Nivolumab and ipilimumab with concurrent stereotactic radiosurgery for intracranial metastases from non-small cell lung cancer: analysis of the safety cohort for non-randomized, open-label, phase I/II trial.

BACKGROUND: Up to 20% of patients with non-small cell lung cancer (NSCLC) develop brain metastasis (BM), for which the current standard of care is radiation therapy with or without surgery. There are no prospective data on the safety of stereotactic radiosurgery (SRS) concurrent with immune checkpoint inhibitor therapy for BM. This is the safety cohort of the phase I/II investigator-initiated trial of SRS with nivolumab and ipilimumab for patients with BM from NSCLC. PATIENTS AND METHODS: This single-institution study included patients with NSCLC with active BM amenable to SRS. Brain SRS and systemic therapy with nivolumab and ipilimumab were delivered concurrently (within 7 days). The endpoints were safety and 4-month intracranial progression-free survival (PFS). RESULTS: Thirteen patients were enrolled in the safety cohort, 10 of whom were evaluable for dose-limiting toxicities (DLTs). Median follow-up was 23 months (range 9.7-24.3 months). The median interval between systemic therapy and radiation therapy was 3 days. Only one patient had a DLT; hence, predefined stopping criteria were not met. In addition to the patient with DLT, three patients had treatment-related grade ≥3 adverse events, including elevated liver function tests, fatigue, nausea, adrenal insufficiency, and myocarditis. One patient had a confirmed influenza infection 7 months after initiation of protocol treatment (outside the DLT assessment window), leading to pneumonia and subsequent death from hemophagocytic lymphohistiocytosis. The estimated 4-month intracranial PFS rate was 70.7%. CONCLUSION: Concurrent brain SRS with nivolumab/ipilimumab was safe for patients with active NSCLC BM. Preliminary analyses of treatment efficacy were encouraging for intracranial treatment response.

Concurrent intrathecal and intravenous nivolumab in leptomeningeal disease: phase 1 trial interim results.

There is a critical need for effective treatments for leptomeningeal disease (LMD). Here, we report the interim analysis results of an ongoing single-arm, first-in-human phase 1/1b study of concurrent intrathecal (IT) and intravenous (IV) nivolumab in patients with melanoma and LMD. The primary endpoints are determination of safety and the recommended IT nivolumab dose. The secondary endpoint is overall survival (OS). Patients are treated with IT nivolumab alone in cycle 1 and IV nivolumab is included in subsequent cycles. We treated 25 patients with metastatic melanoma using 5, 10, 20 and 50 mg of IT nivolumab. There were no dose-limiting toxicities at any dose level. The recommended IT dose of nivolumab is 50 mg (with IV nivolumab 240 mg) every 2 weeks. Median OS was 4.9 months, with 44% and 26% OS rates at 26 and 52 weeks, respectively. These initial results suggest that concurrent IT and IV nivolumab is safe and feasible with potential efficacy in patients with melanoma LMD, including in patients who had previously received anti-PD1 therapy. Accrual to the study continues, including in patients with lung cancer. ClinicalTrials.gov registration: NCT03025256 .

Cardiac Angiosarcomas: Risk of Brain Metastasis and Hemorrhage Warrants Frequent Surveillance Imaging and Early Intervention.

PURPOSE: We evaluated a cohort of patients with cardiac angiosarcomas (CA) who developed brain metastases (BM) to define outcomes and intracranial hemorrhage (IH) risk. METHODS: We reviewed 26 consecutive patients with BM treated between 1988 and 2020 identified from a departmental CA (n=103) database. Causes of death were recorded, and a terminal hemorrhage (TH) was defined as an IH that caused death or prompted a transfer to hospice. RESULTS: The prevalence of BM was 25% (n=26/103). A total of 23 patients (88%) had IH, including 21 (81%) at initial BM diagnosis, of which 18 (86%) required hospitalization. The median platelet count at the time of IH was 235k (interquartile range, 108 to 338k).Nearly all patients died of disease (n=23, 88%) and most patients died from TH (n=13, 57%). TH occurred at BM presentation in 6 (46%) patients, whereas 3 (23%) had TH from known but untreated lesions, 2 (15%) had continued uncontrolled IH during radiation therapy, and 2 (15%) from new BM. Platelet count <50k was not associated with TH (P=0.25).Subsequent IH occurred in 9 patients (35%), and importantly, no patients who completed radiation therapy (n=10) for BM died from TH. CONCLUSION: Patients with CA frequently develop BM, and the risk of IH is high, resulting in an alarming rate of TH despite normal platelet counts. Therefore, early diagnosis and intervention are warranted. We recommend surveillance brain imaging, and importantly, once BM is detected, prompt local therapy is warranted to try and mitigate the risk of TH.

