Impact of hippocampal sparing radiotherapy on neurocognitive function in postoperative buccal mucosa cancer patients with delineated infratemporal fossa: a retrospective cohort study

Introduction

Background

Hippocampal sparing radiotherapy is commonly practised in cases of metastatic brain tumors treated with whole-brain radiation therapy (WBRT), as radiation-induced injury to the hippocampus leads to deficits in learning, memory, and spatial processing (1). The RTOG 0933 study demonstrated that WBRT using intensity-modulated radiation therapy (IMRT) with hippocampal avoidance was associated with improvement of memory loss (2). Hippocampal sparing has been largely studied in brain metastasis (2) and primary brain tumors (3-7) as well as in nasopharyngeal (8-12), maxillary sinus (13), pituitary (14), oropharyngeal (15), and base-of-skull tumors (16). In our department, a study comparing the achievability of hippocampal sparing in radiotherapy brain tumors with three- dimensional conformal radiotherapy (3D-CRT) and IMRT, and their effects on neurocognitive function (NCF) (4). The study emphasized that anatomical location of the tumor plays a key role in deciding for or against hippocampal sparing. Hippocampal sparing is not usually done in radiotherapy planning of buccal mucosa cancer where it is at risk of receiving incidental irradiation due to its anatomical proximity and dose spill in IMRT.

Rationale and knowledge gap

Hippocampus a crucial part of the memory circuit in the brain. Irradiation of the brain parenchyma results in hypoxic injury, especially affecting the CA-1 sub-region of the hippocampus, which is crucial for memory formation and recall. The neural stem cell component of the hippocampus may explain its susceptibility to ionizing radiation damage and subsequent neurocognitive decline. In one study, deterioration of memory function occurred in 30–60% patients with primary brain tumors 8–18 months after cranial irradiation (17,18), but this is sparsely discussed in head and neck cancers where hippocampus is at risk for incidental irradiation, particularly in Bucco-aveolar cancers.

Nangia et al. (19) were first to report the incidental irradiation of hippocampus in Bucco-alveolar Cancers and demonstrated that with advent of newer radiotherapy techniques like IMRT and volumetric modulated arc therapy (VMAT) hippocampus can be spared. Early-stage buccal mucosa cancers typically have a smaller clinical target volume (CTV) limited to the buccal mucosa, with nodal irradiation confined to levels Ia, Ib, II, III, and IX of the ipsilateral neck according to the nodal stage (17). In advanced stages (T3 or T4), the infratemporal fossa (ITF) is also included in the CTV to avoid recurrence due to the propensity to spread through the inferior alveolar and mental nerve (20). In this subset of locally advanced buccal mucosa cancers, incidental irradiation of the hippocampus due to its anatomical proximity has been noted. Long-term survival in these patients warrants sparing of the hippocampus as an organ at risk (OAR), as well as a means to improve quality of life (21-23).

Objective

We aimed to study the impact of hippocampal sparing radiotherapy on neurocognitive function in postoperative buccal mucosa cancer patients with delineated infratemporal fossa. We present this article in accordance with the STROBE reporting checklist (available at https://tro.amegroups.com/article/view/10.21037/tro-24-20/rc).

Methods

Study setting and description

This Retrospective Cohort Study observational study was conducted at the Department of Radiation Oncology, Shri Ram Murti Institute of Medical Sciences, Bareilly, Uttar Pradesh, India, in December 2023 where Data of patients of carcinoma buccal mucosa which were treated between January 2021 and December 2022 was retrospectively reviewed.

Ethical consideration

The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics board of SRMSIMS (No. SRMS IMS/ECC/2024/04) and individual consent for this retrospective analysis was waived.

Inclusion and exclusion criteria (Figure 1)

Figure 1 Demonstrates the inclusion and the exclusion criteria. ENE, extra-nodal extension; IMRT, intensity-modulated radiation therapy.

All included patients of age more than 18 years, postoperative buccal mucosa cancer, stage (pT3 and pT4, pN0-pN3a), margins negative, extra-nodal extension (ENE) negative where infratemporal fossa was delineated, treated with IMRT technique between January 2021 and December 2022 with a prescribed radiation dose of 60 Gy in 30 fractions delivered at 2 Gy per fraction, 5 days a week. All patients with early stage (pT1, pT2), unresectable, positive surgical margins, extra-nodal extension (where dose prescription was 66 Gy), metastatic disease (M1) were excluded from the study.

