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Background Leptomeningeal disease (LMD) is a relatively uncommon manifestation of advanced cancer. Patients with LMD carry a poor prognosis and often decline rapidly, complicating inclusion in clinical trials. Identification of LMD subsets of greater incidence and more favorable prognosis might facilitate dedicated clinical trials in the future. We hypothesized that patients with breast cancer may represent such a population and sought to assess the relative incidence and prognosis of LMD secondary to breast vs. non-breast primaries. Methods We identified 2411 patients with intracranial metastases secondary to breast (N = 501) and non-breast (N = 1910) primaries at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 1996 and 2020, of whom 112 presented with and an additional 161 subsequently developed LMD. A log-rank test and Cox modeling were used to compare outcomes in patients with breast vs. non-breast primaries. Results Among patients with newly diagnosed intracranial disease, the incidence proportion of concurrent LMD was 11.4% vs. 2.9% among patients with breast vs. non-breast primaries (P Conclusions Patients with breast cancer and LMD may represent an ideal population for clinical trials given the higher incidence and potentially more favorable prognosis seen in this population.

PURPOSE: Children’s Oncology Group study ACNS1123 tested the efficacy of reduced dose and field of radiation therapy (RT) for patients with localized nongerminomatous germ cell tumors (NGGCT) who achieved a complete (CR) or partial response (PR) to chemotherapy. Here, we evaluate the quality of RT and patterns of failure for patients eligible for reduced RT in this phase 2 trial. METHODS AND MATERIALS: Patients with localized NGGCT with CR/PR after induction chemotherapy received reduced RT to 30.6 Gy whole ventricular irradiation and 54 Gy tumor-bed total dose. An atlas was provided to assist with complex RT volumes. Early interventional review was performed for the initial RT plan. Complete RT plans for all patients and images of relapsed patients were centrally reviewed at completion of therapy. RESULTS: Between May 2012 and September 2016, 107 eligible patients were enrolled and 66 achieved a CR/PR after induction chemotherapy (± second-look surgery) and were eligible for reduced RT. Median follow-up was 4.4 years. Median age was 11.0 years (3.7–21.6), and 75% were male. Progression-free survival and overall survival at 4 years were 87.9% ± 4.0% and 92.4% ± 3.3% for 66 evaluable patients, respectively. Eight patients relapsed: 6 with isolated spinal relapse and 2 with disease in the brain and spine. After central review, 62 (94%) patients had RT targets contoured and dose delivered per protocol. None of the patients with deviations (n = 4) have progressed. CONCLUSIONS: Patterns of failure suggest the spine is at risk for recurrence for patients with localized NGGCT who receive reduced RT after a CR/PR to induction chemotherapy. Although survival data are encouraging, the pattern of failure has influenced the next prospective trial design. RT compliance was excellent despite complexity of radiation volumes, suggesting that providing visual guidance in the form of an online atlas contributes to higher quality RT plans.

Supplementary Methods

Supplementary Table 2

Supplemental data

Supplemental Figure 1. Chemical structures of non-FDA approved compounds used in the Study; Supplemental Figure 2. Effect of drugs on growth and target phosphorylation; Supplemental Figure 3. mTOR inhibition does not show dose dependent Radiosensitization; Supplemental Figure 4. MEK162 + RT abrogate spheroid regrowth; Supplemental Figure 5. MEK162 radiosensitizes GBM8 primary spheroid culture and increases γH2AX levels; Supplemental Figure 6. MEK162 abrogates BrdU washout and increases sub-G1 accumulation of BrdU+ cells; Supplemental Figure 7. MEK162 + RT in vivo; Supplemental Table 1: Antibodies used; Supplemental Table 2: Gene signature MEK+RT response

Glioblastoma (GBM) is a highly aggressive and lethal brain cancer type. PI3K and MAPK inhibitors have been studied preclinically in GBM as monotherapy, but not in combination with radiotherapy, which is a key component of the current standard treatment of GBM. In our study, GBM cell lines and patient representative primary cultures were grown as multicellular spheroids. Spheroids were treated with a panel of small-molecule drugs including MK2206, RAD001, BEZ235, MLN0128, and MEK162, alone and in combination with irradiation. Following treatment, spheroid growth parameters (growth rate, volume reduction, and time to regrow), cell-cycle distribution and expression of key target proteins were evaluated. In vivo, the effect of irradiation (3 × 2 Gy) without or with MEK162 (50 mg/kg) was studied in orthotopic GBM8 brain tumor xenografts with endpoints tumor growth and animal survival. The MAPK-targeting agent MEK162 was found to enhance the effect of irradiation as demonstrated by growth inhibition of spheroids. MEK162 downregulated and dephosphorylated the cell-cycle checkpoint proteins CDK1/CDK2/WEE1 and DNA damage response proteins p-ATM/p-CHK2. When combined with radiation, this led to a prolonged DNA damage signal. In vivo data on tumor-bearing animals demonstrated a significantly reduced growth rate, increased growth delay, and prolonged survival time. In addition, RNA expression of responsive cell cultures correlated to mesenchymal stratification of patient expression data. In conclusion, the MAPK inhibitor MEK162 was identified as a radiosensitizer in GBM spheroids in vitro and in orthotopic GBM xenografts in vivo. The data are supportive for implementation of this targeted agent in an early-phase clinical study in GBM patients. Mol Cancer Ther; 17(2); 347–54. ©2017 AACR.See all articles in this MCT Focus section, “Developmental Therapeutics in Radiation Oncology.”

