Pulsed Reduced Dose Rate Research Articles

Pulsed Reduced Dose Rate Re-Irradiation for Patients with Recurrent Grade 2 Gliomas

Abstract BACKGROUND Patients with grade 2 glioma exhibit highly variable survival. Re-irradiation for recurrent disease has limited mature clinical data. We report treatment results of pulsed reduced dose rate (PRDR) radiation for patients with recurrent grade 2 glioma. METHODS A retrospective analysis of 58 patients treated with PRDR from 2000-2021 was performed. Radiation was delivered in 0.2 Gy pulses every three minutes encompassing tumor plus margin. Survival outcomes and prognostic factors on outcome were Kaplan Meier and Cox regression analyses. RESULTS The median survival from date of initial surgery was 8.6 years (95% CI 5.5-11.8 yrs). 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI 8.3-17.0 mo) and progression free survival was 6.2 months (95% CI 3.8-8.6 mo). Overall response rate based on post PRDR MRI was 36%. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months with five patients remaining disease free, the longest at 8.2 and 11.4 years. PRDR was generally well tolerated. CONCLUSIONS To our knowledge, this is the largest reported series of patients with recurrent grade 2 gliomas treated with PRDR radiation for disease recurrence. We demonstrate promising survival and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (>5 years) is observed in selected patients. For the entire cohort, 1p19q co-deletion, KPS, and longer time from initial diagnosis to PRDR were associated with improved survival.

CTNI-48. SURVIVAL, TOXICITY, AND PATIENT REPORTED QOL OUTCOMES FOLLOWING PULSED REDUCED DOSE RATE RE-IRRADIATION WITH CONCURRENT BEVACIZUMAB FOR RECURRENT GRADE 4 GLIOMAS: RESULTS OF A PHASE II STUDY

Abstract Grade 4 gliomas are aggressive primary brain tumors with dismal prognosis despite maximal treatment. Recurrent disease is typically found within the prior radiation treatment field, complicating reirradiation. Pulsed reduced dose rate (PRDR) radiation is a treatment technique that reduces effective dose rate and increases treatment time allowing for intrafraction repair. Bevacizumab is a systemic VEGF inhibitor with efficacy in treating gliomas. We conducted a phase 2 prospective trial combining PRDR radiation with biweekly bevacizumab (10 mg/kg) in patients with recurrent grade 4 gliomas. Radiation was delivered with reduced dose rate delivered in 20 cGy pulses every 3 minutes in 2 Gy daily fractions to a total dose of 54 Gy. Kaplan Meier analysis was utilized to calculate progression free survival (PFS) and overall survival (OS). Toxicities were evaluated based on Common Terminology Criteria for Adverse Event v5.0 criteria. Mini Mental Status Examination (MMSE), as well as FACT-Brain, and FACIT-Fatigue patient reported quality of life (QoL) surveys were collected at baseline and follow up visits. Minimal important difference scores were calculated using by ½ standard deviation method. A total of 36 patients were enrolled, with 77% having previously received additional therapy for recurrent disease prior to study enrollment. Median PFS was 4.9 months and median OS was 6.9 months. No grade 4+ toxicity was observed. Two patients had grade 3 treatment related toxicity (seizure and radiation necrosis, both PRDR related). Treatment related grade 2 toxicity was seen in 44% of patients, primarily fatigue (30%). Clinically significant decrease in mean MMSE score, and FACT-BR QoL metrics across all sub-domains were noted in follow up. No clinically significant difference in mean FACIT-Fatigue QoL metric was observed. In this prospective phase 2 trial, PRDR with concurrent bevacizumab resulted in encouraging survival outcomes with acceptable toxicity in patients with recurrent grade 4 gliomas.

Pulsed Reduced Dose Rate Re-Irradiation for Recurrent Grade 4 Gliomas: A Retrospective Analysis of Safety and Efficacy

Despite maximal treatment, nearly all patients with grade 4 gliomas develop recurrent disease. Treatment options for these patients are limited and overall survival is poor. Re-irradiation may be considered in certain patients, though risk of side effects often limits the effective dose able to be delivered. Pulsed reduced dose rate (PRDR) radiation is a treatment technique that reduces effective dose rate and increases treatment time allowing for intrafraction repair. Here, we report safety and efficacy of PRDR re-irradiation for recurrent grade 4 gliomas. We performed a retrospective review of patients treated with PRDR between 2001 and 2022. Patients were treated with reduced dose rate radiation delivered in 0.2 Gy pulses every 3 minutes in 2 Gy daily fractions. Both 3D conformal and step and shoot IMRT radiation plans were utilized. Toxicities were evaluated based on Common Terminology Criteria for Adverse Events (CTCAE) v5.0 criteria. Kaplan Meier analysis was used to calculate overall survival (OS). Cox regression analysis was performed for multivariate analysis. A total of 168 grade 4 glioma patients treated with PRDR re-irradiation were identified. The median age was 55 years old. The median initial radiation dose was 60 Gy (range 36 Gy - 72 Gy) and the median PRDR dose was 54 Gy (range 37.5 - 60 Gy). Seventy percent of patients received systemic therapy for recurrent disease prior to PRDR, while 30% received PRDR as first treatment for recurrent disease (or following re-resection without other treatment). The median survival following PRDR was 6.3 months. Multivariate analysis showed time since initial radiation of 14+ months (HR 0.66, p = 0.005, 95% CI 0.44 - 0.98), pre-PRDR use of steroids (HR 1.78, p = 0.005, 95% CI 1.2 - 2.66), and Karnofsky performance status of 70 or greater to be a significant predictor of survival (HR = 0.6, p = 0.008, 95% CI 0.44 - 0.98). No grade 4 or 5 toxicity was noted. Grade 3 new onset seizures was noted in 6% of patients, all subsequently controlled with medication. The most common grade 1-2 side effect after treatment was fatigue. In this large, retrospective cohort, PRDR re-irradiation for recurrent grade 4 gliomas was well tolerated with low rates of grade 3 toxicity. Overall survival outcomes were encouraging, especially in heavily pre-treated patients. Prospective studies are ongoing to further evaluate the efficacy of PRDR for recurrent glioma treatment.