Target volume delineation and organs at risk

A CT scan was previously done for radiotherapy planning, with an axial CT slice thickness of 3 mm. Target volume delineation was performed, including postoperative bed, infratemporal fossa, and nodal volumes according to stage (24). All patients had been planned and treated with the same protocols as per the recommendations of International Commission on Radiation Units and Measurements Reports (ICRU) Report 50, 1993, and ICRU Report 62, 1999.

Dose prescription and organ at risk evaluation

An ipsilateral dose of 60 Gy in 30 fractions and contralateral dose of 54 Gy in 27 fractions to the planning target volume (PTV) was planned and previously delivered. The ideal planning objective was a minimum dose of 95% and a maximum dose of 107% relative to the prescribed dose, which was achieved for all patients. The doses that the PTV and OAR received were determined from cumulative dose-volume histograms, as recommended in ICRU Report 83, 2010 (25).

The following OAR dosimetric constraints were prescribed at the time of treatment planning and achieved in all cases: PRV brainstem: D_max <54 Gy; PRV spinal cord: D_max <50 Gy; mandible: D_max <70 Gy; optic nerve: D_max <54 Gy; parotid gland: D_mean <26 Gy; PRV cochlea: D_mean <50 Gy as per Quanititative Analyses of Normal Tissue Effects in the Clinic (QUANTEC) recommendations (26). To minimise the risk of radiation induced acute and late side effects of the organs at risk.

Hippocampal delineation and prescription for IMRT planning

The hippocampus was now delineated in selected patients according to guidelines given by Scoccianti et al. (27), where the temporal horn of the lateral ventricle and the ambient and quadrigeminal cisterns were identified, and the gray matter of the hippocampus was contoured. We then determined whether the following dose constraints were achieved: maximum dose (D_max) <16 Gy, minimum dose (D_min) <9 Gy, dose to 40% of the hippocampal volume <7.3 Gy (28).

Radiotherapy planning

Planning and contouring were done using Varian Eclipse version 13.6 Treatment Planning System (TPS) (Version 8.6.17, Varian Medical System, Inc., Palo Alto, CA, USA). and dosimetric calculations were done using the anisotropic analytical algorithm (AAA). Dose evaluation to the hippocampus was done in previously planned and delivered IMRT patients, who were categorized as Group 1. Group 1 patients were then replanned by incorporating hippocampal dose constraints in the planning process, categorized as Group 2. The dosimetric parameters initially planned in Group 1 and re-planned in Group 2 patients were evaluated to determine whether the hippocampal dose constraints were achieved (Figures 2,3).

Figure 2 Demonstrates the isodose curves in three planes to show the hippocampus dosimetry in original plan where dose constraints to hippocampus was not given: (A) coronal, (B) axial, and (C) sagittal plane.

Figure 3 Demonstrates the isodose curves in three planes to showing hippocampal dosimetry the hippocampus dosimetry after revised plan with dose constraints given to hippocampus: (A) coronal, (B) axial, and (C) sagittal plane.

Dosimetric parameters to be evaluated

PTV dosimetric parameters

The PTV dosimetric parameters evaluated to assess plan quality included V57, D_max, D_mean, D_2%, D_50%, D_98%, homogeneity index (HI) (25) and pConformity index (pCI) (29).

HI

HI was calculated using the following formula: (25)

HI=(D2%−D98%)/D50%[1]

where D_2%, D_50%, and D_98% are the absolute dose delivered to 2%, 50%, and 98% of the PTV, respectively. An HI value of zero indicates a homogenous distribution.

Conformity index (CI)

CI is a measure of the degree of conformity of the absorbed dose distribution to the PTV. In this work, Paddick’s CI (29) was used for evaluation:

CI=(TVPIV)2/(TV×PIV)[2]

where TV_PIV, TV, and PIV are the prescribed isodose volume over the target volume, the target volume, and the prescription isodose volume, respectively.

Neurocognitive function to be evaluated

NCF was assessed using the MMSE after at least 12 months of completion of Radiotherapy, on follow up which was carried out in a local language. The MMSE was interpreted based on severity of neurocognitive function decline, where 24–30 was interpreted as no cognitive impairment, 18–23 as mild cognitive impairment, 0–17 as severe cognitive impairment (30).

