Whole Brain Radiotherapy Dose Research Articles

Real-World Experience with RTOG 0227 Induction for First Line Therapy of Primary CNS Lymphoma (PCNSL)

Introduction PCNSL is an aggressive and rare subtype of extranodal non-Hodgkin Lymphoma affecting the brain, spinal cord, cerebrospinal fluid (CSF), leptomeninges and/or vitreoretinal components. While there have been trials comparing outcomes of consolidation treatment with whole brain radiation therapy (WBRT) versus (vs) autologous hematopoietic cell transplantation (auto-HCT) following different induction regimens in PCNSL, the optimal induction regimen to pair with these forms of consolidation remains controversial. Our group adopted a modified version of the RTOG 0227 induction as our standard PCNSL induction in 2017. This regimen includes 5 cycles of Methotrexate (MTX) at 3.5 g/m 2 and Rituximab (R) at 375-500 mg/m 2, and Temozolomide (TMZ) on cycles 2 and 4. Based on the published phase 2 trial of 53 patients (pts), the regimen is significantly less toxic than more aggressive induction regimens such as MATRiX, especially in older pts or those with comorbidities. We evaluated our real-world outcomes in PCNSL pts treated with RTOG 0227 induction followed by consolidation with either WBRT/TMZ or auto-HCT, at a single academic university hospital. Methods We identified newly diagnosed PCNSL pts treated at a single academic university hospital between 2017 and 2023. Electronic medical records were retrospectively reviewed to collect data including demographics, clinicopathological features, treatment details, response rates, long-term follow up, disease recurrence, and survival. The IELSG prognostic index tool was used for risk assessment. All pts received induction regimen consisting of R (dose between 375- 500 mg/m 2) and 3.5 g/m 2 of MTX with leucovorin on weeks 1, 3, 5, 7 and 9 along with TMZ daily for 5 days on weeks 4 and 8, followed by consolidation with either WBRT/TMZ or auto-HCT. In WBRT cohort, maintenance TMZ was given at 200mg/m 2 daily for 5 days every 28 days, for total of 10 cycles, and dose was reduced if side effects developed. Objective response rate (ORR) and complete response rate (CRR) after induction chemotherapy were calculated. Overall survival (OS) and progression free survival (PFS) at 2 years were estimated with the Kaplan-Meir method (using GraphPad Prism 9.3.1) and compared between the WBRT and auto-HCT cohorts, using the log-rank test. Results A total of 29 PCNSL pts were included in the study. Patient and disease characteristics for the entire cohort, as well as pts treated with WBRT vs auto-HCT consolidation, are shown on the Table. On average (avg), pts received 4 cycles of MTX and 8 cycles of TMZ. Nine (31%) pts developed acute kidney injury and 1 (3.4%) developed transaminitis from MTX. The avg total cumulative TMZ dose was 5913 mg/m 2 and 8 (27.5%) pts required TMZ dose reduction. Treatment related mortality (TRM) following induction was 0%. Eight (27.5%) pts had complete response, 19 (65.5%) had partial response, 1 (3.5%) had stable disease and 1 (3.5%) had disease progression. ORR was 93.1% and CRR was 27.5%. Eighteen (62%) pts received WBRT/TMZ consolidation, while 11 (38%) received auto-HCT consolidation. Median dose of WBRT administered was 36 Gy (23.4 to 36 Gy). Thirteen (72.2%) pts received 36 Gy in 30 fractions (fx) of 1.2 Gy BID, 4 (22.2%) pts received 23.4 Gy in 13 fx of 1.8 Gy OD, and 1 (5.5%) pt received 30.6 Gy in 17 fx of 1.8 Gy OD. Most common conditioning regimen prior to auto-HCT was carmustine/thiotepa (BCNU/TT). With a median follow up of 36 months, 4 (22.2%) pts in WBRT cohort and 1 (9.1%) in auto-HCT cohort had disease recurrence. Two-year PFS was 83% overall, 81% for the WBRT pts and 87% for the auto-HCT pts, with a p value of 0.65 for log-rank comparison of PFS for the WBRT vs auto-HCT pts. Two-year OS was 96% for the entire cohort, 94% for the WBRT pts and 100% for the auto-HCT pts, with a p value of 0.27 for log-rank comparison of OS for the WBRT vs auto-HCT pts. Conclusion In this real-world cohort of PCNSL pts not treated as part of a clinical trial, we observed excellent outcomes using the modified RTOG 0227 induction regimen. PFS and OS at 2 yrs in our cohort exceeds those reported with any prospective clinical trial to date, and with zero TRM to date. This data indicates that the modified RTOG 0227 induction with either WBRT or auto-HCT consolidation represents a very tolerable and highly effective option for first line therapy of PCNSL, for both younger and older pts.

Is reduced-dose whole-brain radiotherapy also feasible in primary CNS lymphoma for curative or salvage purpose?

