Stish, Bradley J.

Purpose The predominant pattern of relapse for patients with B-cell non-Hodgkin lymphoma (NHL) who undergo anti-CD19 Chimeric Antigen Receptor T-cell Therapy (CART) involves sites previously involved by NHL. Bridging radiotherapy (BRT) has shown to be an effective bridging treatment with excellent local control rates. Our previous work defined limited/oligometastatic lymphoma as disease involving <5 sites. This study is the first to report on the role of BRT for patients with limited (<5 involved sites) disease prior to CART. Methods Following Institutional Review Board approval, a retrospective review from 2018 to 2023 across 3 Mayo Clinic sites (Arizona, Florida, and Minnesota) was performed and identified 139 patients with relapsed/refractory (r/r) B-cell NHL without bone marrow involvement who received CART and had <5 disease sites prior to leukapheresis. Ann Arbor staging was used to define the number of involved disease sites. An involved disease site included the Ann Arbor anatomical lymph node region(s) harboring the pathological lymph node(s) or any extranodal lesion. Bridging treatment (radiation and/or systemic therapy) was defined as treatment administered between leukapheresis and CART infusion. The primary endpoint was event-free survival (EFS),defined from CART infusion to any disease progression or initiation of post-CART consolidative/salvage therapy. Secondary endpoints included progression -free survival (PFS),defined from CART infusion to any disease progression, and overall survival (OS), defined from CART infusion to death. Results Prior to CART infusion, 44 (32%) patients received BRT and 95 (68%) did not. Bridging systemic therapy was given to 5 (11%) and 34 (36%) patients in the BRT and no BRT groups, respectively (p=0.003). The median number of involved disease sites prior to leukapheresis was 2 (range: 1-4). There was no significant difference in the baseline characteristics prior to CART infusion between the BRT and no BRT groups, except for extranodal involvement that was more common in the BRT group (Table 1). The median equivalent 2 Gy dose was 27 Gy (Interquartile range 23-34), and the most common BRT regimen was 20 Gy in 5 fractions. Among the 44 BRT patients, 34 received radiation to all visible PET-avid disease sites, and 10 received radiation to some but not all disease sites. The median follow-up was 20 months. The rate of grade ≥2 cytokine release syndrome was 41% in both groups (p=0.99). The rate of grade ≥2 immune effector cell-associated neurotoxicity syndrome was 21% and 37% in the BRT and no BRT groups, respectively (p=0.059). There were no observed grade ≥3 BRT-related toxicities. Objective response rate by PET 5 point scale was higher in the BRT group (93% versus 79%; p=0.036). Crude rates of progression were 30% in BRT and 55% in no BRT patients, with 9/13 (69%) and 43/52 (83%) patients relapsing in pre-existing sites of disease present prior to CART infusion in the BRT and no BRT group, respectively. Seven (16%) BRT patients relapsed in the radiation field. The 2-year EFS was 50% in the BRT group and 39% in the no BRT group (p=0.01). The 2-year PFS was 55% in the BRT group and 45% in the no BRT group (p=0.017). The 2-year OS was 55% in the BRT group and 62% in the no BRT group (p=0.7). Intriguingly, patients who received BRT to all visible PET-avid disease sites (n=34) had further improvement in 2-year EFS (67% vs 39%, p=0.003) and 2-year PFS (71% vs 46%, p=0.008) compared to no BRT or patients who received BRT to some but not all visible disease sites (n=105). Nine patients (2 in BRT and 7 in no BRT groups) received consolidative radiotherapy for day 30 residual disease with only one patient subsequently experiencing progression. Twenty-five patients (6 in BRT and 19 in no BRT groups) received salvage/palliative RT for post-CART relapsed disease. Thirty-seven (39%) patients in the no BRT group remained without disease progression and did not receive radiation in the bridging, consolidative or salvage/palliative setting. Conclusion Bridging radiotherapy prior to CART infusion for patients with limited (<5 involved disease sites) r/r NHL appears to improve response rate, EFS, and PFS without causing significant toxicities. Approximately one third of patients who do not receive BRT will require subsequent post-CART radiation, and another third will remain free of radiation and disease progression.

