Faculty Bibliography

PURPOSE:Guidelines recommend short-course (≤10 fractions) external-beam radiation therapy (EBRT) for bone metastases. Stereotactic body radiation therapy (SBRT) may also improve outcomes; however, routine use is not recommended outside clinical trials. We assessed national radiation therapy trends in complex techniques for bone metastases and associated expenditures. METHODS AND MATERIALS:d or Wilcoxon rank sum tests for categorical and continuous variables, respectively. We identified associations with modality, fractionation, and expenditures using multivariable logistic/linear regression. RESULTS:Among 467,781 radiation episodes for 17 cancer diagnoses, the overall proportion of episodes dedicated to bone metastases (9.4%) was stable from 2015 to 2017, although treatments were increasing in the hospital-affiliated outpatient setting (P < .005). We identified 40,993 episodes for bone metastases, of which 63% were short-course EBRT, 24% were long-course EBRT, 7% were SBRT, and 6% were IMRT. Techniques more common in the hospital-affiliated outpatient setting included short-course EBRT (OPD, 69%, vs FREE, 56%) and SBRT (OPD, 9%, vs FREE, 5%). Techniques more common among free-standing centers included long-course EBRT (OPD, 19%, vs FREE, 31%) and IMRT (OPD, 4%, vs FREE, 9%). From 2015 to 2017, long-course EBRT decreased by an absolute 8%; short-course EBRT, SBRT, and IMRT increased by 4%, 2.5%, and 1%, respectively. The SBRT/IMRT uptake did not differ by setting (P = .4). Differences in expenditures between SBRT and short-course EBRT decreased by a relative 8% in professional and 12% in technical fees. CONCLUSIONS:Approximately 1 in 4 patients received long-course EBRT, with small reductions in use largely replaced by complex treatment modalities. However, expenditures for complex modalities also decreased over time. As alternative payment models take effect, quality metrics are needed to ensure appropriate, effective, and safe delivery of complex technologies.

BACKGROUND:Leptomeningeal metastases (LM) are associated with limited survival and treatment options. While involved-field radiotherapy is effective for local palliation, it lacks durability. We evaluated the toxicities of proton craniospinal irradiation (CSI), a treatment encompassing the entire central nervous system (CNS) compartment, for patients with LM from solid tumors. METHODS:We enrolled patients with LM to receive hypofractionated proton CSI in this phase I prospective trial. The primary endpoint was to describe treatment-related toxicity, with dose-limiting toxicity (DLT) defined as any radiation-related grade 3 non-hematologic toxicity or grade 4 hematologic toxicity according to the Common Terminology Criteria for Adverse Events that occurred during or within 4 weeks of completion of proton CSI. Secondary endpoints included CNS progression-free survival (PFS) and overall survival (OS). RESULTS:We enrolled 24 patients between June 2018 and April 2019. Their median follow-up was 11 months. Twenty patients were evaluable for protocol treatment-related toxicities and 21 for CNS PFS and OS. Two patients in the dose expansion cohort experienced DLTs consisted of grade 4 lymphopenia, grade 4 thrombocytopenia, and/or grade 3 fatigue. All DLTs resolved without medical intervention. The median CNS PFS was 7 months (95% CI: 5-13) and the median OS was 8 months (95% CI: 6 to not reached). Four patients (19%) were progression-free in the CNS for more than 12 months. CONCLUSION:Hypofractionated proton CSI using proton therapy is a safe treatment for patients with LM from solid tumors. We saw durable disease control in some patients.

Metastasis-directed therapy (MDT)-local therapy that is intended to eradicate specific metastatic lesions-has hitherto been used with varying degrees of clinical efficacy and acceptance as a meaningful therapy for metastatic disease. Over the past 25 years, however, the momentum for using MDT to manage patients with metastatic solid tumours has increased, driven by several factors. Among these factors is the recognition that patients with limited metastatic burden could potentially derive survival benefits from MDT. Furthermore, although current systemic therapies are increasingly effective, they are infrequently curative. In addition, technological advances have broadened the spectrum of metastatic lesions that can be treated with ablative intent. Here we aim to briefly review the status of evidence for the clinical benefit of MDT based on current data mainly from trials in patients with oligometastatic disease, discuss the myriad of clinical states that might fall under and beyond the definition of oligometastasis, review technological advances in MDT and their applications beyond oligometastasis, and discuss the need for the continued co-evolution of MDT and systemic therapy as we seek to understand which patients with metastatic cancer can achieve durable remission and how to optimally manage those who cannot.

PURPOSE/OBJECTIVE:For patients with long bone metastases who undergo orthopedic stabilization surgery followed by radiotherapy (RT), it is unclear what extent of hardware coverage by the radiation field is needed for optimal tumor control. METHODS AND MATERIALS/METHODS:Long bone metastases treated with surgical intervention followed by radiation between August 2011 to May 2019 from a single institution were reviewed. Local recurrence, defined as any in-bone recurrence, was identified by chart review. Accompanying demographic and treatment characteristics were recorded. Statistical analysis to evaluate factors associated with tumor recurrence included univariate analysis, multivariate analysis, and propensity score matching. RESULTS: = .026). CONCLUSIONS:In this analysis of mostly patients undergoing conventional radiation, coverage of the whole hardware was associated with reduced local recurrence for patients with long bone metastases, consistent with prior reports. Investigation of approaches to further reduce local recurrence, such as preoperative stereotactic radiation, may be warranted.

BACKGROUND:), and neuroimaging correlate with outcomes after pCSI for LM. METHODS:), and MRIs were examined. Central nervous system progression-free survival (CNS-PFS) and overall survival (OS) from pCSI were determined using Kaplan Meier analysis, Cox proportional-hazards regression, time-dependent ROC analysis, and joint modeling of time-varying effects and survival outcomes. RESULTS:were found. CONCLUSION/CONCLUSIONS:measurement earlier in the LM treatment paradigm.