Recently, reduced-dose whole-brain radiotherapy (WBRT) has been used to treat primary central nervous system lymphoma (PCNSL). However, whether reduced-dose WBRT is also an acceptable option for curative or salvage purposes has not yet been reported. We analyzed the clinical outcomes of patients with PCNSL who received radiotherapy for curative or salvage purposes and compared the clinical outcomes according to the WBRT dose. A total of 66 patients were divided into two groups: those treated with 30Gy (2Gy per fraction) or less WBRT (low-dose WBRT, n = 34) and those treated with more than 30Gy WBRT (high-dose WBRT, n = 32). The median WBRT dose was 25.2 and 49.6Gy in low-dose and high-dose WBRT groups, respectively. The median total radiotherapy dose, including the boost dose, was 50Gy (range, 36.0-55.8Gy). The 3-year overall survival and progression-free survival were 77.8% and 29.8%, respectively. Intracranial relapse occurred in 31 patients (47.0%) at a median of 27 months after RT. Overall survival and progression-free survival did not differ between the two groups. The 3-year intracranial disease control rate did not differ between the two groups (35.2% vs. 41.6%, p = 0.300). Grade 3 or higher neurological toxicities were observed in six patients, of whom five were in the high-dose WBRT group. Reduced-dose WBRT in curative and salvage treatments for PCNSL had no significant negative effect on the intracranial disease control rate or survival. Therefore, without impaired efficacy, use of reduced-dose WBRT appears promising for reduction of neurotoxicity.

Stereotactic radiosurgery versus whole-brain radiotherapy in patients with 4–10 brain metastases: A nonrandomized controlled trial

Background and PurposeThere is no randomized evidence comparing whole-brain radiotherapy (WBRT) and stereotactic radiosurgery (SRS) in the treatment of multiple brain metastases. This prospective nonrandomized controlled single arm trial attempts to reduce the gap until prospective randomized controlled trial results are available. Material and MethodsWe included patients with 4–10 brain metastases and ECOG performance status ≤ 2 from all histologies except small-cell lung cancer, germ cell tumors, and lymphoma. The retrospective WBRT-cohort was selected 2:1 from consecutive patients treated within 2012–2017. Propensity-score matching was performed to adjust for confounding factors such as sex, age, primary tumor histology, dsGPA score, and systemic therapy. SRS was performed using a LINAC-based single-isocenter technique employing prescription doses from 15-20Gyx1 at the 80% isodose line. The historical control consisted of equivalent WBRT dose regimens of either 3Gyx10 or 2.5Gyx14. ResultsPatients were recruited from 2017–2020, end of follow-up was July 1st, 2021. 40 patients were recruited to the SRS-cohort and 70 patients were eligible as controls in the WBRT-cohort. Median OS, and iPFS were 10.4 months (95%-CI 9.3-NA) and 7.1 months (95%-CI 3.9–14.2) for the SRS-cohort, and 6.5 months (95%-CI 4.9–10.4), and 5.9 months (95%-CI 4.1–8.8) for the WBRT-cohort, respectively. Differences were non-significant for OS (HR: 0.65; 95%-CI 0.40–1.05; P =.074) and iPFS (P =.28). No grade III toxicities were observed in the SRS-cohort. ConclusionThis trial did not meet its primary endpoint as the OS-improvement of SRS compared to WBRT was non-significant and thus superiority could not be proven. Prospective randomized trials in the era of immunotherapy and targeted therapies are warranted.

Acute toxicities and cumulative dose to the brain of repeated sessions of stereotactic radiotherapy (SRT) for brain metastases: a retrospective study of 184 patients

BackgroundStereotactic radiation therapy (SRT) is a focal treatment for brain metastases (BMs); thus, 20 to 40% of patients will require salvage treatment after an initial SRT session, either because of local or distant failure. SRT is not exempt from acute toxicity, and the acute toxicities of repeated SRT are not well known. The objective of this study was to analyze the acute toxicities of repeated courses of SRT and to determine whether repeated SRT could lead to cumulative brain doses equivalent to those of whole-brain radiotherapy (WBRT).Material and methodsBetween 2010 and 2020, data from 184 patients treated for 915 BMs via two to six SRT sessions for local or distant BM recurrence without previous or intercurrent WBRT were retrospectively reviewed. Patients were seen via consultations during SRT, and the delivered dose, the use of corticosteroid therapy and neurological symptoms were recorded and rated according to the CTCAEv4. The dosimetric characteristics of 79% of BMs were collected, and summation plans of 76.6% of BMs were created.Results36% of patients developed acute toxicity during at least one session. No grade three or four toxicity was registered, and grade one or two cephalalgy was the most frequently reported symptom. There was no significant difference in the occurrence of acute toxicity between consecutive SRT sessions. In the multivariate analysis, acute toxicity was associated with the use of corticosteroid therapy before irradiation (OR = 2.6; p = 0.01), BMV grade (high vs. low grade OR = 5.17; p = 0.02), and number of SRT sessions (3 SRT vs. 2 SRT: OR = 2.64; p = 0.01). The median volume equivalent to the WBRT dose (VWBRT) was 47.9 ml. In the multivariate analysis, the VWBRT was significantly associated with the total GTV (p < 0.001) and number of BMs (p < 0.001). Even for patients treated for more than ten cumulated BMs, the median BED to the brain was very low compared to the dose delivered during WBRT.ConclusionRepeated SRT for local or distant recurrent BM is well tolerated, without grade three or four toxicity, and does not cause more acute neurological toxicity with repeated SRT sessions. Moreover, even for patients treated for more than ten BMs, the VWBRT is low.

