Abstract
Purpose
Glioblastoma multiforme (GBM) is the most common and aggressive primary brain tumor in adults, with poor survival despite advancements in treatment. Adaptive stereotactic radiation therapy (RT) using a magnetic resonance imaging linear accelerator is an emerging approach for patients with newly diagnosed GBM eligible for conventional fractionation. We hypothesize that adaptive stereotactic RT can provide comparable outcomes with conventional fractionation while reducing treatment burden.
Methods and Materials
We retrospectively reviewed 96 adults with newly diagnosed GBM treated at our institution between 2018 and 2024. Inclusion criteria included the age of 18 years, confirmed GBM diagnosis, and completed treatment. Patients with prior brain irradiation or incomplete treatment were excluded. Propensity score matching was performed to balance demographics, tumor characteristics, and treatment protocols across 5-fraction, 15-fraction, and 30-fraction groups. Statistical analyses included the Fisher exact test, Mann-Whitney U test, Cox proportional hazards models, and Kaplan-Meier survival curves.
Results
After propensity score matching, 17 pairs were matched for 5 versus 30 fractions and 14 pairs for 5 versus 15 fractions. Median overall survival was 21.1 versus 18.2 months (5 vs 15 fractions, P = .77) and 11.7 versus 14.6 months (5 vs 30 fractions, P = .5). Median progression-free survival was 9.0 versus 7.9 months (5 vs 15 fractions, P = .89) and 8.9 versus 9.7 months (5 vs 30 fractions, P = .97). Local failure and grade 3 toxicity rates were similar across groups. O6-methylguanine-DNA-methyltransferase unmethylated status, higher Eastern Cooperative Oncology Group scores, and age 60 years were associated with worse progression-free survival and overall survival. Median travel distances were lower in the 5-fraction group, with a median of 220 miles compared with 877.5 (15 fractions) and 1638 miles (30 fractions). Adaptive RT allowed for real-time tumor monitoring but volumetric changes did not correlate with clinical outcomes.
Conclusions
Adaptive 5-fraction RT demonstrates comparable survival outcomes with conventional fractionation while reducing treatment-related travel burden. Further prospective studies are needed to validate its role in GBM management.
Introduction
Glioblastoma multiforme (GBM) is the most aggressive primary brain tumor, with approximately 250,000 new cases diagnosed globally annually.1 Despite therapeutic advancements, outcomes remain poor.1,2 Standard care involves maximal safe resection, concurrent chemo-radiation therapy, and adjuvant chemotherapy. Conventional radiation therapy (RT) typically involves 6 weeks of daily treatments for healthier patients, whereas older or frail patients often receive shorter, hypofractionated schedules such as 3 weeks.3,4
Shorter hypofractionated RT regimens reduce treatment duration, benefiting patients with poor prognoses or those living far from treatment centers, because long travel times are linked to psychological distress and diminished quality of life (QOL).5, 6, 7, 8 Although 3-week regimens are well-studied, data on ultrahypofractionated regimens remain limited. A pivotal phase 3 study showed that 5-fraction hypofractionated RT is as effective as a 15-fraction course in elderly or frail patients, without added toxicity, making it a practical option for vulnerable populations.9 However, younger, fitter patients are thought to benefit more from standard or slightly accelerated approaches rather than these highly abbreviated regimens. Furthermore, the 5-fraction regimen evaluated in that study was not tested with concurrent temozolomide (TMZ), which remains the optimal treatment backbone for patients eligible for standard chemoradiation.9
Recent research suggests that 5-fraction regimens might also benefit patients eligible for longer RT courses. A trial of 5-fraction stereotactic RT with TMZ showed survival comparable with historical controls and a manageable safety profile at doses up to 35 Gy.10 Health-related QOL assessments indicated stable global QOL, mirroring outcomes of 30-fraction courses, supporting the potential of equal therapeutic efficacy while decreasing treatment-related travel burden.11
Magnetic resonance imaging (MRI) is essential for RT planning, typically using a postoperative scan that may be 4 to 6 weeks old.12, 13, 14 Reliance on outdated images limits insight into tumor evolution during therapy, particularly for poorly responding tumors.15,16 Although some institutions acquire imaging before RT, evidence of dynamic tumor changes during treatment suggests that even these updated scans may fail to capture ongoing disease evolution.17, 18, 19 MRI-linear accelerator (MRI-LINAC) technology now allows daily imaging and real-time adaptive therapy, enabling continuous tumor assessment and reducing radiation exposure to healthy tissue for improved safety.20, 21, 22
Leveraging MRI-LINAC technology in a 5-fraction stereotactic RT regimen allows real-time tumor monitoring and treatment adaptation, potentially reducing treatment burden while maintaining QOL. This study evaluates a potent, MRI-LINAC–based adaptive 5-fraction approach and compares it with standard 30-fraction and 15-fraction treatments in predominantly isocitrate dehydrogenase (IDH)-wildtype GBM. We aimed to assess its feasibility, efficacy, and the degree to which this technology may improve patient-centered outcomes.
Methods and Materials
Patient selection
We performed a retrospective review of adult patients with newly diagnosed GBM who presented to our institution from January 1, 2018, to January 1, 2024. Inclusion criteria were: age ≥18 years; a confirmed histopathological or molecular diagnosis of GBM; and completion of surgical resection, RT, and follow-up care at our institution. We excluded patients with a history of other concurrent malignant neoplasms. A total of 96 patients met these criteria. We collected demographic data, tumor characteristics, and treatment details from electronic medical records. The variable 'sex' was defined as sex assigned at birth, as documented in medical records. Patients treated with MRI-guided adaptive RT were included as part of a prospective registry.
