Patterns of Progression in Patients With Newly Diagnosed Glioblastoma Treated With 5-mm Margins in a Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With Concurrent and Adjuvant Temozolomide.

PURPOSE: In patients with newly diagnosed glioblastoma (GBM), tumor margins of at least 20 mm are the standard of care. We sought to determine the pattern of tumor progression in patients treated with 5-fraction stereotactic radiosurgery with 5-mm margins. METHODS AND MATERIALS: Thirty adult patients with newly diagnosed GBM were treated with 5-fraction stereotactic radiosurgery in escalated doses from 25 to 40 Gy with a 5-mm total treatment margin. Progression was scored as "in-field" if the recurrent tumor was within or contiguous with the 5-mm margin, "marginal" if between 5 and 20 mm, and "distant" if entirely occurring greater than 20 mm. As geometric patterns of progression do not reflect the biologic dose received, we calculated the minimum equi-effective dose in 2 Gy (EQD2) per day at the site of tumor recurrence. Progression was "dosimetrically in-field" if covered by a minimum EQD2 per day of 48 Gy10. RESULTS: From 2010 to 2016, 27 patients had progressed. Progression was in-field in 17 (63%), marginal in 3 (11%), and distant in 7 (26%) patients. In the 3 patients with marginal progression, the minimum EQD2 to recurrent tumor were 48 Gy10, 56 Gy10 (both considered dosimetrically in-field), and 7 Gy10 (ie, dosimetrically out-of-field). Median overall survival was 12.1 months for in-field (95% confidence interval [CI], 8.9-17.6), 15.1 months (95% CI, 10.1 to not achieved) for marginal, and 21.4 months (95% CI, 11.2-33.5) for distant progression. Patients with radiation necrosis were less likely to have in-field progression (1 of 7; 14%) compared with those without radiation necrosis (16 of 20; 80%; P = .003); those with necrosis had a median overall survival of 27.2 months (95% CI, 11.2-48.3) compared with 11.7 months (95% CI, 8.9-17.6) for patients with no necrosis (P = .077). CONCLUSIONS: In patients with newly diagnosed GBM treated with a 5-mm clinical target volume margin, 3 patients (11%) had marginal progression within 5 to 20 mm; only 1 patient (4%) may have dosimetrically benefitted from conventional 20-mm margins. Radiation necrosis was associated with in-field tumor control.

Extreme weekly locoregional hypofractionated radiation in elderly women with non-metastatic breast cancer.

BACKGROUND AND PURPOSE: Breast cancer locoregional (LR) radiation in the elderly requires careful consideration between the benefits of aggressive treatment and its potential toll on these patients. Extreme weekly LR hypofractionated radiation (HFRT), delivering >5 Gy per fraction, may be better suited in such a population. It represents a good compromise between RT omission and exhaustive daily radiation. This study aims to report the local and LR control rate as well as the acute and long-term side effects of the elderly patients treated with HFRT in our institution, and to compare these results to those from the literature. MATERIALS AND METHODS: We conducted a retrospective study by reviewing medical records of elderly patients with breast cancer treated with adjuvant once-weekly LR HFRT between 2011 and 2020. Fifty patients presenting with primary non-metastatic node-positive breast tumors were included. Treatment outcomes including local/LR control and overall survival were reported. Early and late toxicity profiles were also assessed. RESULTS: After a median follow-up of 4.8 years, only one local recurrence in the chest wall occurred and there was no regional recurrence. The distant metastatic rate was 6%. The long-term recurrence-free survival rate was 80% at 5 years. The cause specific survival rate was 90% at 5 years. The overall survival rate was 69.4% and 55.5% at 3 and 5 years, respectively. There were 44 (88%) patients with Grade 1 or 2 early toxicity. There was no Grade 3 or higher acute toxicity registered. Late toxicity was mainly Grade 1 or 2 subcutaneous fibrosis, lymphoedema, and neuropathy except for one patient with Grade 3 fibrosis. CONCLUSION: Extreme LR HFRT is well tolerated with good outcomes and is a good alternative for elderly and frail patients. Our results confirm the efficacy and safety of such a regimen. Further randomized trials assessing both oncologic outcome and toxicity profile are justified.

A phase I/II trial of 5-fraction stereotactic radiosurgery with 5-mm margins with concurrent temozolomide in newly diagnosed glioblastoma: primary outcomes.

