Standard management for high grade glioma is surgery followed by post-operative radiotherapy with concurrent and adjuvant temozolomide. Radiotherapy technique has evolved from whole brain radiotherapy (WBRT) using 2D cobalt to the present standard of care of delivering focal high dose radiation therapy using 3DCRT/IMRT technique. This has led to improved tumor control and survival.
Quality of life is increasingly relevant as patients’ survival improves. Hence, stress is being laid on maintaining a good quality of life of patients after treatment by reducing toxicity of radiation. Toxicities following cranial irradiation can be classified as acute and late.
Acute radiation morbidities include fatigue, erythema, alopecia, headache and rarely, nausea with or without vomiting; these are generally not severe and are usually self-limiting (
Late effects of radiation, especially cognitive impairment, are more worrisome and may become manifest many years later. In the era of 2D-WBRT, post radiotherapy neurological toxicities in the form of memory loss were very common.
Memory is the ability to retain and reproduce impression once perceived intentionally (
5). Short-term memory, also known as working memory, allows recall for a period of several seconds to a minute without rehearsal. Long-term memory can store much larger quantities of information for potentially unlimited duration (sometimes a whole life span).
The hippocampus is essential for consolidation of information from short-term to long-term memory. Hippocampus, which is a part of limbic system, is important for memory, executive functioning, and emotional responses. It is known to be sensitive to radiotherapy (
Though memory impairment is a well-documented side-effect of cranial irradiation, the underlying cause is ill-defined. One possible hypothesis focuses on a neurogenic stem cell compartment in the hippocampus that is highly sensitive to radiation and potentially central to radiation-induced memory impairment. The neurocognitive effects of cranial radiotherapy in patients with gliomas are well-recognized and may be related to the dose delivered to the hippocampi (
3). Preclinical models have shown that hippocampal irradiation can impair spatial learning and memory, however, currently clinical data are lacking.
Hippocampal-sparing is defined as a mean dose to at least 1 hippocampus of less than 30 Gy (
3). This correlates with a dose constraint of 17 Gy in 10 fractions to the hippocampus used in the RTOG 0933 protocol.
After reviewing the literature on neurocognitive effects of cranial irradiation Vinai Gondi et al., (
4) discussed clinical and preclinical data associating damage to neural progenitor cells located in subgranular zone of the hippocampus with radiation-induced neurocognitive decline, specifically in terms of short-term memory formation and recall, the feasibility and risks of sparing the subgranular zone of the hippocampus during whole-brain radiotherapy for brain metastases, and provided a detailed and comprehensive discussion of the rationale for using modern IMRT techniques to spare the subgranular zone of the hippocampus during cranial irradiation.
In a feasibility study, Marsh et al., (
8) concluded that it is possible to spare contralateral limbic circuit, neural stem cell compartment, and hippocampus during partial brain radiotherapy for both high- and low-grade gliomas using IMRT. This approach may reduce late cognitive squeal of cranial radiotherapy.
Pinkham et al., (
3) retrospectively reviewed consecutive patients with WHO grade II and III gliomas treated with IMRT at their institution between January 2009 and August 2012. A total of 18 patients were identified and hippocampal-sparing was achieved in 14 (78%). They concluded that Hippocampal-sparing radiotherapy is feasible in patients with WHO grade II and III gliomas and that IMRT can be used to selectively spare the hippocampi without compromising the dose delivered to the tumour.
As noted in above studies, in our study also, we could achieve bilateral hippocampal sparing in all patients in IMRT arm (21 Gy in contralateral and 29 Gy in ipsilateral Hippocampus). Whereas, in 3DCRT arm, ipsilateral hippocampus could be spared in 60% of patients (24 Gy in contralateral hippocampus and 34 Gy in ipsilateral hippocampus), favoring the IMRT technique for hippocampal sparing post-operative radiation therapy without compromise in delivery of prescribed dose to PTV.
Further, analysis of serial memory function scores showed that in 6 subtests of P.G.I. memory scale (mental balance, delayed recall, verbal retention for similar and dissimilar pairs, visual retention, and recognition), the patients in IMRT arm had maintenance of the score for a period 3 months post radiotherapy while patients in 3DCRT arm showed a decline immediately after radiotherapy. Thus, a trend towards benefit of IMRT is observed allowing for longer preservation of memory function when compared to 3DCRT. This co-relates with bilateral hippocampal sparing, which was achieved in the IMRT arm.
Bilateral hippocampal sparing, with preservation of memory function, is achievable with the IMRT technique for delivery of post-operative radiotherapy in patients with high grade glioma without compromise in prescribed dose delivery.