Feasibility of hippocampus-sparing VMAT for newly diagnosed glioblastoma treated by chemoradiation: pattern of failure analysis

Glioblastoma (GBM), the most common brain cancer in adults, is treated by radiotherapy (RT) plus concurrent and adjuvant temozolomide as first-line treatment in fit patients [1]. Despite the high recurrence rate and the dismal survival of most GBM patients, patients with gross total removal, O⁶-methylguanine-DNA methyltransferase (MGMT) promoter methylation, and/or isocitrate dehydrogenase (IDH) mutation tend to show longer survival [2].

Brain RT is well-known to be related with deterioration of neurocognitive functions. In particular, due to the association between the hippocampal neural stem cells and memory function, irradiation of the hippocampus (HC) results in decline of the cognitive and memory functions [3‐5]. In the treatment of brain metastasis, hippocampus-sparing whole brain RT was proven to be effective in the preserving verbal memory function in a recent clinical trial [6]. Hippocampus-sparing RT (HSRT) was also evaluated in primary brain tumors, using sophisticated RT techniques, especially intensity-modulated RT [7‐17]. We have previously reported that contralateral HC (cHC) can be effectively spared in patients with primary brain tumors via volumetric-modulated arc therapy (VMAT) to preserve the verbal memory function [18].

However, due to the diffuse infiltrative nature of GBM, the oncological safety regarding the risk of recurrence in spared HC should be validated. Here, we report the first report focusing on the progression rate in the cHC region to ensure the oncological safety of RT with maximal sparing of the cHC (cHSRT) for GBM.

Based on this analysis of 82 patients with GBM treated with cHSRT and temozolomide, we did not observe tumor failure at the cHC at initial disease progression, with a 1-year cumulative failure rate at cHC of only 2.8%. Moreover, progression-free and overall survival were not compromised with cHSRT compared to previous studies where patients were treated with temozolomide-based chemoradiation [1, 2].

For primary brain tumors, the safety of compromising the target volume for HC-sparing is not justified. In high-grade gliomas, recurrences are most often located within 2-cm of the original tumor [21], which often makes sparing of the iHC difficult. Moreover, the American Society for Radiation Oncology guidelines for GBM noted that since published data validating the oncological safety for HC-sparing in GBM patients, the panel does not recommend compromising the target coverage for the protection of HC [22]. Hence, the purpose of our strategy was to at least spare the cHC without compromising the coverage of the PTV. We have previously reported that cHSRT can be effectively done in patients with primary brain tumors via VMAT leading to preservation of the verbal memory function [18]. However, the study included patients with heterogeneous histology. For the application of this strategy to aggressive and highly infiltrative high-grade tumors such as GBM, it is necessary to prove the safety of the strategy in respect of survival and relapse patterns. In this study, we have successfully demonstrated the low incidence of failure at the cHC as well as cHC + 1 cm confirming the oncological safety of cHSRT in GBM.

Numerous studies have assessed the association between the treatment margins and recurrence patterns in high-grade gliomas, especially GBM [21]. Typically, RT clinical target volume is delineated with a 2–3-cm margin around the T1-enhancing lesions and/or T2 signal abnormality on MRIs. However, since central/infield recurrence accounts for the majority around 80%, several groups evaluated the pattern of failure after using a reduced margin. It has been reported that reduced margins do not affect the outcome and failure patterns in GBM [21, 23‐25]. Furthermore, Ali and colleagues reported that reduced RT margin results in significant dose reduction for the HC [12]. In our study, we have reduced the cHC dose without violating the recommended target volume delineation using the VMAT technique. In most clinical settings, cHC may locate exclusively outside the PTV even without reduced margins, unless the tumor crosses to the contralateral hemisphere via the corpus callosum.

Moreover, the survival after experiencing disease failure at the cHC or cHC + 1 cm was very poor with most patients dying within 5 months (median, 1.4 months), indicating that cHC-failure occurs mostly at the terminal stage of the disease. Indeed, in most of our patients with cHC, the disease was already disseminated throughout the whole cerebral hemisphere with multiple subependymal seeding lesions, and therefore proceeded to best supportive care. This finding further supports that covering the cHC in the RT field is not a primary concern, and therefore, the cHC can be safely spared. Although the iHC-failure rate seemed to be higher with a failure-free rate of 81.2% at 12 months after a median follow-up period of 11.2 months compared to cHC-failure, no patient who had their iHC spared failed until 6 months of follow-up. Furthermore, all 12 iHC-failures were a subsequent event following a local failure within the PTV, and the iHC was not the site of failure at initial recurrence. Similar to patients experiencing cHC-failure, patients with iHC-failure had a poor median survival period of 5.1 months. The patients who were alive at our last follow-up might demonstrate a similarly poor survival with a longer follow-up since the median follow-up for the alive patients with iHC failure was only 2.5 months. Therefore, according to the results from our study, sparing of the iHC, at least a partial volume, seems reasonable as long as the coverage of the PTV is not violated.

According to our effort to identify the underlying risk factors for cHC-failure, only subventricular zone involvement of the primary tumor laid patients to significantly higher risk for cHC-failure. This was probably due to the increased risk of seeding of tumor cells through the ventricular space considering that the dominant route of cHC-failure was by subependymal seeding. However, this process occurred mostly at the terminal stage of the disease, and the absolute risk of cHC-failure was still very low even in patients with subventricular zone involvement with a 6-month and 12-month cHC failure-free rate of 97.9 and 95.5%, respectively. Therefore, we concluded that cHC-sparing RT in patients with subventricular zone can also be justified.

In general, overall survival of GBM has been considered poor. However, risk stratification according to genetic profiles such as MGMT promoter methylation or IDH gene mutation of the tumor demonstrated a subgroup of patients, although a minority, shows an unexpected long-term survival for GBM [2, 26]. Hence, HSRT could be considered in those GBM patients to maintain cognitive and memory functions. This strategy may also be extended to the treatment of less aggressive brain tumors. However, the association between the integral dose to the normal brain tissue occurring due to arc therapy and the long-term neurocognitive changes should be carefully investigated in low-grade tumors, especially in younger patients. Further studies should clarify the benefit of HSRT in partial brain RT.

This study has several limitations such as the retrospective nature of the study. Moreover, since pre- and post-cHSRT neurocognitive function test was not performed in all patients, the adequate dose-constraint to the cHC as well as the dose-response between neurocognitive decline and irradiated dose of the cHC in GBM patients cannot be identified by the current study. Nevertheless, since previous studies have demonstrated an overt association between irradiation of the HC and cognitive decline [3‐5], the authors believe that the very first study presenting the oncological safety of cHSRT in GBM patients is of value.

In summary, given the low incidence of cHC- and cHC + 1 cm-failure, chemoradiation with cHSRT seems to be safe in newly diagnosed GBM as far as the target volume is not compromised.