Pulsed Reduced Dose Rate (PRDR) Intensity Modulated Radiotherapy for Recurrent Primary Central Nervous System Malignancies: Dosimetric and Clinical Results

<h3>Purpose/Objective(s)</h3> Pulsed reduced dose rate (PRDR) intensity-modulated radiotherapy (IMRT) is a reirradiation approach that may reduce the risk of toxicities in the setting of prior radiotherapy (RT) for recurrent central nervous system (CNS) malignancies. However, toxicities and cumulative doses (in EQD2) to CNS structures are not uniformly reported. We shared our institutional outcomes of PRDR and reported cumulative doses for CNS organs-at-risk (OARs) <h3>Materials/Methods</h3> Consecutive patients diagnosed with recurrent primary CNS tumors treated with PRDR from April 2017 to September 2021 were evaluated. Data collected included number of prior interventions, diagnosis, tumor grade, RT dose and fractionation, cumulative OAR doses, progression-free survival (PFS), overall survival (OS), and adverse events. A systematic review of literature was also performed, and results were compared to this study. <h3>Results</h3> Eighteen patients met inclusion criteria (11 WHO grade 4 glioma, 6 grade 3 glioma, and 1 grade 2 glioma). All patients had at least 1 surgery (range 1-4) and 2 systemic therapy regimens (range 2-6) before PRDR. The median dose for the first course of RT was 59.4 Gy (range: 50-75 Gy) in 33 fractions and the median time from the initial RT to PRDR was 35.6 months (range: 7.0-122.0 months). The median PRDR dose was 45 Gy (range: 36-59.4 Gy) in 25 fractions; the median cumulative EQD2 dose was 107.6 Gy (93.1-132.5 Gy). The median target volume was 134.9 cc (range: 17.9-696.6 cc). The median cumulative EQD2 Dmax values for the brain and brainstem were 111.4 Gy (range: 82.4-175.2 Gy), and 85.4 Gy (range: 14.8-111.6 Gy). At a median follow-up of 6.2 months, grade 2+ treatment-related toxicities were seen in 12 (66.7%) patients. Symptomatic radiation necrosis occurred in 3 (16.7%) patients, the median EQD2 brain Dmax for these patients was 115.9 Gy (110.4-156.7 Gy). In addition, two patients had grade 3 toxicity (fatigue and hearing impairment); no Grade 4+ toxicities were observed. The median PFS and OS after PRDR were 6.3 months (95% Cl: 0.9-11.6 months) and 8.6 months (95% Cl: 4.9-12.3 months), respectively. The systematic review analyzed 5 peer-reviewed studies reporting outcomes for reirradiation with PRDR for 188 patients. The median PRDR dose was 50 Gy (range: 22-60 Gy) in 25 fractions with a median cumulative dose of 110.3 Gy to a median tumor volume of 369.1 cc. At a median follow-up of 8.7 months, the total number of grade 3+ toxicities was 24, but time-dependent analyses were not uniformly reported. <h3>Conclusion</h3> This study supports PRDR reirradiation as a feasible and appropriate strategy for recurrent primary CNS tumors where other options have been exhausted. Despite high cumulative EQD2 to the OARs, the risk of developing high-grade toxicities remains acceptable; the median cumulative brain EQD2 dose for developing necrosis is 115.9 Gy.

Re-Irradiation Using Pulsed Reduced Dose Rate Radiation Therapy in 58 Patients with Recurrent Grade 2 Glioma

