Estimated risk of perihippocampal disease progression after hippocampal avoidance during whole-brain radiotherapy: safety profile for RTOG 0933

Abstract

Background and purpose: RTOG 0933 is a phase II clinical trial of hippocampal avoidance during whole-brain radiotherapy (HA-WBRT) to prevent radiation-induced neurocognitive decline. By quantifying baseline incidence of perihippocampal or hippocampal metastasis, we sought to estimate the risk of developing metastases in the hippocampal avoidance region (the hippocampus plus 5mm margin).

Materials/methods: Patients with < or = 10 brain metastases treated at two separate institutions were reviewed. Axial images from pre-treatment, post-contrast MRIs were used to contour each metastasis and hippocampus according to a published protocol. Clinical and radiographic variables were correlated with perihippocampal metastasis using a binary logistical regression analysis, with two-sided p<0.05 for statistical significance.

Results: 1133 metastases were identified in 371 patients. Metastases within 5mm of the hippocampus were observed in 8.6% of patients (95% CI 5.7-11.5%) and 3.0% of brain metastases. None of the metastases lay within the hippocampus. A 1-cm(3) increase in the aggregate volume of intra-cranial metastatic disease was associated with an odds ratio of 1.02 (95% CI 1.006-1.034, p=0.003) for the presence of perihippocampal metastasis.

Conclusion: With an estimated perihippocampal metastasis risk of 8.6%, we deem HA-WBRT safe for clinical testing in patients with brain metastases as part of RTOG 0933.

Figure 1. Perihippocampal distance of brain metastases

Of the 1133 brain metastases reviewed, 34 (3%) of them lay within 5mm of the hippocampus. However, none of the metastases lay within the hippocampus.

Figure 2. Odds ratio (with 95% confidence interval) of perihippocampal metastasis according to aggregate volume of intracranial metastases

Binary logistic regression analysis was performed for all patients and for patients stratified by primary histology. A trend towards significance was observed for patients with non-small-cell lung cancer (NSCLC) (p=0.109) and melanoma (p=0.067). Statistical significance was observed for all patients (p=0.003) and for patients with small cell lung cancer (SCLC) (p=0.027) and malignancies other than NSCLC, SCLC, melanoma, breast cancer, or renal cell cancer (p=0.033). Patients with renal cell carcinoma were not included in this figure, as none of them had a metastasis within 5 mm of the hippocampus. Patients with breast cancer were not included in this figure, as statistical significance was not observed. Abbreviations: NSCLC, non-small-cell lung cancer, SCLC, small cell lung cancer

Figure 3. Perihippocampal metastasis

Contrast-enhanced T1 sagittal images of a patient who has a metastasis within 5mm of the hippocampus, which represents the hippocampal avoidance volume during HA-WBRT. The green contour represents the hippocampal contour; the red contour represents the hippocampal avoidance region. 32 of 371 patients had metastasis within the hippocampal avoidance volume. Zero patients had a metastasis within the hippocampus, itself.