Phase II trial of proton therapy versus photon IMRT for GBM: secondary analysis comparison of progression-free survival between RANO versus clinical assessment.

BACKGROUND: This secondary image analysis of a randomized trial of proton radiotherapy (PT) versus photon intensity-modulated radiotherapy (IMRT) compares tumor progression based on clinical radiological assessment versus Response Assessment in Neuro-Oncology (RANO). METHODS: Eligible patients were enrolled in the randomized trial and had MR imaging at baseline and follow-up beyond 12 weeks from completion of radiotherapy. "Clinical progression" was based on a clinical radiology report of progression and/or change in treatment for progression. RESULTS: Of 90 enrolled patients, 66 were evaluable. Median clinical progression-free survival (PFS) was 10.8 (range: 9.4-14.7) months; 10.8 months IMRT versus 11.2 months PT (P = .14). Median RANO-PFS was 8.2 (range: 6.9, 12): 8.9 months IMRT versus 6.6 months PT (P = .24). RANO-PFS was significantly shorter than clinical PFS overall (P = .001) and for both the IMRT (P = .01) and PT (P = .04) groups. There were 31 (46.3%) discrepant cases of which 17 had RANO progression more than a month prior to clinical progression, and 14 had progression by RANO but not clinical criteria. CONCLUSIONS: Based on this secondary analysis of a trial of PT versus IMRT for glioblastoma, while no difference in PFS was noted relative to treatment technique, RANO criteria identified progression more often and earlier than clinical assessment. This highlights the disconnect between measures of tumor response in clinical trials versus clinical practice. With growing efforts to utilize real-world data and personalized treatment with timely adaptation, there is a growing need to improve the consistency of determining tumor progression within clinical trials and clinical practice.

A prospective phase II randomized trial of proton radiotherapy vs intensity-modulated radiotherapy for patients with newly diagnosed glioblastoma.

BACKGROUND: To determine if proton radiotherapy (PT), compared to intensity-modulated radiotherapy (IMRT), delayed time to cognitive failure in patients with newly diagnosed glioblastoma (GBM). METHODS: Eligible patients were randomized unblinded to PT vs IMRT. The primary endpoint was time to cognitive failure. Secondary endpoints included overall survival (OS), intracranial progression-free survival (PFS), toxicity, and patient-reported outcomes (PROs). RESULTS: A total of 90 patients were enrolled and 67 were evaluable with median follow-up of 48.7 months (range 7.1-66.7). There was no significant difference in time to cognitive failure between treatment arms (HR, 0.88; 95% CI, 0.45-1.75; P = .74). PT was associated with a lower rate of fatigue (24% vs 58%, P = .05), but otherwise, there were no significant differences in PROs at 6 months. There was no difference in PFS (HR, 0.74; 95% CI, 0.44-1.23; P = .24) or OS (HR, 0.86; 95% CI, 0.49-1.50; P = .60). However, PT significantly reduced the radiation dose for nearly all structures analyzed. The average number of grade 2 or higher toxicities was significantly higher in patients who received IMRT (mean 1.15, range 0-6) compared to PT (mean 0.35, range 0-3; P = .02). CONCLUSIONS: In this signal-seeking phase II trial, PT was not associated with a delay in time to cognitive failure but did reduce toxicity and patient-reported fatigue. Larger randomized trials are needed to determine the potential of PT such as dose escalation for GBM and cognitive preservation in patients with lower-grade gliomas with a longer survival time.

Phase 1 study of spinal cord constraint relaxation with single session spine stereotactic radiosurgery in the primary management of patients with inoperable, previously irradiated metastatic epidural spinal cord compression.

