Moderately hypofractionated versus conventionally fractionated radiation therapy with temozolomide for young and fit patients with glioblastoma: an institutional experience and meta-analysis of literature.

PURPOSE: Shorter hypofractionated radiation therapy (HF-RT) schedules may have radiobiological, patient convenience and healthcare resource advantages over conventionally fractionated radiation therapy (CF-RT) in glioblastoma (GBM). We report outcomes of young, fit GBM patients treated with HF-RT and CF-RT during the COVID-19 pandemic, and a meta-analysis of HF-RT literature in this patient subgroup. METHODS: Hospital records of patients with IDH-wildtype GBM treated with HF-RT (50 Gy/20 fractions) and CF-RT (60 Gy/30 fractions) between January 2020 and September 2021 were reviewed. Overall survival (OS) and progression-free survival (PFS) were estimated using the Kaplan-Meier method. Univariable analysis was performed using Cox regression analysis. A systematic search and meta-analysis of studies from January 2000 to January 2022 was performed. RESULTS: 41 patients were treated (HF-RT:15, CF-RT:26). For both HF-RT and CF-RT groups, median age was 58 years and 80-90% were ECOG 0-1. There were more methylated tumours in the HF-RT group. All patients received concurrent/adjuvant temozolomide. At 19.2 months median follow-up, median OS was 19.8 months and not-reached for HF-RT and CF-RT (p = 0.5), and median PFS was 7.7 and 5.8 months, respectively (p = 0.8). HF-RT or CF-RT did not influence OS/PFS on univariable analysis. Grade 3 radionecrosis rate was 6.7% and 7.7%, respectively. 15 of 1135 studies screened from a systematic search were eligible for meta-analysis. For studies involving temozolomide, pooled median OS and PFS with HF-RT were 17.5 and 9.9 months (927 and 862 patients). Studies using shortened HF-RT schedules reported 0-2% Grade 3 radionecrosis rates. CONCLUSION: HF-RT may offer equivalent outcomes and reduce treatment burden compared to CF-RT in young, fit GBM patients.

Neoadjuvant Stereotactic Radiosurgery: a Further Evolution in the Management of Brain Metastases.

PURPOSE OF REVIEW: Recent randomized evidence has supported the use of resection followed by stereotactic radiosurgery (SRS) as standard of care for patients with a limited number of brain metastases. However, there are known toxicities, including a relatively high incidence of leptomeningeal disease. Neoadjuvant SRS has been proposed to minimize these potential sequalae. This review summarizes the current data and principles for neoadjuvant SRS. RECENT FINDINGS: Recently published studies have demonstrated neoadjuvant SRS to be feasible and to achieve similar oncological outcomes to postoperative SRS. A decreased incidence of leptomeningeal disease and radionecrosis has been observed. Additionally, neoadjuvant SRS can improve accuracy of target volume delineation and decrease the volume of irradiated normal tissue. Neoadjuvant SRS has emerged as a promising sequencing management approach. Its main advantages appear to be in reduction of toxicity. Ongoing trials will further explore this treatment method and establish which patients will benefit most from this technique.

Orbital cavernous venous malformation shrinkage during fractionated stereotactic radiotherapy contributing to the development of radiation retinopathy.

BACKGROUND: Posterior movement of ocular tissue secondary to orbital cavernous venous malformation shrinkage from fractionated stereotactic radiotherapy can allow healthy structures to move into the radiation field during treatment. This may carry an increased risk of radiation-induced retinopathy. METHODS: We present a case of a young female whose radiotherapy treatment for an orbital cavernous venous malformation resulted in a 3 mm reduction in proptosis and subsequent retinopathy. RESULTS: The severity of the patient's radiation-induced radiotherapy exceeded expectations. The venous malformation shrinkage during treatment and ensuing posterior movement of the globe suggested an increased involvement of ocular tissue in the radiation field, prompting consideration of interval neuroimaging and tumour mapping. CONCLUSIONS: We describe and suggest a protocol of onboard neuroimaging during the radiation therapy course to better target tumour volumes and minimise collateral tissue damage. To our knowledge, this has not been previously described in the ophthalmic literature.

