Adjuvant Whole Brain Radiotherapy Research Articles

Could Cerebral Inflammatory Lesions be the Cellular Origin of Primary Central Nervous System Lymphoma?

Primary central nervous system lymphoma (PCNSL) presents a diagnostic enigma due to the inherent absence of lymphoid tissue in the central nervous system (CNS). The hypothesis posits that lymphocytes infiltrating the CNS during inflammatory responses could represent a cellular source for PCNSL, challenging traditional understandings of its etiology. In 2 illustrative cases, patients presented with neurological symptoms initially misdiagnosed as encephalitis and demyelinating disease, respectively. These diagnoses were established based on clinical assessments and initial biopsy findings. Subsequent biopsies, conducted months after the first signs of disease, confirmed the diagnosis of PCNSL in both patients. Identifying CD20-positive tumor cells was pivotal, indicating a B-cell lymphoma origin. Treatment strategies included high-dose methotrexate chemotherapy for both patients. In addition, the second patient underwent adjuvant whole-brain radiotherapy after the chemotherapy regimen. The therapeutic approach significantly reduced tumor size in both cases, with no evidence of recurrence observed during the follow-up period. This outcome underscores the potential efficacy of the chosen interventions. In response to inflammatory lesions, lymphocyte infiltration into the CNS may serve as a pivotal origin for tumor cells in PCNSL. These cases highlight the complexity of diagnosing CNS disorders and suggest that various forms of encephalitis in the early stages could influence the prognosis of lymphoma. This insight into the cellular origins and treatment responses of PCNSL contributes to a broader understanding of its pathophysiology and management.

Rate of pachymeningeal failure following adjuvant WBRT vs SRS in patients with brain metastases

BackgroundStereotactic radiosurgery (SRS) has supplanted whole brain radiotherapy (WBRT) as standard-of-care adjuvant treatment following surgery for brain metastasis (BrM). Concomitant with the adoption of adjuvant SRS, a new pattern of failure termed “Pachymeningeal failure” (PMF) has emerged. MethodsWe reviewed a prospective registry of 264 BrM patients; 145 and 119 were treated adjuvantly with WBRT and SRS, respectively. The Cox proportional hazards model was used to identify variables correlating to outcomes. Outcomes were calculated using the cumulative incidence (CI) method. Univariate (UVA) and multivariate analyses (MVA) were done to identify factors associated with PMF. ResultsCI of PMF was 2 % and 18 % at 12 months, and 2 % and 23 % at 24 months for WRBT and SRS, respectively (p < 0.001). The CI of classic leptomeningeal disease (LMD) was 3 % and 4 % at 12 months, and 6 % and 6 % at 24 months for WBRT and SRS, respectively (P = 0.67). On UVA, adjuvant SRS [HR 9.75 (3.43–27.68) (P < 0.001)]; preoperative dural contact (PDC) [HR 6.78 (1.64–28.10) (P = 0.008)]; GPA score [HR 1.64 (1.11–2.42) (P = 0.012)]; and lung EGFR/ALK status [HR 3.11 (1.02–9.45) (P = 0.045)]; were associated with PMF risk. On MVA, adjuvant SRS [HR 8.15 (2.69–24.7) (P < 0.001)]; and PDC [HR 6.28 (1.51–26.1) (P = 0.012)] remained associated with PMF. ConclusionsPreoperative dural contact and adjuvant SRS instead of adjuvant WBRT were associated with an increased risk of PMF. Strategies to improve pachymeningeal radiation coverage to sterilize at risk pachymeninges should be investigated.

