A Prospective Study Assessing the Efficacy and Toxicity of Stereotactic Body Radiation Therapy for Oligometastatic Bone Metastases.

Purpose: Stereotactic body radiation therapy (SBRT) is a promising treatment for oligometastatic disease in bone because of its delivery of high dose to target tissue and minimal dose to surrounding tissue. The purpose of this study is to assess the efficacy and toxicity of this treatment in patients with previously unirradiated oligometastatic bony disease. Methods and Materials: In this prospective phase II trial, patients with oligometastatic bone disease, defined as ≤3 active sites of disease, were treated with SBRT at Brigham and Women's Hospital/Dana Farber Cancer Center and Beth Israel Deaconess Medical Center between December 2016 and May 2019. SBRT dose and fractionation regimen were not protocol mandated. Local progression-free survival, progression-free survival, prostatic specific antigen progression, and overall survival were reported. Treatment-related toxicity was also reported. Results: A total of 98 patients and 126 lesions arising from various tumor histologies were included in this study. The median age of patients enrolled was 72.8 years (80.6% male, 19.4% female). Median follow-up was 26.7 months. The most common histology was prostate cancer (68.4%, 67/98). The most common dose prescriptions were 27/30 Gy in 3 fractions (27.0%, 34/126), 30 Gy in 5 fractions (16.7%, 21/126), or 30/35 Gy in 5 fractions (16.7%, 21/126). Multiple doses per treatment regimen reflect dose painting employing the lower dose to the clinical target volume and higher dose to the gross tumor volume. Four patients (4.1%, 4/98) experienced local progression at 1 site for each patient (3.2%, 4/126). Among the entire cohort, 2-year local progression-free survival (including death without local progression) was 84.8%, 2-year progression-free survival (including deaths as well as local, distant, and prostatic specific antigen progression) was 47.5%, and 2-year overall survival was 87.3%. Twenty-six patients (26.5%, 26/98) developed treatment-related toxicities. Conclusions: Our study supports existing literature in showing that SBRT is effective and tolerable in patients with oligometastatic bone disease. Larger phase III trials are necessary and reasonable to determine long-term efficacy and toxicities.

Evaluating hematologic parameters in newly diagnosed and recurrent glioblastoma: Prognostic utility and clinical trial implications of myelosuppression.

Background: Glioblastoma (GBM) patients are treated with radiation therapy, chemotherapy, and corticosteroids, which can cause myelosuppression. To understand the relative prognostic utility of blood-based biomarkers in GBM and its implications for clinical trial design, we examined the incidence, predictors, and prognostic value of lymphopenia, neutrophil-to-lymphocyte ratio (NLR), and platelet count during chemoradiation (CRT) and recurrence. Methods: This cohort study included 764 newly diagnosed glioblastoma patients treated from 2005 to 2019 with blood counts prior to surgery, within 6 weeks of CRT, and at first recurrence available for automatic extraction from the medical record. Logistic regression was used to evaluate exposures and Kaplan-Meier was used to evaluate outcomes. Results: Among the cohort, median age was 60.3 years; 87% had Karnofsky performance status ≥ 70, 37.5% had gross total resection, and 90% received temozolomide (TMZ). During CRT, 37.8% (248/656) of patients developed grade 3 or higher lymphopenia. On multivariable analysis (MVA), high NLR during CRT remained an independent predictor for inferior survival (Adjusted Hazard Ratio [AHR] = 1.57, 95% CI = 1.14-2.15) and shorter progression-free survival (AHR = 1.42, 95% CI = 1.05-1.90). Steroid use was associated with lymphopenia (OR = 2.66,1.20-6.00) and high NLR (OR = 3.54,2.08-6.11). Female sex was associated with lymphopenia (OR = 2.33,1.03-5.33). At first recurrence, 28% of patients exhibited grade 3 or higher lymphopenia. High NLR at recurrence was associated with worse subsequent survival on MVA (AHR = 1.69, 95% CI = 1.25-2.27). Conclusions: High NLR is associated with worse outcomes in newly diagnosed and recurrent glioblastoma. Appropriate eligibility criteria and accounting and reporting of blood-based biomarkers are important in the design and interpretation of newly diagnosed and recurrent glioblastoma trials.

Acute toxicity comparison of magnetic resonance-guided adaptive versus fiducial or computed tomography-guided non-adaptive prostate stereotactic body radiotherapy: A systematic review and meta-analysis.

