Early experience with hippocampal avoidance whole brain radiation therapy and simultaneous integrated boost for brain metastases.

PURPOSE: Cranial irradiation results in cognitive decline, which is hypothesized to be partially attributable to hippocampal injury and stem cell loss. Recent advances allow for targeted reduction of radiation dose to the hippocampi while maintaining adequate dose coverage to the brain parenchyma and additional increasing dose to brain metastases, a approach called hippocampal avoidance whole brain radiation therapy with a simultaneous integrated boost (HA-WBRT + SIB.) We review our early clinical experience with HA-WBRT + SIB. MATERIALS AND METHODS: We evaluated treatments and clinical outcomes for patients treated with HA-WBRT + SIB between 2014 and 2018. RESULTS: A total of 32 patients (median age, 63.5 years, range 45.3-78.8 years) completed HA-WBRT + SIB. Median follow-up for patients alive at the time of analysis was 11.3 months. The most common histology was non-small cell lung cancer (n = 22). Most patients (n = 25) were prescribed with WBRT dose of 30 Gy with SIB to 37.5 Gy in 15 fractions. Volumetric modulated arc therapy reduced treatment time (p < 0.0001). Median freedom from intracranial progression and overall survival from completion of treatment were 11.4 months and 19.6 months, respectively. Karnofsky Performance Status was associated with improved survival (p = 0.008). The most common toxicities were alopecia, fatigue, and nausea. Five patients developed cognitive impairment, including grade 1 (n = 3), grade 2 (n = 1), and grade 3 (n = 1). CONCLUSION: HA-WBRT + SIB demonstrated durable intracranial disease control with modest side effects and merits further investigation as a means of WBRT toxicity reduction while improving long-term locoregional control in the brain.

Enrichment of HER2 Amplification in Brain Metastases from Primary Gastrointestinal Malignancies.

BACKGROUND: In nongastric gastrointestinal (GI) cancers, HER2-positive (HER2+) disease is not common. In breast cancer, HER2 status is associated with increased risk of brain metastases and response to HER2-targeted therapy. The purpose of this project was to compare HER2 status in GI cancer brain metastases versus matched prior sites of disease in order to determine if HER2+ disease is more common intracranially. MATERIALS AND METHODS: We identified 28 patients with GI cancer who had craniotomy for brain metastases between 1999 and 2017 with intracranial metastatic tissue available at Massachusetts General Hospital. Twenty-four patients also had tissue from a prior site of disease. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) for HER2 were performed on all samples. A tumor was defined as HER2+ if it had 3+ staining by IHC or amplification by FISH. RESULTS: A prior site of disease (including intracranial metastases) was HER2+ for 13% of evaluable patients: 3 of 11 patients with colorectal cancer and no patients with esophageal or pancreatic cancer. The most recent brain metastases were HER2+ for 32% of patients: 2 of 3 esophageal squamous cell carcinomas, 3 of 10 esophageal adenocarcinomas (ACs), 3 of 14 colorectal ACs, and 1 of 1 pancreatic AC. Only 37.5% of patients with HER2+ brain metastasis had concordant HER2+ prior tissue (κ = 0.38, p = .017). CONCLUSION: In this cohort of patients with GI cancer with brain metastases, HER2+ status was more common intracranially compared with prior sites of disease. These findings suggest that testing HER2 in patients with GI cancer with brain metastases may lead to additional therapeutic options, regardless of HER2 status in previously examined tissue. IMPLICATIONS FOR PRACTICE: HER2 amplification is a well-known driver of oncogenesis in breast cancer, with associated increased risk of brain metastases and response to HER2-directed therapy. In nongastric gastrointestinal (GI) cancers, HER2 amplification is not common and consequently is infrequently tested. The current study shows that brain metastases in patients with GI primary malignancies have a relatively high likelihood of being HER2 positive despite HER2 amplification or overexpression being less commonly found in matched tissue from prior sites of disease. This suggests that regardless of prior molecular testing, patients with GI cancer with brain metastases who have tissue available are likely to benefit from HER2 assessment to identify potential novel therapeutic options.

Increase of pseudoprogression and other treatment related effects in low-grade glioma patients treated with proton radiation and temozolomide.