<h3>Purpose/Objective(s)</h3> Patients with grade 2 glioma exhibit a markedly variable time course of survival ranging from months to over a decade. Re-irradiation for recurrent disease can be valuable for some patients but is less well studied than in the setting of high-grade glioma. We report treatment results of pulsed reduced dose rate (PRDR) radiation for patients with recurrent grade 2 glioma in an effort to prolong survival and limit normal tissue toxicity profiles. <h3>Materials/Methods</h3> We identified consecutive patients from an institutional database initially diagnosed with grade 2 glioma from 2000 to 2021 who underwent pulsed reduced dose rate radiation therapy. Radiation was delivered in 20 cGy pulses every three minutes, most commonly with a 3D conformal, three field technique, encompassing gross disease with a 1-2 cm margin. Kaplan Meier analysis was used to calculate overall survival and progression free survival. <h3>Results</h3> 58 patients with biopsy proven grade 2 glioma were identified. The median survival from initial date of surgery was 9.5 years (95% CI 6.3-12.7 yrs). 82% underwent at least a second resection and 86% received chemotherapy during their treatment course. 69% of patients showed malignant transformation to grade 3 (38%) or grade 4 (31%) glioma. Overall survival following PRDR was 12.6 months (95% CI 8.5-16.7 mo) and progression free survival was 6.3 months (95% CI 4.1-8.6 mo). Overall response rate based on post PRDR MRI was 36% with mixed or partial response, 29% with stable imaging findings, 11% with progression, and 9 cases with no post PRDR imaging. In patients who maintained grade 2 histology at recurrence, overall survival from PRDR was 22.0 months and five patients remain disease free, the longest of which are alive at 9.6 and 5.5 years. 1p19q co-deletion was associated with longer survival following PRDR with median survival for non-codeleted patients of 12.6 months (95% CI 7.9-17.3 mo) versus 33.7 months (95% CI 5.3-62.2 mo) in the co-deleted group (p = 0.18). PRDR was generally well tolerated, with four patients experiencing documented seizures and general fatigue reported as the most common complaint during treatment. <h3>Conclusion</h3> To our knowledge, this is the largest reported series of patients with recurrent grade 2 glioma treated with PRDR radiation for disease recurrence. We demonstrate promising survival efficacy and acceptable toxicity profiles following re-irradiation. In the cohort of patients who maintain grade 2 disease, prolonged survival (> 5 years) is observed in selected patients, 1p19q co-deletion is associated with longer survival.

Evaluation of Pulsed Reduced Dose Rate (PRDR) Intensity Modulated Proton Therapy (IMPT) for Re-Irradiation of CNS Malignancies

<h3>Purpose/Objective(s)</h3> Pulsed reduced dose rate (PRDR) photon therapy has been employed in the re-treatment of CNS malignancies to overcome dose constraints and reduce side effects associated with re-irradiation. The current work describes a methodology to deliver PRDR using modern intensity modulated proton therapy (IMPT) for re-irradiation of CNS tumors as well as a dosimetric treatment planning evaluation to investigate potential dose delivery benefits with IMPT. <h3>Materials/Methods</h3> A typical photon PRDR workflow consists of 10 (dose) pulses of 0.2 Gy/pulse (2 Gy/fx) with an interval of 3 minutes between pulses. This creates an averaged effective treatment dose rate of approximately 7 cGy/min over one treatment fraction. To generate a similar averaged effective dose rate with IMPT, we propose breaking each treatment field into two sub-beams and delivering these sequentially with a temporal gap between deliveries tailored to achieve an average dose rate of 7 cGy/min over a treatment fraction. With most CNS cases treated commonly with three equally weighted IMPT beams to 1.8 Gy/fx, each treatment field delivers 0.6 Gy per fraction to the target. If each field is sub-divided into two deliverable sub-beams combined with a temporal gap of 4-5 mins between sub-beams, an averaged treatment dose rate of 7 cGy/min over the treatment fraction is possible. To evaluate the dosimetric parameters of IMPT-PRDR, 15 previously treated IMRT-PRDR CNS cases were comparatively planned. IMRT plans were planned to the PTV (3 mm expansion of the CTV), while IMPT plans were robustly optimized to the CTV with a 3 mm setup uncertainty and 3.5% range uncertainty. IMRT and IMPT plans were normalized such that 95% of the PTV received 100% of the prescription dose. <h3>Results</h3> Utilizing IMPT-PRDR, the estimated overall fractional treatment time, including imaging and patient setup would be approximately 1 hour. The key driving factors for this treatment time are the gaps between fields and the sub-beam repainting. IMPT-PRDR, treatment plans were dosimetrically compared to IMRT-PRDR treated cases and normalized to ensure comparable coverage to the PTV, and this is reflected by the CTV D99 being within 1% for 4 initial planned cases. Median average normal brain dose for the IMRT-PRDR plans was 16.6 Gy (Range:14.6 Gy to 28.0 Gy), while for the IMPT-PRDR plans was 13.0 Gy (Range: 8.2 Gy to 16.4 Gy). On average, the IMPT-PRDR plan resulted in a 60% reduction (p=0.06) to normal brain dose which is clinically significant, especially considering the re-irradiation nature of these cases. <h3>Conclusion</h3> This work describes a methodology to deliver IMPT-PRDR and combine both the radiobiological advantages of low dose rate therapy with the integral dose sparing of proton therapy. These benefits could be employed in clinical trials in the treatment of CNS cases that have undergone prior radiotherapy with no technical modifications to the IMPT system.

Pulsed-Reduced Dose Rate (PRDR) Radiotherapy for Recurrent Primary Central Nervous System Malignancies: Dosimetric and Clinical Results.

