Background
Improved cure rates and prolonged survival after breast cancer (BC) treatment have resulted in an increasing population of survivors facing varying degrees of chronic adverse effects and treatment-related symptoms.1–4 Among these, cancer-related fatigue (CRF) is extremely common and persistent.5–8 Compared with fatigue experienced by individuals without cancer, CRF is described as more intense, distressing, and less responsive to rest.9–11 Its manifestations can include generalized weakness, decreased motivation and interest to engage in usual activities or emotional lability, and diminished concentration or attention.12–14 CRF is a multifactorial symptom. Younger age, lower socioeconomic status, psychologic distress, concomitant symptoms, unhealthy behaviors such as tobacco use, inactivity, and higher body mass index (BMI) are often associated with higher risk of CRF.8,12 Multiple life domains are negatively impacted by CRF because it can interfere with normal functioning, mood, social relationships, work, sleep, and daily activities.7,10,15,16
Building on mechanisms and pathophysiology underpinning CRF, particularly an increased expression of genes encoding proinflammatory cytokines or other mediators of immunologic activation,12,17–21 some treatment strategies were tested and are now recommended. Meta-analyses, systematic reviews, and randomized trials showed that initiating or maintaining adequate levels of physical activity (PA) can improve CRF for BC survivors, both on treatment and in the posttreatment setting, by acting on the modulation of inflammatory mediators.22–26 Given its multifactorial etiology and strong link with psychologic distress level, the effect of PA on CRF may also be exerted through an action on self-esteem and depressive status.27 Engaging in an active lifestyle and sport activities can help patients with cancer improve global functionality and facilitate cognitively and psychologically demanding tasks such as health-related decision-making processes, empowering their ability to manage symptoms such as CRF. PA was suggested to work on specific skills such as improving problem-solving schemes, training attention and coping, strengthening strategy, tactics and creativity, and enhancing self or introspective processes.28 These skills can be adapted from PA experiences and transferred to a cancer and symptom management context.29,30 Reductions in CRF were also observed with psychosocial therapy that included cognitive behavioral or psychoeducational approaches targeting nonadaptive thoughts, such as catastrophizing.12,26,31
Mind–body interventions, focused on the interactions among brain, mind, body, and behavior,32 include a variety of practices, such as acupuncture, yoga, and mindfulness-based meditation, that have also been tested to treat CRF.26,33 Data from several reviews and clinical trials suggested that acupuncture may be beneficial for persistent CRF.33–40 To date, there are no data showing benefits of other complementary and alternative medicine (CAM) strategies, such as homeopathy or naturopathy, in the posttreatment setting for BC survivors.26,33,41
Regular screening, assessment, education, and appropriate treatment of CRF are considered priorities in modern survivorship care. PA and referral to psychosocial service providers are strongly encouraged to reduce CRF, especially for patients reporting at least moderate-to-severe CRF.26,33 The NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) for CRF include PA and psychosocial interventions as category 1 recommendations for CRF in patients after treatment (high-level evidence, uniform NCCN consensus that the intervention is appropriate).33 Nevertheless, large-scale data on the real-world use of recommended strategies for CRF are lacking. We aimed to describe the uptake of strategies that can help reduce CRF among patients with early-stage BC who have completed primary treatment.
Methods
Data Source
This study used data from CANTO (ClinicalTrials.gov identifier: NCT01993498); study procedures were described previously.42 Briefly, CANTO is a prospective, multicentric cohort of women with stages I–III BC designed to study BC toxicities. Patients exit CANTO at any BC recurrence (other than local) or second cancers. We used data that were collected at diagnosis and during the first and second post–primary treatment completion visits. Primary treatment included surgery, chemotherapy, and/or radiation therapy. Endocrine and anti-HER2 treatment could be ongoing. All participants provided informed consent, and the study was approved by the national regulatory and ethics committee (ID-RCB:2011-A01095-36,11-039).
