This study represents the first use of the complete set of proposed criteria for identifying patients with CRF in a large sample of patients with cancer who have recently completed a course of adjuvant therapy. Prior research has used only a subset of the proposed criteria9
or has applied the full set of criteria in a sample of limited size.10
Of our sample, 26% met full criteria for CRF at the conclusion of the initial course of adjuvant therapy. Our CRF prevalence rate of 26% is a bit higher than the 17% to 21% rates found in prior research with cancer survivors.9,10
However, one would expect a higher prevalence of CRF in those who have recently completed adjuvant therapy, particularly because adjuvant chemotherapy was a risk factor for developing CRF in the current study. Importantly, although only 10% and 26% of respondents met the full set of CRF criteria at the baseline and post-treatment assessments, respectively, 37% and 54%, respectively, acknowledged a 2-week period in the preceding month during which they had experienced significant fatigue or a lack of energy every day or nearly every day (first part of criterion A). Clearly, use of the full set of CRF criteria identified a much more restricted set of cases of significant fatigue.
Although 20% to 25% of our sample evidenced CRF for the first time at the conclusion of adjuvant therapy, CRF was also evidenced in the immediate postsurgical period. Approximately 10% of our sample met criteria for CRF at the baseline assessment, before adjuvant therapy. CRF in the postsurgical period could stem from tumor-related factors or the physical and psychological stresses associated with surgery and a diagnosis of malignant disease. Further study of postsurgical CRF is merited. Although half of the cases of postsurgical CRF resolved by the post-treatment assessment, the remaining half persisted. Whether persistent CRF is associated with greater risk for subsequent “off treatment” fatigue27
is a significant question. Further follow-up is necessary to characterize the long-term trajectory of this early-onset and persistent CRF. It is unknown whether early identification and management of CRF before adjuvant therapy might reduce risk for CRF later in the disease trajectory.
Our hypotheses regarding factors predictive of CRF development were largely supported. In both univariate and multivariate analyses, both a tendency to catastrophize in response to fatigue and receipt of adjuvant chemotherapy were associated with incident CRF at the post-treatment assessment. Relative to women who received adjuvant radiotherapy, women who received adjuvant chemotherapy were more than twice as likely to develop CRF over the course of therapy (OR = 2.23). Likewise, each one-point increment on our measure of Fatigue Catastrophizing was associated with a 14% increase in risk for developing CRF over the course of adjuvant therapy (ie, OR = 1.14). Thus, a difference of six points in Fatigue Catastrophizing scores between two women (OR = 2.19) would represent an increase in risk for developing CRF approximately equivalent to the risk conferred by receipt of adjuvant chemotherapy (OR = 2.23).
Support was weaker for our hypotheses regarding the relationship of CRF to other coping variables. Scores on the IMQ Accommodating to Illness and Focusing on Symptoms subscales were associated with CRF incidence in the univariate analyses. As hypothesized, a tendency to cope with chronic illness by accommodating to one’s illness was associated with reduced risk for developing CRF. Conversely, a greater tendency to cope with chronic illness by focusing attention on one’s symptoms was linked to greater risk for developing CRF in the univariate analyses, although neither variable was significantly associated with CRF incidence or prevalence in the multivariate analyses. The failure to obtain strong support for our hypotheses regarding IMQ subscale scores and risk for CRF is probably due to the generic nature of the IMQ. In contrast to our measure of catastrophizing, the IMQ assesses coping tendencies with respect to illness in general, rather than fatigue in particular. This lack of specificity of measurement with regard to how women coped with fatigue in the context of breast cancer limits the predictive power of the IMQ with regard to subsequent prevalent or incident CRF. More specific measurement of tendencies to focus on fatigue symptoms and to cope with fatigue symptoms through accommodation might have yielded stronger support for our hypotheses.
