Faculty Bibliography

IMPORTANCE/UNASSIGNED:Stereotactic body radiation therapy (SBRT) for spinal metastases improves symptomatic outcomes and local control compared to conventional radiotherapy. Treatment failure most often occurs within the epidural space, where dose is constrained by the risk of radiation myelitis (RM). Current constraints designed to prevent RM after spine SBRT are derived from limited data. OBJECTIVE/UNASSIGNED:To characterize the risk of RM after spine SBRT and to update the dosimetric constraints for preventing it. DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This cohort study was conducted in a single tertiary cancer care center with patients treated for spinal metastases from 2014 to 2023. All included participants had undergone spine SBRT, had a minimum of 1-month follow-up with magnetic resonance imaging (MRI), a maximal cord dose to a voxel (Dmax) greater than 0 Gy, and no overlapping prior radiotherapy. In all, 2051 patients received SBRT to 2835 spinal metastases (levels C1-L2) during the study period. EXPOSURES/UNASSIGNED:Three-fraction spine SBRT to a prescription dose of 27 to 36 Gy. MAIN OUTCOMES AND MEASURES/UNASSIGNED:RM defined as radiographic evidence of spinal cord injury in the treatment field, classified as grade (G) 1 to G4 or G3 to G4 per the Common Terminology Criteria for Adverse Events, version 5.0. Multiple dosimetric parameters of the true spinal cord structure were assessed for an association with risk of RM to determine the important covariates associated with this toxicity. RESULTS/UNASSIGNED:The analysis included 1423 patients (mean [SD] age, 61.6 [12.9] years; 695 [48.8%] females and 728 [51.1%] males) who received SBRT for 1904 spinal metastases. Among them, 30 cases of RM were identified, 19 of which were classified as G3 to G4. Two years after SBRT, the rate of G1 to G4 RM was 1.8% (95% CI, 1.2%-2.5%) and the rate of G3 to G4 RM was 1.1% (95% CI, 0.7%-1.7%). The minimum dose to the 0.1 cm3 of spinal cord receiving the greatest dose (D0.1cc) was the most important covariate on univariable cause-specific hazards regression for RM (for G3 to G4: hazard ratio, 2.14; 95% CI, 1.68-2.72; P < .001). A true cord D0.1cc of 19.1 Gy and Dmax of 20.8 Gy estimated a 1.0% risk (95% CI, 0.3%-1.6% and 0.4%-1.6%, respectively) of G3 to G4 RM 2 years after SBRT. CONCLUSIONS AND RELEVANCE/UNASSIGNED:The findings of this cohort study indicate that a cord (myelogram or MRI-derived) D0.1cc constraint of 19.1 Gy and a Dmax constraint of 20.8 Gy correspond with a 1.0% risk of G3 to G4 RM at 2 years.

There is a much debate regarding optimal selection in patients with metastatic cancer who should undergo local treatment (surgery or radiation treatment) to the primary tumor and/or metastases. Additionally, the optimal treatment of newly diagnosed metastatic cancer is largely unclear. Current prognostication systems to best inform these clinical scenarios are limited, as all metastatic patients are grouped together as having Stage IV disease without further incorporation of patient and disease-specific covariates that significantly impact patient outcomes. Therefore, improving current prognostic scoring systems and incorporation of these covariates is essential to best individualize treatment for patients with metastatic cancer. In this narrative review article, we provide a detailed review of prognostication systems that can be used for both the site of metastasis and primary site to best tailor treatment in these patients. Additionally, we discuss the incorporation and ongoing developments in radiographic, genomic, and biostatistical techniques that can be used as prognostication tools.

Leptomeningeal metastases are increasingly becoming recognized as a treatable, yet generally incurable, complication of advanced cancer. As modern cancer therapeutics have prolonged the lives of patients with metastatic cancer, specifically in patients with parenchymal brain metastases, treatment options and clinical research protocols for patients with leptomeningeal metastases from solid tumors have similarly evolved to improve survival within specific populations. Recent expansion in clinical investigation, early diagnosis, and drug development have given rise to new unanswered questions. These include leptomeningeal metastasis biology and preferred animal modeling, epidemiology in the modern cancer population, ensuring validation and accessibility of newer leptomeningeal metastasis diagnostics, best clinical practices with multi-modality treatment options, clinical trial design and standardization of response assessments, and avenues worthy of further research. An international group of multi-disciplinary experts in the research and management of leptomeningeal metastases, supported by the Society for Neuro-Oncology and American Society of Clinical Oncology, were assembled to reach a consensus opinion on these pressing topics and provide a roadmap for future directions. Our hope is that these recommendations will accelerate collaboration and progress in the field of leptomeningeal metastases and serve as a platform for further discussion and patient advocacy.

