Management of side effects during and post-treatment in breast cancer survivors

Abstract

Cancer-related fatigue, insomnia, and cancer-related cognitive impairment are commonly experienced symptoms that share psychological and physical manifestations. One or more of these symptoms will affect nearly all patients at some point during their course of treatment or survivorship. These side effects are burdensome and reduce patients’ quality of life well beyond their cancer diagnosis and associated care treatments. Cancer-related fatigue, insomnia, and cancer-related cognitive impairment are likely to have multiple etiologies that make it difficult to identify the most effective method to manage them. In this review, we summarized the information on cancer-related fatigue, insomnia, and cancer-related cognitive impairment incidence and prevalence among breast cancer patients and survivors as well as recent research findings on pharmaceutical, psychological, and exercise interventions that have shown effectiveness in the treatment of these side effects. Our review revealed that most current pharmaceutical interventions tend to ameliorate symptoms only temporarily without addressing the underlying causes. Exercise and behavioral interventions are consistently more effective at managing chronic symptoms and possibly address an underlying etiology. Future research is needed to investigate effective interventions that can be delivered directly in clinic to a large portion of patients and survivors.

1 |. INTRODUCTION

Breast cancer is the second most common form of cancer in the United States, but advances in treatment have considerably increased the probability of survival. Currently, there are an estimated 3.1 million breast cancer survivors in the U.S.¹ Many individuals in this growing population experience burdensome physiological and psychological side effects that often begin even before treatment, worsen with treatment, and persist into survivorship. Cancer-related side effects often have detrimental effects on patients’ overall quality of life as they can interfere with activities of daily living.² Importantly, research findings have suggested that some cancer-related side effects are linked to treatment noncompliance and potentially shorter overall survival.^3–5

Cancer-related treatments, such as chemotherapy, radiation, hormonal therapy, and surgery contribute to the burden of side effects experienced by patients.⁶ Recent research findings suggest that tumor physiology itself may also play an important role in causing symptoms that are typically associated with treatment side effects, specifically cognitive deficits.^7–9 This may help explain why certain symptoms sometimes begin before any treatment is started and may compound the side effects experienced upon completion of cancer treatment. A substantial body of literature identifies commonly experienced physiological and psychological symptoms of cancer and its treatments; however, research regarding the etiologies of these symptoms is still in its infancy. In this review, we will summarize the relevant literature characterizing cancer-related side effects as well as the research on pharmaceutical, exercise, and psychological interventions that have demonstrated effectiveness in mitigating the burden of common side effects.

2 |. SYMPTOMS CO-OCCURRENCE

Some researchers and clinicians believe that cancer-related side effects among breast cancer patients typically form symptom clusters.¹⁰ A review of the literature on symptom clusters in breast cancer patients yields inconclusive results, and there is a mounting discussion that symptom clusters do not really exist in the way that we have previously operationalized them. It appears that many symptoms co-occur and exacerbate each other but do not necessarily share common etiology. When symptom clusters are discussed in the literature, they vary across studies in number, ranging from one to five identified symptom clusters. Furthermore, the quality and quantity of the symptoms in a particular cluster also differ across studies.¹⁰ Cancer stage and severity of illness may be related to the inconsistent findings of quality and quantity of the identified symptom clusters. A pooled secondary data-analysis of 154¹¹ individual breast cancer patients’ data (comprising symptom data collected from three different studies) revealed that symptom clusters change over the disease trajectory in terms of severity and type of symptom clusters. However, fatigue, cognitive impairment, and mood symptom clusters tend to persist. Furthermore, physical complaints, including headaches and muscle aches, as well as sleep difficulties are more likely to co-occur earlier in the disease stage. Two studies conducted by Trudel-Fitzgerald et al.^12,13 suggest that the intensity of symptom clusters tend to increase and vary during active treatment (chemotherapy and radiation) and decrease at the end of active treatment. Varying degrees of these symptoms tend to persist even after the treatments are completed in certain patients, highlighting the importance of identifying effective interventions, not only for patients but also for survivors.