Considered together, our results suggest that development of CRF may be linked to coping behaviors. Catastrophizing in response to fatigue symptoms, evidenced by a tendency to react to fatigue with negative self-statements and negative thoughts about the future regarding fatigue, was linked to increased risk for developing CRF. In addition, the development of CRF was linked in some analyses to a tendency to accommodate to illness by organizing and planning one’s life to avoid stress and overexertion (decreases risk) and a tendency to focus on symptoms, as evidenced by a preoccupation with symptoms accompanied by appraisals of helplessness and of one’s life being dominated by illness (increases risk). Although some might question the credibility of a diagnosis of CRF given these links to cognitive and behavioral variables, such skepticism is unwarranted. CRF criteria define a complex of symptoms of a specific duration that have a significant impact on daily functioning. No assumptions about etiology are implied, other than that the observed fatigue is a likely consequence of cancer or cancer therapy. Furthermore, it is well recognized that cognitive and behavioral factors play a prominent role in the development and maintenance of chronic pain,28,29
a syndrome to which CRF has been compared. Consequently, the fact that cognitive and behavioral factors may play a similar role in CRF should not impugn a diagnosis of CRF. Assuming that cognitive and behavioral factors contribute to CRF development, our results suggest that interventions using cognitive-behavioral techniques might be effective in the management of CRF.3,30
We observed a significant relationship between major depressive disorder and CRF. Of patients with CRF at the post-treatment assessment, 17% also met criteria for a concurrent diagnosis of major depressive disorder. In contrast, only 2% of patients without CRF did so. It should be noted, however, that although a concurrent diagnosis of major depression was significantly more likely in women with CRF, more than 80% of patients with CRF did not meet criteria for a major depressive disorder. Although some overlap between symptoms of fatigue and depression may be the norm in the cancer setting,31
only a minority of women with CRF also presented with a diagnosis of major depression. Thus, routine use of antidepressant therapy for managing CRF is probably inappropriate. Furthermore, whereas CRF criteria acknowledge potential comorbidity between CRF and major depression, criterion D for CRF requires determination of whether fatigue symptoms are primarily attributable to a comorbid psychiatric disorder, such as a major depression, or to cancer diagnosis and treatment. This can be difficult, but Cella et al8
have suggested means for making this distinction. They suggest that fatigue attributable to cancer diagnosis and treatment tends to be characterized by less prominent cognitive symptoms, onset coincident with cancer diagnosis and treatment initiation, greater synchronization of symptoms with receipt of adjuvant therapy, and little diurnal fluctuation in symptoms.
The relationship between depression and CRF was further demonstrated in the significant univariate relationship between a history of major depressive disorder and prevalent and incident CRF at the post-treatment assessment. Why a prior major depressive disorder might be associated with enhanced risk for CRF is unclear, although a history of major depressive disorder is considered a predisposing factor for psychological morbidity after cancer diagnosis and treatment.32
In some patients, major depression and CRF might share a common biologic substrate. Alternatively, major depression and CRF might both be linked to poor coping skills or an unsupportive social environment. The mechanism(s) underlying a link between history of major depressive disorder and CRF merit exploration and an individual’s history of depression should be routinely considered in developing an appropriate clinical management plan.
The proposed criteria for defining CRF represent clinical criteria, developed by a panel of experts. Although these criteria can be applied reliably to identify CRF,10
their scientific utility is still being established. The proposed criteria might even require some revision as research data accumulate. In this study, use of the proposed criteria resulted in identification of a set of cases of severe and prolonged fatigue, associated with significant functional impairment, and primarily caused by cancer diagnosis and treatment and not comorbid psychiatric disorder. Most significantly, application of these criteria resulted in identification of groups of patients with CRF and those without that differed profoundly on an array of self-report indices of current QOL and functional status often associated with fatigue. In all instances, group differences greatly exceeded the threshold of 0.5 SD often used to characterize group differences on health status measures as clinically “important” and/or “meaningful.”33–36
Limitations of this study should be noted. Although women with certain comorbidities linked to significant fatigue symptoms (eg, AIDS, multiple sclerosis) were excluded from study, we did not assess physical comorbidity in our sample. Such comorbidities can affect the experience of fatigue and ideally should be included as control variables in future analyses comparing patients with CRF and those without. In addition, we did not assess fatigue in women with breast cancer treated with surgery alone (no adjuvant therapy) or in a comparison group of healthy women without breast cancer. Obviously, criterion C for CRF (are symptoms a consequence of cancer or cancer therapy?) would technically exclude formal diagnosis of CRF in a healthy comparison group. However, collection of information relevant to criteria A, B, and D for CRF from a healthy comparison group or women with breast cancer treated with surgery alone would place our prevalence and incidence rates for CRF in additional, suitable contexts.
In conclusion, the present study suggests that CRF is a common clinical syndrome in women with early-stage breast cancer both before after adjuvant therapy. Approximately 25% of our sample met criteria for CRF, a much lower estimate of fatigue prevalence than the 25% to 99% estimates based on less stringent definitional criteria.3
In contrast, the prevalence of CRF in our study seems to be comparable or even slightly higher than the prevalence of major depression in patients with cancer, noted to be in the 0% to 38% range.37
However, less than 20% of patients with CRF in our study evidenced a concurrent major depression, suggesting the importance of distinguishing these two syndromes. Our results also suggest CRF has a multifactorial and complex etiology. Some factors might predispose a patient to develop CRF (eg, history of major depressive disorder), others might precipitate CRF (eg, adjuvant chemotherapy), and still others might exacerbate or maintain CRF (eg, Fatigue Catastrophizing). Finally, although CRF criteria identified patients reporting profound and debilitating fatigue, the ultimate scientific value of the proposed criteria for CRF remains to be demonstrated. The proposed criteria will be valuable to the extent that they are able to identify a relatively homogeneous clinical syndrome that is empirically linked to specific physical and laboratory findings, specific etiological and maintaining factors, and ultimately specific approaches to clinical prevention and treatment.