Simple SummaryPulsed-reduced dose rate (PRDR) is a technique used to safely deliver re-irradiation by targeting dividing neoplastic cells while permitting intra-therapy sublethal damage repair in previously irradiated normal tissues. However, treatment-related toxicities are not uniformly reported in previous PRDR studies; thus, it is unclear whether the cumulative thresholds (EQD2) for CNS organs-at-risk (OARs) can be designated in a “safe” category. In this study, we evaluated dosimetric data for patients treated with PRDR IMRT for recurrent primary CNS malignancies, generated accumulated equivalent uniform doses with rigid registration of all intracranial treatments, and investigated toxicity as a function of cumulative EQD2. We found that PRDR IMRT re-irradiation is a safe and feasible strategy for appropriately selected recurrent primary CNS tumor patients after exhausting other options. The clinical outcomes were favorable given the unique population treated with this approach (ineligible for other salvage treatments or enrollment onto clinical trials), and the toxicities observed were mild to moderate.Purpose: The objective was to describe PRDR outcomes and report EQD2 OAR toxicity thresholds. Methods: Eighteen patients with recurrent primary CNS tumors treated with PRDR at a single institution between April 2017 and September 2021 were evaluated. The radiotherapy details, cumulative OAR doses, progression-free survival (PFS), overall survival (OS), and toxicities were collected. Results: The median PRDR dose was 45 Gy (range: 36–59.4 Gy); the median cumulative EQD2 prescription dose was 102.7 Gy (range: 93.8–120.4 Gy). The median cumulative EQD2 D0.03cc for the brain was 111.4 Gy (range: 82.4–175.2 Gy). Symptomatic radiation necrosis occurred in three patients, for which the median EQD2 brain D0.03cc was 115.9 Gy (110.4–156.7 Gy). The median PFS and OS after PRDR were 6.3 months (95%CI: 0.9–11.6 months) and 8.6 months (95%CI: 4.9–12.3 months), respectively. The systematic review identified five peer-reviewed studies with a median cumulative EQD2 prescription dose of 110.3 Gy. At a median follow-up of 8.7 months, the median PFS and OS were 5.7 months (95%CI: 2.1–15.4 months) and 6.7 months (95%CI: 3.2–14.2 months), respectively. Conclusion: PRDR re-irradiation is a relatively safe and feasible treatment for recurrent primary CNS tumors. Despite high cumulative dose to OARs, the risk of high-grade, treatment-related toxicity within the first year of follow-up remains acceptable.

Pulsed Reduced-Dose Rate Re-Irradiation With Intensity Modulated Radiation Therapy (IMRT) for Recurrent Primary Central Nervous System Malignancies

Pulsed Reduced-Dose Rate (PRDR) Re-irradiation with Intensity Modulated Radiation Therapy (IMRT) for recurrent primary Central Nervous System (CNS) malignancies was previously reported to be a feasible and well tolerated treatment option. We report our IMRT PRDR outcomes and toxicities for 55 patients with KPS ≥ 70 treated at our institution.We did a retrospective review of our database of 55 patients with recurrent primary CNS tumors treated at our institution treated with PRDR IMRT. Data collected included demographic information, initial diagnosis, prior surgery, radiation, and chemotherapy, toxicities for each treatment, PRDR IMRT plans, dates of progression, and date of death when available.The mean age of our patient population at diagnosis was 40.2 years. 31 patients were male and 24 patients were female. The initial diagnosis was WHO grade IV in 16 patients, 12 grade III, 21 Grade II, 1 Grade I glioma, and 5 patients had other primary CNS malignancies. All patients had at least 1 surgery (range 1-5) followed by initial radiation. The mean number of salvage treatments undergone by our cohort before PRDR IMRT was 2.83 treatments. The mean dose of prior radiation therapy was 57.75 Gy (Range 50.4 Gy to 75 Gy). Mean Karnofsky Performance Status (KPS) at PRDR IMRT was 80. 14 patients had an updated pathologic diagnosis before PRDR; 6 of those had grade III gliomas and 8 had grade IV. The average time from the first radiation treatment to the PRDR was 68.6 months. The dose of PRDR given ranged from 50.4 Gy to 60 Gy at 1.8-2 Gy/fraction (Median 54 Gy in 30 fractions, with one exception of a patient who stopped early). The mean progression free survival (PFS) after PRDR IMRT was 5.59 months. The median PFS was 4.8 months. Overall Survival (OS) from the time of initiation of PRDR was 10.98 months. The treatment was well tolerated with 86.6% of adverse events being grade 1-2. There were 3 grade 3 adverse events and 3 grade 4 side effects all attributed to concurrent chemotherapy. There was no radiation necrosis reported after PRDR IMRT.We report a large institutional series of patients who were treated with PRDR IMRT for recurrent primary CNS malignancies. Our series shows the feasibility, safety and efficacy of PRDR IMRT for re-irradiation for recurrent primary CNS malignancies in our heavily pretreated population with a good performance status. This warrants further prospective studies of PRDR IMRT in a randomized setting.A. Halima: None. S.T. Chao: Honoraria; Varian Medical Systems, Zeiss, AbbVie. Consultant; AbbVie. J.H. Suh: Consultant; Philips, Novocure. Met to discuss current indications for TTF; Novocure. Met during 1 day retreat to discuss future of radiation oncology; Philips. Scientific advisory board; Neutron Therapeutics. J.S. Yu: None. T.A. Chan: None. S.S. Kilic: None. D. Peereboom: None. G. Stevens: None. Y. Rauf: None. E.S. Murphy: None.

