Current Landscape and Future Prospects of Radiation Sensitizers for Malignant Brain Tumors: A Systematic Review.

BACKGROUND: Radiation therapy (RT) is the cornerstone of management of malignant brain tumors, but its efficacy is limited in hypoxic tumors. Although numerous radiosensitizer compounds have been developed to enhance the effect of RT, progress has been stagnant. Through this systematic review, we provide an overview of radiosensitizers developed for malignant brain tumors, summarize their safety and efficacy, and evaluate areas for possible improvement. METHODS: Following PRISMA guidelines, PubMed, EMBASE, Cochrane, and Web of Science were searched using terminology pertaining to radiosensitizers for brain tumor RT. Articles reporting clinical evidence of nonantineoplastic radiosensitizers with RT for malignant central nervous system tumors were included. Data of interest were presumed mechanism of action, median overall survival (OS), progression-free survival (PFS), and adverse events. RESULTS: Twenty-two unique radiosensitizers were identified. Only 2/22 agents (fluosol with oxygen, and efaproxiral) showed improvement in OS in patients with glioblastoma and brain metastasis, respectively. A larger study was not able to confirm the latter. Improved PFS was reported with use of metronidazole, sodium glycididazole, and chloroquine. There was a wide range of toxicities, which prompted change of schedule or complete discontinuation of 9 agents. CONCLUSIONS: Progress in radiosensitizers for malignant CNS tumors has been limited. Only 2 radiosensitizers have shown limited improvement in survival. Alternative strategies such as synthetic drug design, based on a mechanism of action that is independent of crossing the blood-brain barrier, may be necessary. Use of drug development strategies using new technologies to overcome past challenges is necessary.

Long-term outcomes of spinal ependymomas: an institutional experience of more than 60 cases.

PURPOSE: Spinal ependymomas represent the most common primary intramedullary tumors for which optimal management remains undefined. When possible, gross total resection (GTR) is often the mainstay of treatment, with consideration of radiotherapy (RT) in cases of residual or recurrent tumor. The impact of extent of resection and radiotherapy remain understudied. OBJECTIVE: Report on a large institutional cohort with lengthy follow-up to provide information on long-term outcomes and to contribute to limited data assessing the value of extent of resection and RT. METHODS: Patients with pathologically proven primary spinal ependymoma between 1990 and 2018 were identified. Kaplan-Meier estimates were used to calculate progression-free survival (PFS); local-control (LC) and overall survival (OS). Logistic regression was used to analyze variables' association with receipt of RT. RESULTS: We identified 69 patients with ependymoma of which 4 had leptomeningeal dissemination at diagnosis and were excluded. Of the remaining cohort (n = 65), 42 patients (65%) had Grade II spinal ependymoma, 20 (31%) had Grade I myxopapillary ependymoma and 3 (5%) had Grade III anaplastic ependymoma; 54% underwent GTR and 39% underwent RT. With a median follow-up of 5.7 years, GTR was associated with improved PFS. For grade II lesions, STR+RT yielded better outcomes than STR alone (10y PFS 77.1% vs 68.2%, LC 85.7% vs 50%). Degree of resection was the only significant predictor of adjuvant radiotherapy (p < 0.0001). CONCLUSION: Our findings confirm the importance of GTR in spinal ependymomas. Adjuvant RT should be utilized in the setting of a subtotal resection with expectation of improved disease-related outcomes.

Implications of pneumonitis after chemoradiation and durvalumab for locally advanced non-small cell lung cancer.

BACKGROUND: Consolidation durvalumab improved overall survival (OS) in locally advanced non-small cell lung cancer (LA-NSCLC) treated with chemoradiotherapy (CRT) in the PACIFIC trial; however, pneumonitis was increased with durvalumab. We sought to examine real-world outcomes with the PACIFIC paradigm, especially factors associated with pneumonitis, using a multi-institutional review. METHODS: Patients with LA-NSCLC treated with CRT followed by durvalumab from January 2017-February 2019 were identified at 2 institutions. We characterized demographics, tumor factors, radiotherapy, and duration of durvalumab. We examined pneumonitis outcomes including re-challenge success, with secondary endpoints of progression-free survival (PFS) and OS. RESULTS: Thirty-four patients were included with median follow-up of 12 months (range, 3 to 20 months); 94% had stage III disease. The cumulative grade >2 pneumonitis rate was 26.5% with 2 patients developing grade 3 pneumonitis and no grade 4/5 events. Median time to pneumonitis after RT was 2.4 months (range, 0 to 4.9 months). Pneumonitis management included median prednisone dose of 60 mg for median taper of 6 weeks with durvalumab held for median of 4.5 weeks (range, 2 to 8 weeks); 70% of pneumonitis patients received durvalumab re-challenge, with pneumonitis recurring in 14% of patients. 3-month and 6-month pneumonitis-free-survival were 76.9% and 73.6%, respectively; 9- and 12-month OS were 96% (75.1-99.8%), 86.6% (63.5-95.5%), respectively; 9- and 12-month PFS were 68% (47.5-82.5%), 48.7% (25.3-68.3%). Pneumonitis development did not significantly impact PFS or OS (P>0.05). CONCLUSIONS: Among LA-NSCLC patients treated with CRT followed by consolidation durvalumab, more than 25% developed symptomatic pneumonitis. In this small case series, pneumonitis did not appear to negatively impact survival, and durvalumab re-challenge appeared feasible after pneumonitis treatment with steroids.

