Whole Brain Radiotherapy Dose Research Articles

Prognostic factors of primary brain metastasis from SCLC treated by whole-brain radiotherapy

AbstractBackground:Small-cell lung cancer (SCLC) has poor prognosis owing to the high risk of distant metastasis.Purpose:To identify the prognosticators of brain metastasis from SCLC treated by whole-brain radiotherapy.Material and methods:We evaluated patients diagnosed with primary brain metastasis from SCLC between 1 January 2010 and 30 September 2019. Age, sex, disease stage at the first examination, time to the diagnosis of brain metastasis, state of other lesions at the diagnosis of brain metastasis, haematological parameters, neurologic symptoms, whole-brain radiotherapy dose, imaging findings of the brain metastasis (single or multiple), and chemotherapy and radiotherapy status were investigated for correlations with survival from the diagnosis of brain metastasis.Results:A total of 24 participants were evaluated. After radiotherapy, the median survival period was 118·5 (22–998) days, and 21 patients died during the follow-up period. Multivariate stepwise analysis of the four parameters of lactate dehydrogenase (LDH) level (within vs. above the reference value), platelet level (continuous variable), neurologic symptoms (with versus. without), and NSE (neuron-specific enolase) level (continuous variable) identified the following significant differences: neurologic symptoms were 3·81 (95% CI 1·07–13·5, p = 0·04), and NSE was 1·01 (95% CI 1·00–1·01, p = 0·04).Conclusion:NSE and neurologic symptoms are prognosticators of brain metastasis from SCLC treated by whole-brain radiotherapy.

Consolidative or palliative whole brain radiation for secondary CNS diffuse large B-Cell lymphoma

We analyzed 25 patients receiving whole brain radiation (WBRT) for secondary CNS lymphoma (SCNSL), grouped by consolidative intent (after complete/partial response, n = 13) vs. palliative intent (initial CNS treatment, primary refractory disease, or CNS progression, n = 12). Median WBRT dose for the consolidative and palliative cohorts were 24 Gy and 30 Gy, respectively. For 13 patients receiving consolidative WBRT, median OS was 24 months from WBRT and 2-year OS was 64%. Three patients had CNS relapse at 2, 9, and 24 months after consolidative WBRT. For 12 patients receiving palliative WBRT, median OS was 3 months from WBRT and two-year OS was 8%. All 10 patients with neurologic symptoms had documented improvement. In conclusion, consolidative WBRT after chemotherapy response led to reasonable long-term survival and may be an effective strategy for SCNSL, especially transplant-ineligible patients and/or isolated CNS recurrence. Palliative WBRT effectively improved neurologic symptoms, but survival was usually only months.

Whole brain radiotherapy with partial hair-sparing technique-a feasibility study

Introduction: Whole brain radiotherapy (WBRT) is a common palliative treatment for brain metastases from solid tumours. Traditionally, it is given with opposed lateral fields causing total alopecia as hair-bearing scalp skin receives the full dose. Volumetric modulated arc therapy (VMAT) can deliver WBRT with a simultaneous integrated boost (SIB) to larger metastases whilst minimising dose to critical structures such as the hippocampus. This feasibility study aimed to test the hypothesis that a reduced dose to the scalp using a VMAT hair-sparing WBRT protocol would spare scalp hair and reduce alopecia at four weeks post treatment without compromising disease control at three months. Methods: The Hair Spare study (01.07 WBRTMel sub-study SS01.13) was an investigator-initiated, prospective feasibility study. A VMAT hair-sparing WBRT protocol was developed to limit the dose to the scalp to 16 Gray (Gy) in 15 fractions. The primary objective was the rate of alopecia at 4 weeks post RT as measured by CTCAE v4 and clinician and patient perception. Quality of life (QoL) was assessed at baseline, one month and three months post treatment with validated instruments including European Organisation for Research and Treatment of Cancer (EORTC) QoL Questionnaire (QLQ-C15-PAL+4) plus four additional questions specifically relating to hair, a visual analogue scale (VAS) to measure the perception of hair loss severity, and the total Chemotherapy-Induced Alopecia Distress Scale (CADS). Results: Nine patients with brain metastases from melanoma (6), breast (2) and lung (1) cancer were enrolled at the Mater Sydney Hospital, Crows Nest, Australia. At 4 weeks, 5 patients were evaluable: 4 reported moderate alopecia (CTCAE v4 Grade 2) and 1 reported mild alopecia (CTCAE v4 Grade 1). All 5 wore wigs or scarves to hide hair loss. Any amount of hair loss impacted QoL. Reduced hair loss compared to complete alopecia, as usually found with conventional WBRT, did not translate to a mean improvement in QoL. There was no symptomatic intracranial progression of disease while the patients remained on study. Two patients had MRI at 3 months, and both had evidence of intracranial progression of disease within the volume that had received prescription WBRT dose. From the data collected it seems that VMAT hair-sparing WBRT was well-tolerated. Conclusion: VMAT hair-sparing WBRT partially spared scalp hair at four weeks post WBRT and did not compromise symptomatic disease control during the study. The treating oncologists observed that the hair grew back quicker than with conventional WBRT, and that combined cytotoxic chemotherapy was additive to RT-induced alopecia. However, the study was not optimal in that data collection was hampered by patient availability. The patient population was too unwell to be followed up according to the protocol.