Outcomes of surgery and subsequent therapy for central nervous system oligoprogression in EGFR-mutated NSCLC patients

BackgroundOligoprogression is an emerging issue in patients with epidermal growth factor receptor (EGFR)-mutated non-small cell lung cancer (NSCLC). However, the surgical treatment for central nervous system (CNS) oligoprogression is not widely discussed. We investigated the outcomes of craniotomy with adjuvant whole-brain radiotherapy (WBRT) and subsequent therapies for CNS oligoprogression in patients with EGFR-mutated NSCLC.MethodsNSCLC patients with CNS oligoprogression were identified from a tertiary medical center. The outcomes of surgery with adjuvant WBRT or WBRT alone were analyzed, along with other variables. Overall survival and progression-free survival were analyzed using the log-rank test as the primary and secondary endpoints. A COX regression model was used to identify the possible prognostic factors.ResultsThirty-seven patients with CNS oligoprogression who underwent surgery or WBRT were included in the study after reviewing 728 patients. Twenty-one patients underwent surgery with adjuvant WBRT, and 16 received WBRT alone. The median overall survival for surgery and WBRT alone groups was 43 (95% CI 17–69) and 22 (95% CI 15–29) months, respectively. Female sex was a positive prognostic factor for overall survival (OR 0.19, 95% CI 0.06–0.57). Patients who continued previous tyrosine kinase inhibitors (OR 3.48, 95% CI 1.06–11.4) and induced oligoprogression (OR 3.35, 95% CI 1.18–9.52) were associated with worse overall survival. Smoking history (OR 4.27, 95% CI 1.54–11.8) and induced oligoprogression (OR 5.53, 95% CI 2.1–14.7) were associated with worse progression-free survival.ConclusionsSurgery combined with adjuvant WBRT is a feasible treatment modality for CNS oligoprogression in patients with EGFR-mutated NSCLC. Changing the systemic-targeted therapy after local treatments may be associated with improved overall survival.

Cost Analysis of Adjuvant Whole-Brain Radiotherapy Treatment Versus No Whole-Brain Radiotherapy After Stereotactic Radiosurgery and/or Surgery Among Adults with One to Three Melanoma Brain Metastases: Results from a Randomized Trial.

PurposeWe aimed to compare Australian health system costs at 12 months for adjuvant whole-brain radiotherapy (WBRT) treatment after stereotactic radiosurgery (SRS) and/or surgery versus observation among adults with one to three melanoma brain metastases. We hypothesized that treatment with adjuvant WBRT and subsequent healthcare would be more expensive than SRS/surgery alone.MethodsThe analysis was conducted alongside a multicentre, randomized phase III trial. A bespoke cost questionnaire was used to measure healthcare use, including hospitalizations, specialist and primary care visits, imaging, and medicines over 12 months. Mean per-patient costs were calculated based on the quantity of resources used and unit costs, reported in Australian dollars ($AU), year 2018 values. Skewness of cost data was determined using normality tests and censor-adjusted costs reported using the Kaplan–Meier sample average method. The analysis of difference in mean costs at each 2-month time point and at 12 months was performed and checked using Kruskal–Wallis, generalized linear models with gamma distribution and log link, modified Park test, ordinary least squares, and non-parametric bootstrapping.ResultsIn total, 89 patients with similar characteristics at baseline were included in the cost analysis (n = 43 WBRT; n = 46 observation). Hospitalization cost was the main cost, ranging from 63 to 89% of total healthcare costs. The unadjusted 12-monthly cost for WBRT was $AU71,138 ± standard deviation 41,475 and for observation $AU69,848 ± 33,233; p = 0.7426. The censor-adjusted 12-monthly cost for WBRT was $AU90,277 ± 36,274 and $AU82,080 ± 34,411 for observation. There was no significant difference in 2-monthly costs between groups (p > 0.30 for all models).ConclusionsMost costs were related to inpatient hospitalizations associated with disease recurrence. Adding WBRT after local SRS/surgery for patients with one to three melanoma brain metastases did not significantly increase health system costs during the first 12 months.Trial RegistrationACTRN12607000512426, prospectively registered 14 September 2007.Supplementary InformationThe online version contains supplementary material available at 10.1007/s41669-022-00332-8.