Single-Fraction Versus Fractionated Preoperative Radiosurgery for Resected Brain Metastases: A PROPS-BM International Multicenter Cohort Study.

PURPOSE: Preoperative stereotactic radiosurgery (SRS) is a feasible alternative to postoperative SRS for resected brain metastases (BM). Most reported studies of preoperative SRS used single-fraction SRS (SF-SRS). The goal of this study was to compare outcomes and toxicity of preoperative SF-SRS with multifraction (3-5 fractions) SRS (MF-SRS) in a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). METHODS AND MATERIALS: Patients with BM from solid cancers, of which at least 1 lesion was treated with preoperative SRS followed by planned resection, were included from 8 institutions. SRS to synchronous intact BM was allowed. Exclusion criteria included prior or planned whole brain radiation therapy. Intracranial outcomes were estimated using cumulative incidence with competing risk of death. Propensity score matched (PSM) analyses were performed. RESULTS: The study cohort included 404 patients with 416 resected index lesions, of which SF-SRS and MF-SRS were used for 317 (78.5%) and 87 patients (21.5%), respectively. Median dose was 15 Gy in 1 fraction for SF-SRS and 24 Gy in 3 fractions for MF-SRS. Univariable analysis demonstrated that SF-SRS was associated with higher cavity local recurrence (LR) compared with MF-SRS (2-year: 16.3% vs 2.9%; P = .004), which was also demonstrated in multivariable analysis. PSM yielded 81 matched pairs (n = 162). PSM analysis also demonstrated significantly higher rate of cavity LR with SF-SRS (2-year: 19.8% vs 3.3%; P = .003). There was no difference in adverse radiation effect, meningeal disease, or overall survival between cohorts in either analysis. CONCLUSIONS: Preoperative MF-SRS was associated with significantly reduced risk of cavity LR in both the unmatched and PSM analyses. There was no difference in adverse radiation effect, meningeal disease, or overall survival based on fractionation. MF-SRS may be a preferred option for neoadjuvant radiation therapy of resected BMs. Additional confirmatory studies are needed. A phase 3 randomized trial of single-fraction preoperative versus postoperative SRS (NRG-BN012) is ongoing (NCT05438212).

Radiation necrosis and therapeutic outcomes in patients treated with linear accelerator-based hypofractionated stereotactic radiosurgery for intact intracranial metastases.

INTRODUCTION: Balancing disease control and treatment-related toxicities can be challenging when treating higher-risk brain metastases (BMs) that are larger in size or eloquent anatomical locations. Hypofractionated stereotactic radiosurgery (hfSRS) is expected to offer superior or equal efficacy with lower toxicity profile compared with single-fraction SRS (sfSRS). We report the efficacy and toxicity profiles of hfSRS in a consecutive cohort of patients to support this predicted benefit from hfSRS for high-risk BMs. METHODS: We retrospectively analysed 185 consecutive individual lesions from 152 patients with intact BMs treated with hfSRS between 1 July 2016 and 31 October 2019 and followed up to 30 April 2022 with serial brain magnetic resonance imaging (MRI). The primary endpoint was the event of radiation necrosis (RN). Local control (LC) rate and distant brain failure (DBF) were reported as secondary outcomes. Kaplan-Meier method was used to report the cumulative incidence of RN and overall survival and the incidence of DBF. Potential risk factors for RN were assessed using univariable Cox regression analysis. RESULTS: The median follow-up was 38.0 months, and the median survival post-SRS was 9.5 months. The cumulative incidence rate of RN was 13.2% (95% CI: 7.0-24.7%), and 18.1% of patients with confirmed RN were symptomatic. Higher mean dose delivered to planning target volume (PTV) (HR 1.22, 95% CI: 1.05-1.42, P = 0.01), higher mean BED10 (biological equivalent dose assuming a tissue α / ß ratio of 10) (HR 1.12, 95% CI: 1.04-1.2, P < 0.001), and higher mean BED2 (HR 1.02, 95% CI: 1-1.04, P = 0.04) delivered to the lesion was associated with increased risk of RN. LC rate was 86% and the cumulative incidence of DBF was 36% with a median onset of 28.4 months. CONCLUSIONS: Our results support the predicted radiobiological benefit of the use of hfSRS in high-risk BMs to limit treatment-related toxicity with low risk for symptomatic RN comparable with lower risk population receiving sfSRS while achieving satisfactory local disease control.

