Headache outcomes of a sleep behavioral intervention in breast cancer survivors: Secondary analysis of a randomized clinical trial

Abstract

Background: Breast cancer survivors often have persisting headache. In a secondary analysis of the Brief Behavioral Therapy for Cancer-Related Insomnia (BBT-CI) clinical trial (ClinicalTrials.gov identifier NCT02165839), the authors examined the effects of BBT-CI on headache outcomes in patients with breast cancer.

Methods: Patients with breast cancer who were receiving chemotherapy were randomly assigned to receive either the BBT-CI intervention or the Healthy EAting Education Learning for healthy sleep (HEAL) control intervention, and both were delivered over 6 weeks by trained staff. Headache outcomes and heart rate variability (HRV) were measured at baseline, 6 weeks, 6 months, and 12 months. Mixed-effects models were used to examine longitudinal headache outcomes in the groups according to the intention to treat. Principal component analysis and agglomerative hierarchical clustering were conducted to reduce 16 variables for data-driven phenotyping.

Results: Patients in the BBT-CI arm (n = 73) exhibited a significant reduction in headache burden over time (P = .02; effect size [Cohen d] = 0.43), whereas the reduction was not significant among those in the HEAL arm (n = 66). The first principal component was positively loaded by headache, sleep, fatigue, and nausea/vomiting and was negatively loaded by cognitive, physical, and emotional functioning. Agglomerative hierarchical clustering revealed 3 natural clusters. Cluster I (n = 58) featured the highest burden of headache, insomnia, and nausea/vomiting; cluster II (n = 50) featured the lowest HRV despite a low burden of headache and insomnia; and cluster III (n = 31) showed an inverse relation between HRV and headache-insomnia, signifying autonomic dysfunction.

Conclusions: BBT-CI is efficacious in reducing headache burden in breast cancer survivors. Patient phenotyping demonstrates a headache type featuring sleep disturbance, nausea/vomiting, and low physical functioning-revealing similarities to migraine.

Lay summary: Breast cancer survivors often have persisting headache symptoms. In patients with cancer, treatment of chronic headache disorders using daily medications may be challenging because of drug interactions with chemotherapy and other cancer therapies as well as patients' reluctance to add more drugs to their medicine list. Headache and sleep disorders are closely related to each other. This study demonstrates that a sleep behavioral therapy reduced headache burden in breast cancer survivors. In addition, the majority of headache sufferers had a headache type with similarities to migraine-featuring sleep disturbance, nausea/vomiting, and low physical functioning.

Keywords: behavior therapy; breast neoplasms; clinical trial; headache; sleep initiation and maintenance disorders.

Conflict of interest statement

Conflict of Interest: None.

© 2021 American Cancer Society.

Figures

Figure 1.

CONSORT Flow Diagram of the Clinical Trial. CONSORT = Consolidated Standards of Reporting Trials.

Figure 2.

Observed changes in mean headache score as measured at baseline, 1.5 months, month-6 and month-12 post-intervention for the two treatment arms: BBT-CI (blue line) and HEAL (red line). BBT-CI = Brief Behavioral Therapy for Cancer-related Insomnia; HEAL = Healthy EAting Education Learning.

Figure 3.

Principal Component Analysis plot. PC1 (21% of variability explained) showed a major pattern of variables positively loaded by headache, comorbidities such as insomnia, fatigue, poor sleep, pain, nausea/vomiting and negatively loaded by cognitive, physical, emotional functioning, better global health. PC2 (18% of variability explained) was positively loaded by RMSSD, HF, SDNN and negatively loaded by heart rate, LF/HF ratio, age. Measurements were done using the following: Insomnia, ISI/Insomnia Severity Index; poor sleep, PSQI/Pittsburgh Sleep Quality Index; fatigue, BFI/Brief Fatigue Inventory. Headache, physical function, cognitive function, global health status, and emotional function were derived from EORTC (European Organization for Research and Treatment of Cancer) questionnaire. Abbreviations: PC = Principal Component; SDNN = Standard Deviation of Normal to Normal R-R intervals; RMSSD = Root Mean Square of the Successive Differences; HF = High Frequency power; LF/HF ratio = Low Frequency to High Frequency ratio.

Figure 4.

Heatmap showing results of agglomerative hierarchical clustering analysis with dendrogram. Three major natural clusters of patients were identified as depicted by first branching of the dendrogram above the heatmap. Cluster I (58 patients, right in dendrogram) demonstrated highest levels of headache and comorbidities such as insomnia, fatigue. Cluster II (n = 50, middle in dendrogram) featured lowest HRV outcomes (SDNN, RMSSD, HF). Cluster III (n = 31, left in dendrogram) showed highest physical, emotional, and cognitive function as well as highest level of global health status and HRV. There was comparable number of patients randomized to BBT-CI (green bars) and HEAL (red bars). Abbreviations: BBT-CI = Brief Behavioral Therapy for Cancer-related Insomnia; HEAL = Healthy EAting Education Learning; ISI = Insomnia Severity Index; PSQI = Pittsburgh Sleep Quality Index; BFI = Brief Fatigue Inventory,; SDNN = Standard Deviation of Normal to Normal R-R intervals; RMSSD = Root Mean Square of the Successive Differences; HR = Heart Rate; HF = High Frequency power; LF/HF ratio = Low Frequency to High Frequency ratio.