Outcomes of adjuvant whole-brain radiotherapy versus hypofractionated stereotactic radiotherapy after surgical resection of brain metastases: a propensity score-matched analysis.

To assess the risks of local and distant failure and overall survival time in patients treated with hypofractionated stereotactic radiotherapy (HFSRT) to the postoperative cavity for brain metastases (BMs) compared with patients treated with adjuvant whole-brain radiation therapy (WBRT). Between July 2005 and February 2015, 196 non-randomized patients with 202 resected BMs were treated with post-operative WBRT or HFSRT at a single institution. The propensity score was included as a covariate to compare the interval to local failure, distant brain failure and overall survival time. The matching covariates consisted of the age, Karnofsky performance status, primary disease, number of BMs, extracranial disease status and presence or absence of extracranial metastases. In total, 110 patients (54.5%) received adjuvant WBRT, and 92 HFSRT procedures (45.5%) were delivered after surgery. A Cox model adjusted on the propensity score showed that the brain distant failure was significantly associated with treatment modality. Compared with WBRT, the patients who received HFSRT had a significantly greater risk of developing distant brain recurrence [HR =3.37 (2.13-5.33), P<0.001]. No difference was observed in local failure (HR =1.16, P=0.77) between the groups. In the propensity-matched cohort, the effect of treatment on survival was not significant (P=0.14), but it depended on the time. Within the first 20 months, the patients treated with WBRT had a 2 times higher risk of death than did patients treated with HFSRT [HR =2.17 (1.42-3.32), P=0.0003]. Compared with the standard WBRT after the resection of BMs, stereotactic radiotherapy to the surgical bed produced a comparable local control rate to that of WBRT with a survival advantage in the first 20 months.

Whole brain radiation therapy plus focal boost may be a suitable strategy for brain metastases in SCLC patients: a multi-center study

BackgroundThe treatment for brain metastases in small cell lung cancer (SCLC) is still controversial. The purpose of this study was to compare different brain radiotherapy treatments on SCLC patients with brain metastases.MethodsIn this multi-center retrospective study, SCLC patients who had undergone whole brain radiation therapy (WBRT) or stereotactic radiosurgery (SRS) for brain metastases from January 2012 to December 2018 were retrospectively screened.ResultsA total of 263 eligible SCLC patients were included in this study, among whom, 73 were women and 190 were men. According to accepted brain radiotherapy, the remaining patients were divided into WBRT plus focal radiation boost (WBRT+boost), WBRT, and SRS groups. In pairwise comparisons of the overall survival (OS), WBRT+boost group led to longer survival than did WBRT both in all patients (17.9 vs 8.7 months; P < 0.001) and 140 matched patients (17.9 vs 11.7 months; P = 0.045). There were no significant differences in OS between WBRT+boost and SRS groups in all patients (17.9 vs 14.5 months; P = 0.432). Among 74 matched patients between WBRT+boost and SRS groups, however, patients who received WBRT+boost led to a longer survival than did SRS alone (21.8 vs 12.9 months; P = 0.040). In pairwise comparison of the intracranial progression-free survival time (iPFS), WBRT+boost group also showed survival advantages over WBRT (10.8 vs 6.5 months; P = 0.005) and SRS groups (10.8 vs 7.5 months; P = 0.032).ConclusionDue to the SCLC-derived multiple brain metastases and better survival time, focal radiation boost combined with adjuvant WBRT may be a preferred strategy for SCLC patients with brain metastases.

Management evaluation of metastasis in the brain (MEMBRAIN)-a United Kingdom and Ireland prospective, multicenter observational study.