INTRODUCTION: Concurrent radiotherapy and temozolomide (TMZ) is associated with radiographic pseudoprogression (PsP) in glioblastoma. The occurrence of PsP and other treatment effects is less well understood in low-grade gliomas (LGG). The purpose of this study is to evaluate whether the addition of TMZ to radiotherapy increases the incidence of PsP in adults with LGG treated with proton radiotherapy (PRT). METHODS: Chart review and volumetric MRI-analysis was performed on radiotherapy-naive adults with WHO grade II or IDH mutant WHO grade III gliomas treated with PRT between 2005 and 2015. Progression was defined by histology, new chemotherapy initiation, or progressive increase in lesion volume beyond 40% from baseline. Post treatment related effects (PTRE) were defined as new/increased T2/FLAIR or abnormal enhancement which eventually resolved or stabilized without evidence of progression for a period of 6-12 months. PsP was defined as the subset of PRTE suspicious for progression or volumetrically increased at least 40% from baseline. Pearson's chi-squared test and Cox-proportional hazards models were used for statistical analysis. RESULTS: There were 119 patients meeting inclusion criteria. There was an increased risk of PsP following PRT + TMZ versus PRT-alone (HR = 2.2, p = 0.006, on Cox univariate analysis). Presence of PsP was associated with improved OS (p = 0.02 with PsP as time-varying covariate). CONCLUSIONS: TMZ use, when added to PRT, was associated with increased PsP in patients with LGG; however, patients with PsP tended to achieve longer survival.

The impact of timing of immunotherapy with cranial irradiation in melanoma patients with brain metastases: intracranial progression, survival and toxicity.

Immunotherapy (IT) is increasingly incorporated in the management of metastatic melanoma patients with brain metastases, but the impact of timing of IT with stereotactic radiosurgery (SRS) remains unclear. The aim of this study was to determine the temporal significance of IT in melanoma patients treated with cranial radiation therapy (RT) with respect to patterns of intracranial progression, overall survival (OS), and toxicity. We retrospectively reviewed consecutive melanoma patients with brain metastases undergoing cranial RT and IT between 2008 and 2015. Concurrent IT/RT was defined as IT administration within 30 days of RT. Intracranial progression, OS and radionecrosis were assessed. We identified 74 patients with 136 treated brain metastases. Median OS was 13.9 months. Performance status, pre-SRS surgery, and intracranial progression were correlated with OS. Concurrent IT/RT was used in 35 (47.3%) patients. Patients receiving concurrent IT/RT were less likely to have a BRAF mutation (p = 0.027) and more likely to be treated after 2013 (p = 0.010) compared to non-concurrently treated patients. Patients receiving concurrent IT/RT were more likely to have intracranial progression within 60-days (54.3% vs. 30.8%, p = 0.041). However, 25.7% of concurrent IT/RT patients attained ≥ 1 year intracranial progression-free survival. There were no significant differences in symptomatic radionecrosis (11.4% vs. 12.8%, p = 0.67). In conclusion, although melanoma patients with brain metastases receiving concurrent IT/RT were more likely to exhibit early intracranial disease progression, a significant proportion of non-early-progressors attained durable intracranial control. The combination of IT and cranial RT appears to be efficacious and safe. Prospective studies are required to clarify these retrospective findings.

Neurocognitive effects of proton radiation therapy in adults with low-grade glioma.

To understand neurocognitive effects of proton radiation therapy (PRT) in patients with low-grade glioma, we evaluated 20 patients who received this therapy prospectively and over 5 years with a comprehensive neuropsychological battery. 20 patients were evaluated at baseline and at yearly intervals for up to 5 years with a battery of neuropsychological measures that assessed intellectual, attention, executive, visuospatial and memory functions as well as mood and functional status. We evaluated change in cognitive functioning over time. We analyzed the relationship between cognitive performance and tumor location and also examined whether patients' performance differed from that reported in a study of normative practice effects. Overall, patients exhibited stability in cognitive functioning. Tumor location played a role in performance; those with tumors in the left hemisphere versus in the right hemisphere were more impaired at baseline on verbal measures (p < .05). However, we found greater improvement in verbal memory over time in patients with left than with right hemisphere tumors (p < .05). Results of our study, the first to investigate, in depth, neurocognitive effects of PRT in adults with low-grade gliomas, are promising. We hypothesize that the conformal advantage of PRT may contribute to preservation of cognitive functioning, although larger sample sizes and a longer period of study are required. Our study also highlights the need to consider normative practice effects when studying neurocognitive functioning in response to treatment over time, and the need to utilize comprehensive neuropsychological batteries given our findings that differentiate patients with left and right hemisphere tumors.