AbstractBackgroundProstate cancer (PCa) parenchymal brain metastases are uncommon and troubling observations in the course of the disease. Our study aims to evaluate the prevalence of brain metastases among PCa patients while reporting various therapeutic modalities, clinical features, and oncological outcomes.MethodsWe retrospectively identified 34 patients with parenchymal brain metastasis out of 4575 patients using a prospectively maintained database that contains clinicopathologic characteristics of PCa patients between January 2012 and December 2021. Based on the three treatment modalities used, the patients were divided into three groups: stereotactic radiosurgery (SRS), whole brain radiotherapy (WBRT), and systemic therapy alone. The Kaplan–Meier curve was used to calculate overall survival [OS] probability and the Cox proportional hazards regression model was used to compare between groups.ResultsAt the time of brain metastasis diagnosis, the median age was 66 years, the median (interquartile range [IQR]) prostate‐specific antigen (PSA) was 2.2 (0.1–26.6) ng/ml and the median (IQR) months from initial PCa diagnosis to brain metastasis development was 70.8 (27.6–100.9). The median (IQR) primary Gleason score was 8 (7–9) and over a median (IQR) follow‐up time of 2.2 (1.2–16.5) months, 76.5% (n = 26) of the patients died. Thirteen (38.2%) patients had solitary lesion, whereas 21 (61.8%) had ≥2 lesions. The lesions were supratentorial in 19 (55.9%) patients, infratentorial in six (17.6%), and both sides in nine (26.5%). Among all 34 patients, 10 (29.4%) were treated with SRS, seven (20.6%) with WBRT, and 17 (50%) with systemic therapy alone. OS varied greatly between the three treatment modalities (log‐rank test, p = 0.049). Those who were treated with SRS and WBRT had better OS compared with patients who were treated with systemic therapy alone (hazard ratio: 0.37, 95% confidence interval: 0.16–0.86, p = 0.022).ConclusionsIn our single‐institutional study, we confirmed that PCa brain metastasis is associated with poor survival outcomes and more advanced metastatic disease. Furthermore, we found that SRS and WBRT for brain metastasis in patients with recurrent PCa appear to be associated with improved OS as compared with systemic therapy alone and are likely secondary to selection bias.

Abstract Purpose/Objectives: Proton therapy is under investigation in breast cancer as a strategy to reduce heart and lung exposure, which is associated with late cardiopulmonary adverse events and secondary malignancy. To date, studies investigating postmastectomy radiotherapy (PMRT) with protons have used conventional fractionation. We hypothesized that condensing treatment to 15 fractions would be safe based on evidence that breast cancer is more sensitive to higher dose fractions than surrounding normal tissues. Materials/Methods: We conducted a randomized non-inferiority phase II trial comparing conventional and hypofractionated proton PMRT with primary endpoint of 24-month complication rate (defined as grade 3 or higher late adverse events using CTCAE, v 4.0 and/or unplanned surgical intervention in patients undergoing mastectomy with reconstruction). With a 10% non-inferiority margin the study ensured 80% power and had a one sided-type I error rate of 0.05. Cardiotoxicity was assessed with serial transthoracic conventional and 2-dimensional speckle tracking echocardiography (2D-STE). Eligibility included age ≥ 18 years with non-inflammatory breast cancer resected by mastectomy with indications for PMRT. Assignment of treatments was balanced with respect to immediate breast reconstruction (IBR). Conventional fractionation group received 50 Gy in 25 fractions of 2 Gy, and hypofractionation group received 40.05 Gy in 15 fractions of 2.67 Gy (RBE 1.1). Target volume included the chest wall and axillary, supraclavicular, and internal mammary lymph nodes. All patients were treated with multi-field optimized pencil beam scanning (intensity modulated proton therapy). Results: Between 2016 and 2018, 82 patients were enrolled and randomized (41 conventional, 41 hypofractionation). Median patient age was 52 years. 