BACKGROUND: Stereotactic body radiotherapy (SBRT) is gaining wider adoption for prostate cancer management but there remain significant toxicity risks when delivering prostate SBRT with standard techniques. Magnetic resonance-guided daily adaptive SBRT (MRg-A-SBRT) offers technological advantages in precision of radiation dose delivery, but the toxicity profile associated with MRg-A-SBRT compared to more standardly used fiducial or computed tomography-guided non-adaptive prostate SBRT (CT-SBRT) remains unknown. METHODS: A meta-analysis to compare acute toxicity rates associated with MRg-A-SBRT and CT-SBRT for prostate cancer was performed in compliance with PRISMA guidelines. MEDLINE (PubMed) and Google Scholar were searched for prospective studies of prostate SBRT that were published between January 1, 2018 and August 31, 2022. Random effects and fixed effects models were used to estimate pooled toxicity rates, and meta-regression was performed to compare toxicity between MRg-A-SBRT and CT-SBRT study groups. RESULTS: Twenty-nine prospective studies were identified that met the inclusion criteria and included a total of 2547 patients. The pooled estimates for acute grade 2 or higher (G2+) genitourinary (GU) and gastrointestinal (GI) toxicity for MRg-A-SBRT were 16% (95% confidence interval [CI], 10%-24%) and 4% (95% CI, 2%-7%) and for CT-SBRT they were 28% (95% CI, 23%-33%) and 9% (95% CI, 6%-12%), respectively. On meta-regression, the odds ratios for acute G2+ GU and GI toxicities comparing MRg-A-SBRT and CT-SBRT were 0.56 (95% CI, 0.33-0.97, p = .04) and 0.40 (95% CI, 0.17-0.96, p = .04), respectively. CONCLUSION: MRg-A-SBRT is associated with a significantly reduced risk of acute G2+ GU or GI toxicity compared to CT-SBRT. Longer follow-up will be needed to evaluate late toxicity and disease control outcomes. PLAIN LANGUAGE SUMMARY: Magnetic resonance imaging-guided daily adaptive prostate stereotactic radiation (MRg-A-SBRT) is a treatment that may allow for delivery of prostate radiation more precisely than other radiotherapy techniques, but it is unknown whether this reduces side effects compared to standardly used computed tomography-guided SBRT (CT-SBRT). In this systematic review and meta-analysis combining data from 29 clinical trials including 2547 patients, it was found that the risk of short-term urinary side effects was reduced by 44% and the risk of short-term bowel side effects was reduced by 60% with MRg-A-SBRT compared to CT-SBRT.

Spinal Cord Delineation Based on Computed Tomography Myelogram Versus T2 Magnetic Resonance Imaging in Spinal Stereotactic Body Radiation Therapy.

Purpose: Spinal cord delineation is critical to the delivery of stereotactic body radiation therapy (SBRT). Although underestimating the spinal cord can lead to irreversible myelopathy, overestimating the spinal cord may compromise the planning target volume coverage. We compare spinal cord contours based on computed tomography (CT) simulation with a myelogram to spinal cord contours based on fused axial T2 magnetic resonance imaging (MRI). Methods and Materials: Eight patients with 9 spinal metastases treated with spinal SBRT were contoured by 8 radiation oncologists, neurosurgeons, and physicists, with spinal cord definition based on (1) fused axial T2 MRI and (2) CT-myelogram simulation images, yielding 72 sets of spinal cord contours. The spinal cord volume was contoured at the target vertebral body volume based on both images. The mixed-effect model assessed comparisons of T2 MRI- to myelogram-defined spinal cord in centroid deviations (deviations in the center point of the cord) through the vertebral body target volume, spinal cord volumes, and maximum doses (0.035 cc point) to the spinal cord applying the patient's SBRT treatment plan, in addition to in-between and within-subject variabilities. Results: The estimate for the fixed effect from the mixed model showed that the mean difference between 72 CT volumes and 72 MRI volumes was 0.06 cc and was not statistically significant (95% confidence interval, -0.034, 0.153; P = .1832). The mixed model showed that the mean dose at 0.035 cc for CT-defined spinal cord contours was 1.24 Gy lower than that of MRI-defined spinal cord contours and was statistically significant (95% confidence interval, -2.292, -0.180; P = .0271). Also, the mixed model indicated no statistical significance for deviations in any of the axes between MRI-defined spinal cord contours and CT-defined spinal cord contours. Conclusions: CT myelogram may not be required when MRI imaging is feasible, although uncertainty at the cord-to-treatment volume interface may result in overcontouring and hence higher estimated cord dose-maximums with axial T2 MRI-based cord definition.

Phase I study of a novel glioblastoma radiation therapy schedule exploiting cell-state plasticity.

