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© 2001 American Society for Clinical Oncology Late Medical Complications and Fatigue in Hodgkin’s Disease SurvivorsByFrom the Unit for Applied Clinical Research, Faculty of Medicine, Norwegian University of Science and Technology, and Palliative Care Unit, Department of Oncology, Trondheim University Hospital, Trondheim; Department of Behavioral Sciences in Medicine and Division of Heart and Lung Diseases, National Hospital, University of Oslo; and Norwegian Radium Hospital, Oslo, Norway. Address reprint requests to Heidi Knobel, MD, Unit for Applied Clinical Research, Trondheim University Hospital, Norwegian University of Science and Technology, N-7006 Trondheim, Norway; email: heidi.knobel{at}medisin.ntnu.no
PURPOSE: Long-term medical complications, such as cardiac, pulmonary, and thyroid dysfunction, are frequent among Hodgkin’s disease survivors (HDSs). Chronic fatigue is also highly prevalent among HDSs. Few studies have explored possible etiologic explanations for fatigue. The aim of this study was to explore whether late cardiac, pulmonary, and thyroid complications after curative treatment for Hodgkin’s disease (HD) may explain the high level of fatigue among HDSs. PATIENTS AND METHODS: Four-hundred fifty-nine patients treated for HD at the Norwegian Radium Hospital from 1971 to 1991 were included in a cross-sectional, follow-up study of subjective health status. Fatigue (physical [PF] and mental), was measured by the Fatigue Questionnaire. A subcohort of the HDSs (116 patients) treated from 1980 to 1988 were included in a separate study in which long-term cardiac, pulmonary, and thyroid complications were assessed. All patients had received radiotherapy, and 63 patients had received additional chemotherapy. The present study comprised 92 patients (mean age, 37 years; range, 23 to 56 years) who participated in both studies. RESULTS: HDSs with pulmonary dysfunction were more fatigued than HDSs with normal pulmonary function (PF 10.9 v 8.9; P < .05). Gas transfer impairment was the most prevalent pulmonary dysfunction, and three times as many patients with gas transfer impairment reported chronic fatigue (duration, 6 months or longer), compared with patients without pulmonary dysfunction (48% v 17%, P < .01). No associations were found between cardiac sequelae or hypothyroidism and fatigue. CONCLUSION: Pulmonary dysfunction is associated with fatigue in HDSs. Cardiac sequelae was not associated with fatigue in HDSs. We question the absence of an association between thyroid complications and fatigue.
FATIGUE IS A common complaint in the normal population; 11% of the Norwegian population has chronic fatigue.1 Fatigue is also a common symptom in several diseases, such as multiple sclerosis, systemic lupus erythematosus, and heart failure, and among patients with psychiatric disorders.2-6 In cancer patients, fatigue may be the first manifestation of an underlying disease process or it may reflect an advanced stage of the disease.7,8 Cancer treatment may induce or worsen the fatigue.9,10 Despite the high prevalence of fatigue, it is generally poorly understood, and the mechanisms behind fatigue remain unclear. Hodgkin’s disease (HD) primarily affects young adults. Treatment modalities with megavoltage irradiation and/or chemotherapy have improved survival rates, and more than 90% of patients with stage I and II disease and 75% of all patients with HD are expected to be cured with modern treatment modalities.11-13 Intensive multimodal cancer treatment, including the treatment for HD, will produce acute side effects depending on the specific treatment strategies used. The long-term consequences of the treatment used and/or the disease itself may have a major influence on both somatic and psychologic domains. Cardiopulmonary and thyroid complications are frequent in Hodgkin’s disease survivors (HDSs).14,15 Pericarditis and myocardial infarction, along with accelerated coronary artery disease and valvular injury, are the major cardiac complications after radiotherapy.16,17 Furthermore, chemotherapy regimens containing anthracyclines may contribute to the cardiac injuries.18 Pulmonary complications after mantle-field irradiation are first observed clinically as an acute radiation pneumonitis 3 to 4 months after completion of radiotherapy. This is followed by radiation fibrosis, which evolves over time to reach a stable appearance 9 to 12 months after completion of treatment.19,20 The development of radiation pneumonitis depends on the lung volume included in the radiation field, the fraction size, and the length of the treatment. Radiation-induced lung injury may be enhanced by chemotherapy regimens, particularly those containing bleomycin. Through lung function testing, the incidence of pulmonary toxicity after treatment with bleomycin