Clinical features
Clinical variables included patient age at diagnosis, tumor histology, extent of surgical resection, and dates of clinical and imaging follow-up. Recorded outcomes included disease progression, tumor response, treatment-related toxicity, and death. Treatment variables encompassed concurrent therapies administered during or within one week of radiation, details of adjuvant systemic therapy, and radiation treatment dates, doses, and fractionation schedules.
We classified patterns of tumor progression based on the recurrence volume relative to the 95% isodose line as follows: in-field (>80% of recurrent volume), marginal (20%-80%), or distant (<20%).23, 24, 25, 26
Grade 3 cerebral edema was defined according to the National Cancer Institute Common Terminology Criteria for Adverse Events, based on clinical symptoms and imaging findings. Patients were classified as having grade 3 cerebral edema if they exhibited symptoms requiring hospitalization for corticosteroids or initiation of Avastin treatment. Imaging was reviewed to confirm that the neurologic symptoms were not attributable to tumor progression.
To assess the treatment-related travel burden, we calculated the total travel distance for each patient by determining the shortest route from their home address to our radiation oncology department using Google Maps, then multiplying by the total number of radiation treatment visits.
Imaging findings
We defined tumor extent using gadolinium-enhanced T1-weighted MRI to identify enhancing lesions and T2 FLAIR sequences to detect abnormal signal changes. The gross tumor volume (GTV) was subdivided into 2 components: GTV1, which included the residual postcontrast enhancing tumor and/or the resection cavity, and GTV2, which encompassed all abnormal T2 FLAIR signal areas. We determined the extent of resection from the neurosurgeon’s operative report and confirmed these findings with postresection imaging.
RT groups
We stratified patients into 3 groups based on their fractionation schedule: 30-fraction, 15-fraction, or 5-fraction regimens.
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30-fraction group: Patients received daily RT, with a total dose of 60 Gy delivered in 2-Gy fractions over a 6-week period. Treatment was administered using a conventional LINAC. Contouring was provider-dependent, with patients treated according to Radiation Therapy Oncology Group (RTOG) or European Organisation for Research and Treatment of Cancer (EORTC) guidelines. In general, cases with large T2 FLAIR abnormalities were contoured based on RTOG guidelines, whereas cases with smaller tumors were more likely contoured following EORTC guidelines. A 5 to 10 mm margin was added to define the clinical target volume (CTV), and an additional 3 mm margin was applied to create the planning target volume (PTV).
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15-fraction group: Patients received daily RT (40 Gy total) on a conventional LINAC delivered over 3 weeks. A 5 to 10 mm margin was added to the GTV or FLAIR abnormality to create the CTV, followed by a 0 to 3 mm expansion for the PTV.
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5-fraction group: Patients in the 5-fraction group received radiation every other day, with total doses ranging from 25 to 35 Gy, delivered on an MRI-LINAC. The GTV, encompassing the resection cavity and any residual enhancing tumor, received 30 to 35 Gy. No additional margins were added around the GTV (ie, GTV = PTV35). The CTV included the T2 FLAIR abnormality plus a 5-mm margin, received 25 to 30 Gy, and likewise had no additional margin expansions (ie, CTV = PTV25-30). Radiation was delivered over a period of 2.5 to 3 weeks. Concurrent TMZ (75 mg/m2 daily) was administered throughout the 3 weeks of treatment and stopped on the final day of RT.
Statistical analyses
We compared clinical and treatment-related variables between patients receiving adaptive stereotactic RT and those undergoing conventional treatment using the Fisher exact test for categorical data and the Mann-Whitney U test for continuous data. We used competing risk regression analyses to assess local control, grade 3+ vasogenic edema, and grade 3+ bone marrow toxicity, treating death as a competing risk. Cumulative incidence rates were calculated using the tidycmprsk R package, with Gray’s test employed to assess statistical significance. Cox proportional hazard models were constructed using the survival R package to evaluate the time to local failure (LF), grade 3+ vasogenic edema, and grade 3+ bone marrow toxicity. For LF, a sensitivity analysis was conducted in which patients who died without confirmed local progression were reclassified as experiencing LF unless a clearly documented unrelated cause of death was identified.
Overall survival (OS) and progression-free survival (PFS) were used to measure treatment efficacy. OS was defined as the time from initial diagnosis to death, and PFS as the time from initial diagnosis to radiologically confirmed progression. Kaplan-Meier survival curves were generated for both OS and PFS, and survival distributions were compared using the log-rank test.
To reduce selection bias and improve group comparability, we performed propensity score matching (PSM). Propensity scores were estimated via logistic regression, incorporating patient age, tumor volume, preradiation performance status, resection type, and O6-methylguanine-DNA methyltransferase (MGMT) and IDH mutation status. One-to-one nearest neighbor matching with replacement and a caliper width of 0.1 standard deviations were employed.
All statistical analyses were performed using SPSS (version 28.0.0.0) and R (version 4.3.3).
Results
Nineteen patients were identified in the 5-fraction group, 20 in the 15-fraction group, and 69 in the 30-fraction group. After applying inclusion and exclusion criteria, the final cohort included 19 patients in the 5-fraction group, 21 in the 15-fraction group, and 56 in the 30-fraction group. Detailed baseline characteristics for each group are summarized in Table 1.
Table 1.