Patterns of Failure after Stereotactic Radiosurgery vs. Whole Brain Radiotherapy for Resected Brain Metastases: Central Imaging Review of the N107C/CEC.3 (Alliance) Phase III Clinical Trial

<h3>Purpose/Objective(s)</h3> Whole brain radiotherapy (WBRT) has historically been the main instrument to decrease intracranial progression after resection of brain metastases. The previously reported NCCTG N107C/CEC.3 (Alliance) randomized phase III clinical trial of WBRT vs. stereotactic radiosurgery (SRS) demonstrated that overall survival did not significantly differ between arms, while SRS was associated with less cognitive decline than WBRT. However, the initial analysis also showed that local tumor bed control (LC) was significantly worse with SRS than WBRT, with an unexpectedly low 12-month LC rate of 60.5% in patients receiving post-operative SRS. To further investigate LC, a central imaging review was performed. <h3>Materials/Methods</h3> In N107C/CEC.3, 194 patients were randomized to SRS (n=98) or WBRT (n=96). SRS dose was dependent on resection cavity volume and ranged from 12 Gy to 20 Gy all in a single fraction, and WBRT dose was 30 Gy in 10 fractions or 37.5 Gy in 15 fractions. For this analysis, patients with local failure (LF) or leptomeningeal failure that had imaging available were centrally reviewed by two radiation oncologists to verify pattern of failure. Patient and treatment characteristics were assessed for association with updated outcomes after central review using Cox proportional hazards, Pearson's chi-square, or Kruskal-Wallis tests. <h3>Results</h3> Seventy-three patients with LF or leptomeningeal failure determined by their local site were centrally reviewed. After adding patients with no LF or leptomeningeal failure, 185 (95% of total enrolled) patients were included in this analysis as 9 patients with LF did not have imaging available for central review. Of 59 patients initially determined to have LF, 20 were determined on central review to be free of LF. Accordingly, after central review post-operative SRS was no longer associated with significantly lower rates of LC than WBRT (79.2% vs. 86.5% 12-month LC, respectively, p=0.099). After central review, the interrelated variables of tumor diameter, target volume, and prescription dose were associated with risk of LF. Patients with resection cavities > 3 cm had higher rates of LF than those with smaller cavities (23.5% vs. 12.6% 12-month LF rate, respectively; p=0.010). Larger target volume was associated with increased risk of LF (HR: 1.05, 95% CI: 1.01 – 1.09, p=0.008), while higher prescription dose was associated with lower risk of LF (HR: 0.81, 95% CI: 0.67 – 0.96, p=0.018). <h3>Conclusion</h3> In contrast to the initial report, after central review SRS was not associated with significantly higher rates of LF than WBRT. Patients with larger surgical cavities had higher rates of LF, though it is unclear whether this is related to cavity size, biology, or radiation dose. Randomized data comparing single to multifraction SRS in larger surgical cavities is awaited.

Abstract P1-21-01: Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (KROG 1612)

Abstract Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM &amp;gt;4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p=0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p&amp;lt;0.001; HER2+, 18.5%, p=0.004; TNBC, 16.9%, p=0.071). Multivariate analysis of cohort B showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM &amp;gt;4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p=0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 &amp;gt;37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS. Citation Format: Jae Sik Kim, Kyubo Kim, Wonguen Jung, Kyung Hwan Shin, Seock-Ah Im, Hee-Jun Kim, Yong Bae Kim, Jee Suk Chang, Jee Hyun Kim, Doo Ho Choi, Yeon Hee Park, Dae Yong Kim, Tae Hyun Kim, Byung Ock Choi, Sea-Won Lee, Suzy Kim, Jeanny Kwon, Ki Mun Kang, Woong-Ki Chung, Kyung Su Kim, Won Sup Yoon, Jin Hee Kim, Jihye Cha, Yoon Kyeong Oh, In Ah Kim. Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (KROG 1612) [abstract]. In: Proceedings of the 2021 San Antonio Breast Cancer Symposium; 2021 Dec 7-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2022;82(4 Suppl):Abstract nr P1-21-01.