3 |. OVERVIEW OF SYMPTOM MANAGEMENT STRATEGIES

3.1 |. Pharmaceutical interventions

Pharmaceutical interventions are typically not very effective in treating side effects of cancer that have behavioral origins, such as fatigue, cancer-related cognitive impairment, or insomnia. Medications may address the symptom itself, but not the behavior that perpetuates the symptom. One category of pharmacological interventions that show promise are nutraceuticals, such as melatonin for sleep^14,15 and omega supplementation for cancer-related fatigue.^16,17 However, many of those examined have shown limited effectiveness, such as chamomile tea.¹⁸ Importantly, some nutraceuticals can be toxic, such as kava,¹⁹ or result in withdrawal delirium and cardiac complications, as was seen with valerian root.²⁰ With so little information currently available regarding the etiology of side effects, it is difficult to identify the appropriate physiological target intervention for pharmacotherapies.

3.2 |. Psychological interventions

An alternative to pharmacological interventions for treating side effects is psychological treatments. Many of the behavioral interventions are rooted in the diathesis stress model.²¹ This model proposes a mechanism that helps explain how acute symptoms might become well-established or chronic. Spielman and Glovinsky²² postulated that certain patients have predisposing factors that make them vulnerable to the development of insomnia. For example, being female and older make it biologically more difficult for patients to sleep and predispose them to have a lower threshold for insomnia development under stress (a precipitating factor). A diagnosis of cancer and its treatment is certainly a stressor that can precipitate the development of acute insomnia. In an attempt to alleviate their symptoms patients may engage in behaviors that ultimately perpetuate their insomnia. The Spielman model provides the basis for Cognitive Behavioral Therapy for Insomnia (CBT-I). For example, a patient may start spending more time in bed or take more naps during the day in the hopes that this would reduce her tiredness or fatigue, when in fact it may aggravate her insomnia by disrupting the sleep wake and circadian cycles. Behavioral interventions target these perpetuating behaviors to reduce sleep problems and help patients develop a more regular sleep schedule. A behavioral therapist would encourage the patient to avoid compensatory techniques, such as napping during the day or lounging in bed, or would introduce stimulus control techniques, such as reserving bed for sleep and sex only to reduce the number of associations with bed that are not conducive for sleep (staying awake, worrying, watching TV).

3.3 |. Exercise interventions

The scientific community has recognized the potential for exercise to counteract many cancer-related side effects. Research has demonstrated exercise is effective in ameliorating fatigue,^23–29 improving physical functioning and fitness,³⁰ depression and anxiety,³¹ improving body image,³¹ health-related quality of life^32,33 and cognitive impairment,^34–36 and reducing inflammation^37,38 as well as other toxicities stemming from cancer treatments.^39,40 In addition, preliminary evidence points to the fact that regular exercise might confer a survival advantage,⁴¹ and it is associated with higher overall quality of life^31,42 for both cancer patients and survivors.

In 2011, the American College of Sports Medicine published public health guidelines recommending that cancer patients and survivors perform (1) 150 minutes of moderate-intensity aerobic exercise (walking, ballroom dancing, gardening) or 75 minutes of vigorous aerobic exercise per week (race walking, jogging, hiking uphill) and (2) 20–30 minutes of moderate-intensity anaerobic muscle-strengthening exercises at least twice a week.⁴³ It is important to highlight that patients and survivors should seek the advice of their oncologist and/or primary care physician before starting a new exercise routine, work with professionals who are qualified to prescribe exercise for cancer patients and survivors, and obtain individualized exercise prescriptions that account for type of cancer, disease progression, comorbidities, physical limitations, age, and other relevant factors.^28,43–45 Unfortunately, it is estimated up to 70% of breast cancer survivors do not meet these ACSM public health recommendations and do not discuss exercise with their oncology care team.^46–49 However, research shows that cancer survivors of all ages want their oncology providers to initiate discussions about exercise and make appropriate referrals timely in the treatment trajectory.^49,50 Given the benefits of exercise during and after cancer treatments, routine discussions about exercise between members of the oncology care team and cancer patients and survivors in combination with referrals to a qualified exercise physiologist could significantly improve cancer treatment adherence, side effect burden, recovery, quality of life, as well as disease-free and overall survival in breast cancer patients and survivors.

3.4 |. Complementary and alternative medicine interventions

There are reports of improvement in cancer-related fatigue from acupressure, light touch, and massage.^51–53 Polarity therapy,^53,54 (which is energy or light touch intervention), tai chi,^55–59 and yoga^60,62–67 may be effective for treating insomnia, anxiety, depression, impaired cardiovascular function, impaired muscular function, cancer-related fatigue, and quality of life. Tai chi^55–59 and yoga^60,62–67 also meet the criteria for being defined as exercise, and the interventions that have been shown to be most effective require similar metabolic energy expenditure to that of low- to moderate-intensity exercise.^{55–60,62–68} A recent review of 12 studies has shown acupunture’s positive signal for treating anxiety, insomnia, depression, and improving quality of life in cancer patients and survivors.⁶⁹ It is important to note that most of the acupuncture studies in treating side effects in cancer patients are of weak methodological quality and, therefore, are in need of replication using more sophisticated research designs, such as randomized clinical trials.⁶⁹

In the next section, we will review research on specific types of cancer-related side effects and their treatments.