BACKGROUND: Patients with previously irradiated metastatic epidural spinal cord compression (MESCC) who are not surgical candidates are at high risk of neurologic deterioration due to disease in the setting of limited treatment options. We seek to establish the feasibility of using salvage spine stereotactic radiosurgery (SSRS) allowing for spinal cord dose constraint relaxation as the primary management of MESCC in inoperable patients monitoring for radiation related toxicity and radiographic local control (LC). METHODS: Inoperable patients with previously irradiated MESCC were enrolled on this prospective Phase 1 single institution protocol. Single fraction SSRS was delivered to a prescription dose of 18 Gy. Spinal cord constraint relaxation was performed incrementally from an initial allowable Dmax cohort of 8 Gy to 14 Gy in the final planned cohort. Patients were monitored every 3 months with follow-up visits and MRI scans. RESULTS: The trial was closed early due to slow accrual. From 2011 to 2014, 11 patients were enrolled of which 9 patients received SSRS. Five patients were in the 8 Gy cord Dmax cohort and 4 in the 10 Gy cord Dmax cohort.The median overall survival (OS) was 11.9 months (95% CI 7.1, 22 months). Of the 9 patients treated with SSRS, 1 died prior to post-SSRS evaluation. Of the remaining 8 patients, 5 experienced a local failure. Three of the five were treated with surgery while two received systemic therapy. Two of the five failures ultimately resulted in loss of neurologic function. The median LC was 9.1 months (95%CI 4.8, 20.1 months). With a median clinical follow-up of 6.8 months, there were no cases of RM. CONCLUSIONS: Despite the limited life expectancy in this high-risk cohort of patients, strategies to optimize LC are necessary to prevent neurologic deterioration. Larger prospective trials exploring optimal dose/fractionation and cord constraints are required.

Patient Outcomes after Reirradiation of Small Skull Base Tumors using Stereotactic Body Radiotherapy, Intensity Modulated Radiotherapy, or Proton Therapy.

Purpose The aim of this study was to evaluate outcomes of patients who received reirradiation for small skull base tumors utilizing either intensity modulated radiotherapy (IMRT), stereotactic body radiotherapy (SBRT), and proton radiotherapy (PRT). Methods Patients who received IMRT, SBRT or PRT reirradiation for recurrent or new small skull base tumors (< 60 cc) between April 2000 and July 2016 were identified. Those with < 3 months follow-up were excluded. Clinical outcomes and treatment toxicity were assessed. The Kaplan-Meier method was used to estimate the local control (LC), regional control (RC), distant control (DC), progression free survival (PFS), and overall survival (OS). Results Of the 75 patients eligible, 30 (40%) received SBRT, 30 (40%) received IMRT, and 15 (20%) received PRT. The median retreatment volume was 28 cc. The median reirradiation dose was 66 Gy in 33 fractions for IMRT/PRT, and 45 Gy in 5 fractions for SBRT. The median time to reirradiation was 41 months. With a median follow-up of 24 months, the LC, RC, DC, PFS, and OS rates were 84%, 79%, 82%, 60%, and 87% at 1 year, and 75%, 72%, 80%, 49%, and 74% at 2 years. There was no difference in OS between radiation modalities. The 1- and 2-year late Grade 3 toxicity rates were 3% and 11% respectively.. Conclusions Reirradiation of small skull base tumors utilizing IMRT, PRT, or SBRT provided good local tumor control and low rates of Grade 3 late toxicity. A prospective clinical trial is needed to guide selection of radiation treatment modalities.

Ventricular apparent diffusion coefficient measurements in patients with neoplastic leptomeningeal disease.