IMPORTANCE/UNASSIGNED:For patients with nonspine bone metastases, short-course radiotherapy (RT) can reduce patient burden without sacrificing clinical benefit. However, there is great variation in uptake of short-course RT across practice settings. OBJECTIVE/UNASSIGNED:To evaluate whether a set of 3 implementation strategies facilitates increased adoption of a consensus recommendation to treat nonspine bone metastases with short-course RT (ie, ≤5 fractions). DESIGN, SETTING, AND PARTICIPANTS/UNASSIGNED:This prospective, stepped-wedge, cluster randomized quality improvement study was conducted at 3 community-based cancer centers within an existing academic-community partnership. Rollout was initiated in 3-month increments between October 2021 and May 2022. Participants included treating physicians and patients receiving RT for nonspine bone metastases. Data analysis was performed from October 2022 to May 2023. EXPOSURES/UNASSIGNED:Three implementation strategies-(1) dissemination of published consensus guidelines, (2) personalized audit-and-feedback reports, and (3) an email-based electronic consultation platform (eConsult)-were rolled out to physicians. MAIN OUTCOMES AND MEASURES/UNASSIGNED:The primary outcome was adherence to the consensus recommendation of short-course RT for nonspine bone metastases. Mixed-effects logistic regression at the bone metastasis level was used to model associations between the exposure of physicians to the set of strategies (preimplementation vs postimplementation) and short-course RT, while accounting for patient and physician characteristics and calendar time, with a random effect for physician. Physician surveys were administered before implementation and after implementation to assess feasibility, acceptability, and appropriateness of each strategy. RESULTS/UNASSIGNED:Forty-five physicians treated 714 patients (median [IQR] age at treatment start, 67 [59-75] years; 343 women [48%]) with 838 unique nonspine bone metastases during the study period. Implementing the set of strategies was not associated with use of short-course RT (odds ratio, 0.78; 95% CI, 0.45-1.34; P = .40), with unadjusted adherence rates of 53% (444 lesions) preimplementation vs 56% (469 lesions) postimplementation; however, the adjusted odds of adherence increased with calendar time (odds ratio, 1.68; 95% CI, 1.20-2.36; P = .003). All 3 implementation strategies were perceived as being feasible, acceptable, and appropriate; only the perception of audit-and-feedback appropriateness changed before vs after implementation (19 of 29 physicians [66%] vs 27 of 30 physicians [90%]; P = .03, Fisher exact test), with 20 physicians (67%) preferring reports quarterly. CONCLUSIONS AND RELEVANCE/UNASSIGNED:In this quality improvement study, a multicomponent set of implementation strategies was not associated with increased use of short-course RT within an academic-community partnership. However, practice improved with time, perhaps owing to secular trends or physician awareness of the study. Audit-and-feedback was more appropriate than anticipated. Findings support the need to investigate optimal approaches for promoting evidence-based radiation practice across settings.

PURPOSE/OBJECTIVE:Treatment decisions for leptomeningeal disease (LMD) rely on patient risk stratification, since clinicians lack objective prognostic tools. The introduction of rare cell capture technology for identification of cerebrospinal fluid tumor cells (CSF-TCs), such as CNSide assay, improved the sensitivity of LMD diagnosis, but prognostic value is unknown. This study assesses the prognostic value of CSF-TC density in patients with LMD from solid tumors. METHODS:We conducted a retrospective cohort study of patients with newly diagnosed or previously treated LMD from a single institution who had CNSide assay testing for CSF-TCs from 2020 to 2023. Univariable and multivariable survival analyses were conducted with Cox proportional-hazards modeling. Maximally-selected rank statistics were used to determine an optimal cutpoint for CSF-TC density and survival. RESULTS:Of 31 patients, 29 had CSF-TCs detected on CNSide. Median (interquartile range [IQR]) CSF-TC density was 67.8 (4.7-639) TCs/mL. CSF cytology was positive in 16 of 29 patients with positive CNSide (CNSide diagnostic sensitivity = 93.5%, negative predictive value = 85.7%). Median (IQR) survival from time of CSF-TC detection was 176 (89-481) days. On univariable and multivariable analysis, CSF-TC density was significantly associated with survival. An optimal cutpoint for dichotomizing survival by CSF-TC density was 19.34 TCs/mL. The time-dependent sensitivity and specificity for survival using this stratification were 76% and 67% at 6 months and 65% and 67% at 1 year, respectively. CONCLUSIONS:CSF-TC density may carry prognostic value in patients with LMD from solid tumors. Integrating CSF-TC density into LMD patient risk-stratification may help guide treatment decisions.