Summary of patient characteristics and treatment details before performing the PSM
| Variable | 5-fraction (n = 19) | 15-fraction (n = 21) | 30-fraction (n = 56) | P value |
|---|---|---|---|---|
| Sex, n (%) | .97 | |||
| Male | 13 (68.4) | 15 (71.43) | 40 (71.40) | |
| Female | 6 (31.6) | 6 (28.60) | 16 (28.60) | |
| Age, M (SD), years | 67 (13.66) | 66 (10.34) | 60 (12.60) | .008 |
| ECOG prior RT, M (SD) | 1 (0.78) | 1 (0.59) | 1 (0.64) | .418 |
| WHO grade IV, n (%) | 19 (100) | 21 (100) | 56 (100) | 1.000 |
| Surgery before, n (%) | .49 | |||
| GTR | 12 (63.15) | 9 (42.85) | 23 (41.06) | |
| STR | 4 (21.05) | 5 (23.81) | 17 (30.36) | |
| BX | 3 (15.79) | 7 (33.33) | 16 (28.57) | |
| None | 0 | 0 | 0 | |
| Treatment details | - | |||
| Number of fractions (range) | 5 (5-5) | 15 (9-15) | 30 (13-30) | |
| Total dose, Gy (range) | 35 (25-35) | 40 (24-40) | 60 (26-60) | |
| RT completed as planned, n (%) | 19 (100) | 20 (95.23) | 54 (96.43) | |
| MGMT status, n (%) | .10 | |||
| Methylated | 7 (36.84) | 8 (38.10) | 19 (33.93) | |
| Unmethylated | 11 (57.89) | 7 (33.33) | 17 (30.36) | |
| n/a* | 1 (5.26) | 6 (28.57) | 20 (35.71) | |
| IDH status, n (%) | .34 | |||
| Wild type | 18 (94.74) | 20 (95.23) | 46 (82.14) | |
| Mutated | 1 (5.26) | 1 (4.76) | 5 (8.93) | |
| n/a | 0 | 0 | 5 (8.93) | |
| EGFR status, n (%) | .007 | |||
| Amplified | 7 (36.84) | 5 (23.81) | 19 (33.93) | |
| Not amplified | 12 (63.16) | 8 (38.10) | 14 (25.00) | |
| n/a | 0 | 8 (38.10) | 23 (41.07) | |
| TERT, n (%) | .001 | |||
| Mutated | 18 (94.74) | 10 (47.62) | 23 (41.07) | |
| Nonmutated | 1 (5.26) | 4 (19.05) | 8 (14.29) | |
| n/a | 0 | 7 (33.33) | 25 (44.64) | |
| CDKN2A/B, n (%) | .013 | |||
| Mutated | 11 (57.89) | 9 (42.86) | 21 (37.5) | |
| Nonmutated | 8 (42.11) | 4 (19.05) | 11 (19.64) | |
| n/a | 0 | 8 (38.10) | 24 (42.86) | |
| GTV T1 postcontrast, M (SD) | 59.60 (69.15) | 81.40 (71.01) | 72.85 (62.25) | |
| Concurrent TMZ, n (%) | 19 (100) | 18 (85.72) | 50 (89.29) | .26 |
| Adjuvant TMZ, n (%) | 18 (94.74) | 14 (66.67) | 40 (71.43) | .08 |
Abbreviations: PSM = propensity score matching; n = number of patients; M = median; SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; RT = radiation therapy; GTR = gross total resection; STR = subtotal resection; BX = biopsy; MGMT = O(6)-methylguanine-DNA methyltransferase; IDH = isocitrate dehydrogenase; EGFR = epidermal growth factor receptor; TERT = telomerase reverse transcriptase; GTV = gross tumor volume; TMZ = temozolomide.
MGMT status undefined (n/a) was considered methylated for analysis purposes.
Fifteen versus 5 fractions
A PSM analysis comparing the 15-fraction and 5-fraction groups yielded 14 matched pairs (n = 28). The median age at diagnosis was 66.5 years in the 15-fraction group and 67 years in the 5-fraction group, with a median Eastern Cooperative Oncology Group (ECOG) performance status of 1 in both groups. In both groups, gross total resection (GTR) was most common, with 9 of 14 in the 15-fraction group and 8 of 14 patients in the 5-fraction group undergoing GTR before RT. A summary of matched characteristics is provided in Table 2.
Table 2.
