A comparison between long-term survivors of Hodgkin's disease and their siblings on fatigue level and factors predicting for increased fatigue

A. K. Ng1,*, S. Li2, C. Recklitis3, D. Neuberg2, S. Chakrabarti1, B. Silver1 and L. Diller3

1 Department of Radiation Oncology, Brigham and Women's Hospital; Departments of 2 Biostatistics and Computational Biology, and 3 Pediatric Oncology, Dana-Farber Cancer Institute, Boston, MA, USA

* Correspondence to: Dr A. Ng, Brigham and Women's Hospital, Dana-Farber Cancer Institute, 75 Francis Street, ASB1-L2, 02115 Boston, MA, USA. Tel.: 1-617-732-6310. E-mail: ang{at}lroc.harvard.edu


    Abstract
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Purpose: To compare the level of fatigue in survivors of Hodgkin's disease and their siblings, and to explore factors associated with increased fatigue.

Methods: Survivors of Hodgkin's disease 5 years or more from diagnosis and their siblings completed a questionnaire study. Fatigue level was measured using the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) instrument, with lower scores reflecting increased fatigue. Multiple regression models were used to identify factors associated with fatigue level in the two populations.

Results: Five hundred and eleven survivors (median age 44 years; range 16–82) and 224 siblings (median age 44 years; range 16–79) returned the completed questionnaire. The response rates were 61% and 58%, respectively. Compared with siblings, survivors were significantly more likely to report the presence of cardiac disease (26% versus 16%; P = 0.001) and hypothyroidism (65% versus 3%; P <0.001), and had a significantly lower mean FACIT-F score (40.7 and 42.2; P = 0.05). On multivariable analysis, factors significantly associated with increased fatigue in survivors were reports of cardiac disease (P <0.001), psychiatric condition (P <0.001), history of tobacco use (P = 0.004) and low exercise frequency (P = 0.03). For siblings, the only independent factor associated with increased fatigue was low exercise frequency (P = 0.03).

Conclusions: Survivors of Hodgkin's disease were more fatigued than their siblings. The difference was modest but statistically significant. The significant association between fatigue and cardiac disease suggests the importance of screening for underlying cardiac dysfunction in survivors with symptoms of fatigue. The association between fatigue and smoking history may be due to exacerbation of late medical complications of Hodgkin's disease by tobacco use.

Key words: cancer survivors, fatigue, Hodgkin's disease, late effects


    Introduction
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
A number of studies have demonstrated that survivors of Hodgkin's disease have a higher level of fatigue than either the general population or other long-term cancer survivors [1Go–3Go]. Persistent diminished energy level has been reported in about one-third of patients years after cure of their Hodgkin's disease [4Go–6Go]. Chronic fatigue is strongly associated with various medical and psychiatric conditions. Among survivors of Hodgkin's disease, the fatigue may also be related to other known late effects of Hodgkin's disease therapy, including hypothyroidism, cardiovascular disease, lung scarring and muscle atrophy [7Go–10Go]. One study showed that pulmonary dysfunction was significantly associated with increased fatigue in long-term survivors of Hodgkin's disease [11Go].

Limited data are available documenting the etiology of fatigue in this patient population. Understanding the causes of fatigue in these patients may guide physicians in evaluating and treating some of the health-related long-term sequelae of Hodgkin's disease. Effective treatment of the underlying health problems, in addition to potentially improving survival, may also improve the energy level and quality of life of these patients. Although some of the factors related to fatigue may not be treatable or modifiable, recognizing these factors allows identification of subsets of vulnerable patients who may especially benefit from fatigue reduction strategies, such as an exercise program [12Go], cognitive behavioral therapy to improve coping skills [13Go, 14Go] or pharmacological intervention [15Go, 16Go].

In this study, we compared the level of fatigue in a cohort of long-term survivors of Hodgkin's disease with that of their siblings. In addition, we correlated the fatigue level with specific health problems and other non-clinical factors including demographic profile and socioeconomic status.


    Methods
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Study procedure
We conducted a cross-sectional questionnaire study on patients treated for Hodgkin's disease between 1969 and 1996 at our institution, and their siblings, who served as the control population. The patients were derived from a pre-existing Hodgkin's disease database that captures all Hodgkin's disease patients seen at the Department of Radiation Oncology at our institution. The database contained detailed information on initial disease characteristics, treatments received, relapse history and salvage therapy. The database is updated on a regular basis to ensure up-to-date follow-up information.