This study explores the feasibility and potential dosimetric and time efficiency benefit of proton Pencil Beam Scanning (PBS) craniospinal irradiation with a single posterior-anterior (SPA) brain field. The SPA approach was compared to our current clinical protocol using Bilateral Posterior Oblique brain fields (BPO). Ten consecutive patients were simulated in the head-first supine position on a long BOS frame and scanned using 3 mm CT slice thickness. A customized thermoplastic mask immobilized the patient's head, neck, and shoulders. A vac-lock was used to secure the legs. PBS proton plans were robustly optimized with 3mm setup errors and 3.5% range uncertainties in the Eclipse V15.6 treatment planning system (n = 12 scenarios). In order to achieve a smooth gradient dose match at the junction area, at least 5 cm overlap region was maintained between the segments and 5 mm uncertainty along the cranial-cauda direction was applied to each segment independently as additional robust optimization scenarios. The brain doses were planned by SPA or BPO fields. All spine segments were planned with a single PA field. Dosimetric differences between the BPO and SPA approaches were compared, and the treatment efficiency was analyzed according to timestamps of beam delivery. Results: The maximum brain dose increases to 111.1 ± 2.1% for SPA vs. 109.0 ± 1.7% for BPO (p < 0.01). The dose homogeneity index (D5/D95) in brain CTV was comparable between techniques (1.037 ± 0.010 for SPA and 1.033 ± 0.008 for BPO). Lens received lower maximum doses by 2.88 ± 1.58 Gy (RBE) (left) and 2.23 ± 1.37 Gy (RBE) (right) in the SPA plans (p < 0.01). No significant cochlea dose change was observed. SPA reduced the treatment time by more than 4 minutes on average and ranged from 2 to 10 minutes, depending on the beam waiting and allocation time. SPA is dosimetrically comparable to BPO, with reduced lens doses at the cost of slightly higher dose inhomogeneity and hot spots. Implementation of SPA is feasible and can help to improve the treatment efficiency of PBS CSI treatment.

PURPOSE/UNASSIGNED:Colorectal liver metastases (CLMs) represent a radioresistant histology. We aimed to investigate CLM radiation therapy (RT) outcomes and explore the association with treatment parameters. METHODS AND MATERIALS/UNASSIGNED:This retrospective analysis of CLM treated with RT at Memorial Sloan Kettering Cancer Center used Kaplan-Meier analysis to estimate freedom from local progression (FFLP), hepatic progression-free, progression-free, and overall survival (OS). Cox proportional hazards regression was used to evaluate association with clinical factors. Dose-response relationship was further evaluated using a mechanistic tumor control probability (TCP) model. RESULTS/UNASSIGNED:< .001) on univariate analyses, which remained significant or marginally significant on multivariate analyses. A mechanistic Tumor Control Probability (TCP) model showed a higher 2-Gy equivalent dose needed for local control in patients who had been exposed to ≥ 3 lines of chemotherapy versus 0 to 2 (250 ± 29 vs 185 ± 77 Gy for 70% TCP). CONCLUSIONS/UNASSIGNED:In a large single-institution series of heavily pretreated patients with CLM undergoing liver RT, low BED10 and multiple prior lines of systemic therapy were associated with lower local control and OS. These results support continued dose escalation efforts for patients with CLM.