BACKGROUND: We sought to determine the maximum tolerated dose (MTD) of 5-fraction stereotactic radiosurgery (SRS) with 5-mm margins delivered with concurrent temozolomide in newly diagnosed glioblastoma (GBM). METHODS: We enrolled adult patients with newly diagnosed glioblastoma to 5 days of SRS in a 3 + 3 design on 4 escalating dose levels: 25, 30, 35, and 40 Gy. Dose limiting toxicity (DLT) was defined as Common Terminology Criteria for Adverse Events grades 3-5 acute or late CNS toxicity, including adverse radiation effect (ARE), the imaging correlate of radiation necrosis. RESULTS: From 2010 to 2015, thirty patients were enrolled. The median age was 66 years (range, 51-86 y). The median target volume was 60 cm3 (range, 14.7-137.3 cm3). DLT occurred in 2 patients: one for posttreatment cerebral edema and progressive disease at 3 weeks (grade 4, dose 40 Gy); another patient died 1.5 weeks following SRS from postoperative complications (grade 5, dose 40 Gy). Late grades 1-2 ARE occurred in 8 patients at a median of 7.6 months (range 3.2-12.6 mo). No grades 3-5 ARE occurred. With a median follow-up of 13.8 months (range 1.7-64.4 mo), the median survival times were: progression-free survival, 8.2 months (95% CI: 4.6-10.5); overall survival, 14.8 months (95% CI: 10.9-19.9); O6-methylguanine-DNA methyltransferase hypermethylated, 19.9 months (95% CI: 10.5-33.5) versus 11.3 months (95% CI: 8.9-17.6) for no/unknown hypermethylation (P = 0.03), and 27.2 months (95% CI: 11.2-48.3) if late ARE occurred versus 11.7 months (95% CI: 8.9-17.6) for no ARE (P = 0.08). CONCLUSIONS: The per-protocol MTD of 5-fraction SRS with 5-mm margins with concurrent temozolomide was 40 Gy in 5 fractions. ARE was limited to grades 1-2 and did not statistically impact survival.

Nodular Leptomeningeal Disease-A Distinct Pattern of Recurrence After Postresection Stereotactic Radiosurgery for Brain Metastases: A Multi-institutional Study of Interobserver Reliability.

PURPOSE: For brain metastases, surgical resection with postoperative stereotactic radiosurgery is an emerging standard of care. Postoperative cavity stereotactic radiosurgery is associated with a specific, underrecognized pattern of intracranial recurrence, herein termed nodular leptomeningeal disease (nLMD), which is distinct from classical leptomeningeal disease. We hypothesized that there is poor consensus regarding the definition of LMD, and that a formal, self-guided training module will improve interrater reliability (IRR) and validity in diagnosing LMD. METHODS AND MATERIALS: Twenty-two physicians at 16 institutions, including 15 physicians with central nervous system expertise, completed a 2-phase survey that included magnetic resonance imaging and treatment information for 30 patients. In the "pretraining" phase, physicians labeled cases using 3 patterns of recurrence commonly reported in prospective studies: local recurrence (LR), distant parenchymal recurrence (DR), and LMD. After a self-directed training module, participating physicians completed the "posttraining" phase and relabeled the 30 cases using the 4 following labels: LR, DR, classical leptomeningeal disease, and nLMD. RESULTS: IRR increased 34% after training (Fleiss' Kappa K = 0.41 to K = 0.55, P < .001). IRR increased most among non-central nervous system specialists (+58%, P < .001). Before training, IRR was lowest for LMD (K = 0.33). After training, IRR increased across all recurrence subgroups and increased most for LMD (+67%). After training, ≥27% of cases initially labeled LR or DR were later recognized as nLMD. CONCLUSIONS: This study highlights the large degree of inconsistency among clinicians in recognizing nLMD. Our findings demonstrate that a brief self-guided training module distinguishing nLMD can significantly improve IRR across all patterns of recurrence, and particularly in nLMD. To optimize outcomes reporting, prospective trials in brain metastases should incorporate central imaging review and investigator training.

Stereotactic Radiosurgery and Hypofractionated Radiotherapy for Glioblastoma.

Glioblastoma is the most common primary brain tumor in adults. Standard therapy depends on patient age and performance status but principally involves surgical resection followed by a 6-wk course of radiation therapy given concurrently with temozolomide chemotherapy. Despite such treatment, prognosis remains poor, with a median survival of 16 mo. Challenges in achieving local control, maintaining quality of life, and limiting toxicity plague treatment strategies for this disease. Radiotherapy dose intensification through hypofractionation and stereotactic radiosurgery is a promising strategy that has been explored to meet these challenges. We review the use of hypofractionated radiotherapy and stereotactic radiosurgery for patients with newly diagnosed and recurrent glioblastoma.