Survival time and prognostic factors after whole-brain radiotherapy of brain metastases from of breast cancer.

BackgroundBreast cancer has a poor prognosis due to the high risk of distant metastasis.PurposeTo identify the prognosticators of brain metastasis from breast cancer treated by whole-brain radiotherapy.Material and MethodsWe evaluated patients diagnosed with primary brain metastasis without carcinomatous meningitis from breast cancer and had undergone whole-brain radiotherapy as initial treatment between 1 January 2010 and 30 September 2019. We investigated associations between overall survival time from diagnosis using cranial contrast-enhanced magnetic resonance imaging (MRI)/computed tomography (CT) and the following parameters: (i) age; (ii) sex; (iii) time to appearance of brain metastasis; (iv) other metastasis at appearance of brain metastasis; (v) blood test; (vi) symptoms at time of brain metastasis; (vii) whole-brain radiotherapy dose; (viii) whether whole-brain radiotherapy was completed; (ix) course of chemo- or radiotherapy; (x) subtype; (xi) additional irradiation after whole-brain radiotherapy; (xii) pathology; and (xiii) imaging findings.ResultsWe evaluated 29 consecutive female patients (mean age 55.2 ± 12.1 years). Median overall survival time after diagnosis on cranial contrast-enhanced MRI/CT was 135 days (range 16–2112 days). Multivariate stepwise analysis of the three parameters of lactate dehydrogenase, dose, and subtype identified the following significant differences: Hazard Ratio (HR) for dose (discontinued, 30 Gy/10 fractions, 31.5 Gy/11 fractions, 32.5 Gy/11 fractions, 37.5 Gy/15 fractions) was 0.08 (95% confidence interval [CI] 0.02–0.30, P < 0.01), and HR for subtype (luminal, HER2, triple-negative) was 2.70 (95% CI 1.16–6.243, P < 0.01).ConclusionHER2-type and 37.5 Gy/15 fractions are good prognostic factor after whole-brain radiotherapy in breast cancer with brain metastases.

Tolerability of radiation with concurrent temozolomide and effect on survival in chemo-refractory CNS lymphoma.

e14554 Background: There is no consensus for the treatment of central nervous system lymphoma (CNSL) refractory to first line high dose methotrexate-based chemotherapy. Whole brain radiation (WBRT) has often been used but may lead to unacceptable neurocognitive dysfunction. We examined our institutional experience with treating CNSL with radiotherapy (RT) and concurrent temozolomide (TMZ) including the resultant acute and long term toxicities. Methods: This single institution IRB approved retrospective study examined treatment, toxicity, and outcome variables in adults with primary or secondary CNS lymphoma. Inclusion criteria were brain-directed RT and development of the treatment plan at our institution. Three main RT field designs were used, including low and high dose WBRT and low dose WBRT with a focal boost to residual disease (WBRT+boost). We assessed relationships between treatment approach (RT field design and concurrent TMZ use) and clinical outcomes and toxicities using multivariable logistic regression models and Kaplan-Meier methods. Toxicity was recorded using the Common Terminology Criteria for Adverse Events version 5. Results: A total of 93 patients with median age of 57 years (range 24 – 86) treated from 2004 – 2019 were included, and 26 patients received concurrent TMZ. The RT field design of low dose WBRT (median dose: 23.4Gy) plus focal boost (median dose: 21.6Gy) was associated with favorable overall survival (OS) and progression free survival (PFS) without any significant difference in Grade 3+ toxicity compared to low dose WBRT (p = 0.20) or WBRT without boost (p = 0.80). Concurrent TMZ with RT was associated with significantly improved OS (HR 0.46, p = 0.025) and CNS PFS (HR 0.49, p = 0.019). Four of nine (44%) Grade 3+ non-hematologic toxicities occurred in patients receiving concurrent TMZ (p = 0.40). The most common non-hematologic toxicities included fatigue and nausea. Long term neurocognitive dysfunction was similar whether or not patients received concurrent TMZ (21% in TMZ group vs 23% in non-TMZ group; OR 0.87, 95% CI 0.25 – 2.68, p = 0.82) and irrespective of RT field design (WBRT+boost vs low dose WBRT p = 0.25, WBRT+boost vs WBRT without boost p = 0.19). Conclusions: Our findings suggest that concurrent TMZ use with brain RT for chemo-refractory CNSL is a promising strategy, with improved survival and no major additional toxicity. Further research that includes rigorous neurocognitive assessments is needed in prospective clinical trials to guide treatment approaches using concurrent TMZ with brain RT in CNSL patients.

Institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases.

e14504 Background: The management of melanoma with multiple brain metastases (MBM) is complex given improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a radiotherapy technique with limited outcomes data. We report our institutional outcomes for MBM patients receiving WBRT and assess whether certain clinical factors impact prognosis. Methods: A retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000-2018 treated with WBRT, with or without systemic treatments, were included. Post-WBRT brain MRI scans were assessed at timed intervals for radiographic response. Clinical and treatment variables associated with overall survival (OS), progression free survival (PFS), intracranial failure-free survival (IFFS), and local failure-free survival (LFFS) were assessed. Data was collected on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits. Results: Of 1347 patients treated with WBRT from 2000-2018, 63 patients had melanoma. 69% of patients had ≥5 brain metastases at the time of WBRT, 68% had extracranial disease, and 71% received steroids during their overall treatment course. Most had received previous therapies and had WBRT as a last resort. Median WBRT dose was 30 Gray over 10 fractions. Median follow-up was 4.0 months. Six-month OS, PFS, IFFS, and LFFS were 52.7%, 20.4%, 52.3%, and 43%. Median OS, PFS, IFFS, and LFFS were 7.0 months, 2.2 months, 6.1 months, and 4.9 months. Performance status correlated with OS on univariate and multivariate analysis. BRAFi was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07-0.79, p = 0.019), although this was not seen on multivariate analysis. There was a 19% rate of memory deficits. Among the 46 patients with post-WBRT brain scans, 17% had radionecrosis and 28% had intralesional hemorrhage. Not all radiographically noted radiotoxicities were clinically significant, although hemorrhage decreased IFFS on both univariate and multivariate analysis. Conclusions: Outcomes for MBM patients receiving WBRT indicate that WBRT remains a worthy option to control intracranial disease. Treatment-related effects such as hemorrhage, necrosis, or cognitive changes are considerations. Median PFS and IFFS suggest that systemic disease control continues to be the greater issue. The role of WBRT should be re-evaluated in the modern era, which features advanced imaging detection ability, newer systemic agents, and improved steroid avoidance strategies.

Hippocampal changes in inflammasomes, apoptosis, and MEMRI after radiation-induced brain injury in juvenile rats

PurposeThe aim of this study was to characterize changes in hippocampal inflammasomes, pyroptosis and apoptosis in juvenile rats after brain irradiation and to assess whether manganese-enhanced magnetic resonance imaging (MEMRI) reflected those changes.Materials and methodsFour-week-old male Sprague-Dawley rats received a whole-brain radiation dose of 15 Gy or 25 Gy. Hippocampal inflammasomes and apoptosis were measured using Western blot analysis at 4 days and 8 weeks after irradiation. MEMRI and magnetic resonance spectroscopy (MRS) were performed at the same time points.ResultsNeither the 15 Gy nor 25 Gy group showed changes in the expression of inflammasome proteins absent in melanoma 2 (AIM2), gasdermin-D (GSDMD), nucleotide oligomerization domain-like receptor protein 1 (NLRP1) and NLRP3 at 4 days or 8 weeks after radiation injury (P > 0.05). Furthermore, the expression levels of the inflammatory cytokines interleukin-1β (IL-1β) and IL-18 were not significantly different among the groups (P > 0.05). The expression levels of cleaved caspase-1 and -3, indicators of apoptosis, were higher in the irradiation groups than in the control group at 4 days post irradiation, especially for caspase-3 (P < 0.05), but this increase was slightly attenuated at 8 weeks after radiation injury. Four days post irradiation, the MEMRI signal intensity (SI) in the irradiation groups, especially the 25 Gy group, was significantly lower than that in the control group (P < 0.05). Eight weeks after radiation injury, the SI of the 15 Gy group and the 25 Gy group recovered by different degrees, but the SI of the 25 Gy group was still significantly lower than that of the control group (P < 0.05). On day 4 post irradiation, the metabolic ratio of N-acetylaspartate (NAA) to creatine (Cr) in the 15 Gy group and 25 Gy group was significantly lower than that in the control group (P < 0.05). The NAA/Cr ratio in the 15 Gy group recovered to control levels at 8 weeks (P > 0.05), but the NAA/Cr ratio in the 25 Gy group remained significantly lower than that in the control group (P < 0.05).ConclusionRadiation-induced brain injury is dose-dependently associated with apoptosis but not inflammasomes or pyroptosis, and the change in apoptosis can be detected by MEMRI.