Summary of patient characteristics and treatment details of patients selected after PSM, comparing the 5-fraction, 15-fraction, and 30-fraction groups
| Variable | 5-fraction (n = 14) | 15-fraction (n = 14) | P value | 5-fraction (n = 17) | 30-fraction (n = 17) | P value |
|---|---|---|---|---|---|---|
| Sex, n (%) | ||||||
| Male | 9 (64.29) | 9 (64.29) | 1.0 | 11 (64.71) | 13 (76.47) | .71 |
| Female | 5 (35.71) | 5 (35.71) | 6 (35.29) | 4 (23.53) | ||
| Age, M (SD), years | 67 (14.5) | 66.5 (10.3) | .75 | 66 (13.73) | 63 (9.34) | .43 |
| ECOG prior RT, M (SD) | 1 (0.88) | 1 (0.68) | .84 | 1 (0.83) | 1 (0.85) | .38 |
| WHO grade IV, n (%) | 14 (100) | 14 (100) | 1.0 | 17 (100) | 17 (100) | 1.0 |
| Surgery before, n (%) | ||||||
| GTR | 8 (57.14) | 9 (64.29) | 1.0 | 10 (58.82) | 9 (52.94) | 1.0 |
| STR | 3 (21.43) | 2 (14.29) | 4 (23.53) | 4 (23.53) | ||
| BX | 3 (21.43) | 3 (21.43) | 3 (17.65) | 4 (23.53) | ||
| None | 0 | 0 | 0 | 0 | ||
| MGMT status, n (%) | ||||||
| Methylated | 6 (42.86) | 6 (42.86) | 1.0 | 7 (41.18) | 4 (23.53) | .46 |
| Unmethylated | 7 (50) | 7 (50) | 9 (52.94) | 11 (64.71) | ||
| n/a* | 1 (7.14) | 1 (7.14) | 1 (5.88) | 2 (11.76) | ||
| IDH status, n (%) | ||||||
| Wild type | 13 (92.86) | 13 (92.86) | 1.0 | 16 (94.12) | 17 (100) | 1.0 |
| Mutated | 1 (7.14) | 1 (7.14) | 1 (5.88) | 0 | ||
| EGFR status, n (%) | ||||||
| Amplified | 5 (35.71) | 3 (21.43) | 1.0 | 6 (35.29) | 10 (58.82) | .07 |
| Not amplified | 9 (64.29) | 8 (57.14) | 11 (64.71) | 4 (23.53) | ||
| n/a | 0 | 3 (21.43) | 0 | 3 (17.65) | ||
| TERT, n (%) | ||||||
| Mutated | 13 (92.86) | 8 (57.14) | .15 | 16 (94.12) | 12 (70.59) | 1.0 |
| Nonmutated | 1 (7.14) | 4 (28.57) | 1 (5.88) | 5 (29.41) | ||
| n/a | 0 | 2 (14.29) | 0 | 0 | ||
| CDKN2A/B, n (%) | ||||||
| Mutated | 8 (57.14) | 9 (64.29) | .23 | 10 (58.82) | 8 (47.06) | .72 |
| Nonmutated | 6 (42.86) | 2 (14.29) | 7 (41.18) | 4 (23.53) | ||
| n/a | 0 | 3 (21.43) | 0 | 5 (29.41) | ||
| GTV T1 postcontrast, M (SD) | 27.08 (72.8) | 34.61 (46.4) | .60 | 27.54 (65.54) | 28.5 (28.06) | .84 |
| GTV FLAIR, M (SD) | 66.21 (75.3) | 76.3 (66.8) | .98 | 64.70 (71.74) | 72.74 (40.71) | .66 |
| Concurrent TMZ, n (%) | 14 (100) | 13 (92.86) | 1.00 | 17 (100) | 16 (94.12) | 1.00 |
| Adjuvant TMZ, n (%) | 13 (92.86) | 12 (86) | .60 | 16 (94.12) | 13 (76.47) | .34 |
Abbreviations: PSM = propensity score matching; n = number of patients; M = median; SD = standard deviation; ECOG = Eastern Cooperative Oncology Group; RT = radiation therapy; GTR = gross total resection; STR = subtotal resection; BX = biopsy; MGMT = O(6)-methylguanine-DNA methyltransferase; IDH = isocitrate dehydrogenase; EGFR = epidermal growth factor receptor; TERT = telomerase reverse transcriptase; GTV = gross tumor volume; TMZ = temozolomide.
MGMT status undefined (n/a) was considered methylated for analysis purposes.
The median follow-up time for this comparison was 18.8 months, with a median follow-up of 23.3 months in the 15-fraction group and 13.8 months in the 5-fraction group. Median OS was 18.2 months in the 15-fraction group and 21.1 months in the 5-fraction group (P = .77) (Fig. 1A). PFS was also similar, with medians of 7.9 months and 9.0 months for the 15-fraction and 5-fraction groups, respectively (P = .89), as shown in Kaplan-Meier survival curves (Fig. 1B).
Figure 1.
Kaplan-Meier survival curves for (A) overall survival for 15 versus 5 fractions, (B) progression-free survival for 15 versus 5 fractions, (C) overall survival for 30 versus 5 fractions, and (D) progression-free survival for 30 versus 5 fractions.
The cumulative incidence of LF at 12 months, based on the sensitivity analysis, was 65% in the 15-fraction group and 45% in the 5-fraction group, with no statistically significant difference between the groups (P = .88) (Fig. 2A). Univariate analysis of factors, including sex, age, treatment group, extent of resection, MGMT status, and tumor volume, revealed no significant predictors of OS. However, MGMT unmethylation was associated with worse PFS and LF, as detailed in Table 3. Grade ≥3 cerebral edema occurred in 36% in the 15-fraction group and 15% of patients in the 5-fraction group at 12 months (P = .30) (Fig. 3A). Grade ≥3 bone marrow toxicity was 35% in both groups (P = .38) (Fig. 3B). The results of our univariate analysis of factors influencing central nervous system (CNS) toxicity are summarized in Table E1.
Figure 2.
Cumulative incidence of local failure in the (A) 5-fraction versus 15-fraction and (B) 5-fraction versus 30-fraction groups.
Table 3.