PURPOSE/UNASSIGNED:Leptomeningeal disease (LMD) is clinically detected in 5% to 10% of patients with solid tumors and is a source of substantial morbidity and mortality. Prognosis for this entity remains poor and treatments are palliative. Radiation therapy (RT) is an essential tool in the management of LMD, and a recent randomized trial demonstrated a survival benefit for proton craniospinal irradiation (CSI) in select patients. In the setting of this recent advance, we conducted a review of the role of RT in LMD from solid tumors to evaluate the evidence basis for RT recommendations. METHODS AND MATERIALS/UNASSIGNED:In November 2022, we conducted a comprehensive literature search in PubMed, as well as a review of ongoing clinical trials listed on ClinicalTrials.gov, to inform a discussion on the role of RT in solid tumor LMD. Because of the paucity of high-quality published evidence, discussion was informed more by expert consensus and opinion, including a review of societal guidelines, than evidence from clinical trials. RESULTS/UNASSIGNED:Only 1 prospective randomized trial has evaluated RT for LMD, demonstrating improved central nervous system progression-free survival for patients with breast and lung cancer treated with proton CSI compared with involved-field RT. Modern photon CSI techniques have improved upon historical rates of acute hematologic toxicity, but the overall benefit of this modality has not been prospectively evaluated. Multiple retrospective studies have explored the use of involved-field RT or the combination of RT with chemotherapy, but clear evidence of survival benefit is lacking. CONCLUSIONS/UNASSIGNED:Optimal management of LMD with RT remains reliant upon expert opinion, with proton CSI indicated in patients with good performance status and extra-central nervous system disease that is either well-controlled or for which effective treatment options are available. Photon-based CSI traditionally has been associated with increased marrow and gastrointestinal toxicities, though intensity modulated RT/volumetric-modulated arc therapy based photon CSI may have reduced the toxicity profile. Further work is needed to understand the role of radioisotopes as well as combined modality treatment with intrathecal or central nervous system penetrating systemic therapies.

BACKGROUND:Most patients with metastatic cancer eventually develop resistance to systemic therapy, with some having limited disease progression (ie, oligoprogression). We aimed to assess whether stereotactic body radiotherapy (SBRT) targeting oligoprogressive sites could improve patient outcomes. METHODS:We did a phase 2, open-label, randomised controlled trial of SBRT in patients with oligoprogressive metastatic breast cancer or non-small-cell lung cancer (NSCLC) after having received at least first-line systemic therapy, with oligoprogression defined as five or less progressive lesions on PET-CT or CT. Patients aged 18 years or older were enrolled from a tertiary cancer centre in New York, NY, USA, and six affiliated regional centres in the states of New York and New Jersey, with a 1:1 randomisation between standard of care (standard-of-care group) and SBRT plus standard of care (SBRT group). Randomisation was done with a computer-based algorithm with stratification by number of progressive sites of metastasis, receptor or driver genetic alteration status, primary site, and type of systemic therapy previously received. Patients and investigators were not masked to treatment allocation. The primary endpoint was progression-free survival, measured up to 12 months. We did a prespecified subgroup analysis of the primary endpoint by disease site. All analyses were done in the intention-to-treat population. The study is registered with ClinicalTrials.gov, NCT03808662, and is complete. FINDINGS:From Jan 1, 2019, to July 31, 2021, 106 patients were randomly assigned to standard of care (n=51; 23 patients with breast cancer and 28 patients with NSCLC) or SBRT plus standard of care (n=55; 24 patients with breast cancer and 31 patients with NSCLC). 16 (34%) of 47 patients with breast cancer had triple-negative disease, and 51 (86%) of 59 patients with NSCLC had no actionable driver mutation. The study was closed to accrual before reaching the targeted sample size, after the primary efficacy endpoint was met during a preplanned interim analysis. The median follow-up was 11·6 months for patients in the standard-of-care group and 12·1 months for patients in the SBRT group. The median progression-free survival was 3·2 months (95% CI 2·0-4·5) for patients in the standard-of-care group versus 7·2 months (4·5-10·0) for patients in the SBRT group (hazard ratio [HR] 0·53, 95% CI 0·35-0·81; p=0·0035). The median progression-free survival was higher for patients with NSCLC in the SBRT group than for those with NSCLC in the standard-of-care group (10·0 months [7·2-not reached] vs 2·2 months [95% CI 2·0-4·5]; HR 0·41, 95% CI 0·22-0·75; p=0·0039), but no difference was found for patients with breast cancer (4·4 months [2·5-8·7] vs 4·2 months [1·8-5·5]; 0·78, 0·43-1·43; p=0·43). Grade 2 or worse adverse events occurred in 21 (41%) patients in the standard-of-care group and 34 (62%) patients in the SBRT group. Nine (16%) patients in the SBRT group had grade 2 or worse toxicities related to SBRT, including gastrointestinal reflux disease, pain exacerbation, radiation pneumonitis, brachial plexopathy, and low blood counts. INTERPRETATION:The trial showed that progression-free survival was increased in the SBRT plus standard-of-care group compared with standard of care only. Oligoprogression in patients with metastatic NSCLC could be effectively treated with SBRT plus standard of care, leading to more than a four-times increase in progression-free survival compared with standard of care only. By contrast, no benefit was observed in patients with oligoprogressive breast cancer. Further studies to validate these findings and understand the differential benefits are warranted. FUNDING:National Cancer Institute.