Prognostic factors for survival in colorectal cancer patients with brain metastases undergoing whole brain radiotherapy: multicenter retrospective study

Whole brain radiotherapy (WBRT) is a mainstay of the treatment for brain metastases (BM). We evaluated prognostic factors in colorectal cancer (CRC) patients undergoing WBRT for BM. The medical records of 106 CRC patients undergoing WBRT for BM between 2000 and 2014 at three institutions were reviewed. Patient and tumor factors were analyzed to identify the prognostic factors for overall survival (OS) calculated from the date of BM diagnosis to the date of death or last follow-up. Surgical resection of BM was performed in six patients. The dose of WBRT was 30 Gy, and boost radiotherapy or stereotactic radiosurgery (8–23 Gy) was given to 15 patients. Systemic therapy for BM was administered in one patient before WBRT and 26 patients after WBRT. The median follow-up time was 3.9 months (range, 0.4–114.1 months). The median OS time was 3.9 months, and the 1-year OS rate was 18.2%. Older age (>65 years), multiple BM (≥3), elevated level of carcinoembryonic antigen (CEA, >5 ng/ml) at BM diagnosis, and extracranial metastases were adverse prognostic factors for OS. Patient with 0–1 factor showed better OS (at 1 year, 76.9%) than patients with 2 factors (16.7%) or 3–4 factors (4.2%; p < 0.001). In conclusion, we evaluated age, the number of BM, CEA level, and extracranial metastases as the prognostic factors for OS in CRC patients undergoing WBRT. Our result might be useful to develop prognostic models predicting survival for patients whom WBRT is intended for.

Relationship between WBRT total dose, intracranial tumor control, and overall survival in NSCLC patients with brain metastases - a single-center retrospective analysis

BackgroundThe relationship between whole brain radiotherapy (WBRT) dose with intracranial tumor control and overall survival (OS) in patients with non-small cell lung cancer (NSCLC) brain metastases (BM) is largely unknown.MethodsWe retrospectively analyzed 595 NSCLC BM patients treated consecutively at the Fourth Hospital of Hebei Medical University between 2013 to 2015. We assigned the patients into 4 dose groups of WBRT: none, < 30, 30–39, and ≥ 40 Gy and assessed their relationship with OS and intracranial progression-free survival (iPFS). Cox models were utilized. Covariates included sex, age, KPS, BM lesions, extracranial metastasis, BM and lung tumor resection, chemotherapy, targeted therapy, and focal radiotherapy modalities.ResultsPatients had a mean age of 59 years and were 44% female. Their median survival time (MST) of OS and iPFS were 9.3 and 8.9 months. Patients receiving none (344/58%), < 30 (30/5%), 30–39 (93/16%), and ≥ 40 (128/22%) Gy of WBRT had MST of OS (iPFS) of 7.3 (6.8), 6.0 (5.4), 10.3 (11.9) and 11.9 (11.9) months, respectively. Compared to none, other WBRT groups had adjusted HRs for OS - 1.23 (p > 0.20), 0.72 (0.08), 0.61 (< 0.00) and iPFS - 1.63 (0.03), 0.71 (0.06), 0.67 (< 0.01). Compared to 30–39 Gy, WBRT dose ≥40 Gy was not associated with improved OS and iPFS (all p > 0.40). Stratified analyses by 1–3 and ≥ 4 BM lesions and adjustment analyses by each prognostic index of RPA class, Lung-GPA and Lung-molGPA supported these relationships as well.ConclusionsCompared to none, WBRT doses ≥30 Gy are invariably associated with improved intracranial tumor control and survival in NSCLC BM patients.