In recent years an increasing number of patients with cerebral metastasis (CM) have been referred to the neuro-oncology multidisciplinary team (NMDT). Our aim was to obtain a national picture of CM referrals to assess referral volume and quality and factors affecting NMDT decision making. A prospective multicenter cohort study including all adult patients referred to NMDT with 1 or more CM was conducted. Data were collected in neurosurgical units from November 2017 to February 2018. Demographics, primary disease, KPS, imaging, and treatment recommendation were entered into an online database. A total of 1048 patients were analyzed from 24 neurosurgical units. Median age was 65 years (range, 21-93 years) with a median number of 3 referrals (range, 1-17 referrals) per NMDT. The most common primary malignancies were lung (36.5%, n = 383), breast (18.4%, n = 193), and melanoma (12.0%, n = 126). A total of 51.6% (n = 541) of the referrals were for a solitary metastasis and resulted in specialist intervention being offered in 67.5% (n = 365) of cases. A total of 38.2% (n = 186) of patients being referred with multiple CMs were offered specialist treatment. NMDT decision making was associated with number of CMs, age, KPS, primary disease status, and extent of extracranial disease (univariate logistic regression, P < .001) as well as sentinel location and tumor histology (P < .05). A delay in reaching an NMDT decision was identified in 18.6% (n = 195) of cases. This study demonstrates a changing landscape of metastasis management in the United Kingdom and Ireland, including a trend away from adjuvant whole-brain radiotherapy and specialist intervention being offered to a significant proportion of patients with multiple CMs. Poor quality or incomplete referrals cause delay in NMDT decision making.

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.

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.

Phase 3 international trial of adjuvant whole brain radiotherapy (WBRT) or observation (Obs) following local treatment of 1-3 melanoma brain metastases (MBMs).

9500 Background: The role of adjuvant WBRT in MBMs is controversial. This trial compares WBRT with Obs after local treatment of 1-3 MBMs. Methods: The primary endpoint is distant intracranial failure (DIF) within 12 months of randomization. The a priori neurocognitive function (NCF) endpoint is Hopkins Verbal Learning Test-Revised (HVLT-R) delayed recall at 4 months. Secondary endpoints include local failure (LF), overall survival (OS) and global quality of life (QoL). Analyses were conducted on intention-to-treat basis with nominal two-sided significance level 5%. Drug therapy was allowed. Effective drugs became available during trial and their impact was analysed. Results: Of 586 eligible patients (pts), 215 consented from 31 sites in 3 countries (Australia, UK and Norway) between 2009 and 2017. Eight (0.04%) who withdrew or had no data collected were excluded. 107 randomized to Obs and 100 to WBRT. Mean age 62 years, 67% males, 61% with single MBM of mean size 2cm, 67% had extracranial disease at randomization. The two arms were well matched. NCF was completed by English speakers; 50 WBRT and 70 Obs at baseline, declining to 26 and 35 respectively at 4 months. Within 12 months, 54 (50.5%) Obs had DIF compared with 42 (42.0%) WBRT pts (OR 0.71; 95%CI 0.41-1.23; p = 0.222). There was no difference in LF (p = 0.100) or OS (log-rank p = 0.861). 53% (Obs) and 59% (WBRT) pts were alive at 12 months. There was no significant between-group difference in mean intervention effect on global QoL (p = 0.083). Pts who received T-cell checkpoint inhibitors and/or mitogen-activated protein kinase (MAPK) pathway inhibitors and WBRT before or within 12 months of randomization had DIF rate 29% compared with Obs and no systemic therapy had 44%, but was not significant (p = 0.228). Obs had greater relative improvement from baseline in HVLT-R at every timepoint. At 4 months, Obs had 20.9% improvement from baseline in HVLT-R-delayed recall compared to 2.7% decline in WBRT; overall adjusted average intervention effect 23.6% (95%CI 9.0, 38.2; p = 0.0018). There was no difference in time to cognitive failure or in proportions with global cognitive impairment. Conclusion: This level one evidence shows WBRT does not improve outcomes in MBMs. This practice-changing trial justifies the recent move away from WBRT that occurred during the course of the trial. Clinical trial information: NCT01503827.