Role of DOSE Escalation in whole Brain Radiotherapy for Brain Metastasis in Patients with a Favorable Survival Prognosis

Background: Brain metastases is a major health care problem and is the most common intracranial cancer in adults. These patients may benefit from intensive treatments including neurosurgery and radiosurgery but many patients cannot receive such treatment, and whole brain radiotherapy (WBRT) alone is the only option. The most common WBRT schedule is 30 Grays (Gy) in 10 fractions (fr). However there is need to develop fractionation schedules, but total dose still remain dilemma.The Purpose of this study to assess the potential benefit of dose escalation beyond 30 Gy. Patients and methods: Total 120 patients with multiple brain metastases, previously untreated with WBRT were randomly assigned into two arms. All patients have favorable survival prognosis. Seventy patients received a total 30Gy in 10fr, 3Gy/fr administered daily 5days/week in arm A and 50 patients received 39Gy in 13fr, with same schedule in arm B. Both arms were compared for local control (LC) and overall survival (OS). Results: The LC rate at 18 months was 11% after 30 Gy and 24% after 39 Gy (p value=0.068). The survival rate at18 months was 21% after 30 Gy and 38% after 39Gy (OS 21% vs. 38%, hazard ratio 0.593; 95% CI: .395-.891; p value=0.047). On subgroup analysis of primary tumor, the 18 months LC rate was 16% vs 53% in Breast (p value=0.020) and10% vs 11% in Lung cancer (p value=0.809) in arm A and B respectively; the 18 months OS rate was 14% vs26% in Lung (P value=0.160) and 37% vs 73% in Brest cancer (p value=0.034) in arm A and B respectively. Conclusion: Escalation of the WBRT dose beyond 30 Gy resulted in better outcomes, particularly for patients with primary breast cancer.

Autophagy Inhibition Reduces Irradiation-Induced Subcortical White Matter Injury Not by Reducing Inflammation, but by Increasing Mitochondrial Fusion and Inhibiting Mitochondrial Fission

Radiotherapy is an effective tool in the treatment of malignant brain tumors, but irradiation-induced late-onset toxicity remains a major problem. The purpose of this study was to investigate if genetic inhibition of autophagy has an impact on subcortical white matter development in the juvenile mouse brain after irradiation. Ten-day-old selective neural Atg7 knockout (KO) mice and wild-type (WT) littermates were subjected to a single 6-Gy dose of whole-brain irradiation and evaluated at 5 days after irradiation. Neural Atg7 deficiency partially prevented myelin disruption compared to the WT mice after irradiation, as indicated by myelin basic protein staining. Irradiation induced oligodendrocyte progenitor cell loss in the subcortical white matter, and Atg7 deficiency partly prevented this. There was no significant change between the KO and WT mice in the number of microglia and astrocytes in the subcortical white matter after irradiation. Transcriptome analysis showed that the GO mitochondrial gene expression pathway was significantly enriched in the differentially expressed genes between the KO and WT group after irradiation. Compared with WT mice, expression of the mitochondrial fusion protein OPA1 and phosphorylation of the mitochondrial fission protein DRP1 (P-DRP1) were dramatically decreased in KO mice under physiological conditions. The protein levels of OPA1and P-DRP1 showed no differences in WT mice between the non-irradiated group and the irradiated group but had remarkably increased levels in the KO mice after irradiation. These results indicate that inhibition of autophagy reduces irradiation-induced subcortical white matter injury not by reducing inflammation, but by increasing mitochondrial fusion and inhibiting mitochondrial fission.

NQPC-5 Does high-dose methotrexate-based chemotherapy for relapsed primary CNS lymphoma increase a risk of leukoencephalopathy with prior whole brain radiotherapy?

Backgrounds: Standard care for primary central nervous system lymphoma (PCNSL) comprises high-dose (HD) methotrexate (MTX) -based chemotherapy with or without consolidation whole brain radiotherapy (WBRT). HD-MTX administration following WBRT has been suggested to increase a risk of leukoencephalopathy. However, given that there are no other agents with efficacy similar to or better than MTX, patients with relapsed PCNSL may often be treated with regimens containing HD-MTX if the initial MTX treatment achieved a long-term complete remission. Here, we retrospectively analyzed prevalence and an extent of white mater damages in association with prior WBRT in patients with relapsed PCNSL treated with HD-MTX based therapy. Patients & methods: Among 79 patients with relapsed/refractory PCNSL in a total of 162 patients with newly-diagnosed PCNSL treated in our institution from April, 2000 to February, 2021, 35 patients were identified with evaluable KPS, MMSE, and Fazekas scale data at both baseline and follow-up periods. Of the 35 patients, 22 were treated with chemotherapy at a relapse (10 with prior WBRT, while 12 without WBRT), and were included in this preliminary study. Results: In the WBRT group (male/female: 5/5), median age was 65 years (range, 45–73), initial median KPS was 70 (40–90), and median WBRT dose was 27 Gy (23.4–40). Median progression-free survival (mPFS) was 11.8 months, and median overall survival (mOS) was not reached. In the non-WBRT group (M/F 8/4), median age 75 (62–84), initial mKPS 80 (50–90), mPFS 16.2 m, and mOS not reached. Initial KPS and MMSE score tended to be worse in WBRT group, presumably due to enrichment of patients with poorer performance status and more comorbidities. A decline in the Fazekas score was not associated with MMSE deterioration.Conclusions: The preliminary analysis was not informative enough, and further extensive imaging analysis will be exploited.