Lithium treatment reverses irradiation-induced changes in rodent neural progenitors and rescues cognition

Cranial radiotherapy in children has detrimental effects on cognition, mood, and social competence in young cancer survivors. Treatments harnessing hippocampal neurogenesis are currently of great relevance in this context. Lithium, a well-known mood stabilizer, has both neuroprotective, pro-neurogenic as well as antitumor effects, and in the current study we introduced lithium treatment 4 weeks after irradiation. Female mice received a single 4 Gy whole-brain radiation dose on postnatal day (PND) 21 and were randomized to 0.24% Li2CO3 chow or normal chow from PND 49 to 77. Hippocampal neurogenesis was assessed on PND 77, 91, and 105. We found that lithium treatment had a pro-proliferative effect on neural progenitors, but neuronal integration occurred only after it was discontinued. Also, the treatment ameliorated deficits in spatial learning and memory retention observed in irradiated mice. Gene expression profiling and DNA methylation analysis identified two novel factors related to the observed effects, Tppp, associated with microtubule stabilization, and GAD2/65, associated with neuronal signaling. Our results show that lithium treatment reverses irradiation-induced loss of hippocampal neurogenesis and cognitive impairment even when introduced long after the injury. We propose that lithium treatment should be intermittent in order to first make neural progenitors proliferate and then, upon discontinuation, allow them to differentiate. Our findings suggest that pharmacological treatment of cognitive so-called late effects in childhood cancer survivors is possible.

Optimizing Whole Brain Radiation Therapy Dose and Fractionation: Results From a Prospective Phase 3 Trial (NCCTG N107C [Alliance]/CEC.3)

Whole brain radiation therapy (WBRT) remains a commonly used cancer treatment, although controversy exists regarding the optimal dose/fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. NCCTG N107C [Alliance]/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the dose/fractionation that would be used for all patients treated at that site (either 30 Gy in 10 fractions or 37.5 Gy in 15 fractions). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher's exact tests. Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fractions (53%), and 43 were treated with 37.5 Gy in 15 fractions (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology was more frequent with protracted WBRT: 72% vs 45%, P = .01), and 93% of patients completed the full course of WBRT. A more protracted WBRT dose regimen (37.5 Gy in 15 fractions) did not significantly affect time to cognitive failure (hazard ratio [HR], 0.9; 95% confidence interval [CI], 0.6-1.39; P = .66), surgical bed control (HR, 0.52 [95% CI, 0.22-1.25], P = .14), intracranial tumor control (HR, 0.56 [95% CI, 0.28-1.12], P = .09), or overall survival (HR, 0.72 [95% CI, 0.45-1.16], P = .18). Although there was no reported radionecrosis, there is a statistically significant increase in the risk of at least 1 grade ≥3 adverse event with 37.5 Gy in 15 fractions versus 30 Gy in 10 fractions (54% vs 31%, respectively, P = .03). This post hoc analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with the lengthened course of WBRT. For patients with brain metastases where WBRT is recommended, shorter course hypofractionated regimens remain the current standard of care.

NTCP Modeling of Xerostomia Related to Parotid Dose from Whole-Brain Radiation Therapy