The oncogenic transcription factor STAT3 is aberrantly activated in 70% of breast cancers, including nearly all triple-negative breast cancers (TNBCs). Because STAT3 is difficult to target directly, we considered whether metabolic changes driven by activated STAT3 could provide a therapeutic opportunity. We found that STAT3 prominently modulated several lipid classes, with most profound effects on N-acyl taurine and arachidonic acid, both of which are involved in plasma membrane remodeling. To exploit these metabolic changes therapeutically, we screened a library of layer-by-layer (LbL) nanoparticles (NPs) differing in the surface layer that modulates interactivity with the cell membrane. We found that poly-l-glutamic acid (PLE)–coated NPs bind to STAT3-transformed breast cancer cells with 50% greater efficiency than to nontransformed cells, and the heightened PLE-NP binding to TNBC cells was attenuated by STAT3 inhibition. This effect was also observed in densely packed three-dimensional breast cancer organoids. As STAT3-transformed cells show greater resistance to cytotoxic agents, we evaluated whether enhanced targeted delivery via PLE-NPs would provide a therapeutic advantage. We found that cisplatin-loaded PLE-NPs induced apoptosis of STAT3-driven cells at lower doses compared with both unencapsulated cisplatin and cisplatin-loaded nontargeted NPs. In addition, because radiation is commonly used in breast cancer treatment, and may alter cellular lipid distribution, we analyzed its effect on PLE-NP–cell binding. Irradiation of cells enhanced the STAT3-targeting properties of PLE-NPs in a dose-dependent manner, suggesting potential synergies between these therapeutic modalities. These findings suggest that cellular lipid changes driven by activated STAT3 may be exploited therapeutically using unique LbL NPs.

In vitro cell line IC50 values and mutational status.

The mTOR signaling is dysregulated prominently in human cancers including glioblastoma, suggesting mTOR as a robust target for therapy. Inhibitors of mTOR have had limited success clinically, however, in part because their mechanism of action is cytostatic rather than cytotoxic. Here, we tested three distinct mTOR kinase inhibitors (TORKi) PP242, KU-0063794, and sapanisertib against glioblastoma cells. All agents similarly decreased proliferation of glioblastoma cells, whereas PP242 uniquely induced apoptosis. Apoptosis induced by PP242 resulted from off-target cooperative inhibition of JAK2 and protein kinase C alpha (PKCα). Induction of apoptosis was also decreased by additional on-target inhibition of mTOR, due to induction of autophagy. As EGFR inhibitors can block PKCα, EGFR inhibitors erlotinib and osimertinib were tested separately in combination with the JAK2 inhibitor AZD1480. Combination therapy induced apoptosis of glioblastoma tumors in both flank and in patient-derived orthotopic xenograft models, providing a preclinical rationale to test analogous combinations in patients.Significance:These findings identify PKCα and JAK2 as targets that drive apoptosis in glioblastoma, potentially representing a clinically translatable approach for glioblastoma.

Supplementary Figures S1-S6.

Purpose: 131I-metaiodobenzylguanidine (MIBG) is a radiopharmaceutical with activity in neuroblastoma. Vorinostat is a histone deacetylase inhibitor that has radiosensitizing properties. The goal of this phase I study was to determine the MTDs of vorinostat and MIBG in combination.Experimental Design: Patients ≤ 30 years with relapsed/refractory MIBG-avid neuroblastoma were eligible. Patients received oral vorinostat (dose levels 180 and 230 mg/m2) daily days 1 to 14. MIBG (dose levels 8, 12, 15, and 18 mCi/kg) was given on day 3 and peripheral blood stem cells on day 17. Alternating dose escalation of vorinostat and MIBG was performed using a 3+3 design.Results: Twenty-seven patients enrolled to six dose levels, with 23 evaluable for dose escalation. No dose-limiting toxicities (DLT) were seen in the first three dose levels. At dose level 4 (15 mCi/kg MIBG/230 mg/m2 vorinostat), 1 of 6 patients had DLT with grade 4 hypokalemia. At dose level 5 (18 mCi/kg MIBG/230 mg/m2 vorinostat), 2 patients had dose-limiting bleeding (one grade 3 and one grade 5). At dose level 5a (18 mCi/kg MIBG/180 mg/m2 vorinostat), 0 of 6 patients had DLT. The most common toxicities were neutropenia and thrombocytopenia. The response rate was 12% across all dose levels and 17% at dose level 5a. Histone acetylation increased from baseline in peripheral blood mononuclear cells collected on days 3 and 12 to 14.Conclusions: Vorinostat at 180 mg/m2/dose is tolerable with 18 mCi/kg MIBG. A phase II trial comparing this regimen to single-agent MIBG is ongoing. Clin Cancer Res; 21(12); 2715–21. ©2015 AACR.

Supplementary Figure S1. PP242 induced apoptosis through a mitochondrial-dependent pathway. Supplementary Figure S2. PP242 showed potent blockade of p-MARCKS, but not p-STAT3Y705 in GBM6 cells. Supplementary Figure S3. Effects of PKC, JAK2, and mTOR inhibitors on cell proliferation and apoptosis. Supplementary Figure S4. Cooperative blockade of PKCα and JAK2 drives apoptosis. Supplementary Figure S5. Efficacy and tolerability of combination therapy in mice.