Study Cohort
In the present analysis, we used data until the second posttreatment visit among 9,595 patients who entered CANTO from 2012 to 2017. Women with CRF assessment at the first posttreatment visit (n=7,902; 82.4%) were included (Figure 1).
CONSORT diagram of patient population.
Abbreviations: CAM, complementary and alternative medicine; CRF, cancer-related fatigue.
aPatients providing data on physical activity and healthcare consultations were more likely to be better educated and enrolled from larger CANTO centers, although no major differences were present compared with nonrespondents.
Citation: Journal of the National Comprehensive Cancer Network 20, 13; 10.6004/jnccn.2021.7051
CONSORT diagram of patient population.
Abbreviations: CAM, complementary and alternative medicine; CRF, cancer-related fatigue.
aPatients providing data on physical activity and healthcare consultations were more likely to be better educated and enrolled from larger CANTO centers, although no major differences were present compared with nonrespondents.
Citation: Journal of the National Comprehensive Cancer Network 20, 13; 10.6004/jnccn.2021.7051
CONSORT diagram of patient population.
Abbreviations: CAM, complementary and alternative medicine; CRF, cancer-related fatigue.
aPatients providing data on physical activity and healthcare consultations were more likely to be better educated and enrolled from larger CANTO centers, although no major differences were present compared with nonrespondents.
Citation: Journal of the National Comprehensive Cancer Network 20, 13; 10.6004/jnccn.2021.7051
Variables of Interest
Outcome Variables
Outcomes of interest were assessed at the second posttreatment visit (∼1 year after primary treatment completion).
Physical Activity
The WHO Global Physical Activity Questionnaire (GPAQ)-16 was used to assess sedentary behavior and the duration and intensity of PA.43 As per WHO recommendations, patients reporting ≥10 metabolic equivalents of task (MET) h/week qualified as sufficiently active (corresponding to 150 min/week of moderate-intensity PA or 75 min/week of vigorous PA, or an equivalent combination),43 whereas patients engaging in <10 MET h/week qualified as insufficiently active. Categories for change in PA between the first and second posttreatment visits were therefore “maintained or increased” PA (sufficiently active before and after or insufficiently active before and sufficiently active after) versus “decreased or persistently insufficient” PA (sufficiently active before and insufficiently active after or insufficiently active before and after).
Consultations With Other Healthcare Providers
Per CANTO protocol, patients were systematically asked by trained clinical research nurses during health examinations if and how many times they had consulted with one of the following providers since the first posttreatment visit: psychologist, psychiatrist, acupuncturist, or other CAM practitioner (homeopath and/or naturopath). Therefore, these types of consultations were explored as outcomes.
Independent Variable
CRF was reported at the first posttreatment visit (∼3–6 months after treatment completion) using the validated French versions of the EORTC Core Quality of Life Questionnaire (QLQ-C30) and QLQ-FA12.42,44–48 CRF was categorized as severe if patients scored ≥40 out of 100, based on previously defined thresholds of clinical importance8,49 (details provided in supplemental eAppendix 1, available with this article at JNCCN.org).
Covariates
Other variables were categorized as per Table 1.
Cohort Characteristics of Participants With Posttreatment CRF Data
Statistical Analysis
Cohort characteristics were summarized for the whole cohort and described by global CRF status at first posttreatment visit (severe vs nonsevere). Uptake of PA recommendations and other consultations was then analyzed. We used multivariable logistic regression models to evaluate the odds of maintaining or increasing PA and of participating in other consultations between the first and second posttreatment visits according to CRF status as reported at the first posttreatment visit, adjusting for age, BMI, comorbidities, anxiety and depression, education, income, tumor stage and subtype, breast and axillary surgery, chemotherapy, and center volume. Two sets of models were fit by outcome: (1) global CRF, and (2) physical, emotional, and cognitive CRF dimensions as independent variables. We used a distinct regression model for each outcome. Variations in sedentary time (continuous) were assessed using multivariable random-effect mixed models, adjusted for CRF, time, CRF-by-time interaction, and covariates.