We recently reported an association between parotid dose and xerostomia in patients receiving whole brain radiation therapy (WBRT). The purpose of this analysis is to perform normal tissue complication probability (NTCP) modeling to further explore the parotid dosimetric indices associated with patient-reported xerostomia. Patients receiving WBRT (25-40 Gy in 10-20 fractions) for any diagnosis were enrolled on a prospective observational study. WBRT was delivered with 3D-conformal radiation therapy using standard opposed lateral fields covering C1. The parotids were not prospectively delineated, but retrospectively delineated and considered one structure for analysis. Patients completed the University of Michigan Xerostomia Questionnaire (Xerostomia score, scaled 0-100, higher is worse) and a 4-point dry mouth “bother” score (1-Not at all, 2-A little, 3-Quite a bit, 4-Very much) at baseline, conclusion of WBRT, 2 weeks, 1 month (primary endpoint), 3 months, and 6 months post-WBRT. The clinical data were fitted by the Lyman-Kutcher-Burman (LKB) and Relative Seriality (RS) NTCP models using outcomes at 1 month post-RT. We defined toxicity as a ≥20 point worsening in xerostomia score, or a ≥2 point worsening in bother score. 55 patients who reached the primary time point of 1 month were eligible for analysis. Median WBRT dose was 30 Gy in 10 fractions. Median parotid mean dose was 17Gy (Range, 11-28Gy) and median parotid V20Gy was 48% (Range, 24-84%). Xerostomia score increased by ≥20 in 19 patients (35%), and bother score increased by ≥2 points in 11 patients (20%). Parotid V5Gy-V20Gy were found to correlate best with toxicity, with AUC 0.68 for xerostomia score and 0.69 to 0.71 for bother score. AUC values for parotid mean dose were 0.64 and 0.65 for xerostomia score and bother score respectively. The values for the D50, m and n parameters of the Lyman-Kutcher-Burman model were 22.3Gy, 0.84 and 1.0, respectively for xerostomia score and 28.4Gy, 0.55 and 1.0 for bother score. Similarly, the values for the D50, γ and s parameters of the Relative Seriality model were 23.5Gy, 0.28 and 0.0001, respectively for xerostomia score and 32.0Gy, 0.45 and 0.0001 for bother score. A statistically significant toxicity Odds Ratio of 8.6 and 9.1 was observed in patients with parotid V20Gy > 48% for xerostomia score and bother score, respectively. Clinically significant xerostomia was fairly common after WBRT and correlated well with parotid V5Gy-V20Gy. The dose-response for xerostomia could be determined by fitting the clinical data with the LKB and RS NTCP models. These data support the need for minimization of parotid dose in patients receiving WBRT. Additionally, they can be very useful in prospective treatment plan optimization and evaluation.

Optimizing Whole Brain Radiotherapy Dose and Fractionation: Results from a Prospective Phase III Trial (NCCTG N107C (Alliance)/CEC.3)

Whole brain radiotherapy (WBRT) remains a commonly employed cancer treatment today, although controversy exists regarding the optimal dose and fractionation to optimize intracranial tumor control and minimize resultant cognitive deficits. We sought to utilize the results of N107C/CEC.3, a prospective clinical trial for patients with brain metastases, to evaluate the impact of WBRT dose and fractionation on tumor control, overall survival (OS), and toxicity. N107C/CEC.3 randomized 194 patients with brain metastases to either stereotactic radiosurgery alone or WBRT after surgical resection. Among the 92 patients receiving WBRT, sites predetermined the fractionation schedule that would be used for all patients treated at that site (either 30 Gy in 10 fractions (fx), or 37.5 Gy in 15 fx). Analyses were performed using Kaplan-Meier estimates, log rank tests, and Fisher’s exact tests, where appropriate. Among 92 patients treated with surgical resection and adjuvant WBRT, 49 were treated with 30 Gy in 10 fx (53%), and 43 were treated with 37.5 Gy in 15 fx (47%). Baseline characteristics, including cognitive testing, were well balanced between groups with the exception of primary tumor type (lung cancer histology more frequent with protracted WBRT, 74% vs. 47%, p=0.01), and 93% of patients completed the full course of WBRT. Protracted WBRT dose/fx did not impact time to cognitive failure (hazard ratio, HR=0.91, p=0.64), surgical bed control (HR=0.52, p=0.14), intracranial tumor control (HR=0.56, p=0.09), or OS (HR=0.73, p=0.18). Although there were no reports of radionecrosis, there is a statistically significant increase in the risk of at least one grade 3 or higher adverse event with 37.5 Gy/15 fx vs. 30 Gy/10 fx (54% vs. 31%, respectively, p=0.03). This unplanned analysis does not demonstrate that protracted WBRT courses reduce the risk of cognitive deficit, improve tumor control in the hypoxic surgical cavity, or otherwise improve the therapeutic ratio. Adverse events were significantly higher with lengthened courses. For patients with brain metastases where WBRT is recommended, a short course hypofractionated regimen remains the current standard of care. Support: U10CA180821, U10CA180882; U10CA180863; U10CA180868; NCT01372774; Alliance NCORP grant UG1CA189823.