Statistical analysis

In our retrospective cohort study, after collection of data; data cleaning was done for patients not meeting the inclusion criteria. Sample size was calculated using a complete enumeration method, where all patients presenting to our department between January 2021 and December 2022 were included, no pre-determined sample size calculation was used. The statistical software used was IVM SPSS version 22. The continuous variables were presented in terms of mean ± standard deviation, categorical variables were presented in terms of frequency and percentage.

Normality test was done, independent t-test or Mann-Whitney U test was used after verifying the assumption of normality. A P value <0.05 was considered significant at 5% level of significance for one-tailed t-test.

Results

The study included a total of 46 patients (Table 1), in which there were 45 males, and 1 female, 12 patients belonging to AJCC group stage III, 34 patients belonging to stage IVA.

In the study population, 30 patients had an incidental dose to the hippocampus exceeding the constraints. The mean dosimetric parameters of the ipsilateral hippocampus were as follows: D_min =3.8 Gy (1.5–11.2 Gy), D_max =27.5 Gy (8.17.4–38.03 Gy), and D_40% =13.5 Gy (3.6–24.9 Gy); and those of the contralateral hippocampus were as follows: D_min =2.8 Gy (1.3–7.25 Gy), D_max =15.25 Gy (7.8–23.8 Gy), and D_40% =8.3 Gy (2.8–16 Gy).

After replanning, all 30 patients achieved the dose constraints to the hippocampus with acceptable PTV parameters. The mean ipsilateral hippocampal parameters were as follows: D_min =2.43 Gy (0.5–7.3 Gy), D_max =12.7 Gy (3.08–15.6 Gy), and D_40% =4.9 Gy (2.4–7.2 Gy); and those of the contralateral hippocampus were as follows: D_min =2.1 Gy (0.6–3.9 Gy), D_max =10.38 Gy (3.2–14.3 Gy), and D_40% =4.09 Gy (1.6–7 Gy).

No significant difference between PTV parameters and OAR parameters was observed after replanning, as shown in Tables 2,3, respectively. However, upon replanning, a statistically significant decrease in all hippocampal dose constraints was observed, as shown in Table 4.

We analysed the relationship between hippocampal irradiation and clinical implications in terms of MMSE for 21 out of 46 patients. We found that only one patient had an MMSE score of <24 (i.e., 23), suggestive of mild neurocognitive decline, as seen in Table 5. MMSE testing of the remaining patients could not be performed, as they either could not be contacted or had expired.

Discussion

Key findings

The study retrospectively evaluated patients of postoperative radiotherapy of buccal mucosa cancer, in which 30 patients had an incidental dose to the hippocampus exceeding the constraints, but upon replanning, the dose constraints could be achieved.

In postoperative radiotherapy of buccal mucosa cancer, incidental irradiation of the hippocampus due to its anatomical proximity and low dose spill in IMRT may lead to radiation induced damage. Although this dose spillage to the hippocampus has been associated with memory decline in cases of tumors with anatomically proximity to the hippocampus (2-15), there is a paucity of data of hippocampal sparing among buccal mucosa cancer patients receiving postoperative radiotherapy.

Strengths and limitations

The strength of our study is that we used a clinical test i.e., MMSE to examine the endpoint of neurocognitive decline. Moreover, MMSE can be used for varied levels of literacy and is readily available in the local language, is a quick screening tool for memory decline. The limitation of our study is that though our data demonstrate the feasibility of hippocampal sparing in postoperative radiotherapy among buccal mucosa cancer patients, mild neurocognitive decline in one out of 21 patients is not sufficient to conclude that the radiation dose received by the hippocampus is directly proportional to the extent of NCF decline. Longer follow up is needed to note whether this NCF decline is transient, and whether the remaining patients also develop memory deficit as time after treatment increases. Moreover, the lack of baseline MMSE testing, makes it difficult to quantify the memory decline or the lack of it.

Comparison with similar research

A study by Chaturvedi et al. (4) done at our institution evaluated hippocampal sparing in 22 patients with brain tumors treated with 3D-CRT. Alternate IMRT plans were regenerated for these patients, with no significant difference observed in the hippocampus dosimetric parameters. The study demonstrated that the anatomic proximity of the tumor plays a role in deciding the feasibility of hippocampal sparing in patients with primary brain tumors. Gondi et al. (2) demonstrated the importance of hippocampal sparing in patients with brain metastasis, as NCF decline was seen with a hippocampal D_40% equivalent dose in 2 Gy fractions (EQD2) of more than 7.3 Gy, and in WBRT under a hippocampal D_max exceeding 16 Gy and a D100 exceeding 9 Gy. A study by Hofmaier (5) evaluated hippocampal sparing using volumetric modulated arc therapy (VMAT) among 27 glioblastoma patients who received a prescribed dose of 60 Gy in fractions of 2 Gy. It was concluded that a dose reduction to the contralateral hippocampus was feasible without compromising other treatment parameters, and was easier to achieve in relatively smaller PTVs.