Outcomes From Whole-Brain Reirradiation Using Pulsed Reduced Dose Rate Radiation Therapy

PurposeRecurrent intracranial metastases after whole-brain irradiation pose a clinical challenge owing to the escalating morbidity associated with their treatment. Although stereotactic radiosurgery is increasingly being used, there are still situations in which whole-brain reirradiation (ReRT) continues to be appropriate. Here, we report our experience using whole-brain pulsed reduced dose rate radiation therapy (PRDR), a method that delivers radiation at a slower rate of 0.067 Gy/min to potentially increase sublethal damage repair and decrease toxicity. Methods and MaterialsPatients undergoing whole-brain ReRT with PRDR from January 1, 2001 to March 2019 were analyzed. The median PRDR ReRT dose was 26 Gy in 2 Gy fractions, resulting in a median total whole-brain dose of 59.5 Gy. Cox regression analysis was used for multivariate analysis. The Kaplan-Meier method was used for overall survival, progression free survival, and to evaluate the ReRT score. Binary logistic regression was employed to evaluate variables associated with rapid death. ResultsSeventy-five patients were treated with whole-brain PRDR radiation therapy. The median age was 54 (range, 26-72), the median Karnofsky performance status (KPS) was 80, and 86.7% had recursive partitioning analysis scores of 2. Thirty-two patients had over 10 metastases and 11 had leptomeningeal disease. The median overall survival was 4.1 months (range, 0.29-59.5 months) with a 1 year overall survival of 10.4%. Age, KPS, dexamethasone usage, and intracranial disease volume were significantly correlated with overall survival on multivariate analysis. A KPS ≤70 was associated with rapid death after radiation. The prognostic value of the ReRT score was validated. The most common acute toxicities were fatigue (23.1%) and headache (16.9%). ConclusionsIn this large cohort of patients with advanced intracranial metastases, PRDR achieves acceptable survival and may decrease toxicity associated with ReRT. PRDR is an easily implemented technique and is a viable treatment option for ReRT of brain metastases.

RTHP-35. RE-IRRADIATION USING PULSED REDUCED DOSE RATE RADIATION THERAPY IN PATIENTS WITH GRADE 2 GLIOMAS

Abstract BACKGROUND The time course of progressive grade 2 glioma can span nearly a decade. However, much less is known about re-irradiation in this cohort than in high grade patients. Pulsed reduced dose rate (PRDR) radiation therapy is a method of radiation delivery, which may spare normal tissues by slowing the rate of radiation delivery to allow repair. METHODS We identified consecutive patients from an institutional database initially diagnosed with grade 2 glioma from 2001 to 2017 who underwent pulsed reduced dose rate radiation therapy. Radiation was delivered in 20 cGy pulses every three minutes, most commonly with a 3D conformal, three field technique, encompassing gross disease with a 1–2 cm margin. Kaplan Meier method was utilized to analyze patient outcomes. RESULTS 35 patients with grade 2 glioma were identified. The median survival from the date of the first surgery was 103 months (95% CI 78–129 mo). 71% underwent at least a second resection and 86% of patients receiving chemotherapy. 80% of patients underwent transformation to grade 3 (51%) or grade 4 (29%) glioma. Overall survival from PRDR was 9.8 months (95% CI 4.5–14.5mo) and progression free survival was 6.2 months (95% CI 5.1–7.4) in all patients. Overall response rate was 37%. In patients who remained grade 2 histology, overall survival was 13.3 months and two patients remain disease free at 83 and 34 months with overall response of 71%. Four seizures were documented, otherwise treatment was well tolerated. CONCLUSIONS Progressive grade 2 glioma can progress and evolve over nearly the course of a decade. This study demonstrates the efficacy of re-irradiation in prolonging survival in these patients by delaying progression. In patients who remain with grade 2 disease, prolonged salvage of their disease appears possible.

RTHP-37. RE-IRRADIATION OF GLIOMATOSIS CEREBRI WITH WHOLE BRAIN PULSED REDUCED DOSE RATE RE-IRRADIATION

Abstract BACKGROUND Gliomatosis cerebri was removed from the 2016 WHO classification but the clinical problem of gliomatosis remains. For many of these patients, re-irradiation of the whole brain may be the only option. We have employed pulsed reduced dose rate (PRDR) radiation therapy to limit the toxicity of whole brain re-irradiation in this patient population. METHODS Consecutive patients were identified from an institutional database of patients treated with PRDR radiation to the whole brain between 2001 and 2016. Patients were treated by delivering a 20 cGy pulse of radiation every 3 minutes to opposed lateral fields with custom blocks using 6 MV photons, delivering radiation at an effective dose rate of 6.67 cGy/minute. RESULTS A total of sixteen patients were identified who underwent re-treated with WBRT. The median age was 45 (28–66) with a median KPS of 80 (range 60–100). 15 of 16 patients had high grade gliomas. The most common dose was 30 Gy in 15 fractions (range 24–41.4 Gy), giving a median total dose of 90.75 Gy (range 61.4–100.8 Gy). Median overall survival from re-irradiation was 3.8 months (range 0.1–17.0 months) and overall survival from first progression was 11.2 months. 25% of patients survived over 6 months following treatment and the overall response rate was 25% (3 PRs, 1 stable). No grade 4 or grade 5 toxicities were attributable to pulsed reduced dose rate radiation therapy. CONCLUSIONS PRDR radiation therapy provides a potential therapeutic intervention for progressive gliomatosis cerebri, providing a treatment option that can be implemented where no trial is available. As survival is short, these results will assist in counseling patients in considering re-irradiation versus supportive care.