Association of Neurosurgical Resection With Development of Pachymeningeal Seeding in Patients With Brain Metastases

Neurosurgical resection represents an important management strategy for patients with large, symptomatic brain metastases and increasingly is followed by stereotactic radiation as opposed to whole-brain radiation. Whether neurosurgical resection is associated with tumor spread beyond the resection site and adjuvant stereotactic radiation field remains unknown. To characterize the association and incidence of pachymeningeal seeding with neurosurgical resection in patients with brain metastases treated with adjuvant stereotactic radiation. Retrospective cohort study of a consecutive sample of patients with newly diagnosed brain metastases managed with neurosurgical resection and stereotactic radiation (n = 318) vs radiation alone (n = 870) between 2001 and 2015. Incidence of pachymeningeal seeding (dural and/or outer arachnoid) and leptomeningeal disease in patients treated with neurosurgical resection and stereotactic radiation vs radiation alone and the risk factors and outcomes associated with pachymeningeal seeding in patients treated with neurosurgical resection followed by stereotactic radiation. In 1188 patients with newly diagnosed brain metastases, 133 men and 185 women (mean [SD] age, 58.9 [11.5] years) underwent neurosurgical resection. Resection was found to be associated with pachymeningeal seeding (36 of 318 patients vs 0 of 870 patients; P < .001) but not leptomeningeal disease (hazard ratio [HR], 1.14; 95% CI, 0.73-1.77; P = .56). In total, 36 (8.4%) of 428 operations were complicated by pachymeningeal seeding, with a higher incidence noted with resection of previously irradiated vs unirradiated metastases (HR, 2.39; 95% CI, 1.25-4.57; P = .008). Patients with pachymeningeal seeding had relatively low rates of subsequent development of new brain metastases and leptomeningeal disease (8 [16%] of 51 and 6 [13%] of 48, respectively). Among patients with pachymeningeal seeding, neurologic death primarily owing to progressive pachymeningeal disease accounted for 26 (72%) of 36 deaths, but when treated with salvage radiation, 49.1% of patients survived 1 year or longer. In the era of omission of adjuvant whole-brain radiation after neurosurgical resection, pachymeningeal seeding beyond the stereotactic radiation field represents a notable oncologic event that often proves difficult to salvage. However, in some patients, disease control can be achieved with radiotherapeutic approaches.

Evolution in the Role of Stereotactic Radiosurgery in Patients with Multiple Brain Metastases: An International Survey

Currently no firm consensus exists regarding the use of stereotactic radiosurgery (SRS) alone versus whole brain radiation (WBRT) +/- SRS in patients with multiple brain metastases. The International Gamma Knife Research Foundation (IGKRF) conducted a survey to review international practice patterns. Through 2 international radiosurgery societies, clinicians who are involved in the radiosurgical management of patients with brain metastases (i.e. Neurosurgeons, Radiation Oncologists, Medical Physicists, Neuro-Oncologists, and Medical Oncologists as appropriate) were invited to complete a questionnaire. Respondents selected therapeutic options based on brief case vignettes and could select (1) SRS alone, (2) SRS with adjuvant WBRT, (3) WBRT alone, or (4) omission of upfront local radiation. Respondents were also asked what clinical factors drove their recommendation. Common histologies such as non-small cell lung cancer (NSCLC), breast cancer, and melanoma were included. A total of 71 respondents replied to the survey, 43 of whom were academic (60%). The respondents included 41 radiation oncologists (57%), 24 neurosurgeons (34%), and 6 (8%) other clinicians. The majority of respondents (87%) had 5 or more years of experience in the role of SRS. For a patient with 7 NSCLC brain metastases, all under 1 cm, and stable extracranial disease, 77% would perform SRS alone and 17% would recommend WBRT alone. For a patient with 7 or more brain metastases, the majority selected SRS alone irrespective of tumor histology (NSCLC, breast, melanoma, p > 0.5). However, neurosurgeons would more often utilize SRS alone or SRS combined with WBRT compared to radiation oncologists ( p = 0.002). Key clinical factors in selecting SRS alone were KPS (82% of respondents), total volume of metastases (81%), number of metastases (80%), and less so tumor histology (42%). Sixty percent of respondents would perform SRS alone for 12 brain metastases in a melanoma patient who was also receiving immunotherapy and 49% would recommend SRS alone for a patient with 12 NSCLC metastases on a tyrosine kinase inhibitor. While important clinical factors were outlined, the number of brain metastases and histology are not the only drivers in the use of SRS. Most centers with international expertise routinely use SRS for patients with oligometastatic brain disease. While 75% clinicians prefer SRS alone for up to 7 tumors, 50% would select SRS alone for up to ten tumors. Patients with small total volume of brain disease, high KPS, or who are receiving novel systemic chemotherapy or immunotherapy are often recommended to undergo SRS. Compared to radiation oncologists, neurosurgeons more often recommend SRS regardless of the number of brain metastases emphasizing the importance of additional studies that clarify the roles of SRS and WBRT in patients with oligometastatic brain disease.

