Based on this comprehensive analysis of 371 patients with 1133 brain metastases at presentation, we observed brain metastases within 5mm of the hippocampus in 8.6% of patients, with an estimated upper limit of the 95% confidence interval of 11.5%. Of the 1133 brain metastases reviewed, 3.0% lay within 5mm of the hippocampus. However, none of the metastasis lay within the hippocampus.
From this, we conclude that 91.4% of newly diagnosed patients will be eligible for HA-WBRT of brain metastases. Although response rates after WBRT without hippocampal avoidance vary, complete or partial responses have been documented in more than 60% of patients in randomized controlled studies conducted by the RTOG, with intracranial disease control observed in approximately 50% of patients at 6 months [7
]. It is currently not possible to provide a direct estimate of the risk of developing a metastasis after HA-WBRT, since such a comprehensive dataset does not exist. However, if we assume that the risk of developing subsequent brain metastasis in the hippocampal avoidance region scales in the same proportion as that at presentation, we can conclude that a patient treated with HA-WBRT will derive 91.4% of the relative benefit of WBRT in terms of radiographically evident intracranial lesions, with a lower 95% confidence limit of 88.5%. This modest increase in risk of intra-cranial progression with hippocampal avoidance may be partially compensated by the possibility of salvage with radiosurgery, which remains to be validated. Should salvage radiosurgery be used for a perihippocampal recurrence, we expect that given the very steep radiation dose falloff with stereotactic radiosurgery, only some but not all of the potential neurocognitive benefit of hippocampal avoidance will be lost.
Importantly, we observed that none of the 1133 brain metastases reviewed in this analysis lay within the hippocampus. The identification of a hippocampal metastasis depends on the anatomic definition of the hippocampus, which can be susceptible to inter-observer variability. provides examples of our approach to hippocampal contouring and of perihippocampal metastases. Our approach to hippocampal contouring is based on a prior published protocol for manual hippocampal contouring [4
], as well as an unpublished population-based hippocampal template that we have developed through the deformable co-registration of 100 manual hippocampal contours. In addition, our approach to hippocampal contouring will be adopted in the RTOG 0933 phase II clinical trial of HA-WBRT through credentialing and quality assurance review to be conducted centrally by our research group [4
]. As a result, we deem our findings to be a reliable first estimate of the likelihood of hippocampal and perihippocampal disease progression after HA-WBRT.
In addition, we observe that the aggregate volume of intracranial metastatic disease predicts for risk of metastasis within 5 mm of the hippocampus. Though binary logistic regression analysis demonstrates statistical significance, the clinical significance of this predictive relationship is relatively small, with an odds ratio of 1.02. That is, each cubic centimeter increase in intracranial metastatic volume increases the odds of a perihippocampal metastasis by a factor of 1.02. Based on this model, aggregate intracranial metastatic volume would need to equal or exceed 35 cubic cm before reaching the upper limit of our estimated 95% confidence interval for risk of perihippocampal disease progression. Of the 371 patients who presented with up to 10 brain metastases, 25 (6.7%) were observed to have an aggregate intracranial metastatic volume equal to or larger than 35 cubic cm.
We have previously described a similar analysis in a smaller dataset, involving 100 patients, and observed 8% of patients to have a perihippocampal metastasis at presentation [4
]. The upper limit of the 95% confidence interval in that study was 15.2%. We sought to expand our analysis in order to provide a more accurate estimate of the upper limit of the 95% confidence interval and thus the safety profile of HA-WBRT. Between the two studies, the similar percentage of patients with perihippocampal metastasis (8.6% on this review; 8% on the prior review) and similar rate of brain metastases within 5mm of the hippocampus (3.0% on this review; 3.3% on the prior review) point to the reproducibility of our methodology in reviewing two separate institutional databases. By enlarging our patient database, we have reduced the standard error and, in so doing, improved the accuracy of our risk estimate. Based on these data, we conclude that HA-WBRT is safe for clinical testing. Through the RTOG (RTOG 0933), we have developed a multi-institutional phase II clinical trial of HA-WBRT in patients with brain metastases (). This trial has been approved by the Division of Cancer Prevention at the National Cancer Institute and is scheduled to open in 2010.
Study schema for RTOG 0933 phase II trial of hippocampal avoidance during WBRT (HA-WBRT) for brain metastases.