BACKGROUND: Glioblastomas comprise heterogeneous cell populations with dynamic, bidirectional plasticity between treatment-resistant stem-like and treatment-sensitive differentiated states, with treatment influencing this process. However, current treatment protocols do not account for this plasticity. Previously, we generated a mathematical model based on preclinical experiments to describe this process and optimize a radiation therapy fractionation schedule that substantially increased survival relative to standard fractionation in a murine glioblastoma model. METHODS: We developed statistical models to predict the survival benefit of interventions to glioblastoma patients based on the corresponding survival benefit in the mouse model used in our preclinical study. We applied our mathematical model of glioblastoma radiation response to optimize a radiation therapy fractionation schedule for patients undergoing re-irradiation for glioblastoma and developed a first-in-human trial (NCT03557372) to assess the feasibility and safety of administering our schedule. RESULTS: Our statistical modeling predicted that the hazard ratio when comparing our novel radiation schedule with a standard schedule would be 0.74. Our mathematical modeling suggested that a practical, near-optimal schedule for re-irradiation of recurrent glioblastoma patients was 3.96 Gy × 7 (1 fraction/day) followed by 1.0 Gy × 9 (3 fractions/day). Our optimized schedule was successfully administered to 14/14 (100%) patients. CONCLUSIONS: A novel radiation therapy schedule based on mathematical modeling of cell-state plasticity is feasible and safe to administer to glioblastoma patients.

Longitudinal symptoms and temporal trends in palliative care, palliative radiotherapy, and anti-cancer treatment near end of life among patients with metastatic cancer.

BACKGROUND: Early specialty palliative care (PC) integration improves oncologic outcomes. We aimed to examine longitudinal relationships between specialty PC and palliative radiotherapy (RT), temporal distribution of symptoms, and predictors of earlier specialty PC. METHODS: We retrospectively reviewed 135 patients with metastatic cancer who received palliative RT at our institution (7/2017-2/2018) and who had died by final study follow-up (6/2021). Descriptive statistics summarized frequencies of clinical visits and symptoms over relative survival time (quartiles 1-3: first 75% of life remaining from metastatic diagnosis to death versus quartile 4: last 25% of life remaining from metastatic diagnosis to death). Logistic regression analyses revealed predictors of receiving earlier (quartiles 1-3) versus later (quartile 4) specialty PC. RESULTS: There were 16.3%, 10.4%, 26.7%, and 46.7% of palliative RT consultations, compared to 4.7%, 7.6%, 14.0%, and 73.7% of specialty PC visits, that occurred in quartiles 1, 2, 3, and 4, respectively. On multivariable analysis, pain significantly predicted for receiving earlier specialty PC [odds ratios (OR) =15.34; 95% confidence interval (CI): 2.16-324.23; P=0.020], while patients with ≥2 prior chemotherapy regimens were less likely to have received earlier specialty PC (OR =0.16; 95% CI: 0.04-0.58; P=0.009). The most common reasons for first specialty PC visit were addressing pain (61.0%) and goals of care (19.5%). Overall, 73.3% (99/135) of patients were referred to hospice and 9.6% (13/135) received either palliative RT, chemotherapy, or surgery within 30 days of death. CONCLUSIONS: Nearly 47% of palliative RT visits compared with 74% of specialty PC visits occurred in the last quarter of life from metastatic diagnosis to death. Multidisciplinary efforts are needed to manage longitudinal symptoms and offer goal-concordant care.

Comparison of Pulmonary Toxicity after Total Body Irradiation- and Busulfan-Based Myeloablative Conditioning for Allogeneic Hematopoietic Stem Cell Transplantation in Pediatric Patients.

Pulmonary toxicity after allogeneic hematopoietic stem cell transplantation (allo-HSCT) for childhood leukemia and myelodysplastic syndrome (MDS), along with the impact of different myeloablative conditioning regimens, remain incompletely described. Here we compared the acute and long-term incidence of pulmonary toxicity (PT) after total body irradiation (TBI)- and busulfan-based myeloablative conditioning. We conducted this retrospective cohort study of 311 consecutive pediatric patients with leukemia or MDS who underwent allo-HSCT at Dana-Farber Cancer Institute/Boston Children's Hospital between 2008 and 2018. PT was graded using Common Terminology Criteria for Adverse Events version 5.0. The primary objective was to compare the cumulative incidence of grade ≥3 and grade 5 PT after TBI-based and busulfan-based myeloablative conditioning using Gray's test. Secondary objectives were to determine factors associated with PT and overall survival (OS) using competing risk analysis and Cox regression analyses, respectively. There was no significant difference between the TBI-conditioned group (n = 227) and the busulfan-conditioned group (n = 84) in the incidence of grade ≥3 PT (29.2% versus 34.7% at 2 years; P = .26) or grade 5 pulmonary toxicity (6.2% versus 6.1% at 2 years; P = .47). Age (hazard ratio [HR], 1.70, 95% confidence interval [CI], 1.11 to 2.59; P = .01), grade ≥2 PT prior to allo-HSCT or preexisting pulmonary conditions (HR, 1.84, 95% CI, 1.24 to 2.72; P < .01), acute graft-versus-host disease (GVHD) (HR, 2.50; 95% CI, 1.51 to 4.14; P < .01), and chronic GVHD (HR, 2.61; 95% CI, 1.26 to 5.42; P = .01) were associated with grade ≥3 PT on multivariable analysis. Grade ≥3 PT was associated with worse OS (81.1% versus 61.5% at 2 years; P < .01). In pediatric allo-HSCT recipients, rates of PT were similar in recipients of TBI-based and recipients of busulfan-based myeloablative conditioning regimens. Age, the presence of PT or preexisting pulmonary conditions prior to transplantation, and the development of either acute or chronic GVHD were associated with grade ≥3 PT post-transplantation. Furthermore, the occurrence of grade 3-4 PT post-transplantation was associated with inferior OS.