Sensitivity analyses were performed as follows: (1) factors potentially influencing use of specific strategies (affecting ability to participate in PA or prompting other consultations) were included, particularly (a) patient-reported outcomes (PROs) such as pain (EORTC QLQ-C30), systemic therapy adverse effects, and arm symptoms (EORTC QLQ-BR23), and (b) clinician-documented toxicities such as arthralgia, myalgia, and neuropathy (CTCAE version 4.0); (2) CRF was modeled as continuous; and (3) endocrine and anti-HER2 therapy were included after removing subtype.
We hypothesized that women experiencing severe CRF would rely more heavily on strategies that are highly recommended to relieve this symptom (ie, PA and mental healthcare services delivering psychosocial interventions [NCCN category 1 recommendation]33). We also hypothesized a substantial diversity in the way these strategies are integrated in the care pathway, due to variance in circumstances and resources.33 Statistical significance was defined with a 2-sided P value of 0.017 to accommodate some multiple comparisons among primary outcomes of interest (ie, PA, psychologic, and psychiatric consultations). Acupuncture and CAM service use were considered exploratory outcomes. Statistical analysis was performed using SAS 9.4 (SAS Institute Inc).
Results
Cohort Characteristics
Among the whole cohort, the mean [SD] global CRF score was 36.2 [25.7] and 2,873 patients (36.4%) reported severe global CRF (score ≥40)8 during the first posttreatment visit. Patients with severe CRF were younger and had higher BMI, worse anxiety and/or depression scores, lower education level and/or income, worse PROs, and worse treatment-related toxicities than patients without severe CRF (Table 1). Patients reported mean [SD] scores of 33.2 [24.3] for physical, 23.3 [26.5] for emotional, and 18.0 [23.4] for cognitive CRF, whereas severe CRF was prevalent among 35.8% (n=2,814), 22.6% (n=1,776), and 14.1% (n=1,107) for each dimension, respectively (supplemental eTable 1).
Global CRF and Recommendations Uptake
Table 2 and supplemental eTable 1 describe exposure to PA and use of consultations with other healthcare providers between first and second posttreatment visits by global CRF status and by CRF dimension, respectively. Overall, 4,035 patients (64.4%) met recommendations on PA between the first and second posttreatment visits (Table 2). Patients with severe global CRF at the first visit had lower odds of meeting PA recommendations between first and second visits (60.4% vs 66.7%; adjusted odds ratio [aOR], 0.82; 95% CI, 0.71–0.94; P=.004) than those with nonsevere CRF (Table 3). Particularly, the proportion of patients maintaining sufficient levels of PA was lower among severely fatigued patients (44.0% vs 53.7% among nonseverely fatigued) (Table 2). Accordingly, sedentary time significantly increased for patients with severe CRF who were sufficiently active at the first visit, but not among those who were insufficiently active (mean change [95% CI], +0.30 [+0.03 to +0.51] and −0.07 [−0.37 to +0.22] h/d, respectively; P<.0001 for interaction) (supplemental eTable 2).
Physical Activity and Consultations With Other Healthcare Providers by Global CRF Status
Association Between Global CRF, Uptake of Physical Activity Recommendations, and Consultations With Other HCPs
There were 677 patients (9.8%) who consulted with a psychologist, 479 (6.9%) who consulted with a psychiatrist, 529 (7.7%) who consulted with an acupuncturist, and 675 (9.8%) who consulted with a CAM practitioner (Table 2). Compared with patients without severe global CRF, those with severe CRF had a slightly higher propensity to participate in a psychology (13.8% vs 7.5%; aOR, 1.29; 95% CI, 1.05–1.58; P=.014), psychiatry (10.4% vs 5.0%; aOR, 1.39; 95% CI, 1.10–1.76; P=.0064), acupuncture consultation (9.8% vs 6.5%; aOR, 1.46; 95% CI, 1.17–1.82; P=.0008), or CAM (12.5% vs 8.2%; aOR, 1.49; 95% CI, 1.23–1.82; P<.0001) (Table 3).