Supplemental Figure 1. PCR cycle count for NET mRNA expression in peripheral blood mononuclear cells from 7 patients obtained on Day 1 and/or 3 of protocol therapy.

Purpose:Adavosertib (AZD1775), an inhibitor of WEE1 kinase, potentiates replicative stress induced by oncogenes or chemotherapy. Antitumor activity of adavosertib has been demonstrated in preclinical models of pediatric cancer. This phase I trial was performed to define dose-limiting toxicities (DLT), recommended phase II dose (RP2D), and pharmacokinetics of adavosertib in combination with irinotecan in children and adolescents with relapsed or refractory solid tumors or primary central nervous system tumors.Patients and Methods:Using a 3+3 escalation design, five dose cohorts of the combination of adavosertib and irinotecan (50/70; 65/70; 65/90; 85/90; 110/90 mg/m2/day) delivered on days 1–5 of a 21-day cycle were studied. Pharmacokinetics and analysis of peripheral blood γH2AX was performed.Results:Thirty-seven patients were enrolled; 27 were evaluable. The median (range) age was 14 (2–20) years. Twenty-five (93%) received prior chemotherapy (median, three regimens) and 21 (78%) received prior radiotherapy. Eleven patients had a primary central nervous system (CNS) malignancy. Common toxicities were hematologic and gastrointestinal. Two patients receiving adavosertib (110 mg/m2) in combination with irinotecan (90 mg/m2) experienced dose-limiting grade 3 dehydration. A patient with Ewing sarcoma had a confirmed partial response and 2 patients (ependymoma and neuroblastoma) had prolonged stable disease (≥ 6 cycles). Pharmacokinetics of adavosertib were variable but generally dose proportional and clearance was lower in younger patients.Conclusions:Adavosertib (85 mg/m2) in combination with irinotecan (90 mg/m2) administered orally for 5 days was the MTD in children and adolescents with solid and CNS tumors.

In vitro response to co-inhibition of MAPK and mTOR pathways in BRAFV600E mutated AM-38 glioma cells.

S1. Patient Characteristics of eligible (n=37) and MTD/RP2D evaluable (n=27) patients S1B. Diagnosis of eligible (n=37) and MTD/RP2D evaluable (n=27) patients. S2. In Cycle 1, All Hematologic and Non-Hematologic toxicities related to protocol therapy in evaluable patients (N=27)

Purpose: Alteration of the BRAF/MEK/MAPK pathway is the hallmark of pediatric low-grade gliomas (PLGGs), and mTOR activation has been documented in the majority of these tumors. We investigated combinations of MEK1/2, BRAFV600E and mTOR inhibitors in gliomas carrying specific genetic alterations of the MAPK pathway.Experimental Design: We used human glioma lines containing BRAFV600E (adult high-grade: AM-38, DBTRG, PLGG: BT40), or wild-type BRAF (pediatric high-grade: SF188, SF9427, SF8628) and isogenic systems of KIAA1549:BRAF-expressing NIH/3T3 cells and BRAFV600E-expressing murine brain cells. Signaling inhibitors included everolimus (mTOR), PLX4720 (BRAFV600E), and AZD6244 (MEK1/2). Proliferation was determined using ATP-based assays. In vivo inhibitor activities were assessed in the BT40 PLGG xenograft model.Results: In BRAFV600E cells, the three possible doublet combinations of AZD6244, everolimus, and PLX4720 exhibited significantly greater effects on cell viability. In BRAFWT cells, everolimus + AZD6244 was superior compared with respective monotherapies. Similar results were found using isogenic murine cells. In KIAA1549:BRAF cells, MEK1/2 inhibition reduced cell viability and S-phase content, effects that were modestly augmented by mTOR inhibition. In vivo experiments in the BRAFV600E pediatric xenograft model BT40 showed the greatest survival advantage in mice treated with AZD6244 + PLX4720 (P < 0.01).Conclusions: In BRAFV600E tumors, combination of AZD6244 + PLX4720 is superior to monotherapy and to other combinatorial approaches. In BRAFWT pediatric gliomas, everolimus + AZD6244 is superior to either agent alone. KIAA1549:BRAF-expressing tumors display marked sensitivity to MEK1/2 inhibition. Application of these results to PLGG treatment must be exercised with caution because the dearth of PLGG models necessitated only a single patient-derived PLGG (BT40) in this study. Clin Cancer Res; 22(21); 5312–21. ©2016 AACR.

