PCI with hippocampal avoidance

Patient concern regarding neurotoxicity is the most common reason for PCI omission.23 Memory decline, changes in appetite, nausea, and vomiting as well as hair loss are a major treatment concern.

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However, the diagnosis of SCLC generally appears to negatively impact health-related quality of life (QOL) in comparison to the normal population in several functions such as daily activity, physical functioning, cognitive and emotional functioning.24 A systematic review of literature published in 2017 described that the impact on health-related QOL may be least in both LS- and ES-SCLC patients who responded to treatment, and greatest in ES patients who were treatment naïve.24 Importantly, QOL measured by patient-reported QOL scores after PCI showed a significant decline in QOL for up to 3 months after the completion of treatment.7

Prospective studies assessing QOL of patients in observation vs. PCI groups after initial treatment response are inconclusive. In the study by Le Péchoux et al, QOL was evaluated before PCI and routinely during follow-up up till 3 years. PCI was associated with mild deterioration of communication deficit, weakness of legs, intellectual deficit and memory dysfunction.10 However, further analyses reported that PCI was associated with a decline in Hopkins Verbal Learning Test-Revised (HVLT-R) and self-reported cognitive functioning. Additionally, due to the increased risk of developing chronic neurotoxicity in patients with 36 Gy, a total PCI dose of 25 Gy remains the standard of care for patients with LS-SCLC patients attaining a complete response to initial chemoradiotherapy.10,25

A randomized Phase 3 trial of PCI in patients with locally advanced non-small-cell lung cancer did not find any significant differences in global cognitive function or QOL after PCI, but there was a significant decline in memory HVLT at 1 year.26

Importantly, a study by Simó et al revealed neuropsychological deficits together with notable brain-specific structural changes after chemotherapy and PCI, suggesting that chemotherapy and especially PCI are associated with the development of cognitive and structural brain toxic effects.27 Another study detected different markers of neuronal injury after PCI. These cerebrospinal markers such as neurofilament, T-tau or the levels of secreted amyloid precursor protein-α and -β could potentially be used to assess the individual risk of developing long-term symptoms of chronic encephalopathy after PCI.28 However, prospective larger trials with robust neurocognitive assessments and longer follow-up periods are needed to confirm these results.

In order to prevent neurocognitive decline, important brain regions such as the limbic circuit and hippocampal formation should be identified as organs/regions at risk. These regions are in reasonable suspicion to be responsible for memory and higher neurocognitive function and are mainly represented in the hippocampal region. The incidence of BM in the perihippocampal region has not been well investigated. Only limited information is available and earlier studies show that metastasis incidence in the perihippocampal region can vary from 4% to 27%.20,21,29

Earlier studies estimated the perihippocampal metastasis risk at 8.6% and claimed safety of hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) for clinical testing.21 However, in other studies focusing on hippocampal metastasis, Korkmaz et al reported a hippocampal metastasis rate of 32% and questioned the usage of HA-WBRT. The prospective single-arm Phase-2 study (RTOG 0933) revealed that conformal avoidance of the hippocampus during whole-brain radiotherapy (WBRT) is associated with preservation of memory using the HVLT-R and QOL.22 Unfortunately, the median survival time was short (less than 7 months) and the assessments were performed from baseline up to 6 months.

Another small prospective study by Redmond et al showed a median follow-up time of 16.7 months and a 2-year-survival rate of 88%.20 Interestingly, there was no significant neurocognitive performance decline between baseline and 6 or 12 months for any of the tests. Only two patients developed metastases in the underdosed region.

However, the patient collective was limited (n=20) and larger studies should determine the potential benefit of hippocampal sparing.

Modern radiation techniques such as intensity-modulated radiotherapy permit administration of high radiation doses with avoidance of the perihippocampal regions. Nevertheless, the potential benefit of hippocampal sparing in limiting the neurocognitive decline caused by brain irradiation must be questioned by an increase of failure in the spared regions. Additionally, the potential survival benefit of PCI is important, but maintaining QOL by avoiding the physical and neurocognitive complications should be critically discussed with the patient in order to enhance shared decision-making.30 Currently, a host of randomized Phase 2/3 trials is underway to clarify this benefit including cognitive and QOL assessment (NCT02736916, NCT02906384/ZJCH-HA-PCI, NCT02397733, NCT01780675/M12PHA, NCT02635009/NRG-CC003 trials).

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In summary, HA-WBRT could prevent neurocognitive decline, but the incidence of metastases in perihippocampal regions after PCI should be critically evaluated. The results of ongoing Phase 3 trials are highly warranted to confirm the findings from smaller studies to fully endorse the routine usage of hippocampus avoidance in clinical practice.

PCI und drug neuroprotection

There are several substances in preclinical studies that have demonstrated a positive effect on neuroprotection. However, till date, only a few substances have been tested within the ramifications of a Phase 3 study. The RTOG 0614 trial randomized 554 patients to receive placebo or the N-methyl-d-aspartate receptor antagonist memantine (20 mg/d) as a neuroprotectant, within 3 days of initiating radiotherapy for 24 weeks.

Memantine was well tolerated with a similar toxicity profile vs. placebo. In the memantine arm, there were fewer declines in delayed recall at 24 weeks, but the difference was non-significant. The memantine arm had significantly longer time to cognitive decline; the probability of cognitive function failure at 24 weeks was 53.8% vs. 64.9% in the memantine vs. placebo arm. Superior results were seen in the memantine arm for executive function at 8 and 16 weeks and for processing speed and delayed recognition at 24 weeks.31 Although the primary endpoint was technically non-significant, the updated NCCN guidelines for management of SCLC recommend considering memantine during and after administration of PCI.

In addition, donepezil, a neurotransmitter modulator was also evaluated in a Phase 3 placebo-controlled trial that randomized 198 brain tumor survivors ≥6 months after partial- or whole-brain irradiation of which 8% underwent PCI to receive a single daily dose (5 mg for 6 weeks, 10 mg for 18 weeks) of donepezil or placebo. The authors concluded that treatment with donepezil did not significantly improve the overall composite score (primary endpoint), but it did result in modest improvements in several cognitive functions, especially among patients with greater pre-treatment impairments.32 Currently, there are a number of Phase 3 studies assessing the role of neuroprotectants within the context of PCI (NCT01553916, NCT00006349).