Pulsed Reduced Dose Rate for Reirradiation of Recurrent Breast Cancer

PurposeLocoregionally recurrent breast cancer within a previously irradiated field requires weighing the benefits of reirradiation against the increased rates of toxicity. Here we evaluate the outcomes of patients treated with pulsed reduced dose rate (PRDR) radiation therapy with concurrent low-dose capecitabine as a method to increase the therapeutic ratio of re-treatment. Methods and MaterialsPatients treated from November 2000 to June 1, 2018 with PRDR radiation therapy at University of Wisconsin were identified. Patients were re-treated to a median dose of 54 Gy (range, 37.5-66 Gy) using PRDR radiation therapy, delivering radiation at an apparent dose rate of 6.67 cGy/min to allow for increased sublethal damage repair of normal tissues. The median cumulative dose was 109.8 Gy. Twenty-two patients were treated with concurrent capecitabine, most frequently at 500 mg twice per day. The Kaplan–Meier method was used for survival analysis, and Cox regression analysis was used for univariate and multivariate analysis. ResultsForty-three patients were identified who underwent reirradiation for locoregionally recurrent invasive breast cancer, with a median follow-up of 20.5 months. Twenty-four patients had gross disease. Nineteen patients had simultaneous metastatic disease. The complete response rate was 83.3% in treated patients with gross disease. Locoregional recurrence–free survival was 81.3% and 73.8% for all patients at 1 and 2 years, respectively. Overall survival for patients with localized disease was 95.7% at 1 year and 91.1% at 2 years. The rate of acute grade 3 radiation dermatitis was 25.6% with no other acute grade 3 toxicities. Grade 3 late toxicity occurred in 18.6% of patients. ConclusionsPRDR radiation therapy with capecitabine was a well-tolerated and effective method for treating patients with recurrent breast cancer. Prospective studies are necessary to compare side effects and efficacy with conventional dose rate reirradiation and to evaluate the potential role for capecitabine in the recurrent setting.

Large volume re-irradiation for recurrent meningioma with pulsed reduced dose rate radiotherapy

Meningiomas comprise up to 30% of primary brain tumors. The majority of meningioma patients enjoy high rates of control after conventional therapies. However, patients with recurrent disease previously treated with radiotherapy have few options for salvage treatment, and systemic interventions have proven largely ineffective. The aim of this study was to determine whether pulsed reduced dose rate radiotherapy (PRDR) was well tolerated in a small cohort of patients with recurrent meningioma. We retrospectively identified eight patients with recurrent intracranial meningioma treated with PRDR from April 2013 to August of 2017 at a single institution. All patients had radiographic and/or pathologic evidence of progression prior to treatment and had previously completed conventional radiotherapy. Acute and late toxicities were graded based on CTCAE 4.0. Of eight patients, six had histologically confirmed atypical meningiomas upon recurrence. All patients were re-treated with IMRT at an apparent dose rate of 0.0667Gy/min. Median time between radiation courses was 7.7years. Median PRDR dose was 54Gy in 27 fractions to a median volume of 261.6cm3. Two patients (25%) had in field failure with a median follow up of 23.3months. PFS at 6months was 100%. All but one (87.5%) patient was still alive at last follow up. No patient experienced grade ≥ 2 acute or late toxicities. PRDR re-irradiation was well tolerated and appeared effective for a small cohort of patients with recurrent meningioma previously treated with radiotherapy. A phase II trial to assess this prospectively is in development.

Abstract P2-11-19: Safety and efficacy of re-irradiation for locoregional breast cancer recurrences using pulsed reduced dose rate technique and concurrent capecitabine

