Innovation in the Treatment of Insomnia in Breast Cancer Survivors

In this issue of the Journal, Zachariae et al. present a randomized controlled trial among breast cancer survivors with insomnia, comparing an Internet‐delivered cognitive behavioral therapy for insomnia (iCBT‐I) with a waitlist control (1). Outcomes were assessed via the Internet, including insomnia severity, sleep quality, and fatigue, as well as sleep diaries over two weeks. The active intervention, iCBT-I, showed robust improvements in insomnia severity and sleep quality, and also reduced daytime symptoms of fatigue, with effects maintained over a six-week follow-up.

The importance of these results is several fold. Cancer survivors commonly report sleep disturbance (2), and breast cancer survivors show a prevalence rate of insomnia that is twice that found in the general population (3). Insomnia has substantial clinical implications in cancer survivors. Indeed, an expanding literature suggests that persistent sleep difficulties in cancer survivors lead to daytime impairments, reduce quality of life, contribute to cancer-related fatigue and depression, increase inflammation, and contribute to reduced survival, possibly by altering tumor progression (4). Treatments that target insomnia that can be implemented and disseminated for the growing number of cancer survivors are needed.

As the authors explain, CBT-I is the recommended first choice treatment for chronic insomnia (5), with effects comparable or superior to those found for pharmacotherapy (6). However, awareness of this therapy and its efficacy remains low among oncologists and patients. Furthermore, CBT-I is typically delivered face to face, which limits access, especially in cancer care settings, due to the lack of trained clinicians and to the expense of this behavioral intervention. Given this context, the positive results of this randomized controlled trial are even more compelling, as iCBT-I overcomes barriers of access to provide an innovative method for dissemination of an efficacious insomnia treatment to cancer survivors.

There are some important methodological aspects of the study by Zachariae et al. (1) that warrant discussion. Meta-analytic findings have demonstrated the efficacy of face-to-face-delivered CBT-I in cancer survivors (7), and two systematic reviews have found that iCBT-I is also effective in the treatment of insomnia in adult populations (8,9). However, for the vast majority of prior randomized controlled trials, iCBT-I has been evaluated in relation to an inactive waitlist or treatment as usual comparison arm. Without an active comparator arm, such as sleep hygiene education, it is not known whether the benefits of iCBT-I, as shown by Zachariae et al. (1), might be due in part to nonspecific expectations. A further question concerns the comparability of iCBT-I to face-to-face CBT-I; to date, only one study has evaluated whether iCBT-I is noninferior to CBT-I in the treatment of insomnia in adults (10), and no study has examined this question in cancer survivors, nor tested whether iCBT-I is as durable in the long-term maintenance of insomnia remission as face-to-face-delivered CBT-I. Finally, it also critical to consider other end points aside from sleep improvements (6). Insomnia impacts functioning during the day, and this study found improvements in fatigue but did not evaluate outcomes of psychological distress, depressive symptoms, sleepiness, or quality of life. Because breast cancer survivors show an increased prevalence of depressive symptoms and depression for years after diagnosis and treatment (11) and insomnia is an independent risk factor for depression (12), further research is needed to evaluate whether iCBT-I might also improve depression and other domains of daytime functioning with the potential to prevent incident or recurrent depression in cancer survivors.

Given that distress is associated with cancer diagnosis and treatment and is thought to precipitate and perpetuate insomnia (13), other innovative “outside the clinic” approaches that target stress mechanisms may also have a role in the treatment of insomnia. Such scalable and community-accessible treatments include mind-body interventions such as mindfulness meditation and movement meditations such as tai chi, which already show a high level of acceptance in community samples and cancer survivors; among breast cancer survivors, up to 50% report annual use of meditation or tai chi to promote health (14). An emerging literature now suggests that these mind-body interventions show efficacy in the treatment and possibly prevention of insomnia. Indeed, in older adults who have subsyndromal insomnia, mindfulness meditation was found to produce improvements in outcomes of sleep, depression, and fatigue as compared with an active comparator sleep hygiene education, with effect sizes comparable to gains found with CBT-I (15). Moreover, in breast cancer survivors, tai chi has been found to yield robust rates of insomnia treatment response, with nearly complete remission of insomnia symptoms (16), which were noninferior to CBT-I. Tai chi and CBT-I also showed equivalent improvements in outcomes of daytime functioning including depression, fatigue, and sleepiness. Importantly, these gains were durably maintained over a year of follow-up (16). Similarly, a mindfulness-based stress reduction treatment was found to be noninferior to CBT-I in the treatment of insomnia among a heterogeneous sample of cancer survivors, although noninferiority was found only at five months of follow-up (17).

Persistent insomnia is a risk factor for mortality, as well as adverse cancer, cardiovascular, and mental health outcomes (4). Hence, one of the most exciting challenges is to evaluate whether treatment of insomnia improves long-term health outcomes, and such research can now be feasibly implemented using one of several community-accessible interventions given that these treatment approaches can be adequately scaled to detect benefits for cancer-related and other outcomes. An extension of this line of work focuses on the adverse trajectories of mechanisms of disease risk, namely inflammation and cellular aging, with evidence that markers of inflammation (C-reactive protein) and cellular aging (ie, telomere shortening) predict cancer incidence, cardiovascular disease, and earlier mortality (4). Insomnia is shown to be associated with increases in inflammation (18), as well as activation of inflammatory signaling (19–22), accelerated telomere erosion (23), epigenetic aging (24), and promotion of other cellular aging dynamics. Importantly, interventional strategies that target insomnia are being found to alter the course of these biological mechanisms of aging, and both CBT-I and mind-body interventions reverse cellular and genomic markers of inflammation (4,25,26). Hence, targeting sleep may represent a third lifestyle pillar, along with diet and physical activity, to promote health.

In summary, Zachariae et al. show that an Internet-guided, self-care intervention, iCBT-I, improves sleep outcomes and fatigue in breast cancer survivors (1). An opportunity for the future will be to establish whether the gold standard treatment for insomnia, CBT-I, or other strategies commonly used in the community to prevent and treat insomnia, can effectively reduce the long-term morbidity associated with sleep disturbance in cancer survivors.

Note

Affiliations of author: Cousins Center for Psychoneuroimmunology, Semel Institute for Neuroscience and Human Behavior, Department of Psychiatry and Biobehavioral Sciences, David Geffen School of Medicine, University of California, Los Angeles, CA.

The author has no conflicts of interest to disclose.

References

Author notes