Prognostic Role of Pre-Treatment Symptoms for Survival of Patients Irradiated for Brain Metastases

Discussion

Despite recent developments favoring the treatment with neurosurgery or radiosurgery alone, a considerable number of patients with brain metastases are still candidates for WBRT (1). When aiming to provide an individual treatment including the WBRT regimen appropriately addressing the patient's personal situation and needs, the patient's remaining lifetime should be regarded.

For most patients with a short survival time, short-course WBRT with 5×4 Gy is the preferred regimen. In a previous study of 442 patients treated with WBRT alone for more than three brain metastases, 5×4 Gy was not inferior to 10×3 Gy with respect to survival and intracerebral control (2). Grade 3 radiation-related acute toxicity rates were 9% and 6%, respectively (p=0.35). For selected patients with very limited survival prognoses, best supportive care (BSC) including corticosteroids without WBRT may be considered. In a randomized trial of patients with brain metastases from non-small cell lung cancer and very poor prognoses, BSC including dexamethasone was not inferior to BSC combined with 5×4 Gy of WBRT (9). In the WBRT group, more episodes of drowsiness, hair loss, nausea, and dry or itchy scalp were recorded. However, serious adverse events were not more common. The difference between mean quality-adjusted life-years was only 4.7 days, i.e. 41.7 days in the BSC alone group and 46.4 days in the BSC plus WBRT group. Thus, WBRT did not provide a significant benefit for this group of patients.

In patients with more favorable survival prognoses, intracerebral control and survival are also important endpoints. These patients are not uncommon, and a considerable number receive WBRT without local treatment. For example, in the study performed to create the RPA classification, all patients received WBRT without local treatment. The 236 patients of RPA class 1 (representing 20% of the entire cohort) had a median survival time of 7.1 months (5). In the study creating the GPA classification, 9% (N=102) of patients had a median survival of 11.0 months, and an additional 16% (N=168) of patients had a median survival of 6.9 months (6). Patients with longer expected survival were reported to achieve better intracerebral control and survival with longer-course WBRT including total doses >30 Gy. A retrospective study of 184 patients with favorable prognoses compared 10×3 Gy and 20×2 Gy (4). Survival rates at 1 and 2 years were 50% and 14%, respectively, after 10×3 Gy, and 61% and 30%, respectively, after 20×2 Gy. Intracerebral control rates at 1 and 2 years were 28% and 11%, respectively, after 10×3 Gy, and 44% and 20%, respectively, after 20×2 Gy.

It becomes obvious that precise estimation of a patient's prognosis is important to optimally tailor the treatment. Several major scoring tools addressing this aspect exist (5-8). However, they are relatively complex and require complete tumor staging prior to the start of treatment which may result in a considerable treatment delay. Such delay is generally not acceptable for patients with brain metastases requiring relief of their debilitating symptoms. Thus, a very simple and fast tool would be preferable, particularly for patients with a poor performance status and severe brain symptoms. This study aimed to provide such a tool, simply based on the number of significant pre-treatment symptoms. In a large cohort of 1,907 patients treated with WBRT alone, 10 major pre-treatment symptoms were recorded. The majority of patients presented with one (42%) or two (33%) symptoms. Fewer than 10% were symptom-free, and 16% of patients had three or more symptoms. On univariate analysis, the number of symptoms was significantly inversely associated with survival. However, on multivariate analysis, significance was not achieved. Thus, the number of symptoms was not an independent predictor of survival and appeared not useful for the creation of a survival score. As the survival rates of patients with 0-2 symptoms were almost identical at 3 and 6 months and still similar at 9 and 12 months, we performed an additional analysis to investigate the potential prognostic value of the number of symptoms and compared 0-2 to ≥3 symptoms. However, again the results were significant on univariate but not on multivariate analysis. When interpreting these results, one should take into account the limitations of this study, mainly its retrospective design. Retrospective studies always bear the risk of hidden selection biases. Another limitation of the study is that it has not yet been externally validated. Since all patients included in this study received WBRT alone, the results cannot be generalized to other treatments for brain metastases including neurosurgical resection alone, radiosurgery alone and such local therapies combined with WBRT.

Since the number of symptoms was not significant on multivariate analyses, we feel that it cannot replace existing scoring tools designed to predict the survival prognoses of patients irradiated for brain metastases. It may only serve for orientation. One may consider re-evaluation of the existing scoring tools after the exclusion of visceral metastases as a predictive factor to avoid the need for complete tumor staging, which often results in a delay of treatment. This may also be considered for diagnosis-specific scoring tools (10-15).

In conclusion, the number of symptoms was not an independent predictor of survival in patients irradiated for brain metastases and, therefore, cannot replace existing tools. It may only serve for orientation. Since existing tools are based on presence/absence of visceral metastases, they require complete tumor staging. Such staging may result in treatment delay, which is often not acceptable, particularly for patients requiring urgent relief of symptoms. Existing tools may be re-evaluated after exclusion of visceral metastases as an essential component in order to hopefully provide a fast-to-use survival score based on independent prognostic factors.