Patients from the database who were 5 years or more from diagnosis were eligible for this questionnaire study. Patients were first mailed an introductory letter describing the study, and were given the opportunity to opt-out if they chose not to participate. In the introductory letter, the patients were informed that siblings would also be recruited to the study to serve as a comparison group, and an optional sibling recruitment form was included. If the opt-out note was not received after 3 weeks, the questionnaire was mailed to the patient. A reminder letter was sent to the patient if the completed questionnaire was not returned after 4 weeks. A reminder telephone call was made if the completed questionnaire was not returned after another 4 weeks. Using information from the completed sibling recruitment form, one sibling per patient (closest in age and same gender if available) was contacted and recruited using the above algorithm. This questionnaire study was approved by the Institutional Review Board of the Dana-Farber/Harvard Cancer Center.

Measures
The questionnaire is a 500-item survey adapted from the Childhood Cancer Survivor Study (CCSS) questionnaire [17Go], designed to explore a wide range of physical and psychosocial health sequelae in childhood cancer survivors, and which also used siblings as the comparison population. Minor modifications were made to tailor the questionnaire to survivors of Hodgkin's disease. For example, items that were deemed not relevant to patients with Hodgkin's disease, such as ‘loss of a limb’ or ‘loss of an eye’, were deleted. In addition, we added several standardized quality of life instruments to the questionnaire, one of which is the Functional Assessment of Chronic Illness Therapy-Fatigue (FACIT-F) [18Go]. The FACIT-F scale is a 13-item questionnaire that assesses self-reported fatigue and its impact upon daily activities and function. It uses a 5-point Likert-type scale (0 = not at all; 1 = a little bit; 2 = somewhat; 3 = quite a bit; 4 = very much). As each of the 13 items of the FACIT-F scale ranges from 0–4, the range of possible scores is 0–52, with 0 being the worst possible score and 52 the best. To obtain the 0–52 score, each negatively worded item response is recoded so that 0 is a bad response and 4 is good response. All responses are added with equal weight to obtain the total score. This report is limited to the analysis of items in the fatigue subscale and the associated factors.

Among the survivors, disease- and treatment-related factors explored included initial disease stage, treatment exposure, time since diagnosis and relapse history (derived from the Hodgkin's disease database). In both the survivors and the siblings, factors that were evaluated included age, gender, report of cardiac disease, report of psychiatric condition, hypothyroidism, current exercise frequency, tobacco history, marital status, household income and educational level (derived from the questionnaire). Because of the self-reported nature of the medical conditions, a conservative approach was used to avoid over-reporting. For example, respondents with coronary artery disease included only those who gave a positive response to a history of ‘myocardial infarction (heart attack)’, ‘angioplasty (enlarging a heart vessel using a balloon)’ or ‘coronary artery bypass surgery’, while positive responses to history of ‘coronary heart disease (hardening or blockage of arteries supplying the heart muscles)’ or ‘angina pectoris (chest pains due to lack of oxygen to heart requiring medication such as nitroglycerine’, which were less concrete items, were not included. The presence of a psychiatric condition was based on reporting being on psychiatric medications, seeing a mental health professional on a regular basis or having a history of psychiatric hospitalization. Hypothyroidism was defined as answering ‘yes’ to a diagnosis of an underactive thyroid gland or being on thyroid hormone supplements. Current exercise frequency was determined based on a question on the number of days in a week that the respondent engaged in exercise or sports. A positive tobacco history was defined as report of having smoked 100 or more cigarettes in the lifetime of the respondent.

Statistical analysis
Student's t-test or F-test (for more than two groups) was used to compare the mean FACIT-F scores between survivors of Hodgkin's disease and the siblings. P values ≤0.05 were considered statistically significant. All tests of statistical significance were two-sided. Additionally, Fisher's exact test was used to compare the proportion of survivors versus siblings with scores that were below the published US general population mean FACIT-F score [19Go, 20Go]. To identify factors associated with fatigue level, multiple regression models were used, with the FACIT-F score included as a continuous variable. Multiple regression analyses were performed separately for survivors and siblings. In the model for the survivors, time since diagnosis, history of relapse and extent of initial treatment were added.