Novel prognostic classification predicts overall survival of patients receiving salvage whole-brain radiotherapy for recurrent brain metastasis from breast cancer: A recursive partitioning analysis (KROG 16-12)

BackgroundTo investigate outcomes of salvage whole-brain radiotherapy (WBRT) for recurrent brain metastases (BM) from breast cancer (BC), to identify prognostic factors of overall survival (OS), and to propose a novel prognostic classification for OS in these patients. Materials and methodsWe identified 54 patients who had received salvage WBRT as the second brain-focused treatment for recurrent BM from BC (2000–2014). The median follow-up duration was 4.9 months. A recursive partitioning analysis (RPA) was conducted to develop a model to predict OS at the time of salvage WBRT. ResultsThe median OS was 6.8 months. OS according to BC-specific graded prognostic assessment (breast-GPA), modified breast-GPA, and updated breast-GPA did not represent our cohort. In the multivariate analysis, a long time before salvage WBRT (≥16 months), control of primary BC or extracranial metastases, systemic treatment after salvage WBRT, and administration of a biologically effective dose for an α/β of 10 Gy (BED10) of salvage WBRT >37.5 Gy showed superior OS. We proposed three RPA classes based on the control of both primary BC and extracranial metastasis and BED10 of salvage WBRT: class I, class II, and class III. In this model, patients with class I experienced the best OS (34.6 months; class II, 5.0 months; class III, 2.4 months; P < 0.001). ConclusionsIn our RPA classification according to the control of both primary BC and extracranial metastasis and the dose of salvage WBRT, significant differences in OS were observed. The subsequent use of a systemic treatment showed better OS.

Optimizing Whole Brain Radiotherapy Treatment and Dose for Patients With Brain Metastases From Small Cell Lung Cancer.

PurposeThis study aimed to evaluate the survival outcomes of whole brain radiotherapy (WBRT) compared to whole brain radiotherapy plus local radiation boost (WBRT + boost), and further identify whether higher biologically effective dose (BED) of WBRT + boost translates into a survival benefit in small cell lung cancer (SCLC) patients with brain metastasis (BM).MethodsSCLC patients with BM from January 1, 2012, to December 31, 2019, were retrospectively analyzed. Overall survival (OS) and intracranial progression-free survival (iPFS) were evaluated by the Kaplan–Meier method and compared by the log-rank test. Univariate and multivariate regression analyses of prognostic factors for OS were performed using Cox proportional hazards regression models. The cutoff value of BED was determined by the receiver operating characteristic (ROC) curve analysis.ResultsAmong the 180 eligible patients, 82 received WBRT + boost and 98 received WBRT. Both OS and iPFS in the WBRT + boost group were significantly superior to those in the WBRT group (median OS: 20 vs. 14 months, p = 0.011; median iPFS: 16 vs. 10 months, p = 0.003). At a cutoff value of 58.35 Gy in the WBRT + boost group, 52 for the high-BED (>58.35 Gy) group, 30 for the low-BED (≤58.35 Gy) group. High BED was significantly associated with improved OS and iPFS compared with low BED in the WBRT + boost group (median OS: 23 vs. 17 months, p = 0.002; median iPFS: 17 vs. 10 months, p = 0.002).ConclusionsCompared with WBRT alone, WBRT + boost improved OS and iPFS in SCLC patients with BM. High BED (>58.35 Gy) for WBRT + boost may be a reasonable consideration for SCLC patients with BM.

Metformin effects on brain development following cranial irradiation in a mouse model.

Cranial radiation therapy (CRT) is a mainstay of treatment for malignant pediatric brain tumors and high-risk leukemia. Although CRT improves survival, it has been shown to disrupt normal brain development and result in cognitive impairments in cancer survivors. Animal studies suggest that there is potential to promote brain recovery after injury using metformin. Our aim was to evaluate whether metformin can restore brain volume outcomes in a mouse model of CRT. C57BL/6J mice were irradiated with a whole-brain radiation dose of 7 Gy during infancy. Two weeks of metformin treatment started either on the day of or 3 days after irradiation. In vivo magnetic resonance imaging was performed prior to irradiation and at 3 subsequent time points to evaluate the effects of radiation and metformin on brain development. Widespread volume loss in the irradiated brain appeared within 1 week of irradiation with limited subsequent recovery in volume outcomes. In many structures, metformin administration starting on the day of irradiation exacerbated radiation-induced injury, particularly in male mice. Metformin treatment starting 3 days after irradiation improved brain volume outcomes in subcortical regions, the olfactory bulbs, and structures of the brainstem and cerebellum. Our results show that metformin treatment has the potential to improve neuroanatomical outcomes after CRT. However, both timing of metformin administration and subject sex affect structure outcomes, and metformin may also be deleterious. Our results highlight important considerations in determining the potential benefits of metformin treatment after CRT and emphasize the need for caution in repurposing metformin in clinical studies.