Survival of Primary Stereotactic Body Radiation Therapy Compared With Surgery for Operable Stage I/II Non-small Cell Lung Cancer.

BACKGROUND: Stereotactic body radiation therapy (SBRT) is an accepted primary treatment option for inoperable early-stage non-small cell lung cancer (NSCLC). The role of SBRT in the treatment of operable disease remains unclear. We retrospectively evaluated patients with operable early-stage NSCLC who elected to receive primary SBRT, examined factors associated with SBRT, and compared overall survival after surgical resection and SBRT. METHODS: The National Cancer Database was queried for patients with stage I/II, N0 NSCLC from 2004 to 2016. The proportion of patients who refused recommended surgery and were treated with SBRT was calculated. A propensity score predicting the probability of refusing surgery and receiving SBRT was generated and used to match SBRT and resected patients. Long-term overall survival was compared in the matched cohort using the Kaplan-Meier method and Cox regression. RESULTS: We identified 1359 patients (0.98%) who refused recommended surgery and elected SBRT. This proportion increased annually, from 0.1% in 2004 to 1.7% in 2016. Factors associated with SBRT were older age, black race, Medicaid coverage, lower T stage, and more recent diagnosis year. Propensity matching resulted in 1315 well-balanced pairs. Surgery was associated with higher median survival (74 vs 47 months, P < .01) in the matched cohort. Survival benefit persisted after adjusting for covariates on Cox regression (hazard ratio, 1.69; P < .01). CONCLUSIONS: Median survival was significantly higher after surgery compared with SBRT in a risk-adjusted matched cohort of patients judged to be surgical candidates. Operable patients considering primary SBRT should be educated regarding this difference in survival.

Cost-effectiveness of lung MRI in lung cancer screening.

OBJECTIVES: Recent studies with lung MRI (MRI) have shown high sensitivity (Sn) and specificity (Sp) for lung nodule detection and characterization relative to low-dose CT (LDCT). Using this background data, we sought to compare the potential screening performance of MRI vs. LDCT using a Markov model of lung cancer screening. METHODS: We created a Markov cohort model of lung cancer screening which incorporated lung cancer incidence, progression, and mortality based on gender, age, and smoking burden. Sensitivity (Sn) and Sp for LDCT were taken from the MISCAN Lung Microsimulation and Sn/Sp for MRI was estimated from a published substudy of the German Lung Cancer Screening and Intervention Trial. Screening, work-up, and treatment costs were estimated from published data. Screening with MRI and LDCT was simulated for a cohort of male and female smokers (2 packs per day; 36 pack/years of smoking history) starting at age 60. We calculated the screening performance and cost-effectiveness of MRI screening and performed a sensitivity analysis on MRI Sn/Sp and cost. RESULTS: There was no difference in life expectancy between MRI and LDCT screening (males 13.28 vs. 13.29 life-years; females 14.22 vs. 14.22 life-years). MRI had a favorable cost-effectiveness ratio of $258,169 in men and $403,888 in women driven by fewer false-positive screens. On sensitivity analysis, MRI remained cost effective at screening costs < $396 dollars and Sp > 81%. CONCLUSIONS: In this Markov model of lung cancer screening, MRI has a near-equivalent life expectancy benefit and has superior cost-effectiveness relative to LDCT. KEY POINTS: • In this Markov model of lung cancer screening, there is no difference in mortality between yearly screening with MRI and low-dose CT. • Compared to low-dose CT, screening with MRI led to a reduction in false-positive studies from 26 to 2.8% in men and 26 to 2.6% in women. • Due to similar life-expectancy and reduced false-positive rate, we found a favorable cost-effectiveness ratio of $258,169 in men and $403,888 in women of MRI relative to low-dose CT.