Long-Term Evaluation of Combination Treatment of Single Agent HD-MTX Chemotherapy up to Three Cycles and Moderate Dose Whole Brain Irradiation for Primary CNS Lymphoma

High-dose methotrexate (HD-MTX)-based chemotherapy in combination with whole brain radiotherapy (WBRT) has been a common therapy for primary central nervous system lymphoma (PCNSL). The aim of this study was to evaluate the survival benefit of a minimized cycle of HD-MTX monotherapy prior to WBRT. A maximum of three cycles of HD-MTX was combined with a WBRT dose of 30 Gy and an additional localized boost was administered where remnant was observed. A total of 54 patients with newly diagnosed PCNSL were enrolled in this study. The objective response rate for HD-MTX was 80% and the median overall survival was 58.4 months. Responders to HD-MTX demonstrated better survival than patients with resistance. The concentration of MTX in serum and cerebrospinal fluid was not related the chemotherapeutic response. This study demonstrated the efficacy of HD-MTX prior to WBRT and indicated that three cycles of HD-MTX monotherapy may be sufficient in combination with radiotherapy.

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

Guidelines for the diagnosis and management of primary central nervous system diffuse large B-cell lymphoma.

Effect of Whole Brain Radiotherapy Dose on Breast Cancer Brain Metastases Survival

This paper sets to study the effect of whole brain radiotherapy (WBRT) dose on the survival after breast cancer brain metastases (BM) in order to reduce the mortality rates of breast cancer. We collect relevant information on the patient, operation, and post-operation systematic treatment, diagnosis and treatment of BM from the medical record inquiry system. The results show that under implications of multiple factors, local supplement dose, to some extent, has good prognosis tendency, but does not extend the intracranial progression free survival (PFS), while the WBRT dose can. It is the conclusion of this paper that WBRT can improve the overall survival (OS) and PFS, but WBRT cannot further extend the OS after exceeding a certain amount.

33 Is hypofractionation safer than single-fraction radio surgery? The effect of fractionation on radionecrosis

Introduction: Radiation-induced brain necrosis (RN) is a relatively uncommon (5-20%) but potentially severe adverse effect of stereotactic radiosurgery (SRS) for brain metastasis(BM). We attempted to establish the effect of hypo-fractionation on RN rates by reviewing patients having simultaneous multi-fraction and single fraction treatment of BM at our centre. Methods: Patients receiving simultaneous 1 (20-24Gy) or 3 fraction (21-24Gy) SRS treatments were identified in our institution’s database. Serial post-SRS MRIs were reviewed to determine the lesion quotient (LQ), or maximum cross sectional area on T1 plus gadolinium divided by T2 FLAIR sequences. LQ less than 0.3 was considered RN. Result: Twenty-two patients were followed for a median 320 days. Sixteen patients developed radionecrosis in 21 of 62 lesions (33%), four of which were symptomatic (20%). Eleven of these lesions received 3 fractions and ten received one fraction. RN risk increased with increasing tumor volume (log odds ratio=1.12, p=0.04). There was no difference in incidence of RN in patients who received whole brain radiotherapy (WBRT) (p=0.11), hypo-fractionation (p=0.98) or had a higher maximum dose (p=0.71). Radiographic RN, however, did not clear in any patients who developed it. Eight patients developed a local recurrence (12%), six of which occurred in the single fraction group. Conclusion: Radionecrosis was significantly related to tumor volume but not fractionation, WBRT, or maximum dose. Overall, our results indicate patients receiving SRS for multiple brain metastasis have a higher rate of radionecrosis than the literature and poorer survival despite having equivalent local control.

(OA16) Repeat Whole Brain Radiation Therapy Using a Pulsed Reduced Dose Rate Technique

