years (31-91 years). Colorectal adenocarcinoma (CRC) was the most common primary cancer. 73% of patients received prior chemotherapy. Median tumor volume was 40 cm3 (1.6-877 cm3), median SBRT dose was 45 Gy (12-60 Gy) delivered in a median of 3 fractions [1-5]. At a median follow-up of 14 months (1-91 months) the median overall survival (OS) was 22 months. Median OS was greater for patients with CRC (27 mo), breast (21 mo) and gynecological (25 mo) metastases compared to lung (10 mo), other gastro-intestinal (GI) (18 mo) and pancreatic (6 mo) primaries (p < 0.0001). Smaller tumor volumes (< 40 cm3) correlated with improved OS (25 months vs 15 months p = 0.0014). BED10 ≥ 100 Gy was also associated with improved OS (27 months vs 15 months p < 0.0001). Local control (LC) was evaluable in 430 liver metastases from 324 patients. Two-year LC rates was better for BED10 ≥ 100 Gy (77.2% vs 59.6%) and the median LC was better for tumors < 40 cm3 (52 vs 39 months). There was no difference in LC based on histology of the primary tumor. CONCLUSIONS: In a large, multi-institutional series of patients with liver metastasis treated with SBRT, reasonable LC and OS was observed. OS and LC depended on dose and tumor volume, while OS varied by primary tumor. Future prospective trials on the role of SBRT for liver metastasis from different primaries in the setting of multidisciplinary management including systemic therapy, is warranted. TRIAL REGISTRATION: Clinicaltrials.gov: NCT01885299 .

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.

Prospectively-collected, tooth-specific dosimetry correlated with adverse dental outcomes.

OBJECTIVES: To correlate radiation dose to specific tooth-bearing portions of bone with adverse dental outcomes. STUDY DESIGN: Eighty-nine patients treated with intensity-modulated radiation therapy with or without chemotherapy had radiation dose to specific tooth-bearing portions of the mandible and the maxilla. Data were collected prospectively during treatment planning, which resulted in 2490 data points. These patients underwent a comprehensive dental intake evaluation that included measurement of pocket depths and were then followed up with serial dental evaluations for a median of 2.5 years (range 0.2-6.9 years). RESULTS: At the patient level, the 3-year risks of osteoradionecrosis (ORN) and periodontal disease were 2.5% and 36.6%, respectively. For any individual tooth, the risks of ORN and periodontal disease were 0.1% and 5.1%, respectively, at 3 years. Radiation dose to individual tooth-bearing portions of bone was correlated with ORN development (P = .0165). Periodontal disease also demonstrated a significant, but more gradual, dose response (P = .0395). CONCLUSIONS: Adverse dental outcomes directly correlate with increased tooth-specific doses.

Prevention of needle displacement in multifraction high-dose-rate prostate brachytherapy: A prospective volumetric analysis and technical considerations.

PURPOSE: We conducted a prospective study to evaluate needle displacements between prostate high-dose-rate (HDR) brachytherapy fractions and offer technical recommendations to help prevent displacements from the outset. METHODS AND MATERIALS: Planning computed tomography and verification computed tomography scans were obtained at 1-mm slice thickness and prospectively assessed for interfraction needle movement for each fraction of a 2-fraction HDR prostate boost. For both the planning and verification CTs, distances from each needle tip to the centroid of 3 implanted prostate gold seeds were measured. We determined the mean and range of the displacement distances. RESULTS: Thirty-three consecutive patients (66 fractions, 540 needle-pair positions for a total of 1080 needles) were evaluated for changes in the length between the needle tip and centroid displacement. Overall, only 0.2% of the needles had any change greater than 3.5 mm between the needle tip and centroid. The mean amount of displacement was 0.97 mm, with a standard deviation of 0.76 mm. Among the patients, no fraction had more than 1 needle with a variation greater than 3.0 mm. CONCLUSIONS: Needle displacements in HDR prostate brachytherapy have been reported by numerous institutions using various techniques. We report the first study to demonstrate needle displacement of less than 1 mm on average, and we describe our process of care surrounding the implantation.

Dorsal vagal complex of the brainstem: conformal avoidance to reduce nausea.