A small subset of pituitary adenomas grows despite maximal treatment with standard therapies; namely, surgery and radiotherapy. These aggressive tumors demonstrate 2 patterns of growth: they may be locally aggressive or metastasize distantly, either hematogenously or through the spinal fluid. Further surgery and radiotherapy may be helpful for palliation of symptoms, but they are rarely definitive in the management of these malignant tumors. The only chemotherapy with established activity in the treatment of pituitary tumors is the alkylating agent temozolomide. At most, 50% of patients exhibit an objective response to temozolomide and the median time to progression is short; thus, there remains a significant unmet need for effective treatments within this patient population. Several targeted agents have reported activity in this tumor type-including small molecule inhibitors, checkpoint inhibitors, and other biologics-but remain investigational at this time.

BACKGROUND:In patients with metastatic cancer, the bone is the third-most common site of involvement. Radiation to painful bone metastases results in high rates of pain control and is an integral part of bone metastases management. Up to one-third of inpatient consults are requested for painful bone metastases, and up to 60% of these patients had evidence of these lesions visible on prior imaging. Meanwhile recent advances have reduced potential side effects of radiation. Therefore, there is an opportunity to further improve outcomes for patients using prophylactic palliative radiation to manage asymptomatic bone metastases. METHODS/STUDY DESIGN/METHODS:In this trial, 74 patients with metastatic solid tumors and high-risk asymptomatic or minimally symptomatic bone metastases will be enrolled and randomized to early palliative radiation or standard of care. This will be the first trial to assess the efficacy of prophylactic palliative radiation in preventing skeletal related events (SREs), the primary endpoint. This endpoint was selected to encompass patient-centered outcomes that impact quality of life including pathologic fracture, spinal cord compression, and intervention with surgery or radiation. Secondary endpoints include hospitalizations, Bone Pain Index, pain-free survival, pain-related quality of life, and side effects of radiation therapy. DISCUSSION/CONCLUSIONS:In this study, we propose a novel definition of high-risk bone metastases most likely to benefit from preventive radiation and use validated questionnaires to assess pain and impact on quality of life and health resource utilization. Observations from early patient enrollment have demonstrated robustness of the primary endpoint and need for minor modifications to Bone Pain Index and data collection for opioid use and hospitalizations. With increasing indications for radiation in the oligometastatic setting, this trial aims to improve patient-centered outcomes in the polymetastatic setting. TRIAL REGISTRATION/BACKGROUND:ISRCTN Number/Clinical trials.gov, ID: NCT03523351 . Registered on 14 May 2018.

OBJECTIVE:To characterize the clinical outcomes when stereotactic body radiation therapy (SBRT) alone is used to treat high-grade epidural disease without prior surgical decompression, the authors conducted a retrospective cohort study of patients treated at the Memorial Sloan Kettering Cancer Center between 2014 and 2018. The authors report locoregional failure (LRF) for a cohort of 31 cases treated with hypofractionated SBRT alone for grade 2 epidural spinal cord compression (ESCC) with radioresistant primary cancer histology. METHODS:High-grade epidural disease was defined as grade 2 ESCC, which is notable for radiographic deformation of the spinal cord by metastatic disease. Kaplan-Meier survival curves and cumulative incidence functions were generated to examine the survival and incidence experiences of the sample level with respect to overall survival, LRF, and subsequent requirement of vertebral same-level surgery (SLS) due to tumor progression or fracture. Associations with dosimetric analysis were also examined. RESULTS:Twenty-nine patients undergoing 31 episodes of hypofractionated SBRT alone for grade 2 ESCC between 2014 and 2018 were identified. The 1-year and 2-year cumulative incidences of LRF were 10.4% (95% CI 0-21.9) and 22.0% (95% CI 5.5-38.4), respectively. The median survival was 9.81 months (95% CI 8.12-18.54). The 1-year cumulative incidence of SLS was 6.8% (95% CI 0-16.0) and the 2-year incidence of SLS was 14.5% (95% CI 0.6-28.4). All patients who progressed to requiring surgery had index lesions at the thoracic apex (T5-7). CONCLUSIONS:In carefully selected patients, treatment of grade 2 ESCC disease with hypofractionated SBRT alone offers a 1-year cumulative incidence of LRF similar to that in low-grade ESCC and postseparation surgery adjuvant hypofractionated SBRT. Use of SBRT alone has a favorable safety profile and a low cumulative incidence of progressive disease requiring open surgical intervention (14.5%).

The PI5P4Ks have been demonstrated to be important for cancer cell proliferation and other diseases. However, the therapeutic potential of targeting these kinases is understudied due to a lack of potent, specific small molecules available. Here, we present the discovery and characterization of a pan-PI5P4K inhibitor, THZ-P1-2, that covalently targets cysteines on a disordered loop in PI5P4Kα/β/γ. THZ-P1-2 demonstrates cellular on-target engagement with limited off-targets across the kinome. AML/ALL cell lines were sensitive to THZ-P1-2, consistent with PI5P4K's reported role in leukemogenesis. THZ-P1-2 causes autophagosome clearance defects and upregulation in TFEB nuclear localization and target genes, disrupting autophagy in a covalent-dependent manner and phenocopying the effects of PI5P4K genetic deletion. Our studies demonstrate that PI5P4Ks are tractable targets, with THZ-P1-2 as a useful tool to further interrogate the therapeutic potential of PI5P4K inhibition and inform drug discovery campaigns for these lipid kinases in cancer metabolism and other autophagy-dependent disorders.