Favourable outcomes with an initial active surveillance strategy for asymptomatic radiation-induced meningiomas in long-term survivors of paediatric and young adult malignancies.

PURPOSE: Radiation-induced meningiomas (RIM) are the most common secondary neoplasm post cranial radiotherapy, yet optimal surveillance and treatment strategies remain contentious. Herein, we report the clinical outcomes and radiological growth rate of RIM, diagnosed in a cohort of survivors undergoing MRI screening, with the objective of informing clinical guidelines and practice. MATERIALS AND METHODS: Long-term survivors of paediatric or young-adult malignancies, diagnosed with RIM between 1990 and 2015, were identified. Absolute (AGR) and relative (RGR) volumetric growth rates were calculated. Rapid growth was defined as AGR > 2 cm3/year or AGR > 1 cm3/year and RGR ≥ 30% RESULTS: Fifty-two patients (87 RIM) were included. Median age at first RIM diagnosis was 33.9 (range,13.8-54.1) years. Seventy-seven (88%) RIM were asymptomatic at detection. Median follow-up time from first RIM detection was 11 (range, 0.6-28) years. Median absolute and relative volumetric growth rates were 0.05 (IQR 0.01-0.11) cm3 and 26 (IQR 7-79) % per year, respectively. Two (3.3%) RIM demonstrated rapid growth. Active surveillance was adopted for 67 (77%) RIM in 40 patients. Neurological sequelae due to RIM progression were reported in 5% of patients on active surveillance. Surgery was performed for 33 RIM (30 patients): 18 (54.5%) at diagnosis and 15 (45.5%) after active surveillance. Histopathology was WHO Grade 1 (85.2%), 2 (11.1%), 3 (3.7%). Following resection, 10-year local recurrence rate was 12%. During follow-up, 19 (37%) survivors developed multiple RIM. CONCLUSIONS: Asymptomatic RIM are typically low-grade tumours which exhibit slow growth. Active surveillance appears to be a safe initial strategy for asymptomatic RIM, associated with a low rate of neurological morbidity.

Risk Factors for Progression and Toxic Effects After Preoperative Stereotactic Radiosurgery for Patients With Resected Brain Metastases.

Importance: Preoperative stereotactic radiosurgery (SRS) has been demonstrated as a feasible alternative to postoperative SRS for resectable brain metastases (BMs) with potential benefits in adverse radiation effects (AREs) and meningeal disease (MD). However, mature large-cohort multicenter data are lacking. Objective: To evaluate preoperative SRS outcomes and prognostic factors from a large international multicenter cohort (Preoperative Radiosurgery for Brain Metastases-PROPS-BM). Design, Setting, and Participants: This multicenter cohort study included patients with BMs from solid cancers, of which at least 1 lesion received preoperative SRS and a planned resection, from 8 institutions. Radiosurgery to synchronous intact BMs was allowed. Exclusion criteria included prior or planned whole-brain radiotherapy and no cranial imaging follow-up. Patients were treated between 2005 and 2021, with most treated between 2017 and 2021. Exposures: Preoperative SRS to a median dose to 15 Gy in 1 fraction or 24 Gy in 3 fractions delivered at a median (IQR) of 2 (1-4) days before resection. Main Outcomes and Measures: The primary end points were cavity local recurrence (LR), MD, ARE, overall survival (OS), and multivariable analysis of prognostic factors associated with these outcomes. Results: The study cohort included 404 patients (214 women [53%]; median [IQR] age, 60.6 [54.0-69.6] years) with 416 resected index lesions. The 2-year cavity LR rate was 13.7%. Systemic disease status, extent of resection, SRS fractionation, type of surgery (piecemeal vs en bloc), and primary tumor type were associated with cavity LR risk. The 2-year MD rate was 5.8%, with extent of resection, primary tumor type, and posterior fossa location being associated with MD risk. The 2-year any-grade ARE rate was 7.4%, with target margin expansion greater than 1 mm and melanoma primary being associated with ARE risk. Median OS was 17.2 months (95% CI, 14.1-21.3 months), with systemic disease status, extent of resection, and primary tumor type being the strongest prognostic factors associated with OS. Conclusions and Relevance: In this cohort study, the rates of cavity LR, ARE, and MD after preoperative SRS were found to be notably low. Several tumor and treatment factors were identified that are associated with risk of cavity LR, ARE, MD, and OS after treatment with preoperative SRS. A phase 3 randomized clinical trial of preoperative vs postoperative SRS (NRG BN012) has began enrolling (NCT05438212).