4 |. CANCER-RELATED FATIGUE

Cancer-related fatigue is the most common side effect experienced by cancer patients and survivors. A remarkably high number of patients, estimated between 60% and 90%, endorse fatigue at some point during their treatment or survivorship.^70,71 The National Cancer Institute has labeled cancer-related fatigue as one of the five “first tier high priority areas for research” due to its prevalence and debilitating effects on patients’ lives.⁷² Indeed, cancer-related fatigue has been found to be more debilitating than fatigue caused by lack of sleep or exhaustion in non-cancer patients.^73,74 Cancer-related fatigue is often accompanied by other symptoms, such as anxiety and depression, pain, cognitive decline, and insomnia.^71,75 Furthermore, research has shown that cancer-related fatigue might impact patients’ compliance with medical treatments.^76,77 Multiple etiologies may account for the development and continuation of cancer-related fatigue, including hormonal, genetic, medical, inflammatory, and psychological.^78,79 In addition, tumor physiology, cancer treatments, and psychological distress may cause or contribute to cancer-related fatigue.⁷⁸ Given this complex mix of etiologic and contributing factors, there is no single successful approach to treatment of this adverse and highly prevalent symptom.

One treatment that has received increasing attention for cancer-related fatigue is gentle exercise, such as Qigong⁸⁰ and yoga.⁶⁴ A large-scale meta-analysis of 113 studies found that pharmacological interventions for treatment of cancer-related fatigue (eg, stimulant medication) showed small effects, and in fact are generally less effective than psychological interventions or exercise, or a combination of those two treatments.²⁴ Psychological intervention, such as cognitive behavioral, psychoeducational, or eclectic interventions, showed moderate effects in the treatment of cancer-related fatigue. This appears to be particularly true for survivors following primary cancer-related treatments. Notably, the combination of psychological treatment and exercise produces mixed results, with some studies showing equivalent effectiveness and with others showing inferior effectiveness as compared to delivering only one of these treatments. The authors of this meta-analysis suggested that the added difficulty and time demands of combined treatments may contribute to their reduced effectiveness in some studies.²⁴

5 |. CANCER-RELATED SLEEP DISORDERS

A vast majority of cancer patients endorse sleep problems, which can include: insomnia, sleep apnea (disordered breathing while asleep), hypersomnolence (excessive sleepiness), parasomnias (abnormal behaviors, movements, emotions, or dreams while sleeping), and sleep-related movement disorder (eg, sleep walking).^81–83 Sleep difficulties have been found to impact a number of physiological and psychological domains, including well-being and overall quality of life. A recent observational study conducted by Palesh et al.³ found that poor sleep efficiency was related to shorter survival probability in breast cancer patients diagnosed with metastatic disease.

We focus here on insomnia as it is the most common cancer-related sleep disorder. Insomnia is defined by an inability to fall asleep, difficulty staying asleep, or waking up earlier than intended. The symptoms have to occur for a minimum of 3 days per week over the period of 3 months or more. The symptoms have to contribute to distress and impairment in functioning.⁸⁴ The incidence of insomnia symptoms is second only to cancer-related fatigue. A large study of 832 cancer patients conducted by Palesh et al.⁸¹ revealed that close to 50% of cancer patients meet criteria that warrant a clinical diagnosis of insomnia (compared to 18.5% in the general population).⁸¹ An additional 35% of cancer patients exhibit at least some sleep disruption (as compared to 14.5% in the general population⁸⁵).

5.1 |. Treatments of cancer-related insomnia

Several treatments for cancer-related insomnia have been studied, including pharmacological and behavioral interventions.