Is There an Indication for First Line Radiotherapy in Primary CNS Lymphoma?

Simple SummaryFirst line whole brain radiotherapy (WBRT) alone is a palliative treatment for patients with primary CNS lymphoma (PCNSL) not suitable for intensive multimodal therapy. Consolidating WBRT after chemotherapy with high-dose methotrexate WBRT has activity comparable to autologous stem cell transplantation (ASCT). However, dose-dependent toxicity of WBRT is a relevant limiting factor. With standard dose, WBRT rates of neuro-cognitive decline are high and should be taken into account. As an alternative, after complete response (CR) low-dose consolidating WBRT carries a lower risk for neurotoxicity and is a treatment option in patients not suitable for ASCT. For patients not achieving CR, the best combined treatment potentially involving focal radiotherapy remains to be determined.Background: Primary CNS Lymphoma is a rare and severe but potentially curable disease. In the last thirty years treatment has changed significantly. Survival times increased due to high-dose methotrexate-based chemotherapy. With intensive regimens involving autologous stem cell transplantation (ASCT), 4-year survival rates of more than 80% can be reached. However, this treatment regimen is not feasible in all patients, and is associated with some mortality. Methods: In this review, current evidence regarding the efficacy and toxicity of radiotherapy in PCNSL shall be summarized and discussed mainly based on data of controlled trials. Results: Being the first feasible treatment whole brain radiotherapy (WBRT) was initially used alone, and later as a consolidating treatment after high-dose methotrexate-based chemotherapy. More recently, concerns regarding activity and neurotoxicity of standard dose WBRT limited its use. On the contrary, latest evidence of some phase II trials suggests efficacy of consolidating WBRT is comparable to ASCT. After complete remission reduced dose WBRT appears as a feasible concept with decreased neurotoxicity. Evidence for use of local stereotactic radiotherapy is very limited. Conclusion: Radiotherapy has a role in the treatment of PCNSL patients not suitable to ASCT, e.g., as consolidating reduced dose WBRT after complete response. Local stereotactic radiotherapy for residual disease should be examined in future trials.

Multicenter study for brain metastasis from breast cancer in Korea: The significance of molecular subtype (Korean Radiation Oncology Group 1612).

e14008 Background: We analyzed the treatment outcome of breast cancer patients with brain metastases (BM) in Korea to identify the prognostic factors and the role of whole brain radiation therapy (WBRT). Methods: Seven hundred thirty patients of breast cancer with BM treated at 17 institutions in Korea from 2000 to 2014 were analyzed. The median follow-up duration was 12 months. The analysis consisted of three cohorts: in cohort A, a total of 730 patients were included; in cohort B, 538 patients with available follow-up imaging after initial brain-directed treatment; and in cohort C, 54 patients receiving salvage WBRT due to recurrent BM after initial Stereotactic radiosurgery or WBRT. Overall survival (OS) was calculated from BM diagnosis in cohort A or from the last day of salvage WBRT in cohort C. Results: Median OS of cohort A was 15 months. In multivariate analysis, histologic grade 3, extracranial metastasis, number of BM &gt; 4, hormone receptor (HR) or HER2 negativity, and shorter time interval to diagnosis of BM were associated with inferior OS. Among 538 patients in cohort B, 201 showed subsequent development of new BM at a median of 11 months after stereotactic radiosurgery or WBRT for the management of initial BM (at 1 year, HR+/HER2- 51.9%, HER2+ 44.0%, and TNBC 69.6%, respectively; p = 0.008). Upfront WBRT reduced subsequent development of new BM, which showed the significant difference among molecular subtypes (HR+/HER2-, 42% reduction at 1 year, p &lt; 0.001; HER2+, 18.5%, p = 0.004; TNBC, 16.9%, p = 0.071). Multivariate analysis showed that shorter time interval to BM, TNBC subtype, extracranial systemic disease, number of BM &gt; 4, and involvement of both tentoria increased subsequent development of new BM. Anti-HER2 therapy for HER2+ patients and upfront WBRT significantly reduced risk of new BM. In cohort C, upfront WBRT prolonged the salvage WBRT-free duration (median 6.9 vs. 8.7 months, p = 0.058). Median OS was 6.8 months after salvage WBRT. Longer interval to salvage WBRT, controlled primary tumor, high dose of salvage WBRT (BED10 &gt; 37.5 Gy), and systemic treatment after salvage WBRT showed better OS. Uncontrolled extracranial systemic disease and salvage WBRT due to local progression without distant intracranial failure showed worse OS. Conclusions: The rates of new BM showed the significant differences among molecular subtypes. Upfront WBRT decreased subsequent development of new BM and this effect was dependent on the molecular subtype as well. Anti-HER2 therapy for HER2+ patients significantly decreased the subsequent development of new BM. On salvage WBRT setting, the patients having high dose of salvage WBRT, stable extracranial systemic disease and subsequent systemic therapy showed better OS.