Kim et al. (6) demonstrated feasibility of Hippocampal sparing using VMAT in primary brain tumors, including grade III/IV brain tumor, pituitary adenoma, and meningioma; they noted that the contralateral hippocampus could be effectively spared through VMAT. Pinkham (7) also discussed the feasibility of hippocampal sparing in grade II and grade III gliomas, and concluded that hippocampal-sparing depends on the volume of the PTV, i.e., PTVs with small volume are able to also achieve hippocampal sparing. All of these studies demonstrate that the proximity of the PTV to the hippocampus is what makes hippocampal sparing challenging in patients with brain tumors. Moreover, as the hippocampus is a bilateral structure, making challenging to generate plans that offer effective bilateral hippocampal sparing. While some studies of gliomas (6,7) demonstrated that NCF decline was not related the volume of brain irradiated but to to the total dose of radiation received by the brain parenchyma. They also reported that neurocognitive deficits are a late side effect of incidental brain radiotherapy especially in subsites with anatomical proximity to the hippocampus.

Among studies of non-central nervous system cancers, most investigate cancers of the nasopharynx. Athiyamaan et al. (8) demonstrated that the hippocampus receives an incidental dose during IMRT in patients of nasopharyngeal cancers, with an average minimum dose to the entire hippocampus ranging between 0.072 and 18.609 Gy, maximum dose to the hippocampus of ranging between 0.595 and 59.832 Gy, and mean dose to the hippocampus of ranging from 0.194 to 34.706 Gy. A study by Dunlop et al. (9) demonstrated the feasibility of generating plans for nasopharyngeal carcinoma that either specifically spared the bilateral hippocampi or spared the whole brain in addition to the hippocampi. Similarly, Gu et al. (10) demonstrated that, with newer modalities such as VMAT, hippocampus dose constraints can be achieved when accounted for in hippocampal sparing VMAT (899±378 cGy) as compared to conventional VMAT (1,518±337 cGy, P<0.001).

Seol et al. (15) reported that Hippocampus also receives incidental radiation in locoregionally advanced Oropharyngeal cancer. The study also emphasized on the feasibility of hippocampal-sparing VMAT in these patients. They first generated plans with no constraints prescribed to the hippocampus, then compared them with hippocampal-sparing plans where the average mean dose to the ipsilateral hippocampus was 3.1 Gy and contralateral hippocampus was 2.5 Gy in the initial plans which reduced to 1.4 and 1.3 Gy upon replanning with hippocampal-sparing, respectively. This demonstrates that the hippocampus is an OAR that demands to be seen. Dose constraints, if accounted for before planning, can be achieved without compromising PTV even in cases of oropharyngeal cancers. A study by Meyers et al. (16) incidental brain irradiation causing studied NCF impairment in 19 patients receiving paranasal sinus irradiation at a dose range of 50–68 Gy by a three-field technique. According to NCF testing (with an average time to test after radiation treatment of six years), 80% of the patients reported decline manifesting as difficulty with visual-motor speed, frontal lobe executive functions, and fine motor coordination; two patients reported frank brain necrosis, three showed brain atrophy, some also reported difficulty in participating in their normal activities due to physical impairment, some also reported pituitary dysfunction.