Aberrant chromatin remodeling and activation of the PI3K pathway have been identified as important mediators of pediatric high-grade glioma (pHGG) and diffuse intrinsic pontine glioma (DIPG) pathogenesis. As inhibition of these pathways are promising therapeutic avenues and radiation is the only modality to prolong survival of patients with DIPG, we sought to explore radiosensitizing functions of such inhibition and to explore mechanisms of action of such agents. Here, we demonstrate that combined treatment with radiotherapy and CUDC-907, a novel first-in-class dual inhibitor of histone deacetylases (HDAC) and PI3K, evokes a potent cytotoxic response in pHGG and DIPG models. CUDC-907 modulated DNA damage response by inhibiting radiation-induced DNA repair pathways including homologous recombination and nonhomologous end joining. The radiosensitizing effects of CUDC-907 were mediated by decreased NFκB/Forkhead box M1 (FOXM1) recruitment to promoters of genes involved in the DNA damage response; exogenous expression of NFκB/FOXM1 protected from CUDC-907–induced cytotoxicity. Together, these findings reveal CUDC-907 as a novel radiosensitizer with potent antitumor activity in pHGG and DIPG and provide a preclinical rationale for the combination of CUDC-907 with radiotherapy as a novel therapeutic strategy against pHGG and DIPG. More globally, we have identified NFκB and FOXM1 and their downstream transcriptional elements as critical targets for new treatments for pHGG and DIPG.Significance: These findings describe the radiosensitizing effect of a novel agent in pediatric high-grade gliomas, addressing a critical unmet need of increasing the radiation sensitivity of these highly aggressive tumors. Cancer Res; 78(14); 4007–21. ©2018 AACR.

Combinatorial index and median-effect plots for BRAFV600E mutated cell lines.

Purpose: Histone deacetylase (HDAC) inhibition causes transcriptional activation or repression of several genes that in turn can influence the biodistribution of other chemotherapeutic agents. Here, we hypothesize that the combination of vorinostat, a HDAC inhibitor, with 131I-meta-iodobenzylguanidine (MIBG) would lead to preferential accumulation of the latter in neuroblastoma (NB) tumors via increased expression of the human norepinephrine transporter (NET).Experimental Design:In vitro and in vivo experiments examined the effect of vorinostat on the expression of NET, an uptake transporter for 131I-MIBG. Human NB cell lines (Kelly and SH-SY-5Y) and NB1691-luc mouse xenografts were employed. The upregulated NET protein was characterized for its effect on 123I-MIBG biodistribution.Results: Preincubation of NB cell lines, Kelly, and SH-SY-5Y, with vorinostat caused dose-dependent increases in NET mRNA and protein levels. Accompanying this was a corresponding dose-dependent increase in MIBG uptake in NB cell lines. Four- and 2.5-fold increases were observed in Kelly and SH-SY-5Y cells, respectively, pretreated with vorinostat in comparison to untreated cells. Similarly, NB xenografts, created by intravenous tail vein injection of NB1691-luc, and harvested from nude mice livers treated with vorinostat (150 mg/kg i.p.) showed substantial increases in NET protein expression. Maximal effect of vorinostat pretreatment in NB xenografts on 123I-MIBG biodistribution was observed in tumors that exhibited enhanced uptake in vorinostat-treated [0.062 ± 0.011 μCi/(mg tissue-dose injected)] vs. -untreated mice [0.022 ± 0.003 μCi/(mg tissue-dose injected); P < 0.05].Conclusions: The results of our study provide preclinical evidence that vorinostat treatment can enhance NB therapy with 131I-MIBG. Clin Cancer Res; 17(8); 2339–49. ©2011 AACR.

This file contains the supplementary figures (S1-S10) with legends and supplementary tables S1-S8. Supplementary Tables S1-S3 contain sequences for siRNA and primers used in RT-PCR, ChIP-PCR. Supplementary Tables S4-S8 contain the p-values for all pairwise comparisons performed in figures 3-6. Figure S1: CUDC-907 inhibits HDAC and PI3K activity. Figure S2: CUDC-907 synergizes with radiation. Figure S3: CUDC-907 reduces tomor cell proliferation in vivo. Figure S4:CUDC-907 induces cell cycle arrest and apoptosis. Figure S5:CUDC-907 enhances radiation induced DNA damage in vitro. Figure S6:Increase in DNA damage marker γ-H2AX is observed in vivo in the presence of CUDC-907. Figure S7:CUDC-907 reduces DNA damage protein. Figure S8: CUDC-907 impairs expression of NFκB and FOXM1. Figure S9:CUDC-907 interferes with nuclear localization of NFκB proteins. Figure S10:NFκB and FOXM1 knockdown induces DNA damage and cell viability.

Combinatorial index and median-effect plots for BRAFWT cell lines.

Supplementary Figure 2 from Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells

Supplementary Figures 1-4 from p53 Small-Molecule Inhibitor Enhances Temozolomide Cytotoxic Activity against Intracranial Glioblastoma Xenografts

Supplementary Figure 3 from Radiation-Induced Caspase-8 Mediates p53-Independent Apoptosis in Glioma Cells

Malignant gliomas are almost uniformly fatal and display exquisite radiation resistance. Glioma cells lacking wild-type (WT) p53 function are more susceptible to radiation-induced apoptosis than their isogenic counterparts expressing WT p53. We explored the mechanisms of such apoptosis and found that, in the absence of WT p53, radiation increases caspase-8 expression and activity. Inhibition of caspase-8 expression using caspase-8 antisense or small interfering RNA (siRNA) oligonucleotides partially blocks radiation-induced apoptosis. In contrast, inhibition of the mitochondrial death pathway by expression of Bcl-2 has no effect on radiation-induced caspase-8 activity or apoptosis. Our data indicate that, in contrast to commonly accepted models of p53-dependent radiation-induced apoptosis, in our cell system, radiation relies on caspase-8 activity to help mediate p53-independent cell death. In a system of inducible E2F1 activity, E2F1 activated caspase-8 and, accordingly, decreased cellular viability, effects that were abolished by caspase-8 siRNA. In this model, in the absence of WT p53, p21Cip1 is not induced, and E2F1 activity is sustained and allows transcription and activation of caspase-8. This model may explain why p53 mutations in adult gliomas paradoxically correlate with improved survival and enhanced response to radiation. (Cancer Res 2006; 66(8): 4223-32)