BACKGROUND: To test the hypothesis that intraventricular ADC values can be used to determine the presence of neoplastic leptomeningeal disease (LMD). MATERIALS AND METHODS: ADC values were measured at multiple sites in the ventricular system in 32 patients with cytologically-proven LMD and 40 control subjects. Multiple linear regression analysis was used to determine the mean difference of ADCs between the LMD and control groups after adjusting for ventricle size and tumor type. Receiver operating characteristics (ROC) analysis was performed and optimal ADC value cut-off point for predicting the presence of LMD. ADC was compared to T1 enhancement and FLAIR signal hyperintensity for determining the presence of LMD. RESULTS: After adjusting for ventricular volume and tumor type, the mid body of lateral ventricles showed no significant difference in ventricular volume and a significant difference in ADC values between the control and LMD groups (p > 0.05). In the mid-body of the right lateral ventricle the AUC was 0.69 (95% CI 0.57-0.81) with an optimal ADC cut off point of 3.22 × 10- 9 m2/s (sensitivity, specificity; 0.72, 0.68). In the mid-body of left lateral ventricle the AUC was 0.7 (95% CI 0.58-0.82) with an optimal cut-off point of 3.23 × 10- 9 m2/s (0.81, 0.62). Using an average value of HU measurements in the lateral ventricles the AUC was 0.73 (95% CI 0.61-0.84) with an optimal cut off point was 3.11 × 10- 9 m2/s (0.78, 0.65). Compared to the T1 post-contrast series, ADC was predictive of the presence of LMD in the mid-body of the left lateral ventricle (p = 0.036). CONCLUSION: Complex interactions affect ADC measurements in patients with LMD. ADC values in the lateral ventricles may provide non-invasive clues to the presence of LMD.

Comparison of tumor delineation using dual energy computed tomography versus magnetic resonance imaging in head and neck cancer re-irradiation cases.

In treatment planning, multiple imaging modalities can be employed to improve the accuracy of tumor delineation but this can be costly. This study aimed to compare the interobserver consistency of using dual energy computed tomography (DECT) versus magnetic resonance imaging (MRI) for delineating tumors in the head and neck cancer (HNC) re-irradiation scenario. Twenty-three patients with recurrent HNC and had planning DECT and MRI were identified. Contoured tumor volumes by seven radiation oncologists were compared. Overall, T1c MRI performed the best with median DSC of 0.58 (0-0.91) for T1c. T1c MRI provided higher interobserver agreement for skull base sites and 60 kV DECT provided higher interobserver agreement for non-skull base sites.

Predictors of survival in metastatic melanoma patients with leptomeningeal disease (LMD).

PURPOSE: Although the survival of most melanoma patients diagnosed with leptomeningeal disease (LMD) is short, some patients can have better outcomes and prolonged survival. A large retrospective cohort of patients was analyzed to identify features associated with survival with LMD from melanoma. METHODS: Clinical characteristics, treatments and survival were collected for melanoma patients diagnosed with LMD from 1999 to 2015. The Kaplan-Meier method was used to estimate overall survival (OS) and Cox proportional hazards regression was used to test statistical significance of associations with survival. Multivariate analysis was performed using Cox proportional regression modeling. RESULTS: 178 melanoma patients with LMD were identified. Median age at LMD diagnosis was 51 years. Most (n = 153) patients received at least one treatment for LMD, including radiation (n = 98), chemotherapy (n = 89), targeted therapy (n = 60), immunotherapy (n = 12), or intrathecal (IT) therapy (n = 64). Median OS from LMD diagnosis was 3.5 months. One-, two-, and five-year OS rates were 22%, 14%, and 9%, respectively. Factors significantly associated with OS on multivariate analysis included Eastern Cooperative Oncology Group [ECOG] performance status > 0 (HR 2.1, P < 0.0001); neurological symptoms (HR 1.6, P < 0.0001); absent systemic disease (HR 0.4, P < 0.0001); and LMD treatment (HR 0.4, P = 0.0024), targeted therapy (HR 0.6, P = 0.0060), or IT therapy (HR 0.5, P = 0.0019). CONCLUSION: Despite their overall poor prognosis a subset of melanoma patients with LMD achieve longer survival. The factors associated with outcomes may be used to guide patient management and to inform the design of future clinical trials for this population.

Superiority of Multidetector Computed Tomography With 3-Dimensional Volume Rendering Over Plain Radiography in the Assessment of Spinal Surgical Instrumentation Complications in Patients With Cancer.