Proton therapy for low-grade gliomas: Results from a prospective trial.

BACKGROUND: In this prospective study, the authors evaluated potential treatment toxicity and progression-free survival in patients with low-grade glioma who received treatment with proton radiation therapy. METHODS: Twenty patients with World Health Organization grade 2 glioma who were eligible for radiation therapy were enrolled in a prospective, single-arm trial of proton therapy. The patients received proton therapy at a dose of 54 Gy (relative biological effectiveness) in 30 fractions. Comprehensive baseline and regular post-treatment evaluations of neurocognitive function, neuroendocrine function, and quality of life (QOL) were performed. RESULTS: All 20 patients (median age, 37.5 years) tolerated treatment without difficulty. The median follow-up after proton therapy was 5.1 years. At baseline, intellectual functioning was within the normal range for the group and remained stable over time. Visuospatial ability, attention/working memory, and executive functioning also were within normal limits; however, baseline neurocognitive impairments were observed in language, memory, and processing speed in 8 patients. There was no overall decline in cognitive functioning over time. New endocrine dysfunction was detected in 6 patients, and all but 1 had received direct irradiation of the hypothalamic-pituitary axis. QOL assessment revealed no changes over time. The progression-free survival rate at 3 years was 85%, but it dropped to 40% at 5 years. CONCLUSIONS: Patients with low-grade glioma tolerate proton therapy well, and a subset develops neuroendocrine deficiencies. There is no evidence for overall decline in cognitive function or QOL.

Survival patterns following brain metastases for patients with melanoma in the MAP-kinase inhibitor era.

Survival with BRAF-mutant metastatic melanoma is prolonged with MAP-kinase pathway inhibitors (MAPKi). Among patients with brain metastases (BM), however, the clinical course of MAPKi-treated patients is not well described. We therefore explored these patients' survival patterns compared to contemporary patients not treated with MAPKi. We analyzed 106 patients who developed melanoma BM between 2007 and 2013. Of these, 37 (35%) received de novo MAPKi for BRAF-mutant disease, which preceded BM in 49%. Immunotherapy was given to 54% of MAPKi-treated patients and 94% of those who did not receive MAPKi. We evaluated the potential influence of patient characteristics, systemic therapies, and BM-directed treatments on time to appearance of new BM and overall survival. With a median follow-up of 8.0 months after initial BM, MAPKi use was an independent predictor of prolonged survival after BM diagnosis (median 14.1 vs 7.0 months, P = 0.03, adjusted hazard ratio 0.39). This survival advantage was driven by the 16.6-month median survival of patients who initiated MAPKi after BM were diagnosed, versus 5.6 months if initiated prior to BM development (P = 0.03). Median survival from the onset of any systemic metastases was 22 months regardless of the timing of MAPKi relative to BM appearance. Time to in-brain progression was longer among patients whose MAPKi course was started after BM diagnosis, but MAPKi initiation prior to BM diagnosis was associated with longer time to intracranial involvement. These findings are consistent with potential MAPKi activity in intracranial melanoma.

Underutilization of radiation therapy in patients with glioblastoma: predictive factors and outcomes.

BACKGROUND: Randomized trials have demonstrated that radiation improves survival in patients with glioblastoma. The purpose of this study was to characterize the risk factors and impact of omission of radiation therapy in such patients. METHODS: The Surveillance, Epidemiology, and End Results (SEER) program was used to identify 22,777 patients diagnosed with glioblastoma between 1988 and 2007. Multivariable logistic regression was employed to identify predictors associated with omission of radiation. Cox regression was used to characterize the impact of omitting radiation on all-cause mortality. RESULTS: Among the entire cohort, 16,863 of 22,777 patients (74%) received radiation, whereas 5914 of 22,777 patients (26%) did not. Factors associated with omission of radiation included older age (OR=1.048 per year increase, 95% CI=1.046-1.051, P<.001), lower annual income (OR=0.93 per $10,000 increase, 95% CI=0.90-0.96, P<.001), African American race (reference=white, OR=1.19, 95% CI=1.03-1.37, P=.02), Hispanic race (OR=1.34, 95% CI=1.19-1.50, P< .001), Asian American race (OR=1.24, 95% CI=1.04-1.48, P<.001), unmarried status (OR=1.71, 95% CI=1.60-1.83, P< .001), and subtotal resection/biopsy (OR=1.82, 95% CI=1.69-1.96, P<.001). The use of radiation was significantly associated with improved overall survival (2-year survival: 14.6% versus 4.2%, P<.001; adjusted HR=2.09, 95% CI=2.02-2.16, P<.001). When the population was restricted to patients <50 years old, these findings remained largely unchanged. CONCLUSIONS: Radiation therapy is associated with survival benefit in patients with glioblastoma, and sociodemographic factors play a significant role in the underutilization of radiation. The underlying causes for these disparities in care require further research.