Background Falls in patients with cancer harbor potential for serious sequelae. Patients with brain metastases (BrM) may be especially susceptible to falls but supporting investigations are lacking. We assessed the frequency, etiologies, risk factors, and sequelae of falls in patients with BrM using 2 data sources. Methods We identified 42 648 and 111 patients with BrM utilizing Surveillance, Epidemiology, and End Results (SEER)-Medicare data (2008-2016) and Brigham and Women’s Hospital/Dana-Farber Cancer Institute (BWH/DFCI) institutional data (2015), respectively, and characterized falls in these populations. Results Among SEER-Medicare patients, 10 267 (24.1%) experienced a fall that prompted medical evaluation, with cumulative incidences at 3, 6, and 12 months of 18.0%, 24.3%, and 34.1%, respectively. On multivariable Fine/Gray’s regression, older age (≥81 or 76-80 vs 66-70 years, hazard ratio [HR] 1.18 [95% CI, 1.11-1.25], P < .001 and HR 1.10 [95% CI, 1.04-1.17], P < .001, respectively), Charlson comorbidity score of >2 vs 0-2 (HR 1.08 [95% CI, 1.03-1.13], P = .002) and urban residence (HR 1.08 [95% CI, 1.01-1.16], P = .03) were associated with falls. Married status (HR 0.94 [95% CI, 0.90-0.98], P = .004) and Asian vs white race (HR 0.90 [95% CI, 0.81-0.99], P = .03) were associated with reduced fall risk. Identified falls were more common among BWH/DFCI patients (N = 56, 50.4% of cohort), resulting in emergency department visits, hospitalizations, fractures, and intracranial hemorrhage in 33%, 23%, 11%, and 4% of patients, respectively. Conclusions Falls are common among patients with BrM, especially older/sicker patients, and can have deleterious consequences. Risk-reduction measures, such as home safety checks, physical therapy, and medication optimization, should be considered in this population.

pLGGs are a group of tumors for which the era of molecular diagnostics has truly shifted treatment paradigms and patient care. The discovery that this group of tumors is driven by single-gene alterations/fusions in the MAPK pathway has resulted in relatively rapid translation into targeted therapy options for patients with this often chronic disease. This translation has been facilitated through efforts of multiple collaboratives and consortia and has led to the development of clinical trials testing the role of targeted therapies in pLGG. Although these developments represent promise, many questions remain regarding these therapies including their long-term toxicities and their potential effects on the natural history of pLGG.

Background Older patients with brain metastases (BrM) commonly experience symptoms that prompt acute medical evaluation. We characterized emergency department (ED) visits and inpatient hospitalizations in this population. Methods We identified 17 789 and 361 Medicare enrollees diagnosed with BrM using the Surveillance, Epidemiology, and End Results (SEER)-Medicare database (2010-2016) and an institutional database (2007-2016), respectively. Predictors of ED visits and hospitalizations were assessed using Poisson regression. Results The institutional cohort averaged 3.3 ED visits/1.9 hospitalizations per person-year, with intracranial disease being the most common reason for presentation/admission. SEER-Medicare patients averaged 2.8 ED visits/2.0 hospitalizations per person-year. For patients with synchronous BrM (N = 7834), adjusted risk factors for ED utilization and hospitalization, respectively, included: male sex (rate ratio [RR] = 1.15 [95% CI = 1.09-1.22], P < .001; RR = 1.21 [95% CI = 1.13-1.29], P < .001); African American vs white race (RR = 1.30 [95% CI = 1.18-1.42], P < .001; RR = 1.25 [95% CI = 1.13-1.39], P < .001); unmarried status (RR = 1.07 [95% CI = 1.01-1.14], P = .02; RR = 1.09 [95% CI = 1.02-1.17], P = .01); Charlson comorbidity score >2 (RR = 1.27 [95% CI = 1.17-1.37], P < .001; RR = 1.36 [95% CI = 1.24-1.49], P < .001); and receipt of non-stereotactic vs stereotactic radiation (RR = 1.44 [95% CI = 1.34-1.55, P < .001; RR = 1.49 [95% CI = 1.37-1.62, P < .001). For patients with metachronous BrM (N = 9955), ED visits and hospitalizations were more common after vs before BrM diagnosis (2.6 vs 1.2 ED visits per person-year; 1.8 vs 0.9 hospitalizations per person-year, respectively; RR = 2.24 [95% CI = 2.15-2.33], P < .001; RR = 2.06 [95% CI = 1.98-2.15], P < .001, respectively). Conclusions Older patients with BrM commonly receive hospital-level care secondary to intracranial disease, especially in select subpopulations. Enhanced care coordination, closer outpatient follow-up, and patient navigator programs seem warranted for this population.