5.1.1 |. Pharmaceutical interventions

Sleep is often treated pharmacologically with three potential classes of medications: (1) non-benzodiazepine hypnotics, (2) benzodiazepines, or (3) sedative antidepressants. Whereas each class of medications can have positive effects on sleep, they each have potential negative consequences that need to be considered when choosing between them. A number of non-benzodiazepine hypnotics are indicated for the treatment of insomnia, including zolpidem, zopiclone, and zaleplon (see Savard and Morin, 2001⁸³ for a review). These medications have been found to produce reliable improvements in sleep at least in the short term. The FDA recommends the use of these particular non-benzodiazepine hypnotics medications over others which include few interactions with other medications, less rebound insomnia, nonsuppression of Slow Wave Sleep (SWS), or Rapid Eye Movement (REM) sleep.⁸⁶ Although non-benzodiazepine hypnotics are generally well tolerated, they can have residual sedation and anterograde amnesia effects (no memory for information learned after the drug was initiated). Furthermore, it is important to highlight that they are not curative of the underlying causes of insomnia, and can potentially be habit forming.

Benzodiazepines including temazepam, estazolam, quazepam, and flurazepam are FDA approved and indicated for the treatment of insomnia (see Rosenberg, 2006⁸⁷ for a review). Advantages associated with benzodiazepines include their short-term effectiveness, few interactions with other medications, and a minor side effect profile due to their short-to-moderate half-life. Disadvantages include addiction potential that makes them unsuitable for long-term use; the high degree of rebound insomnia associated with stopping the medication; and suppression of SWS or REM sleep.^86,87 As with non-benzodiazepines hypnotics, benzodiazepines are not curative.

Sedating antidepressants including trazodone,⁸⁸ amitriptyline,⁸⁹ and doxepin⁸⁹ are antidepressants used to treat insomnia particularly in depressed patients. Unlike non-benzodiazepine hypnotics and benzodiazepines, antidepressants can be used in the long term, without abuse or dependency potential. Although uncommon, a number of potential negative side effects have been associated with the use of antidepressants. These include: (1) moderate hypnotic effects, (2) potential interaction with other medications, (3) cardiac side effects, (4) anticholinergic side effects (eg, dry mouth), (5) suppression of REM sleep, and (6) rebound insomnia.^89,90

Other pharmacological treatments for sleep disruption include melatonin receptor agonists, such as melatonin,⁹¹ antipsychotic medications⁹² (eg, risperidone and olanzapine⁹³), anticonvulsants (eg, gabapentin⁹⁴). Nutraceuticals (eg, valerian root⁹⁵) are also utilized by some patients for management of insomnia.

Although pharmacological interventions have been found to be effective in treating cancer-related insomnia, they are indicated for management of acute rather than chronic insomnia. In contrast, behavioral interventions have the advantage of promoting enduring changes without many negative effects.

5.1.2 |. Psychological interventions

The gold standard behavioral treatment for insomnia is CBT-I. Research studies have demonstrated that CBT-I is as effective as hypnotic medications for treating insomnia in the general population and, importantly, the benefits of CBT-I are maintained after treatment has ended. Data from numerous randomized control trials suggest that CBT-I is effective for the treatment of insomnia in cancer survivors.^96–99 CBT-I involves a combination of stimulus control behaviors (eg, teaching patients to associate their bed with sleep and sex only) and sleep restriction (eg, restricting sleep time to the actual time spent asleep). It also includes brief instructions on how to cope with cognitive distortions pertaining to sleep (eg, “if not today, then tomorrow I will sleep well”).

A modified version of CBT-I, Brief Behavioral Intervention for Insomnia (BBT-I), was developed by Palesh et al.^100–102 that is specifically tailored to meet the needs of cancer patients undergoing chemotherapy. This novel treatment addresses maladaptive coping behaviors (eg, napping, extended time spend in bed) via stimulus control and chronorehabilitation techniques (eg, behavior activation strategies for improving physical activity and light exposure, psychoeducation about circadian rhythms in cancer). It is a brief, patient-friendly treatment that can be delivered directly in the infusion center. In a pilot study with breast cancer patients undergoing chemotherapy, Palesh et al. showed feasibility and acceptability of the intervention across four National Cancer Institute Community Oncology Research Program sites.^100–102

6 |. CANCER-RELATED NEUROCOGNITIVE IMPAIRMENT

Cancer-related neurocognitive impairment is prevalent not only in cancer patients who are currently undergoing treatment, but also in survivors and patients who have not yet begun their cancer treatments. It is estimated that about 40% of cancer patients struggle with neurocognitive impairment prior to the inception of any treatments.¹⁰³ This suggests that tumor pathophysiology itself may contribute to cognitive decline. Approximately 75% of cancer patients notice diminished cognitive capacity during their treatment.¹⁰³ Similarly, 60% of cancer survivors exhibit cognitive decline after completing their treatment. Of these, 30%−40% show no improvement over time while a separate group (30%) show progressive decline over time.¹⁰⁴ The most commonly experienced cognitive deficits in cancer patients include memory loss, attention deficits, slowed processing speed, and difficulties with executive function.^{7,8,103–108}