PURPOSE: To investigate the role of dose to the dorsal vagal complex (DVC) as an emetic stimulus in head-and-neck cancer patients treated with intensity modulated radiation therapy but without chemotherapy. METHODS AND MATERIALS: Seventy consecutively treated patients were analyzed for factors associated with nausea. The DVC was contoured on treatment planning scans using a previously published template and mean dose to the structure was analyzed for dose response. RESULTS: Nausea occurred in 26 of 70 patients (37%). Two patients (3%) experienced grade 2 nausea, with the remainder having grade 1 nausea. On univariate analysis, dose to the DVC, age, and T-stage were the only significant predictors of nausea. The highest quartile of dose to the DVC (>3000 cGy) was associated with an incidence of nausea of 67% compared with less than 30% in each of the other 3 quartiles (P = .0255). CONCLUSIONS: Dose to the DVC of the brainstem appears to correlate with radiation-induced nausea and vomiting. Attentive treatment planning efforts can reduce dose to this critical structure and hopefully minimize the risk of nausea.

Clinical outcomes of image guided radiation therapy (IGRT) with gold fiducial vaginal cuff markers for high-risk endometrial cancer.

OBJECTIVE: To report two year clinical outcomes of image guided radiation therapy (IGRT) to the vaginal cuff and pelvic lymph nodes in a series of high-risk endometrial cancer patients. METHODS: Twenty-six consecutive high-risk endometrial cancer patients requiring adjuvant radiation to the vaginal cuff and regional lymph nodes were treated with vaginal cuff fiducial-based IGRT. Seventeen (65%) received sequential chemotherapy, most commonly with a sandwich technique. Brachytherapy followed external radiation in 11 patients to a median dose of 18 Gy in 3 fractions. The median external beam dose delivered was 47.5 Gy in 25 fractions. RESULTS: All 656 fractions were successfully imaged and treated. The median overall translational shift required for correction was 9.1 mm (standard deviation, 5.2 mm) relative to clinical set-up with skin tattoos. Shifts of 1 cm, 1.5 cm, and 2 cm or greater were performed in 43%, 14%, and 4% of patients, respectively. Acute grade 2 gastrointestinal (GI) toxicity occurred in eight patients (30%) and grade 3 toxicity occurred in one. At two years, there have been no local or regional failures and actuarial overall survival is 95%. CONCLUSION: Daily image guidance for high-risk endometrial cancer results in a low incidence of acute GI/genitourinary (GU) toxicity with uncompromised tumor control at two years. Vaginal cuff translations can be substantial and may possibly result in underdosing if not properly considered.

CyberKnife radiosurgery for trigeminal neuralgia: unanticipated iatrogenic effect following successful treatment.

This case report of 74-year-old man with trigeminal neuralgia is presented to underscore the importance of evaluating the entire treatment plan, especially when delivering large doses where even a low percentage of the prescription dose can contribute a substantial dose to an unintended target. The patient was treated using the CyberKnife stereotactic radiosurgery system utilizing a nonisocentric beam treatment plan with a 5-mm fixed collimator generating 111 beams to deliver 6000 cGy to the 79% isodose line with a maximum dose of 7594 cGy to the target. Two weeks after treatment the patient's trigeminal neuralgia symptoms resolved; however, the patient developed oral mucositis due to the treatment. This case report reviews the cause of mucositis and makes recommendations on how to prevent unintended targets from receiving treatment.

Accelerated fractionation head and neck intensity-modulated radiation therapy and concurrent chemotherapy in the community setting: safety and efficacy considerations.

BACKGROUND: This article reviews our community cancer center's experience treating head and neck cancer primarily with accelerated fractionation intensity-modulated radiation therapy (IMRT), with or without concurrent chemotherapy, focusing on acute toxicity and efficacy. METHODS: Fifty-two patients treated with IMRT at the Penrose Cancer Center between 2002 and 2007 constitute the cohort. The majority (75%) received an accelerated, altered fractionation regimen, typically concomitant boost to 7200 cGy. Concurrent chemotherapy was delivered to 32 (62%). The median follow-up was 24 months. RESULTS: The 2-year actuarial rates of local control, regional control, and distant metastasis-free survival were 100%, 91%, and 94%, respectively. Relapse-free survival and overall survival at 2 years were 89% and 91%, respectively. Overall, 32 of 52 patients (62%) experienced at least 1 type of grade 3 or 4 acute toxicity. CONCLUSION: Accelerated fractionation IMRT, with or without chemotherapy, can be given safely and effectively in a community cancer center setting.

Factors associated with radiation-induced nausea and vomiting in head and neck cancer patients treated with intensity modulated radiation therapy.