From Postoperative to Preoperative: A Case Series of Hypofractionated and Single-Fraction Neoadjuvant Stereotactic Radiosurgery for Brain Metastases.

BACKGROUND: Postoperative stereotactic radiosurgery after resection of brain metastases is currently the standard of care. However, rates of leptomeningeal disease (LMD) after postoperative stereotactic radiosurgery have been reported to be >30%. Neoadjuvant stereotactic radiosurgery (NaSRS) has been proposed as an alternative treatment approach to decrease this risk. OBJECTIVE: To report the local control (LC) and LMD rates in patients undergoing NaSRS. METHODS: Our retrospective multicenter case series included consecutive patients planned for SRS followed by resection of intracranial lesions with a confirmed primary malignancy. Concurrent SRS alone to other intracranial lesions was permitted. Exclusion criteria included previous local treatment to that particular lesion and Eastern Cooperative Oncology Group performance status ≥3. Outcomes reported included LC, distant intracranial control (DC), overall survival, LMD, and radionecrosis (RN) rates. RESULTS: Overall, 28 patients with 29 lesions were eligible for analysis. The median follow-up was 12.8 months. The mean age was 62.5 (range 43-80) years, and 55% were Eastern Cooperative Oncology Group performance status 0 to 1. The most common primary malignancies included non-small cell lung cancer (43%) and melanoma (32%). Hypofractionated SRS was used in 62.1%. The 12-month LC and LMD rates were 91.3% and 4.0%, respectively. The 12-month RN, DC, and overall survival rates were 5.0%, 51.5%, and 60.1%, respectively. CONCLUSION: Compared with postoperative SRS, our study suggests that NaSRS leads to comparable local control with a decreased risk of LMD and RN. This is the first NaSRS series with a majority of patients treated with fractionated SRS. NaSRS is a promising approach for appropriate patients where surgical resection is a component of local therapy.

Barriers and potential solutions to international collaboration in neuro-oncology clinical trials: Challenges from the Australian perspective.

AIM: The neuro-oncology community in Australia is well positioned to collaborate internationally, with a motivated trials group, strong regulatory bodies and an attractive fiscal environment. We sought to identify gaps in the Australian neuro-oncology clinical trials landscape and describe strategies to increase international trial access in Australia. METHODS: We searched clinical trial registries to identify active adult primary brain cancer trials. We compared the participation rate and phase of these trials between tumour types and countries. A survey was distributed to the Cooperative Trials Group for Neuro-Oncology membership to identify barriers and solutions to effective international collaboration. RESULTS: Globally, 307 trials for adult primary brain cancers were identified. These included 50% pharmaceutical agents, 18% cellular therapies and 9% radiation therapy. Twelve adult primary brain cancer trials were actively recruiting in Australia at the time the survey was sent out. There were more early phase brain cancer trials (34%) compared with colorectal and breast cancer (21% and 24%, respectively). In Australia, 92% of brain cancer trials were involving pharmaceutical agents. The most commonly cited barrier was lack of funding for international trials (86%) and insufficient research time (75%). High ranking solutions included increasing the availability of funding for international trials and creating opportunities to develop personal relationships with collaborators. Accreditation of clinical research key performance indicators into practice (88%) and hospital accreditation (73%) also ranked highly. CONCLUSIONS: Participation in international research in Australia could be improved by embedding clinical research targets into institutional funding, provision of funding for early phase studies and streamlining mutual ethics schemes.

Assessment of Candida species colonization and denture-related stomatitis in complete denture wearers.