One in six gay and bisexual men will be diagnosed with prostate cancer in their lifetime. Lesbian, gay, bisexual, and transgender (LGBT) populations are under-represented in cancer research, and guidelines on prostate-specific antigen (PSA) screening are limited. We performed a cross-sectional study to assess patterns of PSA screening and decision-making in this cohort. The Behavioral Risk Factor Surveillance System database was queried for LGBT adults for 2014-2016 and 2018, when PSA questions were asked in the annual survey. Multivariable logistic regression was performed to evaluate the association of LGBT status with PSA screening and informed and shared decision-making. A total of 164 370 participants were eligible for PSA screening, representing a weighted estimate of 1.2 million LGBT individuals. Compared to cisgender (CG) straight individuals, CG gay/bisexual cohorts were more likely to participate in PSA screening (CG gay: odds ratio [OR] 1.07; p 0.001; CG bisexual: OR 1.06; p 0.001). CG gay participants were more likely to make informed decisions (OR 1.10; p 0.001) and engage in shared decision-making (OR 2.55; p 0.001). Select gay populations were more likely to undergo PSA screening recommended by their clinicians and participate in informed and shared decision-making. PATIENT SUMMARY: This large study of sexual and gender minorities in the USA suggests that gay and bisexual individuals were more likely to undergo prostate cancer screening and that select gay individuals were more likely to make informed and shared decisions. However, transgender individuals were less likely to have prostate cancer screening and make informed decisions.

Background Chemotherapy improves overall survival after surgery and radiotherapy for newly diagnosed high-risk IDH-mutant low-grade gliomas (LGGs), but a proportion of patients treated with temozolomide (TMZ) will develop recurrent tumors with TMZ-induced hypermutation. We aimed to determine the prevalence of TMZ-induced hypermutation at recurrence and prognostic implications. Methods We sequenced recurrent tumors from 82 patients with initially low-grade IDH-mutant gliomas who underwent reoperation and correlated hypermutation status with grade at recurrence and subsequent clinical outcomes. Results Hypermutation was associated with high-grade disease at the time of reoperation (OR 12.0 95% CI 2.5-115.5, P = .002) and was identified at transformation in 57% of recurrent LGGs previously exposed to TMZ. After anaplastic (grade III) transformation, hypermutation was associated with shorter survival on univariate and multivariate analysis (HR 3.4, 95% CI 1.2-9.9, P = .024), controlling for tumor grade, subtype, age, and prior radiotherapy. The effect of hypermutation on survival after transformation was validated in an independent, published dataset. Hypermutated (HM) tumors were more likely to develop discontiguous foci of disease in the brain and spine (P = .003). To estimate the overall incidence of high-grade transformation among low-grade IDH-mutant tumors, data from a phase II trial of TMZ for LGG were analyzed. Eight-year transformation-free survival was 53.8% (95% CI 42.8-69.2), and 61% of analyzed transformed cases were HM. Conclusions TMZ-induced hypermutation is a common event in transformed LGG previously treated with TMZ and is associated with worse prognosis and development of discontiguous disease after recurrence. These findings impact tumor classification at recurrence, prognostication, and clinical trial design.

Purpose The use of stereotactic body radiation therapy (SBRT) in pediatric patients has been underreported. We reviewed practice patterns, outcomes, and toxicity of SBRT in this population. Methods and Materials In this multi-institutional study, 55 patients with 107 non-central nervous system lesions treated with SBRT between 2010 and 2016 were reviewed. Treatment response was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) v1.1 and modified RECIST v1.1 criteria for soft-tissue and bone lesions, respectively. Patterns of local failure (LF) were assessed dosimetrically. The cumulative incidence of LF and toxicity were estimated accounting for the competing risk event of death. Predictors of LF were identified through joint frailty models for clustered competing risks. Results The median (range) dose/fraction was 7 (4.5-25) Gy, the total (range) dose/site was 35 (12-45), and the median (range) number of fractions was 5 (1-9). The radiographic response rates of bone and soft-tissue lesions were 90.6% and 76.7%, respectively. Symptom improvement was observed for 62% of symptomatic sites. A total of 27 LFs were documented, with 14 in-field, 9 marginal, and 4 out-of-field LFs. The 1-year estimated cumulative LF rate, progression-free survival, and overall survival were 25.2% (95% confidence interval [CI], 17.2%-36.1%), 17.5% (95% CI, 9.0%-34.1%), and 61% (95% CI, 48.9%-76.1%), respectively. Lesion type (soft tissue vs bone) was the only significant predictor of LF on multivariable analysis (P = .04), with increased hazard for soft-tissue lesions. No acute or late toxicity of grade 4 or higher was observed; the estimated 1-year cumulative incidence of late toxicity of any grade was 7.5% (95% CI, 3.6%-12.1%). Conclusions The SBRT was well tolerated and resulted in radiographic response and symptom palliation in most pediatric patients with advanced disease. The 1-year cumulative LF rate of 25% will serve as a benchmark for further modifications to radiation therapy indications, parameters, and combination therapy.