Abstract Purpose: Locoregionally recurrent breast cancer presents a tremendous therapeutic challenge, but successful treatment can provide a durable cure. Re-irradiation has been performed infrequently in the recurrent setting due to concern for toxicity. Pulsed reduced dose rate radiation is a technique that can decrease the toxicity of re-irradiation by increasing normal tissue repair. Here, we update our previously published results of chest wall re-irradiation with an additional 16 patients and a focus on outcomes and long term toxicities. Methods: Patients treated from 11/09/2000 to 04/21/2016 with pulsed reduced dose rate radiation therapy at the University of Wisconsin were identified by query of Aria radiation oncology record software. Patients were retreated to a median dose of 54 Gy (range 37.5-66 Gy) using pulsed reduced does rate technique, delivering radiation at an apparent dose rate of 0.067 Gy/min to allow for normal tissue repair. The median cumulative dose was 109.8 Gy (range 75 to 236 Gy). Eleven patients underwent comprehensive re-irradiation to the chest wall and locoregional lymphatics, while the remainder underwent re-treatment limited to the site of recurrence. Concurrent capecitabine was given to 15 patients, most frequently at 500mg BID (range 1000 mg to 1500mg daily). The Kaplan-Meier method was used for survival analysis. Results: Thirty-three patients were identified who were treated with pulsed reduced dose rate radiation therapy for locoregionally recurrent invasive breast cancer with a median follow-up of 19.8 months (range 6.8-133.8 months). Sixteen patients were treated with curative intent and 17 patients were treated with palliative intent. Twenty-two patients had gross disease present at the time of treatment, 6 patients had microscopically positive surgical margins, and 5 patients were treated who had negative margins. The 2 year locoregional recurrence free survival was 70.5% by the Kaplan-Meier method for all patients and 81.5% for patients treated with curative intent. Two year overall survival was 43.6% for all patients and 72.2% in patients treated with curative intent. The rate of acute grade 3 skin toxicity was 21.2%. No other acute grade three toxicities occurred. A total of 9 patients (27.2%) developed late grade 3 or greater toxicities, including 4 patients who developed lymphedema, 4 patients who developed non-healing wounds, and one patient who developed both lymphedema and a non-healing wound. Conclusion: Pulsed reduced dose rate radiation therapy with capecitabine is an effective method for treating patients with recurrent breast cancer. The moderate risk of toxicity is warranted in a subset of patients with high risk of disease recurrence or morbidity from disease progression. Further work, including prospective studies, is needed to determine the patients who who will benefit most from this technique. Citation Format: Burr A, Howard S. Safety and efficacy of re-irradiation for locoregional breast cancer recurrences using pulsed reduced dose rate technique and concurrent capecitabine [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P2-11-19.

Review of Pulsed Reduced Dose Rate Re-irradiation for Recurrent Tumors

Pulsed Reduced Dose Rate (PRDR) is an external beam re-irradiation technique that may be appropriate for recurrent tumors in patients who have previously undergone radiation treatment. PRDR is thought to effectively target dividing neoplastic cells that display Low-Dose Hyper-Radiosensitivity (LDHRS) while permitting sub-lethal damage repair in non-proliferating normal tissues. To date, only a few case reports and several retrospective studies have reported on efficacy after PRDR retreatment across several disease sites, including CNS, breast, and nasopharyngeal tumors. In this article, we review available publications of PRDR re-irradiation in patients. Taken together, this research demonstrates that PRDR offers a treatment option for large volume recurrent disease at previously irradiated sites. More research is needed to establish therapeutic benefit and late adverse effects for each disease site.

Intensity modulated radiation therapy with pulsed reduced dose rate as a reirradiation strategy for recurrent central nervous system tumors: An institutional series and literature review

BackgroundPulsed reduced dose rate (PRDR) is a reirradiation technique that potentially overcomes volume and dose limitations in the setting of previous radiation therapy for recurrent central nervous system (CNS) tumors. Intensity modulated radiation therapy (IMRT) has not yet been reported as a PRDR delivery technique. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for CNS reirradiation. Methods and materialsA total of 24 patients with recurrent brain tumors received PRDR reirradiation between August 2012 and December 2014. Twenty-two patients were planned with IMRT. Linear accelerators delivered an effective dose rate of 0.0667 Gy/minute. Data collected included number of prior interventions, diagnosis, tumor grade, radiation therapy dose and fractionation, normal tissue dose, radiation therapy planning parameters, time to progression, overall survival, and adverse events. ResultsThe median time to PRDR from completion of initial radiation therapy was 47.8 months (range, 11-389.1 months). The median PRDR dose was 54 Gy (range, 38-60 Gy). The mean planning target volume was 369.1 ± 177.9 cm3. The median progression-free survival and 6-month progression-free survival after PRDR treatment was 3.1 months and 31%, respectively. The median overall survival and 6-month overall survival after PRDR treatment was 8.7 months and 71%, respectively. Fifty percent of patients had ≥4 chemotherapy regimens before PRDR. Toxicity was similar to initial treatment, including no cases of radiation necrosis. ConclusionIMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent CNS tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated. Prospective studies are necessary to determine the optimal timing of PRDR reirradiation, the role of concurrent systemic agents, and the ideal patient population who would receive the maximal benefit from this treatment approach. SummaryIntensity modulated radiation therapy (IMRT) has not yet been reported as a pulsed reduced dose rate (PRDR) delivery technique for recurrent brain tumors and may allow for safe and comprehensive reirradiation for large volume tumors. We reviewed our IMRT PRDR outcomes and toxicity and reviewed the literature of available PRDR series for recurrent central nervous system tumors. We conclude that IMRT PRDR reirradiation is a feasible and appropriate treatment strategy for large volume recurrent brain tumors resulting in acceptable overall survival with reasonable toxicity in our patients who were heavily pretreated.