Limited salvage options exist for patients with multiple recurrent brain metastases previously treated with whole brain radiation therapy (WBRT). Pulsed reduced dose rate radiation therapy (PRDR) is a biologically-unique irradiation strategy that lowers the effective dose rate, potentially decreasing toxicity to normal tissue by allowing for sublethal damage repair. PRDR has been shown to be safe and effective in patients with gliomas receiving partial brain re-irradiation. To our knowledge, this technique has not been reported before in patients with brain metastases who have received repeat WBRT with PRDR. We report our early outcomes using repeat WBRT with PRDR. We conducted a retrospective review of all brain tumor patients treated with PRDR at our institution. We further analyzed patients with brain metastases previously treated with WBRT who received repeat WBRT with PRDR at the time of clinical and/or radiographic progression. PRDR treatments were delivered with a series of 0.20 Gy pulses given over a 3-minute period, resulting in an apparent dose rate of 0.0667 Gy/min. Patients were treated with parallel-opposed whole brain lateral fields with dose prescribed to isocenter. We identified 26 patients who received WBRT with PRDR from 2012 to 2017 . We excluded 4 patients from further analysis as 2 patients had not received prior WBRT and 2 patient expired during treatment course due to extracranial disease. Primary histology included breast cancer (n=8), melanoma (n=5), NSCLC (n=6), non-seminomatous testicular cancer (n=1), SCLC (n=1) and sarcoma (n=1). Initial WBRT dose regimens included 30 Gy in 10 fractions (n=14), 37.5 Gy in 15 fractions (n=7), and 39.6 Gy in 18 fractions (n=1). KPS was 70-100 for all patients at time of first WBRT. Median time to progression after first WBRT was 7.7 months (range 1.3 - 54.8 months) at which time patients underwent repeat WBRT with PRDR. Patients received daily fractions of 2 – 3 Gy (median = 2 Gy) to a total dose of 20 Gy - 30 Gy (median = 24 Gy). KPS at repeat irradiation was 70-100 and age ranged from 28.3 yrs to 77.0 yrs (mean = 55.38 yrs). With a mean follow-up of 7.1 months (range 0.63 – 33.4 months), mean time to intracranial progression after repeat WBRT with PRDR was 4.7 months (range 0.53 – 15.5 months). Four patients had intracranial disease control after repeat WBRT with PRDR for > 6 months and 1 patient is still alive at the time of this review. No acute grade 3 toxicities were seen as a result of reirradiation based on CTCAE v4.03. Grade 1/2 toxicities included fatigue, anorexia, and alopecia. To our knowledge, this is the first report of repeat WBRT with PRDR. This technique appears to be a safe and feasible option for patients with multiple brain metastases who previously received WBRT. Future prospective studies using this technique are being considered.

Optimal dose and volume for postoperative radiotherapy in brain oligometastases from lung cancer: a retrospective study.

PurposeTo evaluate intracranial control after surgical resection according to the adjuvant treatment received in order to assess the optimal radiotherapy (RT) dose and volume.Materials and MethodsBetween 2003 and 2015, a total of 53 patients with brain oligometastases from non-small cell lung cancer (NSCLC) underwent metastasectomy. The patients were divided into three groups according to the adjuvant treatment received: whole brain radiotherapy (WBRT) ± boost (WBRT ± boost group, n = 26), local RT/Gamma Knife surgery (local RT group, n = 14), and the observation group (n = 13). The most commonly used dose schedule was WBRT (25 Gy in 10 fractions, equivalent dose in 2 Gy fractions [EQD2] 26.04 Gy) with tumor bed boost (15 Gy in 5 fractions, EQD2 16.25 Gy).ResultsThe WBRT ± boost group showed the lowest 1-year intracranial recurrence rate of 30.4%, followed by the local RT and observation groups, at 66.7%, and 76.9%, respectively (p = 0.006). In the WBRT ± boost group, there was no significant increase in the 1-year new site recurrence rate of patients receiving a lower dose of WBRT (EQD2) <27 Gy compared to that in patients receiving a higher WBRT dose (p = 0.553). The 1-year initial tumor site recurrence rate was lower in patients receiving tumor bed dose (EQD2) of ≥42.3 Gy compared to those receiving <42.3 Gy, although the difference was not significant (p = 0.347).conclusionsAdding WBRT after resection of brain oligometastases from NSCLC seems to enhance intracranial control. Furthermore, combining lower-dose WBRT with a tumor bed boost may be an attractive option.

Development of a Survival Score for Patients with Cerebral Metastases from Melanoma.

To develop a survival score for patients receiving whole-brain irradiation (WBI) alone for cerebral metastases from melanoma. Forty-five patients who met the required criteria were included. WBI doses had to be >30 Gy. Six variables were analyzed: age, gender, Karnofsky performance score (KPS), number of cerebral metastases, extracranial metastatic spread and interval from diagnosis of melanoma until WBI. In order to estimate patients' survival scores, variables showing at least a trend (p<0.06) on multivariate analysis were considered. One point was assigned to each variable correlating with better survival rates and zero points to those correlating with worse survival rates. By multivariate analysis, age (p=0.002) achieved significance and KPS (p=0.056) showed a trend. Patients' survival scores were obtained by adding zero or one point from each variable and resulted in three groups of 0, 1 or 2 points. The median survival times of these groups were one, four and ten months (p<0.0001). A survival score was developed for patients assigned to WBI alone for cerebral metastases from melanoma. This new instrument may facilitate the decision for the appropriate WBI-program.