BackgroundVenous thromboembolism is common in patients with solid malignancies and brain metastases. Whether to anticoagulate such patients is controversial given the possibility of intracerebral haemorrhage (ICH). We evaluated the added risk of ICH in patients with brain metastases receiving therapeutic anticoagulation.MethodsWe performed a matched, retrospective cohort study of 291 patients (100 receiving therapeutic anticoagulation vs 191 controls) with brain metastases managed at Brigham and Women’s Hospital/Dana-Farber Cancer Institute between 1998 and 2015. For each patient, all MRI studies of the brain were reviewed to identify ICH. Propensity score matching and multivariable Cox regression were used to mitigate confounding.ResultsThe risk of ICH was comparable in patients receiving anticoagulation versus controls preanticoagulation. Postanticoagulation, we observed significant or borderline-significant associations between anticoagulation and development of any ICH (HR 1.31, 95% CI 0.96 to 1.79, p=0.09), ICH as identified by gradient echo/susceptibility-weighted imaging (HR 1.46, 95% CI 1.06 to 2.01, p=0.02), symptomatic ICH (HR 1.80, 95% CI 1.01 to 3.22, p=0.05), extralesional ICH (HR 5.82, 95% CI 1.56 to 21.7, p=0.009) and fatal ICH (HR 5.68, 95% CI 0.60 to 54.2, p=0.13). Anticoagulation was associated with differentially higher ICH risk in patients with prior ICH versus no prior ICH (HR 2.20 vs 0.68, respectively, p interaction ConclusionsAnticoagulation is associated with clinically significant ICH in patients with brain metastases, especially those with melanoma or prior ICH. The indication for anticoagulation and risk of intracerebral bleeding should be considered on an individual basis among such patients.

Purpose This multi-institutional retrospective study sought to examine the hematologic effects of craniospinal irradiation (CSI) in pediatric patients with medulloblastoma using proton or photon therapy. Methods and Materials Clinical and treatment characteristics were recorded for 97 pediatric patients with medulloblastoma who received CSI without concurrent chemotherapy or with concurrent single-agent vincristine from 2000 to 2017. Groups of 60 and 37 patients underwent treatment with proton-based and photon-based therapy, respectively. Overall survival was determined by Kaplan-Meier curves with log-rank test. Comparisons of blood counts at each timepoint were conducted using multiple t tests with Bonferroni corrections. Univariate and multivariate analyses of time to grade ≥3 hematologic toxicity were performed with Cox regression analyses. Results Median age of patients receiving proton and photon CSI was 7.5 years (range, 3.5-22.7 years) and 9.9 years (range, 3.6-19.5 years), respectively. Most patients had a diagnosis of standard risk medulloblastoma, with 86.7% and 89.2% for the proton and photon cohorts, respectively. Median total dose to involved field or whole posterior fossa was 54.0 Gy/Gy relative biological effectiveness (RBE) and median CSI dose was 23.4 Gy/Gy(RBE) (range, 18-36 Gy/Gy[RBE]) for both cohorts. Counts were significantly higher in the proton cohort compared with the photon cohort in weeks 3 to 6 of radiation therapy (RT). Although white blood cell counts did not differ between the 2 cohorts, patients receiving proton RT had significantly higher lymphocyte counts throughout the RT course. Similar results were observed when excluding patients who received vertebral body sparing proton RT or limiting to those receiving 23.4 Gy. Only photon therapy was associated with decreased time to grade ≥3 hematologic toxicity on univariate and multivariable analyses. No difference in overall survival was observed, and lymphopenia did not predict survival. Conclusions Patients who receive CSI using proton therapy experience significantly decreased hematologic toxicity compared with those receiving photon therapy.

NANT2011-11 evaluatedThe cohort included 99 patients who had at least one biomarker available for analysis. Significant modulation in most biomarkers between baseline, 72 hours, and 96 hours followingPeripheral blood biomarkers relevant to radiation exposure demonstrate significant modulation after 131I-MIBG and concomitant radiation sensitizers impact extent of modulation. Biomarkers related to hematopoietic damage and apoptosis were associated with hematologic toxicity.

Background Prognostic estimates for patients with brain metastases (BM) stem from younger, healthier patients enrolled in clinical trials or databases from academic centers. We characterized population-level prognosis in elderly patients with BM. Methods Using Surveillance, Epidemiology, and End Results (SEER)–Medicare data, we identified 9882 patients ≥65 years old with BM secondary to lung, breast, skin, kidney, esophageal, colorectal, and ovarian primaries between 2014 and 2016. Survival was assessed by primary site and evaluated with Cox regression. Results In total, 2765 versus 7117 patients were diagnosed with BM at primary cancer diagnosis (synchronous BM, median survival = 2.9 mo) versus thereafter (metachronous BM, median survival = 3.4 mo), respectively. Median survival for all primary sites was ≤4 months, except ovarian cancer (7.5 mo). Patients with non-small-cell lung cancer (NSCLC) receiving epidermal growth factor receptor (EGFR)– or anaplastic lymphoma kinase (ALK)–based therapy for synchronous BM displayed notably better median survival at 12.5 and 20.1 months, respectively, versus 2.8 months exhibited by other patients with NSCLC; survival estimates in melanoma patients based on receipt of BRAF/MEK therapy versus not were 6.7 and 2.8 months, respectively. On multivariable regression, older age, greater comorbidity, and type of managing hospital were associated with poorer survival; female sex, higher median household income, and use of brain-directed stereotactic radiation, neurosurgical resection, or systemic therapy (versus brain-directed non-stereotactic radiation) were associated with improved survival (all P Conclusions Elderly patients with BM have a poorer prognosis than suggested by prior algorithms. If prognosis is driven by systemic and not intracranial disease, brain-directed therapy with potential for significant toxicity should be utilized cautiously.

