Faculty Bibliography

PURPOSE/OBJECTIVE:Immune checkpoint inhibition (ICI) alone is not active in mismatch repair-proficient (MMR-P) metastatic colorectal cancer (mCRC), nor does radiotherapy (RT) alone result in objective systemic benefit. However, combined RT plus ICI can induce systemic anti-tumor immunity in pre-clinical and clinical models. EXPERIMENTAL DESIGN/METHODS:In this single-center, phase II study, patients with chemotherapy-refractory MMR-P mCRC received durvalumab 1500 mg plus tremelimumab 75 mg every 4 weeks plus RT. The primary endpoint was objective response rate (ORR) in non-irradiated lesions. Treatment and efficacy were correlated with peripheral immune cell profiles. RESULTS:We enrolled 24 patients, and report outcomes after a median follow up of 21.8 (range: 15.9 to 26.3) months. The ORR was 8.3% (2 patients) (95% confidence interval [CI], 1.0% to 27.0%). The median progression-free survival was 1.8 (95% CI, 1.7 to 1.9) months, median overall survival was 11.4 (95% CI, 10.1 to 17.4) months. Twenty five percent of patients (n=6) had treatment-related grade 3-4 adverse events. We observed increased circulating CD8+ T lymphocyte activation, differentiation, and proliferation in patients with objective response. CONCLUSION/CONCLUSIONS:This combination of RT plus ICI study did not meet the prespecified end point criteria to be considered worthwhile for further study. However, rare instances of systemic immune augmentation and regression in non-irradiated lesions were observed (an abscopal response). Combination durvalumab and tremelimumab plus RT is feasible in MMR-P mCRC with a manageable safety profile. Further studies of novel immunotherapy combinations, and identification of biomarkers predictive of abscopal response are warranted.

The concept of oligometastatic disease has evolved substantially over the past decade. During this time, there has been a transition from retrospective and single-arm prospective studies to randomized evidence suggesting a benefit of local consolidative therapy (LCT) in the setting of limited metastatic non-small cell lung cancer. These trials had constraints and were thus limited in the strength of their conclusions, but led to several other ongoing randomized trials examining the role of LCT. These studies span various disease states (synchronous oligometastatic vs oligoprogressive), the scope of histologies included, and in how they define oligometastases. In addition, parallel biologic work is attempting to integrate relevant biomarkers and molecular classifications, with the ultimate goal of more precisely defining oligometastases and triaging patients to appropriate care. Finally, consensus guidelines have been initiated that provide a framework for designing future studies and for maintaining consistency across analyses that will facilitate the interpretation of results. This review describes the prior randomized data, the limitations therein, and future directions of clinical and preclinical studies that highlight the emerging paradigms for treatment of this select patient cohort.

BACKGROUND:/Objectives: Pancreatic adenocarcinoma (PDAC) metastatic to the leptomeninges is a rare and lethal event. Leptomeningeal disease (LMD) research is limited in PDAC, and insights into clinical descriptors, possible disease predictors, and treatment strategies is necessitated. METHODS:Memorial Sloan Kettering databases were queried with Institutional Review Board approval to identify patients with LMD and PDAC treated between January 2000 and June 2020. Medical record review was used to abstract clinical, genomic, pathologic, and radiographic data. Overall survival was calculated from date of PDAC diagnosis to date of death. Previously published literature on LMD from PDAC was reviewed. RESULTS:Four patients with LMD from PDAC were identified, two males and two females. Age at diagnosis ranged from 57 to 68 years. All four patients had predominant lung metastasis and a relatively low burden of intra-abdominal disease. Somatic testing indicated alterations typical of PDAC and no PDAC defining pathogenic germline mutations were identified. An extended clinical course prior to LMD diagnosis was observed in all patients, ranging from 16 to 148 months. Upon diagnosis of LMD, three patients elected for supportive care and one patient received a limited course of craniospinal radiation. The median survival following diagnosis of LMD was 1.6 months (range 0.5-2.8 months). CONCLUSIONS:LMD from PDAC is a rare occurrence that may be more frequent in patients with lung metastasis and/or a more indolent clinical course. Following diagnosis of LMD, prognosis is poor, and survival is short. New treatment strategies for this manifestation of PDAC are needed.

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.