Faculty Bibliography

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.

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.

CONTEXT:Individual goals and values should drive medical decision making for patients with serious illness. Unfortunately, clinicians' existing strategies to encourage reflection and communication regarding patients' personal values are generally time-consuming and limited in scope. OBJECTIVES:Herein, we develop a novel intervention to facilitate at-home reflection and discussion about goals and values. We then conduct a pilot study of our intervention in a small population of patients with metastatic cancer. METHODS:We first engaged former cancer patients and their families to adapt an existing serious illness communication guide to a worksheet format. We then distributed this adapted "Values Worksheet" to 28 patients with metastatic cancer. We surveyed participants about their perceptions of the Worksheet to assess its feasibility. RESULTS:Of 30 patients approached, 28 agreed to participate. Seventeen participants completed the Values Worksheet, and of those 11 (65%) responded to the follow-up survey. Seven of eleven reported that the Values Worksheet was a good use of time, and nine of eleven would be likely to recommend it to other patients with cancer. Eight of ten reported mild distress, two of ten reported moderate to severe distress. CONCLUSION:The Values Worksheet was a feasible way to facilitate at-home discussions of goals and values for select patients with metastatic cancer. Further research should focus on identifying which patients are most likely to benefit from the Values Worksheet, and should employ the Worksheet as one tool to facilitate reflection on the questions that arise around serious illness, as an adjunct to serious illness conversations with a physician.

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: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.

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.

PURPOSE:Photon involved-field radiotherapy (IFRT) is the standard-of-care radiotherapy for patients with leptomeningeal metastasis (LM) from solid tumors. We tested whether proton craniospinal irradiation (pCSI) encompassing the entire CNS would result in superior CNS progression-free survival (PFS) compared with IFRT. PATIENTS AND METHODS:We conducted a randomized, phase II trial of pCSI versus IFRT in patients with non-small-cell lung cancer and breast cancers with LM. We enrolled patients with other solid tumors to an exploratory pCSI group. For the randomized groups, patients were assigned (2:1), stratified by histology and systemic disease status, to pCSI or IFRT. The primary end point was CNS PFS. Secondary end points included overall survival (OS) and treatment-related adverse events (TAEs). RESULTS:= .19). In the exploratory pCSI group, 35 patients enrolled, the median CNS PFS was 5.8 months (95% CI, 4.4 to 9.1 months) and OS was 6.6 months (95% CI, 5.4 to 11 months). CONCLUSION:Compared with photon IFRT, we found pCSI improved CNS PFS and OS for patients with non-small-cell lung cancer and breast cancer with LM with no increase in serious TAEs.

BACKGROUND:Salvage of recurrent previously irradiated brain metastases (rBrM) is a significant challenge. Resection without adjuvant re-irradiation is associated with a high local failure rate, while reirradiation only partially reduces failure but is associated with greater radiation necrosis risk. Salvage resection plus Cs131 brachytherapy may offer dosimetric and biologic advantages including improved local control versus observation, with reduced normal brain dose versus re-irradiation, however data are limited. METHODS:A prospective registry of consecutive patients with post-stereotactic radiosurgery (SRS) rBrM undergoing resection plus implantation of collagen-matrix embedded Cs131 seeds (GammaTile, GT Medical Technologies) prescribed to 60 Gy at 5 mm from the cavity was analyzed. RESULTS:Twenty patients underwent 24 operations with Cs131 implantation in 25 tumor cavities. Median maximum preoperative diameter was 3.0 cm (range 1.1-6.3). Gross- or near-total resection was achieved in 80% of lesions. A median of 16 Cs131 seeds (range 6-30), with a median air-kerma strength of 3.5 U/seed were implanted. There was one postoperative wound dehiscence. With median follow-up of 1.6 years for survivors, two tumors recurred (one in-field, one marginal) resulting in 8.4% 1-year progression incidence (95%CI = 0.0-19.9). Radiographic seed settling was identified in 7/25 cavities (28%) 1.9-11.7 months post-implantation, with 1 case of distant migration (4%), without clinical sequelae. There were 8 cases of radiation necrosis, of which 4 were symptomatic. CONCLUSIONS:With > 1.5 years of follow-up, intraoperative brachytherapy with commercially available Cs131 implants was associated with favorable local control and toxicity profiles. Weak correlation between preoperative tumor geometry and implanted tiles highlights a need to optimize planning criteria.

PURPOSE/UNASSIGNED:Local treatment for bone metastases is becoming increasingly complex. National guidelines traditionally focus only on radiation therapy (RT), leaving a gap in clinical decision support resources available to clinicians. The objective of this study was to reach expert consensus regarding multidisciplinary management of non-spine bone metastases, which would facilitate standardizing treatment within an academic-community partnership. METHODS AND MATERIALS/UNASSIGNED:A multidisciplinary panel of physicians treating metastatic disease across the Memorial Sloan Kettering (MSK) Cancer Alliance, including community-based partner sites, was convened. Clinical questions rated of high importance in the management of non-spine bone metastases were identified via survey. A literature review was conducted, and panel physicians drafted initial recommendation statements. Consensus was gathered on recommendation statements through a modified Delphi process from a full panel of 17 physicians from radiation oncology, orthopaedic surgery, medical oncology, interventional radiology, and anesthesia pain. Consensus was defined a priori as 75% of respondents indicating "agree" or "strongly agree" with the consensus statement. Strength of Recommendation Taxonomy was employed to assign evidence strength for each statement. RESULTS/UNASSIGNED:Seventeen clinical questions were identified, of which 11 (65%) were selected for the consensus process. Consensus was reached for 16 of 17 answer statements (94%), of which 12 were approved after Round 1 and additional 4 approved after Round 2 of the modified Delphi voting process. Topics included indications for referral to surgery or interventional radiology, radiation fractionation and appropriate use of stereotactic approaches, and the handling of systemic therapies during radiation. Evidence strength was most commonly C (n = 7), followed by B (n = 5) and A (n = 3). CONCLUSIONS/UNASSIGNED:Consensus among a multidisciplinary panel of community and academic physicians treating non-spine bone metastases was feasible. Recommendations will assist clinicians and potentially provide measures to reduce variation across diverse practice settings. Findings highlight areas for further research such as pathologic fracture risk estimation, pre-operative radiation, and percutaneous ablation.