Faculty Bibliography

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.

PURPOSE/OBJECTIVE:Management of CNS involvement in leukemia may include craniospinal irradiation (CSI), though data on CSI efficacy are limited. METHODS:We retrospectively reviewed leukemia patients who underwent CSI at our institution between 2009 and 2021 for CNS involvement. CNS local recurrence (CNS-LR), any recurrence, progression-free survival (PFS), CNS PFS, and overall survival (OS) were estimated. RESULTS:Of thirty-nine eligible patients treated with CSI, most were male (59%) and treated as young adults (median 31 years). The median dose was 18 Gy to the brain and 12 Gy to the spine. Twenty-five (64%) patients received CSI immediately prior to allogeneic hematopoietic cell transplant, of which 21 (84%) underwent total body irradiation conditioning (median 12 Gy). Among 15 patients with CSF-positive disease immediately prior to CSI, all 14 assessed patients had pathologic clearance of blasts (CNS-response rate 100%) at a median of 23 days from CSI start. With a median follow-up of 48 months among survivors, 2-year PFS and OS were 32% (95% CI 18-48%) and 43% (95% CI 27-58%), respectively. Only 5 CNS relapses were noted (2-year CNS-LR 14% (95% CI 5-28%)), which occurred either concurrently or after a systemic relapse. Only systemic relapse after CSI was associated with higher risk of CNS-LR on univariate analysis. No grade 3 or higher acute toxicity was seen during CSI. CONCLUSION/CONCLUSIONS:CSI is a well-tolerated and effective treatment option for patients with CNS leukemia. Control of systemic disease after CSI may be important for CNS local control. CNS recurrence may reflect reseeding from the systemic space.

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.

BACKGROUND AND OBJECTIVE/OBJECTIVE:As novel systemic therapies allow patients to live longer with cancer, the risk of developing central nervous system (CNS) metastases increases and providers will more frequently encounter emergent presentation of brain metastases (BM) and leptomeningeal metastases (LM). Management of these metastases requires appropriate work-up and well-coordinated multidisciplinary care. We set out to perform a review of emergent radiotherapy (RT) for CNS metastases, specifically focusing on BM and LM. METHODS:We review the appropriate pathways for workup and initial management of BM and LM, while reviewing the literature supporting emergent treatment of these entities with surgery, systemic anti-cancer therapy, and RT. To inform this narrative review, literature searches in PubMed and Google Scholar were conducted, with preference given to articles employing modern RT techniques, when applicable. Due to the paucity of high-quality evidence for management of BM and LM in the emergent setting, discussion was supplemented by the authors' expert commentary. KEY CONTENT AND FINDINGS/UNASSIGNED:This work highlights the importance of surgical evaluation, particularly for patients presenting with significant mass effect, hemorrhagic metastases, or increased intracranial pressure. We review the rare situations where emergent initiation of systemic anti-cancer therapy is indicated. When defining the role of RT, we review factors guiding selection of appropriate modality, treatment volume, and dose-fractionation. Generally, 2D- or 3D-conformal treatment techniques prescribed as 30 Gy in 10 fractions or 20 Gy in 5 fractions, should be employed in the emergent setting. CONCLUSIONS:Patients with BM and LM present from a diverse array of clinical situations, requiring well-coordinated multidisciplinary management, and there is a paucity of high-quality evidence guiding such management decisions. This narrative review aims to more thoroughly prepare providers for the challenging situation of emergent management of BM and LM.

PURPOSE/UNASSIGNED:The management of patients with advanced solid malignancies increasingly uses stereotactic body radiation therapy (SBRT). Advanced cancer patients are at risk for developing leptomeningeal metastasis (LM), a fatal complication of metastatic cancer. Cerebrospinal fluid (CSF) is routinely collected during computed tomography (CT) myelography for spinal SBRT planning, offering an opportunity for early LM detection by CSF cytology in the absence of radiographic LM or LM symptoms (subclinical LM). This study tested the hypothesis that early detection of tumor cells in CSF in patients undergoing spine SBRT portends a similarly poor prognosis compared with clinically overt LM. METHODS AND MATERIALS/UNASSIGNED:We retrospectively analyzed clinical records for 495 patients with metastatic solid tumors who underwent CT myelography for spinal SBRT planning at a single institution from 2014 to 2019. RESULTS/UNASSIGNED: = .02). CONCLUSIONS/UNASSIGNED:LM remains a fatal complication of metastatic cancer. Subclinical LM detected by CSF cytology in spine SBRT patients has a similarly poor prognosis compared with standardly detected LM and warrants consideration of central nervous system-directed therapies. As aggressive local therapies are increasingly used for metastatic patients, more sensitive CSF evaluation may further identify patients with subclinical LM and should be evaluated prospectively.

Leptomeningeal metastases/diseases (LMDs) are a late-stage complication of solid tumor or hematologic malignancies. LMD is spread of cancer cells to the layers of the leptomeninges (pia and arachnoid maters) and subarachnoid space seen in 3 to 5% of cancer patients. It is a disseminated disease which carries with it significant neurologic morbidity and mortality. Our understanding of disease pathophysiology is currently lacking; however, advances are being made. As our knowledge of disease pathogenesis has improved, treatment strategies have evolved. Mainstays of treatment such as radiotherapy have changed from involved-field radiotherapy strategies to proton craniospinal irradiation which has demonstrated promising results in recent clinical trials. Systemic treatment strategies have also improved from more traditional chemotherapeutics with limited central nervous system (CNS) penetration to more targeted therapies with better CNS tumor response. Many challenges remain from earlier clinical detection of disease through improvement of active treatment options, but we are getting closer to meaningful treatment.