Univariable analysis of clinical and treatment factors associated with OS, PFS, and LF within the matched cohorts comparing 15 vs 5 fractions and 30 vs 5 fractions
| OS |
PFS |
LF |
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|---|---|---|---|---|---|---|---|---|---|---|
| Variable | HR | 95% CI | P value | HR | 95% CI | P value | HR | 95% CI | P value* | P value† |
| Sex | ||||||||||
| Female | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref |
| Male (15 vs 5 fractions cohort) | 1.07 | 0.36-3.16 | .90 | 1.26 | 0.50-3.12 | .63 | 0.99 | 0.41-2.43 | .99 | .90 |
| Male (30 vs 5 fractions cohort) | 0.69 | 0.26-1.83 | .45 | 0.82 | 0.34-2.01 | .66 | 0.63 | 0.27-1.49 | .30 | .29 |
| Age | ||||||||||
| Age < 60 years | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref |
| Age ≥ 60 years (15 vs 5 fractions cohort) | 6.90 | 0.90-52.92 | .06 | 2.51 | 0.83-7.64 | .11 | 2.22 | 0.70-7.17 | .18 | .21 |
| Age ≥ 60 years (30 vs 5 fractions cohort) | 3.29 | 0.95-11.37 | .06 | 3.36 | 1.14-9.90 | .03 | 2.55 | 0.91-7.15 | .07 | .13 |
| ECOG | ||||||||||
| ECOG 0-1 | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref |
| ECOG 2-3 (15 vs 5 fractions cohort) | 1.59 | 0.43-5.81 | .49 | 1.12 | 0.36-3.41 | .85 | 1.21 | 0.26-5.62 | .80 | .62 |
| ECOG 2-3 (30 vs 5 fractions cohort) | 3.25 | 1.06-9.99 | .04 | 2.39 | 0.80-7.19 | .12 | 1.94 | 0.30-12.36 | .48 | .92 |
| Treatment group | ||||||||||
| 15 or 30 fractions | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref |
| 5 fractions (vs 15) | 1.18 | 0.40-3.46 | .77 | 0.95 | 0.39-2.30 | .90 | 0.87 | 0.35-2.16 | .77 | .88 |
| 5 fractions (vs 30) | 1.36 | 0.55-3.34 | .50 | 0.99 | 0.44-2.23 | .98 | 0.96 | 0.41-2.23 | .93 | .87 |
| Extent of resection | ||||||||||
| STR or biopsy | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref |
| GTR or nGTR (15 vs 5 fractions cohort) | 0.46 | 0.16-1.33 | .15 | 0.42 | 0.18-1.01 | .05 | 0.50 | 0.21-1.23 | .13 | .10 |
| GTR or nGTR (30 vs 5 fractions cohort) | 0.97 | 0.40-2.37 | .95 | 0.86 | 0.38-1.94 | .72 | 1.03 | 0.42-2.53 | .95 | .82 |
| MGMT status | ||||||||||
| Methylated | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref | Ref |
| Unmethylated (15 vs 5 fractions cohort) | 2.45 | 0.85-7.06 | .10 | 5.65 | 2.03-15.75 | .01 | 8.79 | 3.00-25.71 | .01 | .01 |
| Unmethylated (30 vs 5 fractions cohort) | 3.75 | 1.35-10.43 | .01 | 5.14 | 1.89-13.99 | .01 | 7.55 | 2.33-24.41 | .01 | .01 |
| Tumor volume | ||||||||||
| T1 postcontrast (15 vs 5 fractions cohort) | 1.11 | 0.40-3.08 | .84 | 0.94 | 0.38-2.32 | .90 | 0.95 | 0.37-2.40 | .91 | .81 |
| T1 postcontrast (30 vs 5 fractions cohort) | 1.01 | 0.42-2.39 | .99 | 1.01 | 0.47-2.37 | .89 | 1.14 | 0.51-2.57 | .74 | .87 |
| T2 FLAIR (15 vs 5 fractions cohort) | 1.98 | 0.69-5.62 | .20 | 1.47 | 0.62-3.50 | .38 | 1.46 | 0.62-3.45 | .39 | .55 |
| T2 FLAIR (30 vs 5 fractions cohort) | 0.88 | 0.37-2.07 | .76 | 1.03 | 0.46-2.33 | .94 | 1.08 | 0.48-2.41 | .86 | .96 |
Abbreviations: OS = overall survival; PFS = progression-free survival; LF = local failure; HR = hazard ratio; 95% CI = 95% confidence interval; ECOG = Eastern Cooperative Oncology Group; STR = subtotal resection; GTR = gross total resection; nGTR = near gross total resection; MGMT = O(6)-methylguanine-DNA methyltransferase
Cox Model P value.
Gray’s test P value.
Comparisons for both matched cohorts are listed within each row, reflecting the effect of each variable on outcomes within the entire cohort, not direct subgroup comparisons of treatment regimens.
Figure 3.
Cumulative incidence of grade 3+ cerebral edema (A) and bone marrow toxicity (B) in the 5-fraction versus 15-fraction groups, and grade 3+ cerebral edema (C) and bone marrow toxicity (D) in the 5-fraction versus 30-fraction groups.
The burden of travel differed substantially between the groups. The median one-way travel distance was 29.25 miles for the 15-fraction group and 25.4 miles for the 5-fraction group. Throughout the course of treatment, the median total travel distance was 877.5 miles for the 15-fraction group compared with 254 miles for the 5-fraction group.
Thirty versus 5 fractions
A PSM analysis comparing the 30-fraction and 5-fraction groups resulted in 17 matched pairs (n = 34). The median age was 63 years in the 30-fraction group and 66 years in the 5-fraction group, with a median ECOG performance status of 1 in both groups. GTR was the predominant surgical intervention, performed in 9 of 17 in the 30-fraction group and 10 of 17 patients in the 5-fraction group. Matched characteristics for both groups are summarized in Table 2.