Table 3 presents associations of uptake of PA recommendations and consultations with other healthcare providers with demographic, clinical, tumor, and treatment-related covariates. Notably, no significant interactions between severe CRF and anxiety or depressive symptoms related to the use of either psychologic or psychiatric services service emerged. Overall, as shown in supplemental eFigure 1, among those who qualified as non-cases of anxiety or depression, rates of use of mental healthcare services were consistently almost 2-fold for severely versus nonseverely fatigued patients. For example, 12.8% versus 6.9% of them saw a psychologist and 7.3% versus 4.7% saw a psychiatrist and were non-cases of depression, respectively. However, service use rates were generally higher among patients with at least doubtful symptoms, reflecting model results. In addition, psychologic consultations were more frequent among patients without severe CRF when overt symptoms of depression were present (16.9% vs 20.2% for patients with severe and nonsevere CRF, respectively).
CRF Dimensions and Recommendation Uptake
Severe physical CRF was associated with reduced engagement in PA (aOR, 0.74; 95% CI, 0.63–0.86; P=.0001), whereas severe emotional CRF with increased odds of psychologic consultations (aOR, 1.37; 95% CI, 1.06–1.79; P=.017) and severe cognitive CRF with increased psychiatric (aOR, 1.56; 95% CI, 1.16–2.11; P=.0037) and acupuncture consultations (aOR, 1.49; 95% CI, 1.10–2.04; P=.011). No specific patterns emerged for CAM consultations (Table 4).
Association Between CRF Dimensions, Uptake of Physical Activity Recommendations, and Consultations With Other HCPs
Sensitivity Analyses
Analyses incorporating PROs and CTCAE toxicities showed some additional relevant associations, including between pain, systemic therapy adverse effects, and acupuncture use (supplemental eTable 3). Consistent results with main analyses were found modeling CRF as continuous (supplemental eTable 4) and in models including endocrine and anti-HER2 therapy as covariates (data not shown).
Discussion
We evaluated the association between posttreatment CRF and uptake of specific CRF management strategies in the year after treatment completion among patients with early-stage BC. Reporting severe global CRF was associated with reduced uptake of recommended PA levels and with a slightly higher likelihood of consultations with other healthcare practitioners during the year after CRF evaluation. Among patients with severe CRF, 40% did not adhere to PA recommendations, whereas only approximately 14% and 10% consulted with psychologists and psychiatrists, respectively, and 10% consulted with acupuncturists, similar to a nearly 13% who saw a CAM practitioner offering homeopathy and/or naturopathy strategies. There were differential associations across physical, emotional, and cognitive dimensions of CRF.
Recommendations for CRF exist for survivors in the posttreatment setting, including dedicated NCCN and ASCO practice guidelines.26,33 Our study highlights a need to optimize the implementation of available options.
Rest and limitation of physically demanding tasks are often mistakenly reported by patients and providers as strategies to relieve CRF.27 In fact, cancer survivors with CRF should be encouraged to avoid physical inactivity and to engage in any PA type, pace, and intensity to meet exercise recommendations.26,50 However, significant increments in sedentary behavior, which includes time spent sitting or reclining while at work, at home, or traveling, were present among patients who initially qualified as sufficiently active and who also reported severe CRF. Compared with patients without severe CRF, fewer of these patients maintained their initial levels of PA. Severe CRF seemed therefore to represent a major barrier to exercise in our cohort, particularly its physical dimension, which is known to have the highest correlation with global CRF.26 Other factors were previously cited as barriers for patients with cancer that prevent them from engaging in PA, including therapy-related symptoms, higher BMI, more severe depression, and financial difficulties.27 In this study, we could also investigate the contribution of such factors to adherence with PA recommendations, which was, as expected, lower among women with higher BMI and worse depression. In contrast, symptoms such as pain and other treatment-related sequelae seemed to play only a marginal role compared with CRF, which remained significantly associated with reduced uptake of PA recommendations after accounting for all these relevant clinical and contextual factors.
