To our knowledge, this is the first prospective multicenter study assessing patients with malignant brain tumors over a defined period during and after application of chemotherapy and its effects on QoL and levels of depression.
In order to measure nausea, emesis and loss of appetite, we applied the expanded MASCC questionnaire, modified with a numeric rating scale and assessed nausea, emesis and loss of appetite for ten consecutive days, during the c1 and c2 of chemotherapy. Overall, the burden of CINV symptoms was moderate. Interestingly, nausea, emesis and loss of appetite appeared to develop with delay after the application of TMZ during day 1-5 in both c1 and c2. In view of the prominent delayed nausea and emesis observed in this study, it is tempting to speculate that a relevant activation of the NK1 pathway takes place supported by several clinical trials improving nausea by combining a NK1 receptor antagonist to a setron [22-24]. Shorter acting antiemetics should therefore be substituted by longer acting substances like palonosetron or through addition of a NK1 receptor antagonist like aprepitant, rolaprepitant or the fix combination of netupitant and palonosetron [25, 26]. We also observed a tendential decrease of emesis in c2 possibly as a consequence of an adjustment in antiemetic prophylaxis after c1, e.g. increase in palonosetron intake (Table 1). In view of the fact that higher levels of nausea and emesis exhibit significant intercorrelations with depressive symptoms and QoL, constant monitoring and treatment of gastrointestinal side effects seems to be crucial.
While the PHQ-9 score prior to chemotherapy indicated only minimal symptoms of depression in most patients, PHQ-9 scores of 15 or higher in single patients pointed towards moderate to severe pre-existing symptoms of depression in a specific subpopulation. After completion of c1, levels of depression increased significantly. The occurrence of undesired effects of chemotherapy like nausea and emesis or myelosuppression and infections, but also the fear of these symptoms may enhance the psychosocial burden of patients and lead to a higher level of psychological stress [27, 28]. After completion of c2, however, levels of depression decreased. This may point towards a reduced level of stress if patients acquire a certain routine when receiving treatment.
Interestingly, we observed that not only the extent of gastrointestinal symptoms was associated with a significantly higher level of depression after the respective cycle of chemotherapy, but vice versa, patients with higher baseline levels of depression experienced significantly more severe nausea, emesis or loss of appetite. It can be presumed that treatment-resistant or anticipatory nausea during chemotherapy might have psychosomatic causes to a relevant extent [29, 30].
The QLQ-C30 and BN20 questionnaire assessed prior to and after the first and second cycle of chemotherapy indicated fatigue and loss of hair, which may not necessarily have been caused by chemotherapy, but possibly was secondary to previous radiotherapy [31-33]. Interestingly, the QLQ-C30 questionnaire showed a significant increase of nausea at t1 and t2, respectively, and by such underlined the results obtained by the MASCC questionnaire. Global health significantly dropped at t1 and t2. Patients with signs of depressive mood, as indicated by a PHQ-9 score of 15 or higher, were more severely affected by decreased QoL than non-depressed patients. Global health, physical function, role function, social function, future uncertainty and fatigue were significantly impaired already prior to chemotherapy in depressed patients. In the further course of disease, these executing aspects of the patients’ lives deteriorated more markedly than in non-depressed patients. By contrast, emotional functioning, dyspnea, appetite loss, financial difficulties and headache were significantly impaired only during chemotherapy at either t1 or t2.
Due to its design, the results obtained in this pilot study should be interpreted with some caution. At first, the study is not adequately powered for the quantity of QoL parameters assessed with the EORTC QLQ-C30 and BN 20. Second, we investigated a patient series treated at different hospitals with inhomogeneous chemotherapy and antiemetic medication. While most patients received TMZ alone, some patients were treated additionally with lomustine. In addition, we cannot provide information about the consecutive development of depression, CINV or QoL beyond the first two courses of chemotherapy. Although these factors may have influenced the severity of nausea, emesis and loss of appetite, the mode of evaluation established in this study appears to be adequate and the observations on duration of gastrointestinal side effects, intercorrelation with depressive symptoms and effect on QoL seems to be robust enough to draw first conclusions.
Taken together, we observed a relevant interaction between gastrointestinal side effects of chemotherapy and depressive symptoms. CINV may be underestimated in patients with brain tumors, last longer than anticipated, and appears to be aggravated by pre-existing depressive symptoms, severely affecting the QoL of the affected patients. During treatment, CINV should be asked for thoroughly and treated with effective, long-lasting antiemetics not only to reduce gastrointestinal symptoms, but also to prevent depressive mood and impairment of quality of life.
Moreover, quality of life was impaired after initiation of chemotherapy, especially in patients suffering from pre-existing depressive mood. We therefore consider a regular screening of the extent of psychosocial burden and depressive symptoms during the course of disease, as it has become standard within German certified oncological centres, which is of major importance. Early detection and treatment of depression may not only stabilize the patient’s mood, but also prevent deterioration of gastrointestinal symptoms and of QoL.