Reduced Radiotherapy Margins Yield Outcomes Comparable With Standard Margins in HGG

Reduced Radiotherapy Margins in High-Grade

Glioma | Sebastian Kaulitzki – stock.adobe.com

The use of reduced radiotherapy margins did not lead to differences in oncologic outcomes vs the use of conventional RTOG protocol–recommended margins in patients with newly diagnosed high-grade glioma (HGG), according to findings from a multicenter, randomized, open-label trial (IRCT20210215050367N1) that were presented at the 2025 ESMO Sarcoma and Rare Cancers Annual Congress.1

Investigators observed no significant difference in recurrence patterns between study arms (P = .829), with in-field recurrences accounting for most recurrences in both the intervention (84%) and control (83.8%) groups. Marginal and out-field recurrences occurred infrequently (8% and 8%, respectively, in the interventional arm vs 9.2% and 6.9%, respectively, in the control arm).

Furthermore, the median progression-free survival (PFS) was 15.0 months (95% CI, 12.5-17.4) in the intervention group and 19.0 months (95% CI, 13.6-24.3) in the control group (P = .121), supporting the noninferiority of the reduced-margin strategy. The mean PFS was 17.03 months (± 1; 95% CI, 15.05-19.01) in the intervention arm vs 19.48 months (±1.1; 95% CI, 17.16-21.81) in the control arm.

“The current standard of care [SOC] in the management of HGG is maximal surgical resection and postoperative concurrent chemoradiotherapy and maintenance chemotherapy up to 6 cycles,” Seyed Alireza Javadinia, MD, vice president for Research and Technology at Sabzevar University of Medical Sciences in Iran, explained in the presentation. “[This study showed that] a 2-phase radiotherapy approach with reduced margins can provide similar oncologic outcomes [compared with SOC] and minimize the dose to organs at risk. [However], high in-field recurrences in both groups show the need for more investigations for local treatments to enhance the efficacy of treatments.”

Study Background and Rationale

Historically, the phase 3 RTOG 0525 (NCT00304031) and RTOG 0825 (NCT00884741) trial protocols have advocated a 2-phase radiation approach, using a 2-cm clinical target volume (CTV) margin around peritumoral edema and a 2.5-cm CTV margin around the enhancing tumor. More recent ESTRO/ACROP guidelines established in 2023 proposed a CTV margin reduction to 1.5 cm, although consensus on the management of peritumoral edema remains lacking.

Study Design

The multicenter, randomized, open-label, controlled trial evaluated the feasibility, safety, and efficacy of employing reduced radiotherapy margins compared with standard RTOG-defined margins in the adjuvant chemoradiation of adult patients with grade 3 or 4 newly diagnosed HGGs. Eligible patients underwent a 2-phase radiation protocol with concurrent and adjuvant temozolomide in accordance with established treatment strategies. The Stupp protocol was used for patients with grade IV gliomas and consisted of 6 cycles of temozolomide following radiotherapy. The phase 3 CATNON trial (NCT00626990) regimen was used for patients with grade 3 gliomas and consisted of temozolomide alone for 12 cycles post-radiotherapy.

Phase 1 of the trial delivered 46 Gy of radiation to the edema visible on FLAIR-weighted MRI with a 2-cm margin. In phase 2 of the trial, patients were randomly assigned to receive an additional 14 Gy of radiation directed to either of 2 treatment volumes: the surgical cavity and enhancing tumor residue on gadolinium-enhanced T1-weighted MRI with a 1-cm margin (investigational arm), or the same target with a 2-cm margin (control arm).

The primary end point was pattern of recurrence—classified as in-field, marginal, or out-field—based on the percentage of overlap between the 95% isodose line and the recurrent lesion. Specifically, in-field recurrences were defined by more than 80% overlap, marginal recurrences by 20% to 80% overlap, and out-field recurrences by less than 20% overlap. MRI imaging at the time of progression was registered to the original CT simulation images, and the enhancing component of recurrent disease was delineated to assess recurrence volume. Disease progression was defined using McDonald criteria.

Patient Demographics

A total of 258 adult patients with newly diagnosed grade 3 or 4 gliomas were enrolled. Baseline demographic and clinical characteristics were balanced between the intervention and control arms across most variables.

Patients had a mean age of 54.16 years (±11.27) in the intervention group and 56.64 years (±11.49) in the control group (P = .959). The sex distribution was comparable, with males representing 61.5% and 60.0% of patients in the intervention and control arms, respectively (P = .8). Most patients had undergone subtotal resection (intervention arm, 76.2% vs control arm, 86.1%; P = .1), whereas fewer patients underwent gross total resection (14.1% vs 7.8%) or biopsy alone (9.9% vs 6.1%).

The trial included a higher proportion of patients with grade 4 gliomas in the intervention arm (81.2%) compared with the control group (68.7%); this difference reached statistical significance (P = .02). IDH mutation status was available in a subset of patients and was not statistically significantly different between the 2 groups (intervention arm, 20/36, 55.6%; control arm, 30/46, 65.2%; P = .4).

The type of radiation received was comparable across groups, with most patients receiving 3D conformal radiotherapy instead of intensity-modulated radiation therapy (88.8% vs 91.3%; P = .5). The duration of adjuvant chemotherapy was similar between the 2 groups, with a mean of 5.73 ± 3.31 months in the intervention arm and 5.19 ± 2.52 months in the control arm (P = .165).

Regarding target volumes, the median gross target volume at 60 Gy (GTV60) was larger in the intervention group vs the control group (36.5 cm³ vs 23 cm³; P = .3), and a similar trend was observed between the 2 respective arms for GTV46 (93.8 cm³ vs 51.4 cm³; P = .052). The mean CTV at 60 Gy (CTV60) was higher in the intervention group (140.33 ± 103.7 cm³ vs 124.12 ± 127.55 cm³; P = .047); the CTV46 volumes were comparable between these respective arms (201.6 ± 157 cm³ vs 210.5 ± 171.3 cm³; P = .046).

Disclosures: Javadinia reported no disclosures.

Reference

Javadinia SA, Rabiei P, Anvari K, et al. A multicenter, randomized, open-label, controlled trial to compare recurrence pattern of reduced margins vs RTOG protocol in adjuvant chemoradiation of high-grade glioma. ESMO Open. 2025;10(suppl 3):104304. doi:10.1016/j.esmoop.2025.104304