Discussion
extracranial disease, tumor, fatigue, MCI, SRS
PRIMARY TUMOR, DISEASE, TUMOR
At pre-GKRS, and 6 and 12 months after treatment, patients experienced significantly higher fatigue, on all aspects, compared to Dutch controls. At 21 months, patients only experienced significantly higher general and physical fatigue compared to Dutch controls. This may be explained by the more favorable characteristics of the long-term survivors, or due to statistical power issues (as the power at 21 months ranged between 0.09 and 0.87 for the five fatigue subscales).Over the span of 21 months, physical fatigue increased, whereas mental fatigue decreased significantly, while the other aspects of fatigue did not change. For the intervals, there was a significant increase between pre-GKRS and 3 months in general and physical fatigue followed by stable scores. For the long-term survivors, a significant decrease in mental fatigue was found over the span of 21 months while none of the domains significantly increased. The long-term survivors also showed a significant increase in physical fatigue between pre-GKRS and 3 months specifically, which remained stable thereafter.At the individual level, most patients (52.2%) had an MCI increase in physical fatigue between pre-GKRS and 3-months, followed by stable/decreased scores (58.8%–69.8% across intervals). For the other fatigue scales, most patients had stable/decreased fatigue scores across intervals (50.7%–79.2%). However, still 20.8%–49.3% of the patients experienced an MCI increase in fatigue over the different intervals.These group level results are very similar to the results in our prior study (Verhaak et al. An MCI increase in general or physical fatigue in the first three months after GKRS, but not pre-GKRS fatigue, predicted significant reductions in survival time, independently of significant clinical prognostic characteristics. Patients with an MCI increase in general fatigue and physical fatigue had a 39% and 44% decrease in overall survival time respectively, as compared to patients with stable/decreased fatigue scores. Considering similar KPS, similar primary tumor histology, and early increased (versus stable/declined) fatigue, absolute differences in median survival times were 10 to 12 months. This is substantial considering the overall poor prognosis for patients with BM.In this study we included baseline predictors of survival in addition to fatigue. However, we emphasize that fatigue might be best viewed as a prognostic indicator, based on patients’ subjective experience, as opposed to an independent risk factor. There may be other factors, such as extent of disease or systemic treatment, that might influence the relation between an MCI increase in fatigue and survival. For example, tumor burden and/or progression can induce inflammatory processes (including changes in cytokine levels) and dysregulation of the hypothalamic–pituitary–adrenal axis (Ahlberg et al. Missing data are a common challenge in studies using longitudinal patient-reported outcomes, especially when survival is short and the pattern of missing data is likely related to disease status (Leung et al. A limitation of this study is that our patient group might have been less fatigued and in better clinical condition than the general group of patients with BM selected for SRS, as they were willing to participate in a time demanding study. Second, patients may have experienced additional fatigue due to stress at the day of completion of the questionnaire as compared to daily life that may impact their ratings. However, most increase in fatigue was reported in the physical domain, while mental fatigue and motivation domains may be more susceptible to stress.Further research is needed to disentangle the relationship between fatigue and intra- and/or extracranial disease status and survival in patients with BM. However, assessment of extracranial disease status is complex due to different follow-up protocols (diagnostic tools and scan intervals) across hospitals (Nieder and Mehta Up to 21 months after GKRS, feelings of fatigue were present for all different fatigue aspects for a substantial part of the patients, indicating that fatigue is a serious and persistent symptom in these patients. Furthermore, an increase in general or physical fatigue in the first 3 months after GRKS was a significant predictor of shorter survival. There should be more awareness in clinical practice of increased fatigue as potential warning signal for survival.