    Results
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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
Questionnaires were mailed to 1023 eligible survivors of Hodgkin's disease. A total of 511 survivors completed the questionnaire. Forty-three opted out, 290 with known contact information did not respond despite multiple contact attempts and 179 were not reachable because they have moved to an unknown address. After excluding those who were not traceable, the response rate for survivors was 60.6%. Responders and non-responders did not differ in age, initial disease stage distribution, treatment exposure and relapse history. A total of 388 questionnaires were sent to the siblings, and 224 returned the completed questionnaire. Nine opted out and 155 did not respond. The response rate for siblings was 57.7%. Among the 511 survivors and 224 siblings who returned the questionnaire, 506 and 222, respectively, had complete FACIT-F results and these contribute to the study population.

Median ages of survivors and siblings at study entry were 44 years (range 16–82) and 44 years (range 16–79), respectively. Median time from Hodgkin's disease diagnosis among survivors was 15 years (range 5–32). The characteristics of the survivors and siblings are summarized in Table 1. Patients and siblings had comparable age and gender distribution, exercise frequency, tobacco history, report of psychiatric condition (a positive score for having a psychiatric condition was mostly based on a report of anti-depressants or anxiolytics use), marital status, household income and education level. However, patients were significantly more likely than siblings to report the presence of cardiac disease (26% versus 16%; P = 0.001) and hypothyroidism (65% versus 3%; P < 0.001).


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Table 1. Characteristics of participating survivors and siblings

 
The mean FACIT-F score of the survivors was 40.7 ± 9.3 (1 SD) and that of the siblings was 42.2 ± 8.7 (1 SD) (P = 0.05), indicating a greater level of fatigue among the survivors. Using the mean US general population FACIT-F score of 40.1 as a cut-off [19Go], 185 of 506 survivors (37%) and 60 of the 222 siblings (27%) had FACIT-F scores at or below the mean (P = 0.01). We did not compare the FACIT-F scores of the study population with that of the normal population, because the available normal population scores were based on a group with a higher proportion of elderly than our study population [19Go, 20Go].

On univariate analysis among survivors, report of cardiac disease (P < 0.0001), psychiatric condition (P < 0.0001), tobacco history (P < 0.001), lower household income (P = 0.0005) and lower educational level (P = 0.008) were associated with significantly lower FACIT-F scores. Age, gender, treatment exposure, relapse history, time since diagnosis, hypothyroidism on supplements, exercise frequency and marital status did not significantly predict for fatigue. Among siblings, female gender (P = 0.02), psychiatric condition (P < 0.001) and lower exercise frequency (P = 0.04) were significantly associated with lower FACIT-F scores. There was a trend toward lower FACIT-F scores in siblings who reported the presence of cardiac disease, although the association did not reach statistical significance (P = 0.06). Results of the univariate analyses for the survivors and siblings are shown in Table 2.


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Table 2. Univariate analysis on factors associated with FACIT-F scores

 
In a multiple regression analysis assessing fatigue in survivors, presence of cardiac disease (P < 0.001), psychiatric condition (P < 0.001), tobacco history (P = 0.03) and lower exercise frequency (P = 0.03) were significantly associated with lower FACIT-F scores. Among siblings, the only factor independently associated with lower FACIT-F scores was lower exercise frequency (P = 0.03).

Cardiac disease is a known late effect in survivors of Hodgkin's disease [21Go–28Go], and as expected, it was more frequently reported in the survivors than the siblings in their responses to the questionnaire. To better characterize the relationship among cardiac disease, fatigue and Hodgkin's disease survivorship, and to assess whether survivors are more prone to fatigue owing to their underlying cardiac dysfunction, a multiple regression model combining both patients and siblings was compared with the variables used in the earlier model, plus the term ‘subject status’ (survivor versus sibling) and an interaction term of subject status and presence of cardiac disease. Significant variables in the model for increased fatigue were the presence of cardiac disease (P = 0.003), psychiatric condition (P < 0.001), lower exercise frequency (P < 0.001) and tobacco history (P = 0.01). Subject status and the interaction term of status and cardiac disease were not significant (P = 0.43 and 0.62, respectively), suggesting that cardiac disease had a similar contribution to the fatigue level of survivors and siblings. Results of the multiple regression analyses are shown in Table 3.


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Table 3. Multiple regression analyses on factors associated with FACIT-F scores

 

    Discussion
 Top
 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
In this questionnaire study on long-term survivors of Hodgkin's disease and their siblings, survivors, who were at a median of 15 years post-treatment, were found to be more fatigued than their siblings, although the difference in the FACIT-F scores between the two populations was rather modest. Factors independently associated with increased fatigue among survivors were the presence of cardiovascular disease, having a psychiatric condition, history of tobacco use and low exercise frequency.