Evolution in the role of stereotactic radiosurgery in patients with multiple brain metastases: An international survey

ObjectiveCurrently no firm consensus exists regarding utilization of stereotactic radiosurgery (SRS) alone versus whole brain radiation (WBRT) ± SRS in patients with multiple brain metastases. The International Gamma Knife Research Foundation conducted a survey to review international practice patterns. MethodsThrough 2 international radiosurgery societies, clinicians who are involved in the radiosurgical management of patients with brain metastases were invited to complete a questionnaire. Respondents selected therapeutic options based on brief case vignettes and could select (1) SRS alone, (2) SRS with adjuvant WBRT, (3) WBRT alone, or (4) omission of upfront local radiation. ResultsA total of 71 respondents replied to the survey, including 41 radiation oncologists (57%), 24 neurosurgeons (34%), and 6 (8%) other clinicians. For a patient with 7 brain metastases (NSCLC), all under 1 cm, and stable extracranial disease, 77% would perform SRS alone and 17% would recommend WBRT alone. For a patient with 7 or more brain metastases, the majority selected SRS alone, irrespective of tumor histology (p > 0.5). However, neurosurgeons would more often utilize SRS alone or SRS combined with WBRT compared to radiation oncologists (p = 0.002). Key clinical factors in selection were KPS (82% of respondents), total tumor volume (81%), number (80%), and less-so histology (42%). ConclusionRegardless of number of metastases, patients with small total volume of brain disease, high KPS, or who are receiving novel therapies are often recommended to undergo SRS. Neurosurgeons more often recommend SRS, emphasizing the importance of additional studies to clarify the role of SRS in these patients.

Emerging Trends in the Management of Brain Metastases from Non-small Cell Lung Cancer.

To summarize current approaches in the management of brain metastases from non-small cell lung cancer (NSCLC). Local treatment has evolved from whole-brain radiotherapy (WBRT) to increasing use of stereotactic radiosurgery (SRS) alone for patients with limited (1-4) brain metastases. Trials have established post-operative SRS as an alternative to adjuvant WBRT following resection of brain metastases. Second-generation TKIs for ALK rearranged NSCLC have demonstrated improved CNS penetration and activity. Current brain metastasis trials are focused on reducing cognitive toxicity: hippocampal sparing WBRT, SRS for 5-15 metastases, pre-operative SRS, and use of systemic targeted agents or immunotherapy. The role for radiotherapy in the management of brain metastases is becoming better defined with local treatment shifting from WBRT to SRS alone for limited brain metastases and post-operative SRS for resected metastases. Further trials are warranted to define the optimal integration of newer systemic agents with local therapies.