OBJECTIVE: The objective of this study was to compare multidetector computed tomography (MDCT) images with volume-rendered translucent display (VRTLD) series to plain radiographs for evaluating spinal surgical instrumentation after resection and reconstruction for spinal malignancies. METHODS: In 44 patients with tumor resection and spinal reconstruction, 17 with complications, 3 neuroradiologists evaluated plain radiographs, MDCT images alone, VRTLD images alone, and MDCT images with VRTLD images for identifying complications in 3 categories: subsidence/migration, construct fracture, and screw loosening. Each category was scored as 1 (complications), 2 (no complications), or 3 (not sure), and the minimum score was used for analyses. Clinical/surgical outcomes were the reference standard. RESULTS: Sensitivity, specificity, and accuracy (95% confidence interval), respectively, were as follows: MDCT/VRTLD, 100%, 100%, 100% (91.96%-100.00%); MDCT alone, 88.24%, 100%, 95.45% (84.53%-99.44%); VRTLD alone, 82.35%, 96.3%, 90.91% (78.33%-97.47%); plain radiographs, 52.94%, 100%, 81.82% (67.29%-91.81%). CONCLUSIONS: Multidetector computed tomography with VRTLD series seems best for evaluation of spinal instrumentation after tumor resection and reconstruction.

Primary Leptomeningeal Oligodendroglioma, IDH-Mutant, 1p/19q-Codeleted.

We present a case of a 43-year-old woman with a history of headaches and blurry vision. Ophthalmologic examination identified papilledema. MR imaging demonstrated a right parietal region mass with patchy areas of contrast enhancement and focal calcifications. Intraoperative examination and exploration revealed an extra-axial mass with no apparent parenchymal involvement. Microscopic examination revealed solid sheets of tumor cells with clear cell cytologic features and no discernable intra-parenchymal tumor component. Molecular studies demonstrated the presence of IDH1 IDH1 c.395G>A p.R132H and CIC c.601C>T p.R281W mutations and 1p/19q codeletion. The radiographic features, gross appearance, and microscopic and molecular characteristics of the mass support the diagnosis of primary leptomeningeal oligodendroglioma, IDH-mutant, 1p/19-codeleted. This case represents one of a very few reported instances of molecularly-defined solitary, primary, intracranial oligodendroglioma, without definitive involvement of the brain parenchyma.

A prospective in silico analysis of interdisciplinary and interobserver spatial variability in post-operative target delineation of high-risk oral cavity cancers: Does physician specialty matter?

BACKGROUND: The aim of this study was to determine the interdisciplinary agreement in identifying the post-operative tumor bed. METHODS: Three radiation oncologists (ROs), four surgeons, and three radiologists segmented post-operative tumor and nodal beds for three patients with oral cavity cancer. Specialty cohort composite contours were created by STAPLE algorithm implementation results for interspecialty comparison. Dice similarity coefficient and Hausdorff distance were utilized to compare spatial differentials between specialties. RESULTS: There were significant differences between disciplines in target delineation. There was unacceptable variation in Dice similarity coefficient for each observer and discipline when compared to the STAPLE contours. Within surgery and radiology disciplines, there was good consistency in volumes. ROs and radiologists have similar Dice similarity coefficient scores compared to surgeons. CONCLUSION: There were significant interdisciplinary differences in perceptions of tissue-at-risk. Better communication and explicit description of at-risk areas between disciplines is required to ensure high-risk areas are adequately targeted.

Phase 1 Study of Spinal Cord Constraint Relaxation With Single Session Spine Stereotactic Radiosurgery in the Primary Management of Patients With Inoperable, Previously Unirradiated Metastatic Epidural Spinal Cord Compression.