Diminished energy level has been demonstrated in survivors of Hodgkin's disease in a number of studies [2Go, 4Go–6Go, 29Go]. These studies vary in length of follow-up time since the completion of Hodgkin's disease therapy, types of instruments used to measure fatigue and the comparison population. Investigators from Stanford University found that compared with survivors of testicular cancer, survivors of Hodgkin's disease were significantly more likely to report greater fatigue and less likely to have full return of their energy level at a median of 3 years after treatment [3Go]. Using the Profile of Mood States, Kornblith et al. [1Go] reported that with a mean follow-up time of 5.9 years, survivors of Hodgkin's disease had significantly greater fatigue and lower vigor than survivors of acute leukemia. The German Hodgkin's Study Group (GHSG) surveyed 818 patients who were at a median of 5.2 years after Hodgkin's disease therapy using the European Organization for Research and Treatment of Cancer Quality of Life Questionnaire Core 30 (EORTC QLQ-C30) and the Multidimensional Fatigue Inventory (MFI) [6Go]. Compared with normal controls, survivors had a significantly higher level of fatigue on all subscales of the MFI as well as on the fatigue scale of the EORTC QLQ C-30. In a Norwegian study, the level of fatigue among survivors of Hodgkin's disease was compared with normative data using the Fatigue Questionnaire [2Go]. With a mean follow-up time of 12 years, survivors were found to be significantly more fatigued and had longer duration of symptoms of fatigue compared with the normal controls.

In our study, the mean FACIT-F scores between the survivors and the siblings were statistically significant, and a significantly higher proportion of survivors than siblings had scores that were lower than that of the US general population mean FACIT-F score. However, the absolute difference in the mean scores between the groups of 1.5 points is below the minimally important differences for the FACIT-F scale, which has been estimated to be in the range of 3–4 points [20Go, 30Go]. The lack of a more substantial difference between the two groups may in part be due to the use siblings as the comparison group. Siblings may not be representative of a ‘normal’ population, given their experience of a close family member being diagnosed with cancer relatively early in their lives. The reasons for our choice of siblings as the control population, however, were their higher likelihood of responding to the questionnaire, and the fact that they were more likely to share similar childhood exposures and have similar socioeconomic background. Indeed, the Hodgkin's disease survivors and the siblings in this study were comparable in their income level, educational level and marital status. Response shift, or differences in internal standard of fatigue perception [31Go], may also be responsible for the minimal difference in the measured fatigue scores between the two populations. Survivors, because of their prior history of a cancer diagnosis and their personal experience with toxic therapy, may be less affected by a given level of fatigue than their siblings.

While it is not possible to identify all the contributing parameters, older age, the presence of B symptoms at initial presentation, treatment with combined modality therapy, and a history of relapsed disease and salvage therapy are factors that have been shown to be associated with increased fatigue in survivors of Hodgkin's disease. In our study, however, none of the disease- or treatment-related factors were predictive of fatigue level. This is likely due to the long length of time since the completion of treatment in our cohort of survivors compared with the length of follow-up in other studies. The impact of the initial Hodgkin's disease diagnosis and its therapy on their current fatigue level may be eclipsed by some of the concerns that are more at hand.

Others have shown that factors unrelated to the initial Hodgkin's disease or treatment may be associated with increased fatigue in survivors. In the study conducted by the GHSG, Ruffer et al. [6Go] found that an experience of accidents or severe illness, the number of cigarettes smoked per day, gender and family history of cancer significantly predicted for various dimensions of fatigue. Our study also showed that a tobacco history of 100 or more cigarettes is an independent predictor for increased fatigue. Interestingly, this association was found among survivors of Hodgkin's disease but not among the siblings, who had a comparable tobacco history. One postulation is that tobacco use may further exacerbate late medical complications of Hodgkin's disease that are associated with fatigue, as discussed below.

Survivors of Hodgkin's disease are at risk for a number of well-documented medical sequelae [32Go], some of which may contribute to the increased fatigue in these patients. Knobel et al. [11Go] explored the relationship between late medical complications and fatigue in survivors of Hodgkin's disease who were at a mean of 9 years from treatment. Pulmonary dysfunction was significantly associated with increased fatigue, whereas cardiac abnormalities and hypothyroidism were not significant. In a prospective cardiac screening study on 48 survivors at a median of 14.3 years post-treatment, Adams et al. [28Go] found that reduced peak oxygen uptake during exercise significantly correlated with a report of fatigue on the general health status form created for the study, although a validated instrument for fatigue measurement was not used.