A novel study by Nangia et al. (19), which was the first study to demonstrate hippocampal sparing in cancer of the bucco-alveolar region receiving post-op radiotherapy. The study demonstrated that hippocampal sparing is achievable and on doing so, hippocampal D_max EQD2, D_mean EQD2, and D_40% EQD2 significantly reduce from 27 to 10.9 Gy (P=0.002), 14.3 to 6.4 Gy (P=0.002), and 15.5 to 6.6 Gy (P=0.005), respectively, with comparable plans. Our study had similar findings, where, upon replanning, a significant reduction in the hippocampal D_max EQD2, D_mean EQD2, and D_40% EQD2 from 27.7 to 12.7 Gy (P=0.003), 12.43 to 4.9 Gy (P=0.018), and 13.5 to 4.9 Gy (P=0.004), respectively, was noted with comparable planning parameters. Kendall et al. (31) compared radiobiological aspects of treatment plans in IMRT and VMAT for patients with hippocampal avoidance WBRT, and showed that IMRT plans had a higher NTCP value when compared with VMAT. Nangia et al. (19) treated all patients in the hippocampal sparing group with VMAT, except for three patients who received IMRT, whereas only one patient in the non-hippocampal sparing group was treated with VMAT, and none with IMRT. To remove the confounding factor, re planning was done with VMAT for both patient cohorts, and dosimetry was compared, where as our study, patients who were only treated by IMRT were included in the study population. One strength of our study was that we used a clinical endpoint instead of a radiobiological endpoint to assess NCF. Pezzotti et al. (32) evaluated the accuracy of the MMSE in detecting cognitive impairment by comparing NCF scores to those obtained via Alzheimer’s Evaluation Units and concluded that MMSE is sufficiently accurate to detect patients with cognitive impairment, particularly those with dementia. In our study, we performed MMSE for 20 out of 46 patients after a follow-up of 12 months post-radiotherapy, wherein we found that only one patient had a score of <25 (i.e., 23), suggestive of mild neurocognitive decline. He received the maximum dose to the ipsilateral hippocampus in the cohort, with D_max =33.9 Gy. Although deterioration in memory function has been reported in patients with primary brain tumors 8–18 months after cranial irradiation (33), various studies have also found significant cognitive decline only after a longer follow-up of approximately five years after treatment (33,34), whereas those with a shorter follow-up showed only a transient neuro-cognitive decline (35).

Explanations of findings

In postoperative radiotherapy of buccal mucosa cancer, incidental irradiation of the hippocampus has been noted due to its anatomical proximity and low dose spill in IMRT which in turn can lead to NCF decline.

Older radiotherapy techniques such as two-dimensional conventional radiotherapy for head-neck cancers usually consists of a wedge pair portal based on two-dimensional fluoroscopic monitoring with little focus on protecting normal tissues. As 3D-CRT and IMRT improve dose delivery precision while preserving neighboring normal organs and tissues at risk (OAR), they both offer a major improvement over traditional radiation. A series of fixed beams of radiation that are formed by projecting the target volume are used to provide IMRT. The target volume is achieved by geometrically modulating the beam pattern such that the tumor receives an appropriate dosage while sparing the surrounding normal tissue and is more suited to the anatomy of each patient.

Organs at risk when contoured and prescribed with dose constraints can thereby be spared. Therefore, while initially 30 patients of Group 1 who did not achieve hippocampal dose constraints could achieve it upon replanning.

Implications and actions needed

Hippocampus plays pivotal role in memory formation, due to its neural stem cell component is highly susceptible to radiation induced hypoxic injury. This injury can manifest clinically as memory decline. Patients of carcinoma buccal mucosa post-surgery and adjuvant radiation therapy, have a long survival. This warrants for sparing of this banana shaped structure even in non-central nervous tumors which are in close proximity to the hippocampus. Therefore, routine delineation and prescription of dose constraints to the hippocampus should be routinely practiced in IMRT of locally advanced cancer buccal mucosa where infratemporal fossa is being delineated.

Conclusions

Incidental irradiation of the hippocampal region due to the low-dose bath produced by IMRT of locally advanced cancer buccal mucosa tumors may have long-term implications. This OAR can easily be spared when delineated and accounted for during the planning process. Therefore, in patients with locally advanced buccal mucosa cancer where postoperative irradiation is warranted, hippocampal sparing becomes a means to improve quality of life.

Acknowledgments

The authors thank Mr. Ravi Kumar (M.Sc, Statistician) for his vital inputs in the statistical analysis.

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tro.amegroups.com/article/view/10.21037/tro-24-20/rc

Data Sharing Statement: Available at https://tro.amegroups.com/article/view/10.21037/tro-24-20/dss

Peer Review File: Available at https://tro.amegroups.com/article/view/10.21037/tro-24-20/prf

Funding: None.

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tro.amegroups.com/article/view/10.21037/tro-24-20/coif). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki and its subsequent amendments. The study was approved by institutional ethics committee of SRMSIMS (SRMS IMS/ECC/2024/04) and individual consent for this retrospective analysis was waived.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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