PURPOSE: We seek to establish the feasibility of using spine stereotactic radiosurgery (SSRS), allowing for spinal cord dose constraint relaxation, as the primary management of metastatic epidural spinal cord compression (MESCC) in inoperable patients. METHODS AND MATERIALS: Inoperable patients with thoracic MESCC and no history of radiation were enrolled on this prospective phase 1 single-institution protocol. SSRS was delivered to a histology-dependent prescription dose of 18 or 24 Gy. Incremental spinal cord constraint relaxation was performed from a Dmax cohort of 10 Gy up to 16 Gy only if tumor progression occurred and the risk of radiation-induced myelopathy (RM) remained lower than the risk of tumor progression. RESULTS: Thirty-two patients enrolled on the trial; 4, 12, 9, and 7 patients were in the 10 Gy, 12 Gy, 14 Gy, and 16 Gy cord Dmax cohorts, respectively. At baseline, there were 2 sites with MESCC grade 1A, 10 sites with grade 1B, 10 sites with grade 1C, 9 sites with grade 2, and 1 site with grade 3 disease. Among the 28 evaluable patients, the median overall survival was 28.6 months (95% confidence interval [CI], 9.2-48.0 months), and the 1-year local control was 89% (95% CI, 74%- 97%). With a median follow-up of 17 months, there were no cases of RM (upper 95% CI, 12%). In the cohort receiving a cord Dmax of 16 Gy, there were no cases of RM (upper 95% CI, 39%) with a median follow-up of 17 months (range, 12.7-21.0 months). CONCLUSIONS: SSRS is a safe and effective tool in patients with MESCC. In high-risk inoperable patients with MESCC receiving SSRS, dose constraint relaxation of the cord constraint dmax to 16 Gy may be considered to optimize local control, with the acknowledgment that this is based on 6 evaluable patients who received this dose in this trial.

Stereotactic radiosurgery for trigeminal pain secondary to recurrent malignant skull base tumors.

OBJECTIVE: The objective of this study was to assess outcomes after Gamma Knife radiosurgery (GKRS) re-irradiation for palliation of patients with trigeminal pain secondary to recurrent malignant skull base tumors. METHODS: From 2009 to 2016, 26 patients who had previously undergone radiation treatment to the head and neck received GKRS for palliation of trigeminal neuropathic pain secondary to recurrence of malignant skull base tumors. Twenty-two patients received single-fraction GKRS to a median dose of 17 Gy (range 15-20 Gy) prescribed to the 50% isodose line (range 43%-55%). Four patients received fractionated Gamma Knife Extend therapy to a median dose of 24 Gy in 3 fractions (range 21-27 Gy) prescribed to the 50% isodose line (range 45%-50%). Those with at least a 3-month follow-up were assessed for symptom palliation. Self-reported pain was evaluated by the numeric rating scale (NRS) and MD Anderson Symptom Inventory-Head and Neck (MDASI-HN) pain score. Frequency of as-needed (PRN) analgesic use and opioid requirement were also assessed. Baseline opioid dose was reported as a fentanyl-equivalent dose (FED) and PRN for breakthrough pain use as oral morphine-equivalent dose (OMED). The chi-square and Student t-tests were used to determine differences before and after GKRS. RESULTS: Seven patients (29%) were excluded due to local disease progression. Two experienced progression at the first follow-up, and 5 had local recurrence from disease outside the GKRS volume. Nineteen patients were assessed for symptom palliation with a median follow-up duration of 10.4 months (range 3.0-34.4 months). At 3 months after GKRS, the NRS scores (n = 19) decreased from 4.65 ± 3.45 to 1.47 ± 2.11 (p < 0.001); MDASI-HN pain scores (n = 13) decreased from 5.02 ± 1.68 to 2.02 ± 1.54 (p < 0.01); scheduled FED (n = 19) decreased from 62.4 ± 102.1 to 27.9 ± 45.5 mcg/hr (p < 0.01); PRN OMED (n = 19) decreased from 43.9 ± 77.5 to 10.9 ± 20.8 mg/day (p = 0.02); and frequency of any PRN analgesic use (n = 19) decreased from 0.49 ± 0.55 to 1.33 ± 0.90 per day (p = 0.08). At 6 months after GKRS, 9 (56%) of 16 patients reported being pain free (NRS score 0), with 6 (67%) of the 9 being both pain free and not requiring analgesic medications. One patient treated early in our experience developed a temporary increase in trigeminal pain 3-4 days after GKRS requiring hospitalization. All subsequently treated patients were given a single dose of intravenous steroids immediately after GKRS followed by a 2-3-week oral steroid taper. No further cases of increased or new pain after treatment were observed after this intervention. CONCLUSIONS: GKRS for palliation of trigeminal pain secondary to recurrent malignant skull base tumors demonstrated a significant decrease in patient-reported pain and opioid requirement. Additional patients and a longer follow-up duration are needed to assess durability of symptom relief and local control.