New Hypofractionation Radiation Strategies for Glioblastoma.

PURPOSE OF REVIEW: Glioblastoma (GBM) is the most common and lethal primary brain tumor in adults, with a median survival of less than 2 years despite the standard of care treatment of 6 weeks of chemoradiotherapy. We review the data investigating hypofractionated radiotherapy (HFRT) in the treatment of newly diagnosed GBM. RECENT FINDINGS: Investigators have explored alternative radiotherapy strategies that shorten treatment duration with the goal of similar or improved survival while minimizing toxicity. HFRT over 1-3 weeks is already a standard of care for patients with advanced age or poor performance status. For young patients with good performance status, HFRT holds the promise of radiobiologically escalating the dose and potentially improving local control while maintaining quality of life. Through the use of shorter radiotherapy fractionation regimens coupled with novel systemic agents, improved outcomes for patients with GBM may be achieved.

Phase 1/2 Trial of 5-Fraction Stereotactic Radiosurgery With 5-mm Margins With Concurrent and Adjuvant Temozolomide in Newly Diagnosed Supratentorial Glioblastoma: Health-Related Quality of Life Results.

PURPOSE: We report a longitudinal assessment of health-related quality of life (HRQOL) in patients with glioblastoma (GBM) treated on a prospective dose escalation trial of 5-fraction stereotactic radiosurgery (25-40 Gy in 5 fractions) with concurrent and adjuvant temozolomide. METHODS: HRQOL was assessed using the European Organization for Research and Treatment of Cancer (EORTC) quality of life questionnaire core-30 (QLQ-C30) general, the EORTC quality of life questionnaire-brain cancer specific module (QLQ-BN20), and the M.D. Anderson Symptom Inventory-Brain Tumor (MDASI-BT). Questionnaires were completed at baseline and at every follow-up visit after completion of radiosurgery. Changes from baseline for 9 predefined HRQOL measures (global quality of life, physical functioning, social functioning, emotional functioning, motor dysfunction, communication deficit, fatigue, insomnia, and future uncertainty) were calculated at every time point. RESULTS: With a median follow-up time of 10.4 months (range, 0.4-52 months), 139 total HRQOL questionnaires were completed by the 30 patients on trial. Compliance with HRQOL assessment was 76% at 12 months. Communication deficit significantly worsened over time, with a decline of 1.7 points per month (P=.008). No significant changes over time were detected in the other 8 scales of our primary analysis, including global quality of life. Although 8 patients (27%) experienced adverse radiation effects (ARE) on this dose escalation trial, it was not associated with a statistically significant decline in any of the primary HRQOL scales. Disease progression was associated with communication deficit, with patients experiencing an average worsening of 13.9 points per month after progression compared with 0.7 points per month before progression (P=.01). CONCLUSION: On this 5-fraction dose escalation protocol for newly diagnosed GBM, overall HRQOL remained stable and appears similar to historical controls of 30 fractions of radiation therapy. Tumor recurrence was associated with worsening communication deficit, and ARE did not correlate with a decline in HRQOL.

Comparison of radiation regimens in the treatment of Glioblastoma multiforme: results from a single institution.

BACKGROUND: The optimal fractionation schedule of radiotherapy (RT) for Glioblastoma multiforme (GBM) is yet to be determined. We aim to compare different fractionation regimens and identify prognostic factors to better tailor RT for newly diagnosed GBM patients. METHODS: All data for patients who underwent surgery for GBM between January 2005 and December 2012 were compiled. Clinical information was collected using patient charts and government registry. Cox analysis was used to identify variables affecting survival and treatment outcome. RESULTS: The median follow-up time was 13.2 months. Two hundred and seventy-six patients met the inclusion criteria, including 147 patients in the 60 Gy in 30 fractions (ConvRT) group, 86 patients in the 60 Gy in 20 fractions (HF60) group, and 43 patients in the 40 Gy in 15 fractions (HF40) group. Median survival (MS) was 16.0 months with a median progression-free survival (PFS) of 9.23 months in the ConvRT group. This was comparable to outcome in the HF60 group with MS 15.0 months and a median PFS of 9.1 months. Patients in the HF40 group had MS of 8 months, with a median PFS 5.4 months. Cox analysis showed no significant difference in OS between the ConvRT and HF60 groups but worse outcome in the HF40 group (HR 2.22, P=0.04). MGMT methylation, extent of resection, use of chemotherapy, and repeat surgery were found to be significant independent prognostic factors for survival. CONCLUSIONS: HF60 constitutes a safe RT approach that shows survival comparable to standard RT while allowing for a shorter treatment time.