Pre-operative stereotactic radiosurgery treatment is preferred to post-operative treatment for smaller solitary brain metastases

BackgroundWhile the optimal combination of whole-brain radiotherapy (WBRT), stereotactic radiosurgery (SRS) and surgical resection in the treatment of brain metastases, is controversial, the addition of SRS to surgical resction of solitary metastasis may enhance local control while potentially minimizing toxicity associated with adjuvant WBRT. This study seeks to determine whether pre-operative SRS to the lesion versus post-operative SRS to the resection bed may reduce irradiation of adjacent normal brain tissue.MethodsA retrospective study of 12 patients with 13 surgically resected cerebral metastases was performed. The pre-operative contrast-enhancing tumors and post-operative resection cavities plus any enhancing residual disease were contoured to yield the gross target volume (GTV). In turn these GTV’s were uniformly expanded by 3-mm to generate the pre-operative, as well as post-operative planning target volume (PTV.) For each lesion, a 7-static-conformal-beam, non-coplanar plan utilizing 6 MV photons was generated to encompass the PTV within the 85% isodose line. Excess normal brain volume irradiated was defined as the volume outside the GTV receiving the prescribed dose.ResultsWhen lesions were divided into two groups - Group A (pre-operative GTV’s < 15 cc, n = 9) and Group B (pre-operative GTV’s > 15 cc, n = 4) - the average volume of normal brain irradiated was significantly smaller if pre-operative SRS was used for treatment of lesions in Group A (9.5 vs. 16.8 cc, paired t-test, p = 0.0045). In contrast, this volume was smaller for Group B lesions if post-operative SRS was used for treatment of these lesions (27.6 vs. 51.2 cc, p = 0.252). A comparison of groups with respect to mean volume differences between pre- and post-operative SRS was significantly different (two-sample t-test p = 0.016). GTV and the difference between pre- and post-operative volume were highly correlated (Pearson correlation = −0.875, p < 0.0001).ConclusionsPre-operative treatment of smaller metastases may result in reduced radiation dose to normal tissue and, thus, reduced treatment-related morbidity compared to post-operative irradiation of the resection cavity.

Imaging and clinical end points in brain metastases trials.

Imaging and clinical end points in brain metastases trials.

Hypofractionated Stereotactic Radiation Therapy to the Resection Bed for Intracranial Metastases

To retrospectively report the outcomes of a large multicenter cohort of patients treated with surgery and hypofractionated stereotactic radiation therapy (HFSRT) to the resection cavities of brain metastases (BMs). Between March 2008 and February 2015, 181 patients with no prior whole-brain radiation therapy (WBRT) were treated by HFSRT to the surgical bed of BM at the dose of 33Gy (3×11Gy). The primary endpoint was local control. Secondary endpoints were distant brain control, overall survival (OS), risk of radionecrosis, and leptomeningeal disease (LMD). Of the 189 resected lesions, 44% were metastatic from a non-small cell lung cancer primary tumor, and 76% of patients had a single BM at the time of treatment. With a median follow-up of 15months, the 6- and 12-month local control rates were 93% and 88%, respectively. On multivariate analysis, planning target volume (P=.005), graded prognostic assessment score (P=.021), and meningeal contact of BM (P=.032) were predictive of local failure. The 6- and 12-month distant brain control rates were 70% and 61%, respectively. Twenty-six patients (14%) developed signs of LMD at a median time of 3.8months. The preoperative tumor volume was predictive of LMD (P=.029). The median OS was 17months. The 6-, 12-, and 24-month OS rates were 79%, 62%, and 39%, respectively. Recursive partitioning analysis class 3 (P=.02), piecemeal resection (P=.017), and an increasing number of BMs (P<.01) were independent unfavorable prognostic factors for OS. Fifty-four patients (30%) were subsequently treated with salvage WBRT at a median time of 6.5months, and 41% were reirradiated with SRT. Radionecrosis occurred in 19% of cases at a median time of 15months and was associated with the infratentorial location of the BM (P=.0025). This study demonstrated the safety and efficacy of a 3×11Gy HFSRT regimen for the irradiation of BMs resection cavities. It was an alternative to adjuvant WBRT.