Indications exist to refer cancer survivors for psychosocial interventions to address CRF.26 Cognitive behavioral therapy, by targeting dysfunctional thoughts, poor coping strategies, and alterations in sleep patterns, and psychoeducational therapies that offer information about CRF and that correct maladaptive thoughts such as overdramatizing, are capable of improving CRF significantly.51,52 In the CANTO study, the use of consultations with psychologists and psychiatrists seemed to be appropriately impacted by the presence of severe CRF. However, this observation should be discussed in the context of the strong interplay between CRF and symptoms of psychologic distress,12 because the use of mental health services is indicated for such symptoms in both the presence and absence of CRF. Severe CRF is indeed rarely isolated and often occurs as part of the somatic expression of more complex mental conditions, clustering with physical and emotional symptoms of depression and anxiety.26,53,54 Particularly, CRF can represent a symptom of depression, but it might also determine precipitation of a depressed mood by interference with regular functioning and activities.12 In our models, we tried to isolate the contribution of CRF and psychologic distress as drivers of use of psychologic and psychiatric services, showing an independent association with CRF, regardless of adjustment for anxiety and depression levels, with nonsignificant interaction terms. We acknowledge that statistical controls may not be able to fully disentangle this relationship. Use of mental healthcare services was substantially more common if patients reported at least doubtful symptoms of emotional distress, and psychologic support was more frequently used in the absence of severe CRF by patients qualifying as having clinically diagnosed depression. Furthermore, strategies adopted for CRF in our study were strongly correlated with specific symptom dimensions, with psychologic consultations being more commonly used by women with severe emotional CRF complaints (ie, frequently reporting “feelings of helplessness” or “frustration” [EORTC QLQ-FA12]). We may therefore assume that what we are observing is also part of the pattern of referral to mental health services among women with a history of BC who experience actual mood disorders, struggling with clinically meaningful symptoms of psychologic distress in addition to severe CRF.
Nevertheless, our data also speak to the fact that only a minority of women were reported to have seen a mental healthcare provider (9.8% and 6.9% saw a psychologist or psychiatrist, respectively), similar to the 10% rate reported among the general French population with psychologic distress.55,56 Although CANTO is an observational clinical study describing a routinely treated clinical population in which no specific efforts are made to educate patients on how to manage CRF, these data can generate several considerations. We may propose different explanations for the observed low rates of service use. First, patients and providers may be unaware of the rationale and efficacy of using psychosocial approaches to treat CRF because there is often limited attention to CRF correlates falling outside of strictly physical attributes and insufficient understanding of the applicability of approaches such as cognitive behavioral therapy outside of the context of mental or mood disorders.57–60 Second, socioenvironmental pressure persists, building on negative stereotypes and prejudicial beliefs toward mental health services.61 Patients could be hesitant to seek psychosocial support or may be inclined to underreport use. For similar reasons, the referral may occur quite late, when patients are already experiencing severe CRF or overt emotional distress symptoms, and not up front, during the organization of the posttreatment survivorship care plan. This may urge a paradigm shift. When needed, patients with BC should be promptly referred to psycho-oncologic services, and psychotherapists should be included in the multidisciplinary discussions as early as possible. The involvement of general mental healthcare from services in the community should also be considered. Stigmatization may also exert a differential impact on attitudes toward access to psychologic versus psychiatric services. Caregivers, patients, and their families seem to tend to first approach less-stigmatizing health professionals, such as psychologists (but also neurologists and general practitioners), further delaying help-seeking, and resourcing poorly particularly to psychiatrists.61–63 Education on the availability of mental health services to manage CRF should target both providers and patients,33,61 in effort to reduce the stigmatization associated with prevention and management of mental conditions and psychologic distress that can consequently translate into severe CRF symptoms. Third, to increase use rates of psychosocial services among patients with CRF, more work is also needed to move toward the establishment of an improved (and less paternalistic) patient–physician partnership model. This model should promote a more active involvement of patients along the care pathway, supporting a systematic assessment of CRF and other patient-reported symptoms and using tools to monitor psychoemotional status and availability of coping resources, eventually serving as a shared decision aid to trigger timely and effective participation of patients in consultations with mental health specialists.64,65 Finally, psychologic therapy comes with nonreimbursed out-of-pocket costs for patients during posttreatment follow-up in France, representing an additional relevant barrier.