32.9% were staged T3-T4 and 79.3% node positive at diagnosis. 57 of 82 patients (69.5%) elected IBR. The median mean heart dose was 0.49 Gy and the median ipsilateral lung volume receiving 40% of prescription or greater (V40%) was 13.6%. No significant changes on conventional or 2D-STE at end-of-treatment or 3-month follow-up compared to baseline were observed. The rate of ≥ grade 2 acute dermatitis was lower with hypofractionation (44% vs 15%, p = 0.006). Other ≥ grade 2 acute adverse events including esophagitis (0 vs 5%), infection (5% vs 2.4%) and skin hyperpigmentation (7.3% vs 4.8%) were not significantly different between the two arms. With a median follow-up of 38.3 months, the 24-month complication rate was conventional 14.6% vs hypofractionation 17.1% (absolute difference 2.4%, p=0.17, 95% CI [-, 15.7%]). In patients with IBR, 6 of 28 (21.4%) conventional and 7 of 29 (24.1%) hypofractionated patients developed complications (p =0.80). There was no significant difference in 3-year disease-free survival between the conventional (89.4%; 95% CI 80.0 – 99.8%) and hypofractionated (92.4%, 95% CI 84.5 – 100.0%) arms (p = 0.91). One local recurrence occurred in the hypofractionated arm simultaneous with regional and distant relapse. The remaining 6 recurrences were isolated distant events. Conclusions: Proton PMRT provided excellent locoregional control and normal tissue sparing. There were no subclinical echocardiographic changes indicative of radiation-induced cardiac dysfunction. Hypofractionation resulted in comparable disease control, tolerability and reconstruction outcomes as conventional fractionation. Although non-inferiority of hypofractionation could not be established based on the upper bound of the 95% confidence interval for complication rate being greater than 10%, both conventional and hypofractionation may be considered appropriate regimens for ongoing phase 3 randomized trials comparing photon and proton radiotherapy. Citation Format: Robert Mutter, Sharmila Giri, Briant Fruth, Nicholas Remmes, Aman Anand, Kathryn Ruddy, Hector Villarraga, Sebastian Santos Patarroyo, Elizabeth Yan, Kenneth Merrell, Lisa McGee, Tamara Vern-Gross, Bradley Stish, Robert Gao, Judy C. Boughey, Sean Park, Kimberly Corbin, Carlos Vargas. Phase II randomized trial of conventional versus hypofractionated post-mastectomy proton radiotherapy [abstract]. In: Proceedings of the 2022 San Antonio Breast Cancer Symposium; 2022 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2023;83(5 Suppl):Abstract nr GS4-05.

AbstractBackgroundThis study was aimed at developing and validating a decision‐making tool predictive of overall survival (OS) for patients receiving stereotactic body radiation therapy (SBRT) for spinal metastases.MethodsThree hundred sixty‐one patients at one institution were used for the training set, and 182 at a second institution were used for external validation. Treatments most commonly involved one or three fractions of spine SBRT. Exclusion criteria included proton therapy and benign histologies.ResultsThe final model consisted of the following variables and scores: Spinal Instability Neoplastic Score (SINS) ≥ 6 (1), time from primary diagnosis < 21 months (1), Eastern Cooperative Oncology Group (ECOG) performance status = 1 (1) or ECOG performance status > 1 (2), and >1 organ system involved (1). Each variable was an independent predictor of OS (p < .001), and each 1‐point increase in the score was associated with a hazard ratio of 2.01 (95% confidence interval [CI], 1.79–2.25; p < .0001). The concordance value was 0.75 (95% CI, 0.71–0.78). The scores were discretized into three groups—favorable (score = 0–1), intermediate (score = 2), and poor survival (score = 3–5)—with 2‐year OS rates of 84% (95% CI, 79%–90%), 46% (95% CI, 36%–59%), and 21% (95% CI, 14%–32%), respectively (p < .0001 for each). In the external validation set (182 patients), the score was also predictive of OS (p < .0001). Increasing SINS<zaq;6> was predictive of decreased OS as a continuous variable (p < .0001).ConclusionsThis novel score is proposed as a decision‐making tool to help to optimize patient selection for spine SBRT. SINS may be an independent predictor of OS.