Survival in Patients With Spinal Metastatic Disease Treated Nonoperatively With Radiotherapy: Are the SORG-ML Algorithms Relevant?

SUMMARY OF BACKGROUND DATA: The SORG-ML algorithms for survival in spinal metastatic disease were developed in patients who underwent surgery and were externally validated for patients managed operatively. OBJECTIVE: To externally validate the SORG-ML algorithms for survival in spinal metastatic disease in patients managed nonoperatively with radiation. STUDY DESIGN: Retrospective cohort. METHODS: The performance of the SORG-ML algorithms was assessed by discrimination [receiver operating curves and area under the receiver operating curve (AUC)], calibration (calibration plots), decision curve analysis, and overall performance (Brier score). The primary outcomes were 90-day and 1-year mortality. RESULTS: Overall, 2074 adult patients underwent radiation for spinal metastatic disease and 29% (n=521) and 59% (n=917) had 90-day and 1-year mortality, respectively. On complete case analysis (n=415), the AUC was 0.76 (95% CI: 0.71-0.80) and 0.78 (95% CI: 0.73-0.83) for 90-day and 1-year mortality with fair calibration and positive net benefit confirmed by the decision curve analysis. With multiple imputation (n=2074), the AUC was 0.85 (95% CI: 0.83-0.87) and 0.87 (95% CI: 0.85-0.89) for 90-day and 1-year mortality with fair calibration and positive net benefit confirmed by the decision curve analysis. CONCLUSION: The SORG-ML algorithms for survival in spinal metastatic disease generalize well to patients managed nonoperatively with radiation.

Clinical discussion and review of the management of brain metastases.

Brain metastases are common in patients with cancer and are associated with a poor prognosis. Optimal treatment requires an integrative multidisciplinary approach, and therapeutic options may include stereotactic radiosurgery, whole-brain radiation therapy, surgical resection, chemotherapy, and targeted agents. The goals of therapy are to prolong survival, preserve neurologic function, and palliate symptoms. This article outlines the various therapeutic modalities, factors that guide treatment decisions, and medical management of frequently encountered complications of brain metastases.

Natural history and role of radiation in patients with supratentorial and infratentorial WHO grade II ependymomas: results from a population-based study.

Patients with World Health Organization (WHO) grade II supratentorial ependymomas are commonly observed after gross total resection (GTR), although supporting data are limited. We sought to characterize the natural history of such tumors. We used the Surveillance, Epidemiology, and End Results program to identify 112 patients ages 0-77 diagnosed with WHO grade II ependymomas between 1988 and 2007, of whom 63 (56 %) and 49 (44 %) had supratentorial and infratentorial primaries, respectively. Inclusion criteria were strict to ensure patient homogeneity. Of 33 patients with supratentorial tumors after GTR, 18 (55 %) received adjuvant radiation therapy and 15 (45 %) did not. Ependymoma-specific mortality (ESM) was the primary endpoint. With a median follow up of 4.5 years, only 1 of 33 patients with supratentorial ependymoma died of their disease after GTR; the 5-year estimate of ESM in this population was 3.3 % (95 % CI 0.2-14.8 %). Among patients with infratentorial ependymomas after GTR, the 5-year estimate of ESM was 8.7 % (95 % CI 1.4-24.6 %). In patients with subtotally resected tumors, 5-year estimates of ESM in patients with supratentorial and infratentorial primaries were 20.1 % (95 % CI 8.0-36.2 %) and 12.3 % (95 % CI 2.9-28.8 %), respectively. Among the whole cohort, on both univariable and multivariable regression, extent of resection was predictive of ESM, while tumor location and use of radiation were not. After GTR, patients with WHO grade II supratentorial ependymomas have a very favorable natural history with low associated cancer-specific mortality. Observation, with radiation reserved as a salvage option, may be a reasonable postoperative strategy in this population.

