Target delineation for glioblastoma—Is it time to sever historical ties?

Based on old autopsy studies showing that a 2- to 3-cm clinical target volume (CTV) expansion around the primary glioblastoma (GBM) site would cover 90%–100% of recurrences, clinical radiotherapy practice in North America has been to employ large CTV margins beyond the gross tumor volume (GTV).¹ North American clinical trials have typically mandated a large CTV with a 2-cm margin around the fluid attentuated inversion recovery (FLAIR) signal, surgical cavity, and residual tumor for the initial treatment phase followed by a 2-cm margin around the surgical cavity and residual tumor as the boost CTV. While this approach can encompass more potential microscopic disease, a large volume of healthy brain tissue will be irradiated, adversely impact quality of life.²

Why such big margins? The concern has been the possibility of a geographical miss as historically, volumes were manually translated from the MRI to the planning CT due to the lack of adequate fusion software, and sophisticated volumetric MRI techniques. However, despite advances in MR acquisition and treatment planning software, the approach to the CTV has stagnated. In recent years, many trials in Europe and Canada adopted the approach of a 1.5- to 2.0-cm margin beyond the GTV and many centers also reduced their CTV margin with variable inclusion of at-risk FLAIR signal in the CTV.^1,3 Multiple studies reported on patterns of failure following radiotherapy concurrent with chemotherapy for GBM with reduced margins.⁴ In a retrospective study, Minniti et al. showed that inclusion of edema in the GTV with the same CTV expansion of 2.0 cm would not have changed the patterns of failure with most tumor recurrence occurring in-field.⁵ However, patients with tumors with O⁶-methylguanine-DNA-methyltransferase (MGMT) promoter methylation had a higher rate of out-of-field failure. In another study, when the CTV expansion from the GTV, defined as resection cavity and any residual tumor, was reduced from 2.0 to 1.0 cm, there was no difference in patterns of failure. MGMT-methylated GBMs had a higher tendency for distant failure, which would not have been covered by more generous CTV margin expansion or inclusion of edema.⁶ Uniquely, in a well-selected cohort of patients receiving hypofractionated stereotactic radiotherapy using a 0.5-cm CTV beyond the GTV, 63% of failures were in-field, 11% marginal, and distant in 26%.⁷ The authors concluded that applying those typical large CTV margins would have benefited only one patient in the cohort of 27 patients. Upon examination of the literature, the predominant pattern of failure is within the GTV despite the variation in margin expansion.

The findings of the above studies are in keeping with the results in this study by Di Perri et al., who compared the use of 1.5- and 2.0-cm CTV margin expansions for GBMs.⁸ All patients in the 2.0-cm CTV expansion group also had areas of “edema” included in the CTV, and this practice was not included in those treated with a 1.5-cm CTV expansion. Although the GTV was similar between the 2 cohorts, the mean CTV and planning target volume (PTV) reduced from 238.9 to 176.7 cm³ in the 1.5-cm CTV cohort, and the mean doses to the brain, left hippocampus, cochleae, and the pituitary (and the maximum brainstem point dose) were significantly lower.⁸ The in-field failure rates were 91.9% and 86.8% for 1.5-cm versus 2.0-cm CTV expansion, respectively. The corresponding rates for marginal failure were 5.4% versus 10.5%.⁸ There was also no significant difference in overall survival. Of note, IDH mutation status was also available in all the patients. Only 7% and 10.7% of patients in the 1.5-cm versus 2.0-cm CTV cohorts had tumors that were isocitrate dehydrogenase (IDH) mutants, respectively. In other words, patients in this study were a good representation of patients with “true” GBMs based on the most up-to-date WHO classification from 2021. The findings from Di Perri et al. also support those recent European Society for Therapeutic Radiology and Oncology (ESTRO)-European Association for Neuro-Oncology (EANO) guidelines stipulating a CTV expansion of 1.5 cm with the caveat to include non-contrast-enhanced tumor as needed.³

So where do we go from here? Ultimately, modern data do not support the concern of margin reduction increasing the risk of geographical miss. More specifically, multiple studies, including that from Di Perri et al., demonstrate that the routine inclusion of all edema beyond the GTV is unnecessary.^1,4–6,8 However, it is acknowledged that suspicious areas of non-contrast-enhanced tumor showing high signal intensity on T2/FLAIR can be included in the CTV as recommended by the ESTRO-EANO guideline.³ With significant volumes of normal brain tissue and doses to the organs at-risk spared by applying a 1.5-cm CTV expansion beyond the GTV, this practice should be supported in clinical practice and trials.

Further margin reduction strategies as a means of de-escalation may require more rigorous monitoring of the tumor during radiotherapy to account for tumor dynamics, especially in this emerging era of routine treatment adaption. Recent prospective MR imaging studies of patients undergoing chemoradiation from Stewart et al.⁹ and Bernchou et al.¹⁰ have observed dynamics of the residual tumor and cavity resulting in migration of the GTV by more than 5 mm and 10 mm in 50% and 24% of patients, respectively. These findings underscore the importance of MRI guidance when further reducing the CTV margin. The UNITED trial (NCT04726397), which has completed accrual, examines this strategy utilizing a CTV of 5 mm (allowing for at-risk FLAIR to be included) with weekly online adaptative radiotherapy using the Elekta Unity MR-Linac (Elekta AB). Further prospective trials are ongoing evaluating CTV margin reduction coupled with dose escalation in the elderly population, and a 2-phase approach in the younger population based on MR-Linac online adaptive radiotherapy and CTV margin reduction.

For any oncologic treatment, it is crucial to strike a balance between tumor control and potential complications, including decreased quality of life, particularly for a disease that is incurable. Given the body of evidence showing that margin reduction does not result in worsened survival and increased risk of marginal failure, it seems logical to consider severing the historical ties of using generous CTV margins for GBMs.

Funding

None declared.

Conflict of Interest

S.S.L.: Elekta AB, member of ICON Gamma Knife Expert Group and research support; Kuni Foundation, research funding; Hutchinson Center as Lead Academic Participating Site (UG1 CA 233328); Japanese Society for Radiation Oncology, travel expenses; American College of Radiology, Alternate councilor on behalf of American Radium Society and Chair of CARROS Nominating Committee; Radiosurgery Society, Board of Directors and National Medical Director of the Distinction in Practice in Stereotactic Radiotherapy Program; C.-L.T.: Travel accommodations/expenses & honoraria for past educational seminars by Elekta, belongs to the Elekta MR-Linac Consortium, and is an advisor/consultant with Sanofi and Abbvie; A.S.: Grants from Elekta, Varian, Seagen Inc., BrainLAB, consulting fees from Varian, Elekta, BrainLAB, Merck, Abbvie, Roche, honoraria from AstraZeneca, Elekta, Varian, BrainLAB, Accuray, Seagen Inc., travel expenses from Elekta, Varian, BrainLAB, roles on leadership board as Vice President of International Stereotactic Radiosurgery Society and other interests as member of Elekta MR-Linac Research Consortium, member of Elekta Clinical Steering Committee, chair of Elekta Oligometastases Group and Elekta Gamma Knife Icon Group.