Management of breast cancer brain metastases: Focus on human epidermal growth factor receptor 2-positive breast cancer

After the introduction of trastuzumab, a monoclonal antibody that binds to human epidermal growth factor receptor 2 (HER2), the overall survival (OS) among patients with HER2-positive breast cancer has been substantially improved. However, among these patients, the incidence of brain metastases (BM) has been increasing and an increased proportion of them have died of intracranial progression, which makes HER2-positive breast cancer brain metastases (BCBM) a critical issue of concern. For local control of limited BM, stereotactic radiosurgery (SRS) and surgical resection are available modalities with different clinical indications. Postoperative or preoperative radiation is usually delivered in conjunction with surgical resection to boost local control. Adjuvant whole-brain radiotherapy (WBRT) should be deferred for limited BM because of its impairment of neurocognitive function while having no benefit for OS. Although WBRT is still the standard treatment for local control of diffuse BM, SRS is a promising treatment for diffuse BM as the technique continues to improve. Although large molecules have difficulty crossing the blood brain barrier, trastuzumab-containing regimens are critical for treating HER2-positive BCBM patients because they significantly prolong OS. Tyrosine kinase inhibitors are more capable of crossing into the brain and they have been shown to be beneficial for treating BM in HER2-positive patients, especially lapatinib combined with capecitabine. The antiangiogenic agent, bevacizumab, can be applied in the HER2-positive BCBM scenario as well. In this review, we also discuss several strategies for delivering drugs into the central nervous system and several microRNAs that have the potential to become biomarkers of BCBM.

The Impact of a Central Nervous System Event on Cognitive Function After Volumetric Radiosurgery and Adjuvant Whole-Brain Radiation Therapy in Patients With 1 to 10 Brain Metastases

The Impact of a Central Nervous System Event on Cognitive Function After Volumetric Radiosurgery and Adjuvant Whole-Brain Radiation Therapy in Patients With 1 to 10 Brain Metastases

Debate: adjuvant whole brain radiotherapy or not? More data is the wiser choice.

Every year 170,000 patients are diagnosed with brain metastases (BMs) in the United States. Traditionally, adjuvant whole brain radiotherapy (AWBRT) has been offered following local therapy with neurosurgery (NSx) and/or stereotactic radiosurgery (SRS) to BMs. The aim is to increase intracranial control, thereby decreasing symptoms from intracranial progression and a neurological death. There is a rapidly evolving change in the radiation treatment of BMs happening around the world. AWBRT is now being passed over in favour of repeat scanning at regular intervals and more local therapies as more BMs appear radiologically, BMs that may never become symptomatic. This change has happened after the American Society for Radiation Oncology (ASTRO) in Item 5 of its “Choosing Wisely 2014” list recommended: “Don't routinely add adjuvant whole brain radiation therapy to SRS for limited brain metastases”. The guidelines are supposed to be based on the highest evidence to hand at the time. This article debates that the randomised controlled trials (RCTs) published prior to this recommendation consistently showed AWBRT significantly increases intracranial control, and avoids a neurological death, what it is meant to do. It also points out that, despite the enormity of the problem, only 774 patients in total had been randomised over more than three decades. These trials were heterogeneous in many respects. This data can, at best, be regarded as preliminary. In particular, there are no single histology AWBRT trials yet completed. A phase two trial investigating hippocampal avoiding AWBRT (HAWBRT) showed significantly less NCF decline compared to historical controls. We now need more randomised data to confirm the benefit of adjuvant HAWBRT. However, the ASTRO Guideline has particularly impacted accrual to trials investigating this, especially the international ANZMTG 01.07 WBRTMel trial. This is an RCT investigating AWBRT following local treatment in patients with one to three BMs from melanoma. WBRTMel has accrued 196 of a required 220 to date but accrual has slowed. HAWBRT may now never be tested in a randomised setting. Encouraging more data in AWBRT is the wiser choice.