Large volume reirradiation as salvage therapy for glioblastoma after progression on bevacizumab

Outcomes after bevacizumab failure for recurrent glioblastoma (GBM) are poor. Our analysis of 16 phase II trials (n = 995) revealed a median overall survival (OS) of 3.8 months (±1.0 month SD) after bevacizumab failure with no discernible activity of salvage chemotherapy. Thus, the optimal treatment for disease progression after bevacizumab has yet to be elucidated. This study evaluated the efficacy of reirradiation for patients with GBM after progression on bevacizumab. An IRB approved retrospective (2/2008-5/2013) analysis was performed of 23 patients with recurrent GBM (after standard radiotherapy/temozolomide) treated with bevacizumab (10 mg/kg) every 2 weeks until progression (median age 53 years; median KPS 80; median progression free survival on bevacizumab 3.7 months). Within 7-14 days of progression on bevacizumab, patients initiated reirradiation to a dose of 54 Gy in 27 fractions using pulsed-reduced dose rate (PRDR) radiotherapy. The median planning target volume was 424 cm(3). At the start of reirradiation, bevacizumab (10 mg/kg) was given every 4 weeks for two additional cycles. The median OS and 6 month OS after bevacizumab failure was 6.9 months and 65 %, respectively. Reirradiation was well tolerated with no symptomatic grade 3-4 toxicities. Favorable outcomes of reirradiation after bevacizumab failure in patients with recurrent GBM suggest its role as a treatment option for large volume recurrences not amenable to stereotactic radiosurgery. As PRDR is easily accomplished from a technological standpoint, we are in the process of expanding this approach to a multi-institutional cooperative group trial.

Reirradiation of Glioblastoma through the Use of a Reduced Dose Rate on a Tomotherapy Unit

Pulsed Reduced Dose Rate (PRDR) is a method of irradiation designed to minimize radiation-related toxicities in patients undergoing reirradiation for loco-regional reoccurrence of glioblastoma. PRDR delivers a standard 2 Gy fraction delivered on a conventional medical linear accelerator using conventional 3D conformal beam arrangements. To reduce the likelihood of normal tissue complications, radiation is delivered over ten 0.2 Gy sub-fractions with a 3 minute time interval between subfractions to give a maximal time averaged dose rate of 4 Gy/hr. However, a TomoTherapy unit has a fixed output rate of 8 Gy/min. If the dose per fraction is conventionally planned at less than 0.6 Gy/fraction, the result is a clinically unacceptable treatment plan. The method described in this paper involves a virtual grid style blocking scheme, where half of the beam angles are directionally blocked using 15 equally spaced segments surrounding the center of the image set. Ten patients treated using conventional PRDR with an average PTV volume of 353.3 ml were retrospectively re-planned using five techniques (standard 2 Gy fraction, 2 Gy in ten 0.2 Gy fractions without grid blocking, two grid patterns, and a combination plan incorporating both grids) and analyzed with conformation numbers (CN), homogeneity indexes (HI), and dose volumes to normal tissues. Plans were optimized using equal constraints and machine parameters. The grid method allowed for clinically acceptable treatment plans at 0.2 Gy with a treatment time < or = 3 min per subfraction. The average HI was slightly poorer for the combination plan versus the standard 2 Gy fraction plan (0.064 versus 0.027) and the CN was similar over all techniques (0.72 - 0.73) employed. Normal tissue dose volumes for each patient were also similar for each technique. Initial ion chamber measurements agree with predicted values for a 0.2 Gy subfraction. PRDR is deliverable on a TomoTherapy system using our virtual directional blocking method. Results can be slightly improved through the use of two grids alternated on a daily basis. The dose to normal structures for individual patients was similar for all methods.

SU‐GG‐T‐541: A Method of Delivering a Low Dose Fraction Using a TomoTherapy Unit

Purpose: To create a method of delivering PRDR for re‐irradiation of large brain tumors on the TomoTherapy Hi‐ART® system Method and Materials: Pulsed Reduced Dose Rate (PRDR) delivers a standard 2Gy fraction delivered over ten 0.2Gy sub‐fractions with a 3 minute break between sub‐fractions to give a time averaged dose rate of 4Gy/hr. The accelerator on a tomotherapy unit has a fixed output rate of 8Gy/min. If the dose per fraction is conventionally planned at &lt;0.6Gy/fraction, the result is a clinically unacceptable DVH. Our method involves a virtual grid style blocking scheme, where half of the beam angles are blocked using 15 equally spaced directional segments surrounding the center of the image set. Ten patients treated using conventional PRDR with an average PTV volume of 344cc were retrospectively re‐planned using five techniques (standard 2Gy fraction, 2Gy in 0.2Gy fractions without grid blocking, two grid patterns, and a combination dataset incorporating both grids) and analyzed with conformation numbers (CN), homogeneity indexes (HI), and dose volumes to normal tissues. Plans were optimized using equal constraints and machine parameters. Results: Our method allowed for clinically acceptable treatment plans at 0.2Gy with a treatment time ⩽3min per subfraction. The average HI was slightly poorer for the combination plan versus the standard 2Gy fraction (0.064 versus 0.027) and the CN was similar over all techniques (0.72–0.73). Normal tissue dose volumes for each patient were also similar for each technique. Initial ion chamber measurements agree with predicted values for a 0.2Gy subfraction. Conclusion: PRDR is deliverable on a TomoTherapy system using a virtual blocking method. Results can be slightly improved through the use of two grids alternated on a daily basis. The dose to normal structures for individual patients was similar for all methods. Conflict of Interest: The author has a financial interest in TomoTherapy Inc.