In our study, the presence of cardiac disease among survivors of Hodgkin's disease was independently associated with increased fatigue. A trend toward increased fatigue among siblings who reported having cardiac disease was also detected, but the association did not reach statistical significance. Further analysis, however, did not show an increased vulnerability to cardiac health-related fatigue among the survivors. This suggests that the significant association between fatigue and cardiac disease among the survivors was mostly driven by the high prevalence of cardiac abnormalities in this population. One caveat is that self-reports of medical conditions, in particular, positive patient reports of cardiovascular disease, can be inaccurate [33Go]. It is noteworthy, however, that despite our attempts to limit over-reporting by our stringent definition of cardiac disease based on the questionnaire responses, a significant association between fatigue and cardiac disease was still detected.

Hypothyroidism is another well-known complication in survivors of Hodgkin's disease who had received radiation therapy to the neck and upper chest region [34Go–36Go]. One of the symptoms of clinical hypothyroidism is fatigue due to reduced metabolic rate. In the study by Knobel et al. [11Go], however, uncorrected hypothyroidism was not associated with increased fatigue, and the reason for their findings is not entirely clear. In our study, we also did not detect an association between a report of hypothyroidism and fatigue level. However, our conclusion is limited by the fact that most of the patients in this questionnaire study who reported hypothyroidism were taking thyroid hormone replacement therapy.

The relationship between Hodgkin's disease survivorship, psychiatric disease and fatigue is complex. When validated psychiatric screening tools have been used, survivors of Hodgkin's disease have been shown to display increased psychiatric distress [29Go, 37Go]. In our study, however, patients and siblings had a comparable frequency of self-reported psychiatric conditions. Moreover, the presence of a psychiatric condition, most often scored on the basis of being on medications for a mood disorder, was associated with fatigue in both the survivors and the siblings on univariate analysis, but was an independent factor only for the survivors. Owing to the design of the study, it is impossible to sort out the effect of appropriately treated versus under-treated psychiatric condition on fatigue. To better characterize the level of psychiatric distress and its impact on survivors' quality of life, formal measurements of symptom distress using validated instruments will be necessary.

Physical exercise programs have been shown to be effective in reducing the intensity of cancer-related fatigue [38Go–40Go]. Promising pilot data based on a small number of patients are available on the potential role of exercise in reducing fatigue in survivors of Hodgkin's disease [12Go]. In our study, infrequent exercise was the only factor that was independently associated with increased fatigue in both the survivors and the siblings. However, conclusions cannot be drawn about a potential causal relationship between lack of exercise and fatigue in this one-time cross-sectional survey study. A prospective study design is needed to determine whether exercise is an effective form of intervention in reducing fatigue in survivors of Hodgkin's disease.

The population in this questionnaire study on fatigue level in survivors of Hodgkin's disease derives from a database with a long follow-up time, highlighting the persistent nature of the problem. The significant association between cardiac disease and fatigue level underscores the far-reaching ramifications of cardiac complications in these patients, in that both their physical health as well as quality of life are compromised. Another implication of our results is that in the follow-up of survivors of Hodgkin's disease, there should be a low threshold to pursue potential underlying cardiac abnormalities that may warrant intervention in an otherwise healthy patient who complains of fatigue.

For survivors of the more recent era who received adriamycin, bleomycin, vinblastine and dacarbazine (ABVD) chemotherapy, drug-related cardiac and pulmonary sequelae may further contribute to the fatigue. However, the current trend in the treatment of Hodgkin's disease, especially among early-stage patients, is treatment reduction, including use of less toxic chemotherapy regimen, a lower number of cycles of chemotherapy, and smaller radiation field size and lower dose [41Go]. These efforts will hopefully translate into reduced treatment-related late effects. In the meantime, there have been increasing data on the role of screening for occult cardiac disease in survivors of Hodgkin's disease [27Go, 28Go]. Early detection and intervention may potentially limit the impact of these late complications on patients' quality of life and survival.


    Acknowledgements
 
Supported by the Murphy Family Fund and the American Society for Therapeutic Radiology and Oncology (ASTRO) Junior Faculty Award. Presented in part at the 46th ASTRO Annual Meeting, Atlanta, GA, USA, 2004.

Received for publication April 29, 2005. Revision received July 20, 2005. Accepted for publication August 2, 2005.


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 Abstract
 Introduction
 Methods
 Results
 Discussion
 References
 
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