NRG Oncology/RTOG1205: A Randomized Phase II Trial of Concurrent Bevacizumab and Reirradiation Versus Bevacizumab Alone as Treatment for Recurrent Glioblastoma.

PURPOSE: To assess whether reirradiation (re-RT) and concurrent bevacizumab (BEV) improve overall survival (OS) and/or progression-free survival (PFS), compared with BEV alone in recurrent glioblastoma (GBM). The primary objective was OS, and secondary objectives included PFS, response rate, and treatment adverse events (AEs) including delayed CNS toxicities. METHODS: NRG Oncology/RTOG1205 is a prospective, phase II, randomized trial of re-RT and BEV versus BEV alone. Stratification factors included age, resection, and Karnofsky performance status (KPS). Patients with recurrent GBM with imaging evidence of tumor progression ≥ 6 months from completion of prior chemo-RT were eligible. Patients were randomly assigned 1:1 to re-RT, 35 Gy in 10 fractions, with concurrent BEV IV 10 mg/kg once in every 2 weeks or BEV alone until progression. RESULTS: From December 2012 to April 2016, 182 patients were randomly assigned, of whom 170 were eligible. Patient characteristics were well balanced between arms. The median follow-up for censored patients was 12.8 months. There was no improvement in OS for BEV + RT, hazard ratio, 0.98; 80% CI, 0.79 to 1.23; P = .46; the median survival time was 10.1 versus 9.7 months for BEV + RT versus BEV alone. The median PFS for BEV + RT was 7.1 versus 3.8 months for BEV, hazard ratio, 0.73; 95% CI, 0.53 to 1.0; P = .05. The 6-month PFS rate improved from 29.1% (95% CI, 19.1 to 39.1) for BEV to 54.3% (95% CI, 43.5 to 65.1) for BEV + RT, P = .001. Treatment was well tolerated. There were a 5% rate of acute grade 3+ treatment-related AEs and no delayed high-grade AEs. Most patients died of recurrent GBM. CONCLUSION: To our knowledge, NRG Oncology/RTOG1205 is the first prospective, randomized multi-institutional study to evaluate the safety and efficacy of re-RT in recurrent GBM using modern RT techniques. Overall, re-RT was shown to be safe and well tolerated. BEV + RT demonstrated a clinically meaningful improvement in PFS, specifically the 6-month PFS rate but no difference in OS.

Brain metastases after breast-conserving therapy and systemic therapy: incidence and characteristics by biologic subtype.

The characteristics of brain metastases (BM) that develop after breast-conserving therapy (BCT) for early-stage breast cancer (BC) remain incompletely defined. We examined 1,434 consecutive patients with stage I/II invasive BC who received BCT from 1997 to 2006, 91 % of whom received adjuvant systemic therapy, according to BC subtype. Median follow-up was 85 months. Overall 5-year cumulative incidence of BM was 1.7 %; 0.1 % for luminal A, 3.3 % for luminal B, 3.2 % for luminal-HER2, 3.7 % for HER2, and 7.4 % for triple negative (TN). Women who developed BM were more likely at BC diagnosis to be younger (P < .0001) and have node-positive (P < .0001), grade 3 (P < .0001), hormone receptor-negative (P = .006), and HER2-positive (P = .01) tumors. Median time from BC diagnosis to BM was 51.4 months (range, 7.6-108 months), which was longer among luminal versus non-luminal subtypes (P = .0002; median, 61.4 vs. 34.5 months). Thirty-four percent of patients who developed distant metastases (DM) eventually developed BM. Median time from DM to BM was 12.8 months but varied by subtype, including 7.4 months for TN, 9.6 months for luminal B, and 27.1 months for HER2. Eighty-one percent of all BM patients presented with neurologic symptoms. Median number of BM at diagnosis was two, and median BM size was 15 mm, with TN (27 mm) and luminal B (16 mm) exhibiting the largest median sizes. In conclusion, the risk of BM after BCT varies significantly by subtype. Given the large size and symptomatic presentation among luminal B and TN subtypes, earlier BM detection might improve quality of life or increase eligibility for non-invasive treatments including stereotactic radiosurgery. Women with DM from these two BC subtypes have a high incidence of BM with a short latency, suggesting an ideal target population for trials evaluating the utility of MRI screening.