Reduction of immunosuppression combined with whole-brain radiotherapy and concurrent systemic rituximab is an effective yet toxic treatment of primary central nervous system post-transplant lymphoproliferative disorder (pCNS-PTLD): 14 cases from the prospective German PTLD registry.

Post-transplant lymphoproliferative disorders (PTLD) exclusively affecting the central nervous system-primary CNS-PTLD (pCNS-PTLD)-are rare. There is no standard therapy, and previous case series have included heterogeneous treatment approaches. We performed a retrospective, multi-centre analysis of 14 patients with pCNS-PTLD after solid organ transplantation (SOT) treated in the prospective German PTLD registry with reduction of immunosuppression (RI), whole-brain radiotherapy (WBRT), and concurrent systemic rituximab between 2001 and 2018. Twelve of fourteen patients were kidney transplant recipients and median age at diagnosis was 65years. Thirteen of fourteen cases (93%) were monomorphic PTLD of the diffuse large B-cell lymphoma type, and 12/13 were EBV-associated. The median dose of WBRT administered was 40Gy with a median fraction of 2Gy. The median number of administered doses of rituximab (375mg/m2) IV was four. All ten patients evaluated responded to treatment (100%). Median OS was 2.5years with a 2-year Kaplan-Meier estimate of 63% (95% confidence interval 30-83%) without any recorded relapses after a median follow-up of 2.6years. Seven of fourteen patients (50%) suffered grade III/IV infections under therapy (fatal in two cases, 14%). During follow-up, imaging demonstrated grey matter changes interpreted as radiation toxicity in 7/10 evaluated patients (70%). The combination of RI, WBRT, and rituximab was an effective yet toxic treatment of pCNS-PTLD in this series of 14 patients. Future treatment approaches in pCNS-PTLD should take into account the significant risk of infections as well as radiation-induced neurotoxicity.

Single institutional outcomes of whole brain radiotherapy for metastatic melanoma brain metastases

BackgroundThe management of melanoma with brain metastases (MBM) is increasingly complex, especially given recent improvements in targeted agents, immunotherapy, and radiotherapy. Whole brain radiation therapy (WBRT) is a longstanding radiotherapy technique for which reported patient outcomes and experiences are limited. We sought to report our institutional outcomes for MBM patients receiving WBRT and assess whether other clinical factors impact prognosis.MethodsA retrospective review of a single institution database was performed. Patients diagnosed with MBM from 2000 to 2018 treated with WBRT, with or without other 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), distant failure-free survival (DFFS), local failure-free survival (LFFS), and progression-free survival (PFS) were assessed. Data on radiation-induced side effects, including radionecrosis, hemorrhage, and memory deficits, was also captured.Results63 patients with MBM were ultimately included in our study. 69% of patients had 5 or more brain metastases at the time of WBRT, and 68% had extracranial disease. The median dose of WBRT was 30 Gy over 10 fractions. Median follow-up was 4.0 months. Patients receiving WBRT had a median OS of 7.0 months, median PFS of 2.2 months, median DFFS of 6.1 months, and median LFFS of 4.9 months. Performance status correlated with OS on both univariate and multivariable analysis. BRAF inhibitor was the only systemic therapy to significantly impact OS on univariate analysis (HR 0.24, 95% CI 0.07–0.79, p = 0.019), and this effect extended to multivariable analysis as well. Post-WBRT intralesional hemorrhage decreased DFFS on both univariate and multivariable analysis. Of patients with post-treatment brain scans available, there was a 16% rate of radionecrosis, 32% rate of hemorrhage, and 19% rate of memory deficits.ConclusionsOutcomes for MBM patients receiving WBRT indicate that WBRT remains an effective treatment strategy to control intracranial disease. Treatment-related toxicities such as intralesional hemorrhage, necrosis, or neurocognitive side effects are limited. With continued innovations in WBRT technique and systemic therapy development, MBM outcomes may continue to improve. Further trials should evaluate the role of WBRT in the modern context.

Outcomes of Initial Therapy for Synchronous Brain Metastases from Extensive Stage Small Cell Lung Cancer