Several potential mechanisms of action have been implicated that could contribute to the cognitive decline related to cancer and its treatments. These include: inflammatory cascades¹⁰⁹ and the direct neurotoxic effects of treatments, specifically chemotherapy-related damage to neural progenitor cells.¹¹⁰ These mechanisms ultimately result in altered brain network connectivity.^111–114 It is important to highlight that neurocognitive test scores may still fall within the normal range, due to high pre-morbid cognitive ability and/or masking of deficits by neural compensatory systems.¹¹⁵ As a result, cognitive decline is often missed in cancer patients and survivors by routine evaluation.

6.1 |. Treatments of cancer-related neurocognitive impairment

Several treatments for reversing cancer-related neurocognitive decline have shown promising effects.

6.1.1 |. Psychological interventions

Cognitive rehabilitation is a type of manualized intervention conducted in a clinic setting that aims to improve cognitive abilities needed for daily functioning, life skills, and metacognition.¹¹⁶ Components of this intervention focus on specific cognitive weaknesses such as enhancing memory, attention, remote memory, processing speed, and/or visual-spatial skills. Treatment usually begins with psychoeducation regarding cognitive deficits and then focuses on training of self-awareness, self-regulation, and cognitive compensatory strategies. An alternative treatment to the cognitive rehabilitation program in clinic is a computerized cognitive training that can be completed from home. The program typically involves adaptive independent cognitive skills practices, without compensatory strategies. It relies on computerized exercises that aim at strengthening problematic cognitive domains. Both the clinic-based and the home-based interventions have demonstrated promising improvements in cognitive functioning in cancer patients¹¹⁷ and survivors^61,118,119 and in children with cancer-related brain injury,¹²⁰ although cognitive training has shown very limited transfer to real-world skills.

Another potential type of treatment for cancer-related cognitive deficits involves neuromodulation based on real-time neurofeedback. This is a method that helps participants enhance their cognitive functioning by training them to control their own brain activity by monitoring it in real time. Preliminary research conducted with breast cancer survivors has demonstrated positive effects using electroencephalogram (EEG) neurofeedback.¹²¹

6.1.2 |. Exercise

Studies with breast cancer patients have shown improvements in cognitive functioning to be associated with exercise interventions. Patients participating in non-aerobic yoga,⁶⁵ Qigong,³⁶ and Tai Chi³⁴ have shown improvements in processing speed, memory, and executive functioning. However, national guidelines suggest that moderate- to vigorous-intensity aerobic exercise is recommended for long-term brain health.¹²² In addition, as reviews suggest^{27,28,60,123–125} most of the studies conducted to date have been limited by short follow-up periods and were conducted during or shortly after cancer therapy.

6.1.3 |. Pharmaceutical interventions

Trials of medications have shown mixed effects in reducing cognitive impairment in patients with non-central nervous system cancer. Drugs that have been investigated include psychostimulants, such as methylphenidate,¹²⁶ modafinil,^127,128 and dexmethylphenidate with mixed effects.¹²⁹ Animal studies focusing on the impact of chemotherapy on cognition have suggested promising interventions that are centered around preventing oxidative stress associated with chemotherapy, stimulating neurogenesis, and ameliorating chemotherapy-induced cognitive impairments.¹³⁰

7 |. CONCLUSIONS

Cancer-related side effects are prevalent among breast cancer patients and survivors. Pharmacological interventions can sometimes provide immediate relief but are primarily effective for short-term management of symptoms rather than providing a long-term solution. Importantly, pharmaceutical interventions do not address the underlying cause of many symptoms. Other approaches, including exercise and psychological interventions, have shown promise in alleviating symptoms with long-lasting benefits.

Both exercise and psychological interventions have potential and are in need of further randomized control trials that control for cancer-related factors that include treatments received. Gaining a better understanding of the underlying mechanisms associated with the development of toxic side effects is important for identifying and refining these types of interventions. In addition, it is important to make potentially helpful interventions more widely accessible to cancer patients and survivors. This could be achieved by conducting evidence-based brief interventions both in clinical settings through web-based platforms and via telehealth.