In all adult mammals, including humans, new hippocampal granule cells are generated from mitotically active neural stem cells, which are located in the subgranular zone of the dentate gyrus and which migrate into the granular cell layer (8
). Preclinical evidence has associated neurogenesis within the dentate gyrus with normal cognitive function (10
). Cranial irradiation in rat models has been observed to induce apoptosis of these precursor cells and to alter their differentiation toward a gliogenic fate, resulting in a significant reduction in hippocampal neurogenesis (11
) and associated cognitive impairment (2
). Thus, we hypothesize that radiation dose to the hippocampus plays a role, at least in part, in the pathophysiologic process of radiation-induced cognitive impairment.
To explore this hypothesis, we conducted a prospective controlled observational study of adult patients with benign or low-grade brain tumors treated with FSRT and observed a dose—response relationship between radiation dose to the hippocampal dentate gyrus and long-term memory impairment. Specifically, equivalent dose in 2-Gy fractions (EQD2
) (assuming α/β = 2 Gy) to 40% of the bilateral hippocampi greater than 7.3 Gy is associated with long-term impairment in list-learning delayed verbal recall, as measured by the Wechsler Memory Scale-III Word Lists delayed recall test. In addition, fitting data to a nonlinear model using the standard Lyman NTCP model without volume effect demonstrates a significant dose–response relationship with an
to 40% of the bilateral hippocampi of 14.9 Gy and a slope of m = 0.540. The asymmetric 95% confidence intervals for
(12.9–17.1 Gy) and m (0.248–0.765) indicate that our estimates of these values are defined within a limited range. Similar results have been reported by Hsiao and colleagues, who observed a correlation between mean dose to the temporal lobes during intensity-modulated radiotherapy for nasopharyngeal carcinoma and subsequent decline in short-term memory and other cognitive domains (12
). In addition, Jalali et al.
observed a significant correlation between IQ decline and dose to the left temporal lobe (13
). The summation of these clinical observations, therefore, provides a rationale for exploring the hypothesis that conformal avoidance of the hippocampus using intensity-modulated radiotherapy (IMRT) may spare patients some of the cognitive sequelae of cranial irradiation.
Clinical implementation of hippocampal sparing, however, poses several important challenges. Recently, we demonstrated the ability of modern IMRT techniques to selectively spare the bilateral hippocampi of significant doses of radiation during WBRT (6
). For a prescription dose of 30 Gy in 10 fractions to the whole brain, our techniques were able to reduce the EQD2
received by 40% of the bilateral hippocampi (D40%) to approximately 4.6 to 5.4 Gy by use of helical tomotherapy and to approximately 7.1 to 7.5 Gy by use of linear accelerator-based IMRT (). Importantly, these values do not significantly exceed the D40% threshold of 7.3 Gy and are considerably lower than the
to 40% of the bilateral hippocampi of 14.9 Gy established by this prospective observational study, implying that modern IMRT techniques may achieve sufficient hippocampal sparing to potentially prevent radiation-induced memory impairment. We seek to explore this hypothesis through prospective trials of hippocampal sparing during cranial irradiation. One such trial, RTOG 0933, is a multi-institutional Phase II clinical trial of hippocampal avoidance during WBRT in patients with brain metastases. In addition to serving as a feasibility study, RTOG 0933 also seeks to make a statistical comparison of impairment in Hopkins Verbal Learning Test (HVLT)-delayed recall in patients receiving hippocampal avoidance during WBRT with a historical control of patients who received WBRT without hippocampal avoidance. At the time of manuscript submission, RTOG 0933 has been activated and is currently enrolling patients.
Fig. 2 Dose–volume histogram for hippocampal avoidance during whole-brain radiotherapy using (A) helical tomotherapy and (B) linear accelerator–based LINAC-based IMRT. Modified from (6) to include equivalent dose in 2-Gy fractions (assuming α/β (more ...)
The selective effects of cranial irradiation on list-learning delayed verbal recall have been described in previous clinical trials of cranial irradiation. These trials have used the Hopkins Verbal Learning Test-Revised, which is similar in construct to the Wechsler Memory Scale-III Word Lists test, inasmuch as both involve multiple trials of new learning of a 12-item word list followed by delayed free recall. For instance, Chang and colleagues conducted a single-institution Phase III trial of stereotactic radiosurgery (SRS) with or without WBRT in patients with one to three brain metastases. That study was halted because of an interim observation of a twofold increase in the mean posterior probability of impairment in HVLT-delayed recall (52% SRS + WBRT vs. 24% SRS alone) (14
). RTOG 0214 was a Phase III trial of prophylactic cranial irradiation vs. observation in locally advanced non–small-cell lung cancer. Despite not reaching target accrual, this trial also demonstrated a significantly greater decline in HVLT-delayed recall in the prophylactic cranial irradiation arm at 3, 6, and 12 months follow-up (15
High death rates and noncompliance with NCF testing at long-term follow-up have prevented these clinical trials from providing data on the long-term memory effects of cranial irradiation. Our study encountered similar challenges: compliance with 18-month follow-up NCF testing was 62% among experimental patients and 50% among healthy control individuals. An 18-month interval was selected in our study to avoid focus on short-term adverse cognitive changes; instead, we attempted to identify more long-standing and likely fixed cognitive declines. The complication of such a long test–retest interval is the potential inability to maintain compliance by the research participants. Importantly, baseline characteristics did not differ between patients who were compliant and those who were non-compliant with the 18-month NCF follow-up. However, because of the limited sample size, the results could not be adjusted for multiple testing of correlations and therefore should be considered preliminary at this point.
In addition, we unexpectedly observed impairment in working memory, as assessed by the Letter-Number Sequencing and Spatial Span tests, in a third of patients treated with FSRT. Douw and colleagues have similarly demonstrated long-term impairment in working memory after cranial irradiation for low-grade gliomas (16
). Working memory, as originally conceived by Baddeley’s model, has been shown to be independent of the hippocampus and related temporal lobe structures (17
). In that regard, the absence of correlation between impairment in working memory and hippocampal radiation dose in our study is not surprising. However, radiation dose to other regions of the brain such as the prefrontal cortex and striatum may play a role, and efforts are ongoing to explore these hypotheses (18