The median follow-up time for the overall population was 20.2 months, with a median follow-up of 24.4 months in the 30-fraction group and 13.8 months in the 5-fraction group. Median OS was 14.6 months for the 30-fraction group and 11.7 months for the 5-fraction group (P = .5) (Fig. 1C). Median PFS was 9.7 months for the 30-fraction group and 8.9 months for the 5-fraction group (P = .97), as shown in Kaplan-Meier survival curves (Fig. 1D).
The cumulative incidence of LF at 12 months, based on the sensitivity analysis, was 61% in the 30-fraction group and 50% in the 5-fraction group, with no statistically significant difference between the groups (P = .87) (Fig. 2B). Univariate analysis of factors, including sex, age, treatment group, extent of resection, MGMT status, and tumor volume, revealed that age ≥60 years was associated with worse PFS, a higher ECOG performance status was associated with lower OS, and MGMT unmethylation was associated with worse OS, PFS, and LF, as detailed in Table 3.
The incidence of grade ≥3 cerebral edema at 12 months was 17% in the 30-fraction and 28% in the 5-fraction group (P = .68) (Fig. 3C). Bone marrow toxicity was comparable between the groups, with incidences of 59% and 64% in the 30- and 5-fraction groups (P = .95) (Fig. 3D). The results of our univariate analysis of factors influencing CNS toxicity are summarized in Table E2.
The travel burden was markedly reduced for the 5-fraction group. The median one-way travel distance was 27.3 miles in the 30-fraction group compared with 22 miles in the 5-fraction group. Over the entire course of treatment, the median total travel distance was 1638 miles for the 30-fraction group and 220 miles for the 5-fraction group.
Patterns of progression
Among the 18 patients treated with 5 fractions, 10 experienced no progression, including 4 who died without evidence of disease progression. For the sensitivity analysis, these 4 patients were classified as having “local failure” because no other specific cause of death was identified. Among patients with progression, 3 experienced progression inside the field (37.5%), 3 had progression outside the field (37.5%), and 2 exhibited initial progression outside the field/marginally followed by subsequent progression inside the field (25%). In particular, among the 3 patients with only distant progression, 2 were within the 20 mm margin.
Among the 14 patients in the 15-fraction group, 4 showed no progression. Of these, 2 died without evidence of progression: one death was attributed to sepsis, whereas the other, with an unidentified cause, was classified as “local failure” for the sensitivity analysis. Among the patients with progression, 9 had in-field progression (90%), and 1 experienced marginal progression (10%). One case of out-of-field progression was observed in this cohort, concomitant with in-field progression.
In the 30-fraction group, among the 17 patients, 5 had no progression; of these, 3 died without evidence of progression, and 2 remained alive. Of the deceased patients, 2 deaths were attributed to other causes (cardiac arrest and sepsis), whereas the third lacked follow-up imaging and was classified as “local failure” for the sensitivity analysis. Progression patterns included 1 out-of-field (8.33%), 8 in-field (66.67%), and 1 marginal progression (8.33%). Notably, 2 patients experienced initial out-of-field progression followed by subsequent in-field progression (12.67%), both of which were included in the LC analysis.
Adaptive volumes
A total of 18 patients treated with adaptive stereotactic RT were identified for analysis. Based on T1 postcontrast imaging, during treatment, 9 tumors demonstrated a decrease in volume, 8 showed an increase, and 1 remained unchanged (range, –12.6% to 31.1%). The overall median volume change was –0.12%. Among the tumors with a volume decrease, the median change was –2.14% (range, –12.60% to –0.23%), whereas tumors with a volume increase had a median change of 4.46% (range, 0.29% to 31.10%). One patient demonstrated a GTV1 increase exceeding 30% over the treatment course.
On T2 FLAIR imaging, a similar pattern was observed, with 9 tumors decreasing in volume, 8 increasing, and 1 showing no change (range, –11.73% to 35.69%). The overall median volume change based on FLAIR was also –0.12%. For tumors with decreased volume, the median change was –2.14% (range, –11.73% to –0.23%), whereas tumors with increased volume showed a median change of 3.71% (range, 0.29% to 35.69%). Notably, 2 patients exhibited GTV2 increases greater than 30%, driven by expanding FLAIR signal abnormality.
Despite measurable volumetric changes, these adaptations did not demonstrate a correlation with key clinical outcomes. Specifically, changes in T1 postcontrast volumes were not associated with OS (P = .38) or PFS (P = .26), nor were changes in T2-FLAIR volumes (OS, P = .29; PFS, P = .38) (Fig. E1). Similarly, no significant relationship was observed between tumor volume changes and LF (T1 postcontrast, P = .35; T2-FLAIR, P =0.29). Furthermore, alterations in tumor volumes were not predictive of CNS toxicity (T1 postcontrast, P = .26; T2-FLAIR, P = .97).
Discussion
This study provides a novel comparison of 3 RT fractionation schedules—5-fraction adaptive stereotactic RT, 15-fraction hypofractionation, and 30-fraction conventional therapy—in a predominantly younger, better-performing population of patients with newly diagnosed GBM. Importantly, it is among the first to incorporate an MRI-LINAC–based adaptive 5-fraction stereotactic RT regimen into these comparisons. Our findings demonstrate that this adaptive stereotactic RT approach achieves survival outcomes comparable with both standard and hypofractionated regimens, while significantly reducing the treatment-related travel burden, defined here as the total travel distance required for treatment. This reduction highlights potential benefits in convenience and QOL for patients.