BACKGROUND AND OBJECTIVE/OBJECTIVE:Malignant epidural spinal cord compression (MESCC), often presenting with back pain and motor/sensory deficits, is associated with poor survival, particularly when there is loss of ambulation. The purpose of this review is to evaluate the literature and discuss appropriate workup and management of MESCC, specifically in the emergent setting. METHODS:A PubMed search was conducted on "spinal cord compression" and "radiation therapy." Articles were analyzed for the purpose of this narrative review. KEY CONTENT AND FINDINGS/UNASSIGNED:If MESCC is suspected, neurologic examination and complete spine imaging are recommended. Emergent treatment is indicated if there is radiographic evidence of high-grade compression and/or clinically significant motor deficits. Treatment involves a combination of medical management, surgical decompression, radiation therapy (RT), and rehabilitation. For motor deficits, emergent initiation of high dose steroids is recommended. Circumferential surgical decompression ± stabilization followed by RT provides superior clinical outcomes than RT alone. For patients whom surgery is not reasonable, RT alone may provide significant treatment response which depends on radioresponsiveness of the pathology. Systemic therapy, if indicated, is typically reserved till after primary treatment of MESCC, but patients with chemoresponsive tumors may receive primary chemotherapy. The selected RT schedule should be personalized to each patient and commonly is 30 Gy in 10 fractions (fx), 20 Gy in 5 fx, or 8 Gy in 1 fx. MESCC recurrence may be treated with additional RT, if within the spinal cord tolerance, or surgery. Stereotactic body radiation therapy (SBRT) has been used for high grade MESCC in patients with relatively intact neurologic function at a few centers with a very robust infrastructure to support rapid initiation of treatment within a short period of time, but is generally not feasible for most clinical practices. SBRT may be advantageous for low grade MESCC, recurrence, or in the post-operative setting. Detection of MESCC prior to development of high-grade compression or deterioration of neurologic function may allow patients to benefit more from advanced therapies and improve prognosis. CONCLUSIONS:MESCC is a devastating condition; optimal treatment should be personalized to each patient and approached collaboratively by a multidisciplinary team.

PURPOSE:Proton craniospinal irradiation (pCSI) is a promising treatment for patients with solid tumor leptomeningeal metastasis (LM). We hypothesize that genetic characteristics before and changes resulting after pCSI will reflect clinical response to pCSI. We analyzed the cerebrospinal fluid (CSF) circulating tumor DNA (ctDNA) from patients receiving pCSI for LM and explored genetic variations associated with response. EXPERIMENTAL DESIGN:We subjected CSF from 14 patients with LM before and after pCSI to cell-free DNA sequencing using a targeted-sequencing panel. In parallel, plasma ctDNA and primary tumors were subjected to targeted sequencing. Variant allele frequency (VAF) and cancer cell fraction (CCF) were calculated; clonality of observed mutations was determined. Kaplan-Meier analysis was used to associate genomic changes with survival. RESULTS:The median overall survival (OS) for the cohort was 9 months [interquartile range (IQR), 5-21 months]. We showed clonal evolution between tumor and ctDNA of the CSF and plasma with unique mutations identified by compartment. Higher CSF ctDNA mean VAF before pCSI (VAFpre) had worse OS (6 months for VAFpre ≥ 0.32 vs. 9 months for VAFpre < 0.32; P = 0.05). Similarly, increased VAF after pCSI portended worse survival (6 vs. 18 months; P = 0.008). Higher mean CCF of subclonal mutations appearing after pCSI was associated with worse OS (8 vs. 17 months; P = 0.05). CONCLUSIONS:In patients with solid tumor LM undergoing pCSI, we found unique genomic profiles associated with pCSI through CSF ctDNA analyses. Patients with reduced genomic diversity within the leptomeningeal compartment demonstrated improved OS after pCSI suggesting that CSF ctDNA analysis may have use in predicting pCSI response.

PURPOSE/UNASSIGNED:Pseudoprogression mimicking recurrent glioblastoma remains a diagnostic challenge that may adversely confound or delay appropriate treatment or clinical trial enrollment. We sought to build a radiomic classifier to predict pseudoprogression in patients with primary isocitrate dehydrogenase wild type glioblastoma. METHODS AND MATERIALS/UNASSIGNED:-methylguanine-DNA methyltransferase status to predict pseudoprogression. RESULTS/UNASSIGNED:-methylguanine-DNA methyltransferase status into the classifier. CONCLUSIONS/UNASSIGNED:Our results suggest that radiomic analysis of contrast T1-weighted images and magnetic resonance imaging perfusion images can assist the prompt diagnosis of pseudoprogression. Validation on external and independent data sets is necessary to verify these advanced analyses, which can be performed on routinely acquired clinical images and may help inform clinical treatment decisions.