Small cell lung cancer (SCLC) has a propensity for brain metastases, which is associated with poor prognosis. 20% of SCLC patients have synchronous brain metastases at initial diagnosis. We sought to determine predictors of overall survival (OS) and brain progression-free survival (bPFS) in SCLC patients with synchronous brain metastases treated with chemotherapy (chemo) and/or whole brain radiation (WBRT). Among the 836 SCLC patients treated at a single institution between 1998 and 2018, 109 patients with synchronous brain metastases at initial diagnosis were included in this retrospective analysis. Survival was estimated with the Kaplan-Meier method. Factors predictive of OS and bPFS were analyzed using Cox proportional hazards regression modeling and log-rank testing. Of the 109 patients, 18 received chemo without WBRT, 15 received WBRT without chemo, and 76 received chemo and WBRT. Of the 76 patients who received chemo and WBRT, 8 started both concurrently, 35 received chemo first, and 33 received WBRT first. Median WBRT dose was 30 Gy in 10 fractions. The median number of brain lesions at diagnosis was 3, and the median size of the largest metastasis was 2.0 cm. Median OS for the entire cohort was 9 months and median bPFS was 8.4 months. OS was 30.3% at 1 year and 14.4% at 2 years. Increased number of brain lesions was significantly associated with decreased OS. 59 patients presented with neurological symptoms, which was not associated with OS or bPFS. 46 patients had isolated brain metastases (no extracranial metastases), which was not associated with improved OS (p = 0.061) or bPFS (p = 0.17) compared to patients with other extracranial metastatic disease. The median age at diagnosis was 63. Patients younger than 63 years old had improved OS compared to patients age 63 or older, but not bPFS. Patients who received chemo and WBRT had improved OS compared to those who had either chemo or WBRT alone (p<0.001), but there was no difference in bPFS (p = 0.34). There was no significant difference in OS or bPFS depending on the sequence of therapy initiation. For patients who had chemo followed by WBRT, the median time between start of chemo and start of radiation was 103 days (range 6 – 182 days), which was not significantly associated with OS or bPFS. 13 patients received upfront brain metastasis resection, which was associated with improved OS but not bPFS compared to those who did not have surgery. 14 patients received SRS or partial brain radiation as part of their initial therapy, which was not significantly associated with OS or bPFS. 15 patients received salvage brain radiation after WBRT failure, which was associated with improved OS compared to those who did not have salvage radiation (25.5 months vs 8.0 months, p<0.001). The combination of chemo and WBRT was associated with improved OS compared to either modality alone. The sequence of treatment was not associated with OS or bPFS. Shorter time to WBRT after chemo was not significantly associated with OS or bPFS.

Comparing Whole Brain Radiation, 1, 3, And 5 Fraction Stereotactic Radiation In Patients With Brain Metastases

Patients with brain metastases are commonly treated with Radiation therapy (RT). Commonly used RT options include whole brain radiation (WBRT), Stereotactic radiosurgery (1 fraction, fx) or stereotactic radiation therapy (SRT, 2-5 fractions) depending on the number of lesions, primary cancer, KPS and other patient and tumor characteristics. The purpose of this study was to compare 1-year survival outcomes between WBRT, 1 fx SRS, 3 fx SRT and 5fx SRT. A retrospective analysis of 910 treatments with radiation therapy (RT) for 700 patients with brain metastases was performed (2012-2018). Treatment variables were extracted using Oncora software platform. Data for the four treatment groups (1fx, 3fx, 5fx and WBRT) was collected. Baseline characteristics between the treatment groups were compared using Chi-square test, Analysis of Variance, and the Kruskal-Wallis test. Mortality at 1 year was compared between the four treatment groups using a logistic regression model, adjusting for age, gender and KPS. Hosmer-Lemeshow test was used to determine whether the model provided a good fit. Tukey’s method was used to adjust for the multiple comparisons between the 4 treatment groups. P<0.05 was considered statistically significant. SAS 9.4 was used for the statistical analysis. Mean age (SD) was 63.3(12.3) years. Gender distribution was 397 (56.7%) females and 303 (43.3%) males. Treatment modalities were 244(34.9%) 1fx, 65(9.3%) 3fx, 14(2.0%) 5fx and 377(53.9%) whole brain (WBRT). Median 1fx dose was 20Gy, 3fx dose 24Gy and 5fx dose 30Gy and WBRT dose of 30Gy. Treatment groups were similar in term of age (p = 0.44). There were significant differences in the terms of the KPS distributions between treatments (p<0.0001), with median of 80, 80, 80 and 70 for treatments 1fx, 3fx, 5fx and WBRT, respectively although no significant gender differences were observed among the treatment groups (p = 0.44). The overall mortality rate at 1 year was 69.3%, with 136(55.7%), 42(64.6%), 8(57.1%) and 299(79.3%) for 1fx, 3fx, 5fx and WBRT, respectively. In the 6 pairwise comparisons (table1), 1fx had 62% lower odds of death compared to WBRT (OR = 0.38, 95% CI 0.23 to 0.63, p<0.0001). Age was significantly associated with mortality (OR = 1.03, 95% CI 1.02 to 1.05, p<0.0001), with 3% higher odds of 1-year mortality, for every 1-year increase in age. In women, 10 units increase of KPS had 31% lower odds of 1-year mortality (OR = 0.69, 95% CI 0.56 to 0.85, p = 0.001), while not significant in men (OR = 0.93, 95% CI 0.74 to 1.17, p = 0.56). We found that “Non-WBRT” group had 59% lower odds of 1-year mortality (OR = 0.41, 95% CI 0.28 to 0.59, p<0.0001) compared to the WB group. There was no difference in 1-year mortality in the three stereotactic protocols. Single fraction SRS had improved survival compared to WBRT at 1 year. Prospective studies are needed are needed to confirm survival and toxicity in the treatment groups.

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.