When comparing the 5-fraction adaptive stereotactic RT regimen with the conventional 30-fraction schedule, the median OS was 11.7 months for the 5-fraction group and 14.6 months for the 30-fraction group (P = .5), whereas the median PFS was 8.9 months and 9.7 months, respectively (P = .97). The cumulative incidence of LF at 12 months was 50% for the 5-fraction group and 61% for the 30-fraction group (P = .87). Consistent with prior studies, the majority of these local recurrences occurred within the high-dose region (in-field), underscoring the intrinsic aggressiveness of GBM rather than a failure of target coverage. Outcomes for the 30-fraction cohort aligned with historical benchmarks, such as the Stupp et al3 protocol, indicating that our standard regimen group performed within the expected range. Differences in survival and local control between the 5- and 30-fraction groups may reflect variations in baseline patient characteristics, though both schedules achieved OS and PFS values comparable with established norms for newly diagnosed GBM.
In the comparison between the 5-fraction and 15-fraction cohorts, median OS was 21.1 months for the 5-fraction group and 18.2 months for the 15-fraction group (P = .77), whereas median PFS was 9.0 months and 7.9 months, respectively (P = .89). Although these survival measures were not statistically different, the cumulative incidence of LF at 12 months was 45% in the 5-fraction group and 65% in the 15-fraction group (P = .88). As with the 30-fraction comparison, most failures were in-field, reflecting the challenge of achieving durable local control in GBM. Survival outcomes for our 15-fraction and 5-fraction cohorts far exceeded those reported in studies focusing on elderly or frail populations.4,9,27, 28, 29, 30 This discrepancy likely stems from the younger age and better performance status of our patient population, suggesting that suitably selected patients may tolerate and benefit from shorter, more intensified RT courses without a meaningful increase in marginal or distant failures.
In the existing literature on 5-fraction RT, Azoulay et al10 reported a median follow-up of 13.8 months, with a median PFS of 8.2 months and OS of 14.8 months. In our study, patients treated with 5-fraction RT exhibited a median OS of 11.7 months compared with those receiving 30-fraction RT and 21.1 months compared with patients receiving 15-fraction RT. Similarly, the median PFS for the 5-fraction group was 8.9 months relative to the 30-fraction group and 9.0 months compared with the 15-fraction group. Both studies included patients with a median age of approximately 65 years and good performance status. The proportion of patients with MGMT promoter methylation was comparable between our study and that of Azoulay et al,10 with similar rates of unmethylated cases. Additionally, TMZ was consistently administered across both populations. However, notable differences included a smaller number of patients treated with the 5-fraction regimen in our study and a higher proportion of cases involving complete surgical tumor resection (60% vs 40%). Although the average GTV was similar between studies, our study encompassed a broader range of tumor sizes, including significantly larger tumors, with an average of 285 cm3, compared with 81 cm3 in the Azoulay et al10 cohort. These variations highlight the heterogeneity of patient populations and emphasize the need for caution when generalizing findings. The differences in LF rates between our study and the findings reported by Mendoza et al31 can be attributed to variations in follow-up duration and the definitions of progression. Their trial featured a longer follow-up period, reporting LF for 28 of 30 patients. Additionally, the definition of progression used in our study aligns with the most commonly applied criteria in studies using 30- and 15-fraction treatments. In contrast, the trial conducted by Mendoza et al31 employed a definition tailored specifically to their 5-fraction treatment group. For consistency, our study applied the same definition of progression across all 3 treatment groups, prioritizing internal validity in our comparisons. Notably, if we had adopted the same definition as Mendoza et al,31 2 of the 3 patients in our study initially classified as having distant failures would have been reclassified as having marginal failures, with progression occurring within the prescribed dose area of a standard 20-mm CTV margin. These methodological differences underscore the challenges of directly comparing outcomes between studies and highlight the importance of considering context when interpreting LF rates.
All patients receiving 5-fraction adaptive RT in our cohort were treated with concurrent TMZ for approximately 3 weeks, in accordance with institutional protocol. TMZ has been a key component of GBM treatment as highlighted by the Stupp et al3 trial, which showed improved survival when combined with 6-week RT compared with RT alone. This benefit has been confirmed in various studies and meta-analyses, solidifying TMZ as part of the standard of care.32,33 Although shorter RT courses raised concerns about reduced synergy with TMZ, studies using 15-fraction regimens that incorporated concurrent and adjuvant TMZ showed that clinical outcomes remained favorable compared with radiation alone.30 More recent trials, such as that by Azoulay et al,10 demonstrated the efficacy of a shorter course of chemo-RT. Accordingly, our protocol maintained daily TMZ administration during the 5-fraction RT, extending the course over a 2.5- to 3-week treatment period.
Although direct comparisons of QOL between hypofractionated and conventional fractionation schedules in newly diagnosed GBM are lacking, evidence from other cancer types suggests that fewer treatment sessions may improve physical well-being, reduce treatment interruptions, and alleviate financial toxicity.34 In our study, patients treated with the 5-fraction regimen traveled a median total distance of 220 miles over the course of therapy, compared with 1638 miles for those receiving 30 fractions. This substantial reduction in travel burden is clinically meaningful, because long travel distances to cancer treatment centers are linked to decreased QOL, impaired survival, and lower adherence—particularly among older adults, rural residents, individuals from lower socioeconomic backgrounds, and those with advanced disease.35, 36, 37, 38, 39 Excessive travel requirements also contribute to treatment-related financial toxicity and psychological distress, both of which can undermine patient outcomes.5, 6, 7, 8,40, 41, 42 By streamlining the radiation course, hypofractionated regimens may enhance access to high-volume centers, where outcomes are often superior, without incurring prohibitive logistical challenges.43 Moreover, shorter regimens could yield broader societal benefits, including reduced environmental impact from travel.44 Collectively, these considerations highlight the multifaceted advantages of optimizing fractionation schedules to better accommodate patient needs and circumstances.