Correction to: A predictive model for distinguishing radiation necrosis from tumour progression after gamma knife radiosurgery based on radiomic features from MR images.

The original version of this article, published on 24 November 2017, unfortunately contained a mistake.

Analysis of pseudoprogression after proton or photon therapy of 99 patients with low grade and anaplastic glioma.

BACKGROUND AND PURPOSE: Proton therapy is increasingly used to treat primary brain tumors. There is concern for higher rates of pseudoprogression (PsP) after protons compared to photons. The purposes of this study are to compare the rate of PsP after proton vs. photon therapy for grade II and III gliomas and to identify factors associated with the development of PsP. MATERIALS AND METHODS: Ninety-nine patients age >18 years with grade II or III glioma treated with photons or protons were retrospectively reviewed. Demographic data, IDH and 1p19q status, and treatment factors were analyzed for association with PsP, progression free survival (PFS), and overall survival (OS). RESULTS: Sixty-five patients were treated with photons and 34 with protons. Among those with oligodendroglioma, PsP developed in 6/42 photon-treated patients (14.3%) and 4/25 proton-treated patients (16%, p = 1.00). Among those with astrocytoma, PsP developed in 3/23 photon-treated patients (13%) and 1/9 proton-treated patients (11.1%, p = 1.00). There was no difference in PsP rate based on radiation type, radiation dose, tumor grade, 1p19q codeletion, or IDH status. PsP occurred earlier in oligodendroglioma patients treated with protons compared to photons, 48 days vs. 131 days, p < .01. On multivariate analyses, gross total resection (p = .03, HR = 0.48, 95%CI = 0.25-0.93) and PsP (p = .04, HR = 0.22, 95% CI = 0.05-0.91) were associated with better PFS; IDH mutation was associated with better OS (p < .01, HR = 0.22, 95%CI = 0.08-0.65). CONCLUSIONS: Patients with oligodendroglioma but not astrocytoma develop PsP earlier after protons compared to photons. PsP was associated with better PFS.

Retrospective review of metastatic melanoma patients with leptomeningeal disease treated with intrathecal interleukin-2.

OBJECTIVES: Metastatic melanoma patients with leptomeningeal disease (LMD) have an extremely poor prognosis, with a median survival measured in weeks, and few treatment options. Outcomes of a retrospective cohort of patients with LMD that were treated with intrathecal interleukin-2 (IT IL-2) were reviewed to assess the long-term efficacy of this therapy. METHODS: The records of metastatic melanoma patients with LMD who were treated with IT IL-2 from 2006 to 2014 in a Compassionate Investigational New Drug study were reviewed. IL-2 (1.2 mIU) was administered intrathecally via Ommaya reservoir up to five times per week in the inpatient setting for 4 weeks; patients with good tolerance and clinical benefit received maintenance IT IL-2 every 1-3 months thereafter. RESULTS: The cohort included 43 patients. The median age of the patients was 47 years (range 18-71), and 32 (74%) were male. 23 patients (53%) had positive cerebrospinal fluid (CSF) cytology and radiographic evidence of LMD, 8 (19%) had positive CSF cytology only, 9 (21%) had radiographic evidence only and 3 (7%) were diagnosed based on pathology review after craniotomy. The median overall survival (OS) from initiation of IT IL-2 was 7.8 months (range, 0.4-90.8 months), with 1-year, 2-year and 5-year OS rates of 36%, 26% and 13%. The presence of neurological symptoms (HR 2.1, P=0.03), positive baseline CSF cytology (HR 4.1, P=0.001) and concomitant use of targeted therapy (HR 3.0, P=0.02) was associated with shorter OS on univariate analysis. All patients developed symptoms due to increased intracranial pressure which was managed with supportive medications and/or CSF removal, and there were no treatment-related deaths. CONCLUSION: These results demonstrate that despite their historically dismal prognosis a subset of metastatic melanoma patients with LMD treated with IT IL-2 can achieve long-term survival, but these data need to be verified in a prospective trial setting.