Candida species are considered the primary causative agents of denture stomatitis, but their role in colonization and disease in denture wearers remains undefined. In this study, we investigated risk factors associated with progression to Candida-related denture stomatitis in patients using complete dentures, and we genetically identified Candida isolates associated with disease and colonization. We recruited 114 retirement home residents for this study, from whom oral mucosa samples were collected and cultured following oral cavity exams. Morphologic analysis was used to identify potential yeast-positive cultures, which were then characterized further by RFLP analysis. C. albicans was the most frequently recovered species (61; 41.5%), followed by C. glabrata (27; 18.4%), and C. tropicalis (19; 12.9%). In addition, 16 isolates (10.9%) of C. dubliniensis were recovered, which was the first identification of this species in clinical samples from Iran. This study demonstrated a significant association between the duration of denture wear and oral candidiasis. Furthermore, we noted a high prevalence of C. dubliniensis in complete denture wearers.

Post-operative stereotactic radiosurgery following excision of brain metastases: A systematic review and meta-analysis.

BACKGROUND: Following the resection of brain metastases, Stereotactic Radiosurgery (SRS) to the post-operative surgical cavity has increasingly replaced Whole Brain Radiotherapy (WBRT) as the standard of practice. There is however tremendous variation in the way SRS can be delivered and outcomes of SRS are yet to be systemically characterized. METHODS: Pubmed, Medline, Embase, and Cochrane databases were searched through June 2019 to identify papers that examined post-operative SRS after resection of brain metastases. An aggregate data analysis was performed to estimate the pooled rate of local control at 12 months (LC12), radiation necrosis, and leptomengingeal disease dissemination as binary outcomes. We pre-specified a random effects model using the method of DerSimonian and Laird with the Mantel-Haenszel weighting scheme and a fixed continuity correction of 0.5. Heterogeneity was assessed using the I2 statistic. RESULTS: Fifty studies involving 3458 patients were included for analysis. LC12 across all studies was found to be 83.7%. Patients treated with fractionated SRS had better local control than patients treated with single fraction SRS (LC12 87.3% vs 80.0%, p = 0.021) in a univariate analysis. There was no improved LC12 with the addition of a margin (LC12 of 84.3% vs 83.1% with no margin, p = 0.71). Radiation necrosis was rare at 6.9% across all reported studies and leptomeningeal disease was found to be 13% across all reported studies. One year distant brain control was found to be 52.8%. CONCLUSION: Our review supports the use of post-operative SRS to the resection cavity as a safe and efficacious treatment option. Fractionated SRS appears to be beneficial and warrants further exploration.

Hypofractionated stereotactic radiotherapy for benign intracranial tumours of the cavernous sinus.

We present our experience with hypofractionated stereotactic radiotherapy (HSRT) using 15 fractions to treat benign conditions of the cavernous sinus (CS) and emphasise the outcome in terms of cranial nerve (CN) function and toxicity for long term safety and efficacy. We performed a retrospective review of prospectively collected data on 112 patients with benign tumours of the CS treated with HSRT between 1 January 1998 and 31 December 2009. While all tumours involved the CS, a separate analysis was undertaken for meningiomas and pituitary adenomas. The median follow-up was 77 months (range: 2.3-177). Fifty-seven patients (51%) had a diagnosis of meningioma and 55 (49%) had pituitary adenomas. Prior to HSRT, 82 patients (73%) underwent microsurgery. The median tumour volume was 6.6 cm(3) for meningiomas and 3.4 cm(3) for pituitary adenomas (interquartile range: 2.8-7.9), and the mean prescribed dose was 38 Gy (range: 37.5-40.0) to the tumour margin, delivered in 15 fractions. After HSRT, 57% of all preexisting cranial neuropathies either resolved or improved and 38% remained stable, whereas 5% deteriorated. The diagnosis of meningioma was the only variable associated with recovery of cranial neuropathy (p<0.001). Permanent CN complications occurred in three patients (3%). The 5 and 10 year actuarial freedom from progression for patients with meningiomas was 98% and 93%, respectively, and for patients with pituitary adenomas this was 96% and 96%, respectively. We demonstrate low rates of CN morbidity after HSRT and the possibility of resolution or improvement in CN function for common histologies involving the CS.