Long-term outcomes and late toxicity of adult medulloblastoma treated with combined modality therapy: A contemporary single-institution experience.

BACKGROUND: Medulloblastoma (MB) is a rare central nervous system malignancy of adults, with limited contemporary studies to define treatment guidelines and expected late toxicity. METHODS: A single-center, retrospective study was conducted of patients age ≥18 years from 1997-2019 with MB and who were treated with postoperative radiotherapy. Late toxicity was defined as a minimum of 18 months from diagnosis. Overall survival (OS) and progression-free survival (PFS) were characterized using Kaplan-Meier and Cox regression analyses. RESULTS: Fifty-nine patients met criteria, with median age of 25 years (range 18-62 y) and median follow-up of 6.5 years (range 0.7-23.1 y). At diagnosis, 68% were standard-risk, 88% Chang M0, and 22% with anaplastic histology. Gross total resection was achieved in 75%; median craniospinal irradiation dose was 30.6 Gy (relative biological effectiveness [RBE]), median total dose was 54.0 Gy (RBE), 80% received proton radiotherapy; 81% received chemotherapy. 5 year PFS and OS were 86.5% and 95.8%, respectively; 10 year PFS and OS were 83.9% and 90.7%, respectively. Anaplastic histology was associated with worse PFS (P = .04). Among eight recurrences, 25% presented after 5 years. Most common grade ≥2 late toxicities were anxiety/depressive symptoms (30%), motor dysfunction (25%), and ototoxicity (22%). Higher posterior fossa radiation dose was associated with increased risk of late toxicity, including worse cognitive dysfunction (P = .05). CONCLUSIONS: Adults with MB have favorable survival outcomes, but late failures and toxicity are not uncommon. Better understanding of prognostic factors, possibly from molecular subtyping, may help to define more personalized treatments for patients with high risk of recurrence and long-term treatment sequelae.

Adjuvant Radiation Therapy Versus Surveillance After Surgical Resection of Atypical Meningiomas.

PURPOSE: The optimal timing of adjuvant radiation therapy (RT) in the management of atypical meningiomas remains controversial. We compared the outcomes of atypical meningiomas managed with upfront adjuvant RT versus postoperative surveillance. METHODS AND MATERIALS: Patients with intracranial atypical meningiomas who underwent resection between 2000 and 2015 at a single institution were identified. Patients receiving adjuvant RT (n = 51), defined as RT within the first year of surgery before tumor progression/recurrence (P/R), were compared with those undergoing initial surveillance (n = 179). The primary endpoints were radiographic evidence of P/R and time to P/R from surgery. RESULTS: A total of 230 patients were identified. Fifty-one (22%) patients received upfront adjuvant RT, and 179 (78%) underwent surveillance. Compared with the surveillance group, patients who received adjuvant RT had larger tumors (5.2 cm vs 4.6 cm; P = .04), were more likely to have undergone subtotal resection (65% vs 26%; P < . 01), and more often had bone invasion (18% vs 7%; P = .02). On multivariable analysis, receipt of adjuvant RT was associated with a lower risk of P/R compared with surveillance (hazard ratio, 0.21; 95% confidence interval, 0.11-0.41; P < .01). Patients who initially underwent surveillance and then received salvage RT at time of P/R had a shorter median time to local progression after RT compared with patients who developed local P/R after upfront adjuvant RT (19 vs 64 months, respectively; P < . 01). CONCLUSION: Upfront adjuvant RT was associated with improved local control in atypical meningiomas irrespective of extent of initial resection compared with surveillance. Early adjuvant RT should be strongly considered after gross total resection of atypical meningiomas.

Radiation and chemotherapy for high-risk lower grade gliomas: Choosing between temozolomide and PCV.