Advances in MRI-guided RT, particularly using MRI-LINAC systems, create opportunities to refine target volumes for GBM. Although standard CTV expansions attempt to cover subclinical disease, central recurrences remain common, prompting interest in tighter margins that may preserve tumor control.10,26 MRI guidance enables real-time visualization and adaptive replanning, potentially improving precision and allowing reductions in CTV and PTV margins.45, 46, 47 In our study, the 5-fraction schedule did not significantly increase grade ≥3 cerebral edema compared with 15- or 30-fraction regimens. Although the incidence of grade ≥3 cerebral edema was not significantly different between groups, we observed a trend toward higher rates in the 5-fraction cohort compared with the 30-fraction group. Some of these cases may have represented pseudoprogression, which is typically asymptomatic but can occasionally present with clinical symptoms,48 making it difficult to distinguish from treatment-related cerebral edema. Notably, both pseudoprogression and, in some studies, cerebral edema have been associated with improved survival outcomes.10,49 These survival associations raise the possibility that certain treatment-related effects, although radiographically concerning, may reflect favorable biological responses. Conversely, when comparing the 5-fraction cohort to the 15-fraction group, there was a trend toward lower rates of cerebral edema in the 5-fraction group. Evidence from other settings suggests that adaptive, brain-sparing techniques could also reduce systemic toxicities like lymphopenia, permitting dose escalation without excessive adverse effects.50,51 Additionally, MRI-guided RT may lessen neurocognitive decline by limiting exposure to healthy brain structures.22,52 Ongoing trials, such as UNITED (NCT04726397), explore weekly MRI-based recontouring to align treatment fields more closely with tumor dynamics.
The volumetric changes observed during treatment in the adaptive RT cohort may reflect the dynamic nature of the tumor or early treatment effects. Unfortunately, it was difficult to distinguish between the two, and the decision to extend coverage was left to the discretion of the treating physician. In our cohort, these changes did not correlate with clinical outcomes such as OS, PFS, or treatment-related toxicity. This lack of association may be due to the limited magnitude of volume changes or the relatively small sample size, which may have limited our ability to detect significant differences. Considering that some studies have already demonstrated that pretreatment imaging can help predict survival outcomes,53,54 our findings underscore the need for further research to evaluate whether early volumetric changes can serve as reliable biomarkers of treatment response. As MRI-LINAC technology becomes more accessible, integrating perfusion, diffusion, and other functional imaging may guide more personalized adaptation and improve clinical outcomes.55 Future research incorporating functional imaging and radiomic analysis may help clarify the biological relevance of these volumetric fluctuations and enhance early response assessment. In our study, volumetric analysis was limited to the adaptive RT group, because serial MRI imaging was not routinely performed in patients treated with 15- or 30-fraction regimens. As such, direct comparisons of volume changes across treatment groups were not feasible.
Our study has its limitations. The relatively small sample size and retrospective design may introduce selection bias and confounding, potentially limiting the generalizability of our findings. To address this, we employed PSM to balance baseline characteristics between treatment groups. Although this approach helps reduce bias, it also decreases the number of patients available for analysis, limiting statistical power and introducing method-specific limitations.56,57 We considered a pooled analysis to retain a larger sample size; however, significant baseline differences between patients treated with 15- and 30-fraction regimens led us to perform separate PSM for each comparison, aiming to improve internal validity despite reducing overall sample size Additionally, treatment decisions—including patient selection and decision to extend coverage during adaptive planning—were made by different physicians across the study period and were not standardized, potentially introducing variability in clinical practice. Moreover, as with all propensity-matched studies, the risk of residual confounding from unmeasured variables remains. These limitations underscore the need for larger, prospective, randomized trials with comprehensive toxicity evaluations to better understand the impact of adaptive stereotactic RT in GBM.
Conclusions
In conclusion, our findings suggest that a 5-fraction adaptive stereotactic RT may offer comparable OS, PFS, and local control to 15- and 30-fraction regimens in newly diagnosed GBM while reducing treatment-related travel burden. These preliminary results reinforce the feasibility and safety of shorter RT courses in healthier patients and the potential of MRI-guided adaptation to improve patient care. Larger prospective trials are needed to confirm these benefits, refine protocols, and identify patient subgroups that benefit the most.
Declaration of AI and AI-Assisted Technologies in the Writing Process
We confirm that no artificial intelligence (AI) or AI-assisted technologies were used in the creation of this article, aside from basic tools for grammar, spelling, or reference formatting.
Disclosures
None.
Acknowledgments
Luiza Giuliani Schmitt, Michael Dohopolski, and MinJae Lee performed the statistical analysis.
Footnotes
Sources of support: None.
Research data are stored in an institutional repository and will be shared upon request to the corresponding author.
Supplementary material associated with this article can be found in the online version at doi:10.1016/j.adro.2025.101813.
Contributor Information
Michael Dohopolski, Email: Michael.Dohopolski@UTSouthwestern.edu.
Zabi Wardak, Email: Zabi.Wardak@UTSouthwestern.edu.
Appendix. Supplementary materials
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