BACKGROUND AND PURPOSE: To investigate factors associated with radiation-induced nausea and vomiting (RINV) in the setting of head and neck intensity modulated radiation therapy (IMRT). MATERIALS AND METHODS: Forty-three patients treated with IMRT for head and neck cancer between 2002 and 2007 comprise the cohort. The majority (79%) were treated with an accelerated altered fractionation scheme, and concurrent chemotherapy was delivered to 23. A retrospective review of factors associated with nausea was performed. RESULTS: Eighteen patients (42%) reported grade 1 acute nausea, and seven patients (16%) reported grade 2 nausea. Factors significant for grade 1-2 nausea on univariate analysis included dose to the dorsal vagal complex of the mid-medulla, younger age, use of a low neck field, and Amifostine use. Only young age retained significance on multivariate analysis. High-grade nausea was associated with use of Amifostine (p=0.003) and concurrent chemotherapy (p=0.015). CONCLUSIONS: In addition to previously recognized emetic factors, young age and radiation dose to the dorsal vagal complex of the brainstem may play a role in development of nausea during head and neck IMRT.

High-dose-rate brachytherapy for large prostate volumes (> or =50cc)-Uncompromised dosimetric coverage and acceptable toxicity.

PURPOSE: The purpose of this study was to review our single-institution experience using high-dose-rate (HDR) brachytherapy in patients with large-volume prostate glands (> or =50cc). METHODS AND MATERIALS: Fifty-four patients treated with HDR brachytherapy for prostate cancer at the Penrose Cancer Center between 2001 and 2006 were identified as having an ultrasound volume of at least 50cc at the time of implant (range, 50-97.3cc; mean, 61.5cc; median, 57cc; upper quartile, 83.3-97.3cc). Neoadjuvant hormones (17 patients) were not routinely recommended unless the initial ultrasound volume suggested pubic arch interference or the patient's Gleason score or prostate specific antigen prompted use. All patients received HDR brachytherapy as a boost before or after conformal external beam radiation therapy to 4500cGy. Boost brachytherapy doses ranged from 1600 to 1900cGy, given in two to three fractions. RESULTS: The median D(90) (minimal dose to 90% of the prostate) was 109% of prescription dose (range, 95-115%) and the median V(100) (volume receiving 100% of the dose) was 96% (range, 90-99%). V(150) ranged from 10% to 35%, with a median value of 18.3%. Six patients (11%) required temporary placement of a urinary catheter for acute obstructive symptoms after brachytherapy. With a median followup of 1.8 years, there has been a single case of Grade 2 gastrointestinal toxicity and 1 patient has developed a bulbo-urethral stricture requiring dilation. There have been no cases of rectal bleeding. CONCLUSIONS: Large prostate volume is not a contraindication to HDR brachytherapy. Excellent dosimetric coverage can be attained with acceptable acute toxicity.

Low morbidity following high dose rate brachytherapy in the setting of prior transurethral prostate resection.

PURPOSE: We reviewed our single institution experience with high dose rate brachytherapy in patients who underwent prior transurethral prostate resection. MATERIALS AND METHODS: A total of 28 patients treated with high dose rate brachytherapy for prostate cancer at our institution between 2001 and 2006 were identified as having undergone prior transurethral prostate resection. All patients received high dose rate brachytherapy as a boost before or after conformal external beam radiation therapy to 4,500 cGy. Boost brachytherapy doses ranged from 1,600 to 1,900 cGy, given in 2 or 3 fractions. Changes in American Urological Association symptom scores were assessed. RESULTS: Dosimetric goals were adequately achieved in all patients with a median minimal dose to 90% of the prostate of 109% of the prescription dose (range 100% to 117%). The median volume receiving 100% of the prescribed dose was 95% (range 87.9% to 100%) Three patients (11%) required temporary urinary catheter placement for acute obstructive symptoms after brachytherapy. At a median followup of 2.5 years there was 1 case each of grade 1 rectal proctitis, grade 1 hemorrhage and grade 2 cystitis. Two patients had worsening of existing grade 1 urge incontinence to grade 2. No patient had a bulbourethral stricture requiring dilation or new onset incontinence. Patients with a higher baseline American Urological Association score demonstrated significantly improved scores over those with lower baseline scores (less than 15) at least 1 year after treatment. CONCLUSIONS: High dose rate brachytherapy with careful attention to dosimetry is a reasonable treatment option for patients who have undergone prior transurethral prostate resection with the expectation of low morbidity.