PURPOSE: The majority of patients with high-risk lower grade gliomas (LGG) are treated with single-agent temozolomide (TMZ) and radiotherapy despite three randomized trials showing a striking overall survival benefit with adjuvant procarbazine, lomustine, and vincristine (PCV) chemotherapy and radiotherapy. This article aims to evaluate the evidence and rationale for the widespread use of TMZ instead of PCV for high-risk LGG. METHODS AND MATERIALS: We conducted a literature search utilizing PubMed for articles investigating the combination of radiotherapy and chemotherapy for high-risk LGG and analyzed the results of these studies. RESULTS: For patients with IDH mutant 1p/19q codeleted LGG tumors, there is limited evidence to support the use of TMZ. In medically fit patients with codeleted disease, existing data demonstrate a large survival benefit for PCV as compared to adjuvant radiation therapy alone. For patients with non-1p/19q codeleted LGG, early data from the CATNON study supports inclusion of adjuvant TMZ for 12 months. Subset analyses of the RTOG 9402 and EORTC 26951 do not demonstrate a survival benefit for adjuvant PCV for non-1p/19q codeleted gliomas, however secondary analyses of RTOG 9802 and RTOG 9402 demonstrated survival benefit in any IDH mutant lower grade gliomas, regardless of 1p/19q codeletion status. CONCLUSIONS: At present, we conclude that current evidence does not support the widespread use of TMZ over PCV for all patients with high-risk LGG, and we instead recommend tailoring chemotherapy recommendation based on IDH status, favoring adjuvant PCV for patients with any IDH mutant tumors, both those that harbor 1p/19q codeletion and those non-1p/19q codeleted. Given the critical role radiation plays in the treatment of LGG, radiation oncologists should be actively involved in discussions regarding chemotherapy choice in order to optimize treatment for their patients.

Post-operative radiation therapy to the surgical cavity with standard fractionation in patients with brain metastases.

The paradigm for post-operative cavity radiation therapy has shifted to more targeted, less morbid approaches. Single-fraction or hypofractionated radiation therapy is a common approach to treating the postoperative cavity but is associated with a local failure rate 20-40%. We employed an alternative treatment strategy involving fractionated partial brain radiation therapy to the surgical cavity. Patients with brain metastases who underwent radiation treatment 30-42 Gy in 3 Gy/fraction regimens to surgical cavity were retrospectively identified. The 6-month and 12-month freedom from local failure rates were 97.0% and 88.2%. Three patients (7%) experienced local failure at 4, 6, and 22 months. Of these, the histologies were colorectal adenocarcinoma (N = 1) and breast adenocarcinoma (N = 2). The 6-month and 12-month freedom from distant brain metastases rates were 74.1% and 68.8%, respectively, and the 6-month and 12-month overall survival rates were 84.9% and 64.3% respectively. The median overall survival was 39 months, and there were no events of late radionecrosis. Fractionated partial brain irradiation to the surgical cavity of resected brain metastases results in low rates of local failure. This strategy represents an alternative to SRS and WBRT.

Volumetric and actuarial analysis of brain necrosis in proton therapy using a novel mixture cure model.

BACKGROUND AND PURPOSE: High-dose fractionated radiotherapy is often necessary to achieve long-term tumor control in several types of tumors involving or within close proximity to the brain. There is limited data to guide on optimal constraints to the adjacent nontarget brain. This investigation explored the significance of the three-dimensional (3D) dose distribution of passive scattering proton therapy to the brain with other clinicopathological factors on the development of symptomatic radiation necrosis. MATERIALS AND METHODS: All patients with head and neck, skull base, or intracranial tumors who underwent proton therapy (minimum prescription dose of 59.4 Gy(RBE)) with collateral moderate to high dose radiation exposure to the nontarget brain were retrospectively reviewed. A mixture cure model with respect to necrosis-free survival was used to derive estimates for the normal tissue complication probability (NTCP) model while adjusting for potential confounding factors. RESULTS: Of 179 identified patients, 83 patients had intracranial tumors and 96 patients had primary extracranial tumors. The optimal dose measure obtained to describe the occurrence of radiation necrosis was the equivalent uniform dose (EUD) with parameter a = 9. The best-fit parameters of logistic NTCP models revealed D50 = 57.7 Gy for intracranial tumors, D50 = 39.5 Gy for extracranial tumors, and γ50 = 2.5 for both tumor locations. Multivariable analysis revealed EUD and primary tumor location to be the strongest predictors of brain radiation necrosis. CONCLUSION: In the current clinical volumetric data analyses with multivariable modelling, EUD was identified as an independent and strong predictor for brain radiation necrosis from proton therapy.