Acupuncture can also be helpful for patients with CRF.26,33 Nevertheless, only one-tenth of severely fatigued survivors reported participation in posttreatment acupuncture sessions, with pain and other systemic therapy-related effects (particularly related to receipt chemotherapy, as captured by the EORTC QLQ-BR23) also emerging as significant associations with its use. In contrast, we observed very consistent associations linking severe CRF with subsequent consultations with CAM practitioners offering homeopathy and/or naturopathy, similar to findings of other CANTO analyses from our group.66 Patients in the CANTO study reported an interest in strategies for which we have robust evidence, such as psychotherapy, at roughly the same rates as they did for these CAM approaches that lack solid efficacy data and therefore should not be recommended for CRF in the posttreatment setting.41
Some study limitations should be acknowledged, including risk of misreporting, recall bias, and residual Hawthorne effect, because the “awareness of being observed” could affect reported or actual PA among individuals who are cognizant to be on study. Nevertheless, as previously observed, this effect is minimized by the long-term observation and data collection.67 Furthermore, use of specific mind–body strategies, including yoga and mindfulness approaches, was not granularly documented in CANTO. We also acknowledge that CAM therapies encompass a broad range of practices,41 not limited to homeopathy and naturopathy, which we grouped under this definition upon data availability in CANTO. The reason for consultation of healthcare providers and information about decision-making actors of referral plans was not collected in this observational study. Sensitivity analyses correcting for healthcare settings could not be performed (eg, academic vs general hospital), because center of care is not identifiable by law. However, we assessed the volume of patients enrolled by center to address this limitation. Patients were mainly included from reference facilities in centralized cancer care systems and urban areas; therefore, this analysis may mirror practice at larger centers. Nevertheless, this further stresses the need for better CRF care plans, which currently do not seem to be optimally implemented even at facilities exclusively focused on cancer care. Referral patterns and uptake of recommendations may be impacted by the availability of PA programs and mental health services and by access- and cost-related issues within different healthcare systems outside of France. However, our results should be generalizable to other countries with equivalent systems.
CANTO has a number of strengths that we want to highlight. It represents an unparalleled effort in the modern survivorship research arena, and is one of the largest longitudinal studies of women with early BC worldwide addressing complex and multifaceted issues.42 Specific to the present analysis, a wealth of medical, patient-reported, CRF, and healthcare strategy data made CANTO a unique dataset to explore CRF-related questions. CRF was extensively evaluated using a unidimensional scale (QLQ-C30, which is brief and easy to use, mostly capturing the physical impact of CRF), complemented with a multidimensional scale (QLQ-FA12) incorporating emotional and cognitive impacts. Completion rates were high at time points of interest. Finally, several sensitivity analyses confirmed the robustness of our findings.
Conclusions
CANTO data show that, among many posttreatment BC survivors complaining of severe CRF (nearly 1 in 3), strategies that could help improve their condition, such as adhering to exercise guidelines or use of psychosocial services, risk being largely underused or not optimally implemented. Concomitantly, there seems to be a nonnegligible interest in non–evidence-based CAM approaches, such as homeopathy and naturopathy. Personalized survivorship care plans can help optimize the use of strategies to improve a highly prevalent condition such as CRF while patients transition from their primary care into long-term follow-up. Better coordination of care among oncologists, exercise specialists, and other supportive care providers, as part of an integrated CRF management team that also involves community-based services, is needed to improve patient education and provide adequate guidance to alleviate CRF, a complex syndrome with substantial downstream impact.
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