Regression After Whole-Brain Radiation Therapy for Brain Metastases Correlates With Survival and Improved Neurocognitive Function

Jing Li Journal of Clinical Oncology, Vol 25, No 10 (April 1), 2007: pp. 1260-1266

Purpose: Brain metastasis (BM) is a major cause of suffering and health costs in cancer patients. Whole-brain radiation therapy (WBRT) offers tumor shrinking and palliation in many cases, but it has been speculated that these benefits may be outweighed by adverse effects on neurocognitive function (NCF).

Patients and Methods: Two hundred eight BM patients from the WBRT arm of phase III trial PCI-P120-9801 evaluating motexafin gadolinium were analyzed. NCF, assessed by tests of memory, executive function, and fine motor coordination, was correlated to magnetic resonance imaging–measured BM volume. NCF and survival were compared in 135 patients assessable at 2 months with tumor shrinkage below (poor responders) and above (good responders) the population median (45%). Mean NCF scores and BM volume at 4 and 15 months were compared.

Hippocampus avoidance with intensity modulated radiotherapy via helical tomotherapy.

Results: Good responders experienced a significantly improved survival (unidirectional P = .03). For all tests, the median time to NCF deterioration was longer in good compared with poor responders, with statistical significance seen for Trailmaking B (executive function), and two Pegboard tests (fine motor). In long-term survivors, tumor shrinkage significantly correlated with preservation of executive function and fine motor coordination (r = 0.68 to 0.88). During the early follow-up period, the population mean NCF scores were dominated by patients with progressive disease. A small subset of 15-month survivors had stable or improving scores, and greater mean BM reduction.

Conclusion: WBRT-induced tumor shrinkage correlates with better survival and NCF preservation. NCF is stable or improved in long-term survivors. Tumor progression adversely affects NCF more than WBRT does, thus making enhancement of radiation response a worthwhile aim in this patient population.

Although deterioration of QOL and memory in BM patients receiving WBRT has been reported, no prospective randomized studies have specifically teased out the roles of tumor progression compared with WBRT in terms of their effect on NCF. Multiple factors may contribute to NCF deterioration in BM patients: disease progression, radiation, surgery, chemotherapy, medications, or paraneoplastic effects. In this regard, our results show that better control of intracranial disease by WBRT is associated with stabilization and improvement of NCF, indicating that, at least in this population, studied for up to 21 months, the beneficial effect of tumor regression from WBRT on cognition outweighs its potential harm, and disease progression is the main contributor to neurologic decline. These results are consistent with a previous report from the same trial that showed that neurocognitive decline correlates with tumor growth.To our knowledge, our report is the first prospective study that has used a validated and comprehensive NCF tool to fully explore the correlation between preservation of NCF and WBRT-induced tumor volume reduction in BM patients.

An interesting finding from our studies is that patients who demonstrated good radiologic response to WBRT had improvement in their executive function and fine motor coordination, but not memory, although even for this, the trends were in the right direction. This suggests that WBRT, although improving certain aspects of cognition by reducing intracranial tumor burden, may not improve memory to the same extent, and one possible explanation for this is that WBRT might specifically impair hippocampus-related functions such as memory and learning. In rats, a dose as low as 2 Gy can reduce proliferation of neural precursor cells isolated from hippocampi, but not those from whole brain. Therefore, radiation techniques that spare hippocampus or agents that prevent hippocampal damage may help to preserve memory and to reduce the risk and severity of radiation-induced dementia. Our group is currently investigating specific conformal avoidance techniques to reduce radiation doses to the hippocampus during WBRT. With intensity-modulated radiation therapy, especially tomotherapy, it is possible to create dose distributions that deliver the full prescribed dose to the majority of the brain, while keeping the radiation dose to the hippocampus relatively low.

QOL has become an increasingly important end point in addition to conventional measurement of survival in cancer trials. Although it is commonly speculated that deterioration of NCF in BM patients who receive WBRT will negatively influence QOL, few retrospective or prospective studies have explored the relationship between NCF and QOL in this population. In trial PCI-P120-9801, QOL was monitored on a regular basis, and our preliminary analysis has shown that NCF and QOL were correlated in this patient population, suggesting that any efforts to delay NCF decline may help to preserve QOL and, therefore, improve overall patient care.

In summary, we report that WBRT-induced reduction in total BM volume is correlated with improved survival and delay in NCF deterioration. Our study supports the use of techniques to maximize intracranial control, such as WBRT in BM patients. Future study directions include identifying patients who are most likely to respond to WBRT, further exploration of the relationship between NCF and QOL, investigating hippocampus-sparing WBRT, and testing of neuroprotective agents. Also, the relative weighting of WBRT and localized RT should be investigated as a function of the number and size of metastasis at presentation.