Background Diffuse intrinsic pontine gliomas (DIPGs) are a leading cause of brain tumor deaths in children. Current standard of care includes focal radiation therapy (RT). Despite clinical improvement in most patients, the effect is temporary and median survival is less than 1 year. The use and benefit of reirradiation have been reported in progressive DIPG, yet standardized approaches are lacking. We conducted a survey to assess reirradiation practices for DIPG in North America. Methods A 14-question REDCap survey was disseminated to 396 North American physicians who care for children with CNS tumors. Results The response rate was 35%. Participants included radiation-oncologists (63%; 85/135) and pediatric oncologists/neuro-oncologists (37%; 50/135). Most physicians (62%) treated 1 to 5 DIPG patients per year, with 10% treating more than 10 patients per year. Reirradiation was considered a treatment option by 88% of respondents. Progressive disease and worsening clinical status were the most common reasons to consider reirradiation. The majority (84%) surveyed considered reirradiation a minimum of 6 months following initial RT. Doses varied, with median total dose of 2400 cGy (range, 1200-6000 cGy) and fraction size of 200 cGy (range, 100-900 cGy). Concurrent use of systemic agents with reirradiation was considered in 46%, including targeted agents (37%), biologics (36%), or immunotherapy (25%). One-time reirradiation was the most common practice (71%). Conclusion Although the vast majority of physicians consider reirradiation as a treatment for DIPG, total doses and fractionation varied. Further clinical trials are needed to determine the optimal radiation dose and fractionation for reirradiation in children with progressive DIPG.

BACKGROUND Prior literature has suggested synergy between immune checkpoint therapy (ICT) and radiotherapy (RT) for the treatment of brain metastases (BrM), but to the authors' knowledge the optimal timing of therapy to maximize this synergy is unclear. METHODS A total of 199 patients with melanoma and non-small cell lung cancer with BrM received ICT and RT between 2007 and 2016 at the study institution. To reduce selection biases, individual metastases were included only if they were treated with RT within 90 days of ICT. Concurrent treatment was defined as RT delivered on the same day as or in between doses of an ICT course; all other treatment was considered to be nonconcurrent. Multivariable Cox proportional hazards models were used to assess time to response and local disease recurrence on a per-metastasis basis, using a sandwich estimator to account for intrapatient correlation. RESULTS The final cohort included 110 patients with 340 BrM, with 102 BrM treated concurrently and 238 BrM treated nonconcurrently. Response rates were higher with the use of concurrent treatment (70% vs 47%; P

PURPOSE A primary objective of the Children’s Oncology Group (COG) ANBL0532 phase III study was to assess the effect of increasing local dose of radiation to a residual primary tumor on the cumulative incidence of local progression (CILP) in patients with high-risk neuroblastoma. PATIENTS AND METHODS Newly diagnosed patients with high-risk neuroblastoma were randomly assigned or assigned to receive single or tandem autologous stem-cell transplantation (SCT) after induction chemotherapy. Local control consisted of surgical resection during induction chemotherapy and radiotherapy after last SCT. Patients received 21.6 Gy to the preoperative primary tumor volume. For patients with incomplete surgical resection, an additional boost of 14.4 Gy was delivered to the gross residual tumor, for a total dose of 36 Gy. CILP (primary end point) and event-free (EFS) and overall survival (OS; secondary end points) were compared with the COG A3973 historical cohort, in which all patients received single SCT and 21.6 Gy without a boost. RESULTS For all patients in ANBL0532 receiving radiotherapy (n = 323), 5-year CILP, EFS, and OS rates were 11.2% ± 1.8%, 56.2% ± 3.4%, and 68.4% ± 3.2% compared with 7.1% ± 1.4% ( P = .0590), 47.0% ± 3.5% ( P = .0090), and 57.4% ± 3.5% ( P = .0088) for all patients in A3973 receiving radiotherapy (n = 328), respectively. Five-year CILP, EFS, and OS rates for patients in A3973 with incomplete resection and radiotherapy (n = 47) were 10.6% ± 4.6%, 48.9% ± 10.1%, and 56.9% ± 10.0%, respectively. In comparison, 5-year CILP, EFS, and OS rates for patients in ANBL0532 who were randomly assigned or assigned to single SCT and received boost radiotherapy (n = 74) were 16.3% ± 4.3% ( P = .4126), 50.9% ± 7.0% ( P = .5084), and 68.1% ± 6.7% ( P = .2835), respectively. CONCLUSION Boost radiotherapy to gross residual tumor present at the end of induction did not significantly improve 5-year CILP. These results highlight the need for new strategies to decrease the risk of locoregional failure.

The treatment of patients with cancer who test positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2) poses unique challenges. In this commentary, the authors describe the ethical rationale and implementation details for the creation of a novel, multidisciplinary treatment prioritization committee, including physicians, frontline staff, an ethicist, and an infectious disease expert. Organizational obligations to health care workers also are discussed. The treatment prioritization committee sets a threshold of acceptable harm to patients from decreased cancer control that is justified to reduce risk to staff. The creation of an ethical, consistent, and transparent decision‐making process involving such frontline stakeholders is essential as departments across the country are faced with decisions regarding the treatment of SARS‐CoV‐2–positive patients with cancer., This commentary describes the ethical rationale and implementation details for a novel, multidisciplinary, treatment prioritization committee that makes treatment decisions regarding patients with cancer who are positive for severe acute respiratory syndrome coronavirus 2 (SARS‐CoV‐2). This consistent, ethical, and transparent process could be adapted to any oncology department in which there is risk disparity between physician decision makers and the frontline staff who are implementing these decisions.