AbstractBackgroundApplicator conspicuity in ultrasound‐guided brachytherapy procedures is commonly impaired by imaging artifacts or non‐ideal imaging geometry, which can slow down applicator position digitization and increase the geometric uncertainty of the delivered dose distribution.PurposeThe purpose of this study was to improve the conspicuity of high‐dose rate (HDR) brachytherapy needles under B‐mode ultrasound imaging by applying an echogenic surface coating. Our hypothesis was that an echogenic coating would reduce artifacts and improve needle visualization within regions of signal degradation.MethodsIn this study, 17‐gauge, 25‐cm long titanium HDR brachytherapy needles were coated with acoustically reflective microspheres over a 2.5 cm region starting from the needle tip. Three coating thicknesses (27 μm, 40 μm, 64 μm) were compared against an uncoated control needle. The coated and uncoated needles were imaged using B‐mode ultrasound in a tissue‐equivalent prostate phantom and in a cadaverous male pelvis using a transrectal probe. Needle conspicuity was assessed under multiple conditions: a single needle implant, an implant with multiple needles between the probe and the needle of interest, and an angled needle implant. All images were assessed qualitatively for needle conspicuity and the presence of artifacts and quantitatively using grey‐scale image intensity values.ResultsThe 64 μm echogenic coating reduced the magnitude of reverberation artifacts by 31 ± 14% and comet tail artifacts by 40%–70%. The echogenic coating also improved needle contrast, measured by the relative differences in signal intensity compared with the adjacent environment, when needles were angled up to 30° with respect to the transducer probe in the cadaver. The improvements in conspicuity and artifact reduction increased with increasing coating thickness. The performance of the needles coated with the 64 μm thickness was qualitatively superior and yielded high‐contrast, well‐circumscribed signals in the cadaverous male pelvis, even under situations where a needle was acoustically shadowed by multiple other needles.ConclusionsAn echogenic surface coating reduced imaging artifacts and improved needle conspicuity under realistic clinical conditions for ultrasound‐based prostate or gynecological brachytherapy. The improved conspicuity has the potential to improve the efficiency of needle placement and the accuracy of needle position digitization during brachytherapy procedures.

BackgroundPatients with high‐risk prostate cancer (HRPC) have multiple accepted treatment options. Because there is no overall survival benefit of one option over another, appropriate treatment must consider patient life expectancy, quality of life, and cost.MethodsThe authors compared quality‐adjusted life years (QALYs) and cost effectiveness among treatment options for HRPC using a Markov model with three treatment arms: (1) external‐beam radiotherapy (EBRT) delivered with 20 fractions, (2) EBRT with 23 fractions followed by low‐dose‐rate (LDR) brachytherapy boost, or (3) radical prostatectomy alone. An exploratory analysis considered a simultaneous integrated boost according to the FLAME trial (ClinicalTrials.gov identifier NCT01168479).ResultsTreatment strategies were compared using the incremental cost‐effectiveness ratio (ICER). EBRT with LDR brachytherapy boost was a cost‐effective strategy (ICER, $20,929 per QALY gained). These results were most sensitive to variations in the biochemical failure rate. However, the results still demonstrated cost effectiveness for the brachytherapy boost paradigm, regardless of any tested parameter ranges. Probabilistic sensitivity analysis demonstrated that EBRT with LDR brachytherapy was favored in 52% of 100,000 Monte Carlo iterations. In an exploratory analysis, EBRT with a simultaneous integrated boost was also a cost‐effective strategy, resulting in an ICER of $62,607 per QALY gained; however, it was not cost effective compared with EBRT plus LDR brachytherapy boost.ConclusionsEBRT with LDR brachytherapy boost may be a cost‐effective treatment strategy compared with EBRT alone and radical prostatectomy for HRPC, demonstrating high‐value care. The current analysis suggests that a reduction in biochemical failure alone can result in cost‐effective care, despite no change in overall survival.