Identifying Melanoma Patients with 1-3 Brain Metastases Who May Benefit from Whole-brain Irradiation in Addition to Radiosurgery

Discussion

Radiosurgery-alone is commonly used for patients with a very limited number of cerebral metastases due to melanoma. Uncertainty exists regarding the question whether the prognosis of these patients can be improved with the addition of WBRT. Some physicians are concerned that adding WBRT will increase the risk of developing neurocognitive deficits.

A randomized study comparing radiosurgery-alone to radiosurgery-plus-WBRT in patients with very few cerebral lesions from various primary tumors (mostly lung cancer and breast cancer) was stopped after an interim analysis of 58 patients, because patients receiving additional WBRT were significantly more likely to show a decline in neurocognitive function at 4 months than patients assigned to receive radiosurgery-alone (1). At one year, 73% of patients in the radiosurgery-plus-WBRT group and 27% of patients in the radiosurgery-alone group had no cerebral recurrence (p<0.001). One major criticism of this trial was that neurocognitive function was not evaluated at one year. It is possible that neurocognitive function at one year was better after radiosurgery-plus-WBRT than after radiosurgery-alone, since cerebral recurrence has been identified by other authors as the primary cause of neurocognitive deficits in patients irradiated for brain metastasis.

This concept was supported by the findings of Aoyama et al. who evaluated 92 of the 132 patients of their randomized trial comparing radiosurgery-alone to radiosurgery-plus-WBRT with respect to preservation of neurocognitive function (2). At one year, neurocognitive function was preserved in 79% of patients after radiosurgery-plus-WBRT and in 53% of patients after radiosurgery-alone, respectively. The preservation rates at two years were 79% and 43%, respectively. A beneficial effect of the addition of WBRT on cerebral control has also been observed in other studies. In a retrospective study of 144 patients with 1-3 cerebral metastases from different primaries, the cerebral control rates at one year were 66% with and 51% without WBRT (p=0.015) (3). In a randomized trial, 100 patients received radiosurgery-alone and 99 radiosurgery-plus-WBRT for 1-3 cerebral lesions (4). The WBRT reduced the 2-year recurrence rates both at treated sites (31% vs. 19%, p=0.040) and new sites (48% vs. 33%, p=0.023). In both studies, the improvement in cerebral control did not result in improved survival. Due to the latter finding and the fear of WBRT-related toxicities, the treating physicians are often hesitant to add WBRT to radiosurgery in spite of the fact that it significantly improves cerebral control. The concerns regarding WBRT exist in particular in cases of cerebral metastases from melanoma, since melanoma is less radiosensitive compared to other primary tumors leading to brain metastasis and may, therefore, need higher WBRT doses than the most commonly used regimen of 30 Gy in 10 fractions. In the multivariate analyses of a retrospective study of 51 patients who received WBRT-alone for brain metastases from melanoma, doses of 40 Gy in 20 fractions and 45 Gy in 15 fractions were associated with significantly better cerebral control (p=0.020) and survival (p=0.010) when compared to 30 Gy in 10 fractions (5). Similar results were observed for patients with brain metastases from renal cell carcinoma and colorectal cancer (7-9). Such higher WBRT doses are likely associated with a greater risk of neurocognitive deficits. Furthermore, if new cerebral lesions occur after radiosurgery-alone, a second course of radiosurgery or a neurosurgical intervention may be performed as salvage therapy.

Taking into account the pros and cons regarding the addition of WBRT to radiosurgery in patients with brain metastases from melanoma, it is still not clear whether or not WBRT should be added to radiosurgery. A randomized trial has been initiated to contribute to this unanswered question (10). However, another important question is whether a more personalized approach would be beneficial to patients. WBRT may be of benefit for certain patients, whereas other patients may not benefit from such a combined approach. The decision for or against the addition of WBRT should be based on the risk of new brain metastases distant from the treated lesions. In the current study, a tool has been developed that helps estimate the risk of developing new cerebral lesions within 6 months following radiosurgery-alone. Based on two prognostic factors, number of cerebral lesions and extracranial spread, three prognostic groups with significantly different 6-month rates of freedom from new cerebral metastases were designed. Patients of group A had a 6-month rate of only 28% and are, therefore, strong candidates for additional WBRT. The 6-month rate of freedom from new cerebral lesions in patients of group B was 60%. Also in these patients, freedom from new lesions needs to be improved and WBRT should be considered. Patients of group C had a 6-month rate of freedom from new lesions of 92% and, therefore, do not likely need WBRT in addition to radiosurgery. When using these recommendations in clinical routine, one should be aware of the retrospective nature of the data used to develop this new predictive tool.

• Download figure
• Open in new tab
• Download powerpoint

Figure 1.

Freedom from new cerebral lesions: Kaplan-Meier curves of the three prognostic groups A (9 points), B (11-12 points) and C (14 points). The p-value was obtained from the log-rank test.

In summary, this new predictive tool allows the estimation of the risk of new cerebral metastases distant from the irradiated sites after radiosurgery-alone in melanoma patients. Group A (and likely also group B) patients should receive WBRT in addition to radiosurgery in order to improve the rate of freedom from new cerebral lesions. This is of particular importance also because cerebral recurrence is associated with a decline in neurocognitive function.