Neoadjuvant and Adjuvant Nivolumab and Lirilumab in Patients with Recurrent, Resectable Squamous Cell Carcinoma of the Head and Neck.

PURPOSE: Surgery often represents the best chance for disease control in locoregionally recurrent squamous cell carcinoma of the head and neck (SCCHN). We investigated dual immune-checkpoint inhibition [anti-PD-1, nivolumab (N), and anti-KIR, lirilumab (L)] before and after salvage surgery to improve disease-free survival (DFS). PATIENTS AND METHODS: In this phase II study, patients received N (240 mg) + L (240 mg) 7 to 21 days before surgery, followed by six cycles of adjuvant N + L. Primary endpoint was 1-year DFS; secondary endpoints were safety, pre-op radiologic response, and overall survival (OS). Correlatives included tumor sequencing, PD-L1 scoring, and immunoprofiling. RESULTS: Among 28 patients, the median age was 66, 86% were smokers; primary site: 9 oral cavity, 9 oropharynx, and 10 larynx/hypopharynx; 96% had prior radiation. There were no delays to surgery. Grade 3+ adverse events: 11%. At the time of surgery, 96% had stable disease radiologically, one had progression. Pathologic response to N + L was observed in 43% (12/28): 4/28 (14%) major (tumor viability, TV ≤ 10%) and 8/28 (29%) partial (TV ≤ 50%). PD-L1 combined positive score (CPS) at surgery was similar regardless of pathologic response (P = 0.71). Thirteen (46%) recurred (loco-regional = 10, distant = 3). Five of 28 (18%) had positive margins, 4 later recurred. At median follow-up of 22.8 months, 1-year DFS was 55.2% (95% CI, 34.8-71.7) and 1-year OS was 85.7% (95% CI, 66.3-94.4). Two-year DFS and OS were 64% and 80% among pathologic responders. CONCLUSIONS: (Neo)adjuvant N + L was well tolerated, with a 43% pathologic response rate. We observed favorable DFS and excellent 2-year OS among high-risk, previously treated patients exhibiting a pathologic response. Further evaluation of this strategy is warranted.See related commentary by Sacco and Cohen, p. 435.

Salient Constructs for the Development of Shared Decision-Making Tools for HIV Pre-Exposure Prophylaxis Uptake and Regimen Choice: Behaviors, Behavioral Skills, and Beliefs.

The availability of multiple pre-exposure prophylaxis (PrEP) regimens creates a preference-sensitive choice for individuals weighing alternative HIV prevention strategies. Investigating factors that are associated with PrEP uptake and regimen choice are key to developing tools to support that decision. A cross-sectional survey was offered to 536 participants in a PrEP demonstration project for gay, bisexual, and other men who have sex with men across 3 cities in China, of which 412 completed surveys and were included in the analysis. We conducted bivariable analyses followed by multi-variable logistic regressions to examine factors associated with overall PrEP uptake and PrEP regimen choice. Among the 412 participants, 36.9% were daily PrEP users, 28.4% were event-driven users, and 34.7% were non-PrEP users. Higher levels of education, lower PrEP use stigma, and higher perceived benefits of PrEP were associated with greater PrEP uptake. More frequent sex, higher PrEP adherence self-efficacy, higher endorsement of the belief in elevated efficacy of daily over on-demand PrEP, and lower endorsement of a desire for a PrEP method that is only taken when needed led to greater odds of choosing the daily PrEP regimen. As multiple HIV prevention modalities become available, there is a greater need for a shared decision-making approach to support this preference-sensitive choice of HIV prevention method. Our findings suggest salient constructs to inform the development of shared decision-making tools to support regimen choice.