is reported to be up to 40%, depending on the total dose.21 Pulmonary toxicity secondary to treatment with chemotherapy alone is rare. Thyroid dysfunction after mantle-field irradiation for HD is also prevalent and is reported in more than 50% of long-term HDSs.22 Late effects on subjective health among HDSs are less well-documented than the late medical complications.23 Fatigue seems to be one of the most frequently reported symptoms among long-term HDSs.24-26 There is limited knowledge about possible biologic mechanisms that might contribute to persistent fatigue in disease-free patients after successful cancer treatment. A link between depression and fatigue in cancer patients has been suggested.27 However, Loge et al28 found that 50% of the HDSs who suffered from chronic fatigue did not report depression or anxiety at a clinically significant level. Concerning somatic factors, it is well documented that noncancer patients with cardiac failure, chronic lung disease, and hypothyroidism are fatigued.4,5,29,30 Still, we are not aware of any study that has addressed the hypothetical link between the most prevalent late medical complications, such as lung, heart, and thyroid sequelae, and fatigue in HDSs. A recent study demonstrated that the prevalence of chronic fatigue among HDSs was two to three times higher than in the general population.31 No relation to treatment modality was found, but patients with stage IB or IIB had higher levels of fatigue than patients of other disease stages did. A study of a subcohort of these HDSs (n = 116) treated with radiotherapy and chemotherapy uncovered cardiopulmonary sequelae in 56% of the patients 5 to 13 years after treatment.32 Twenty-one percent had cardiac lesions only. Pulmonary sequelae were found in 15% of the patients, and 19% had a combination of both. In this study, we explored the possible association between late cardiac, pulmonary, and thyroid complications along with fatigue after curative treatment for HD. Our hypothesis was that cardiac, pulmonary, and thyroid complications are major contributors to the high level of fatigue in HDSs. We also expected that this high level of fatigue influences the physical performance of HDSs.
Sample All living patients treated for HD at the Norwegian Radium Hospital in the period between 1971 and 1991, 15 to 61 years of age at the time of diagnosis, and 74 years of age or younger by the end of 1993 were invited to participate in a cross-sectional follow-up study (study 1). One of the main purposes of the study was to measure the level of fatigue and the frequency of fatigue cases among HDSs and compare it with normative data extracted from the general population. In 1994, 559 HDSs received a mailed questionnaire, and 459 patients (82%) responded.31 Respondents and nonrespondents did not differ in age at the time of diagnosis, age at the time of study, disease stage, type of treatment, or time from diagnosis. The response rate tended to be higher among females (86%) than males (80%) (P = .05). A subcohort of the subjects in study 1, limited to patients who had been treated between 1980 and 1988 with standardized mediastinal radiotherapy alone or in combination with chemotherapy, were included in a separate study to assess long-term cardiac, pulmonary, or thyroid complications (study 2). Patients aged 50 years or younger at the time of diagnosis and who had been in complete remission for more than 5 years at the time of follow-up were invited to participate. Of the 129 eligible patients, 13 were lost to follow-up. Two patients did not reply to the invitation, five did not attend because of time conflicts (work or school), and six patients did not wish to specify why they declined the invitation. The study comprised 116 (90%) of 129 eligible patients.32-34 The clinical examinations were performed at the outpatient department at the National Hospital of Norway. In the present study, we have included all patients entered onto both studies 1 and 2 (n = 92). Due to the homogeneity of the Norwegian society, all patients who met the inclusion criteria were identified and approached. The only selection criteria were patient consent and completion of mailed questionnaires. At this stage, all available patients were included.
Sample Characteristics
Radiotherapy was given to a mantle field in 85 patients and to a mediastinal field in seven patients. Mean total dose was 40.3 Gy with single fractions of 2.0 Gy (to patients initially treated from 1980 to 1984) or 1.8 Gy (to patients initially treated from mid-1984 on) given 5 days a week. Male and female patients did not differ with respect to mean radiation dose or fractionation. Patients with bulky mediastinal disease were treated with radiation doses comparable to those of the rest of the patients. A selection of standard blocks was adapted to optimize lung shielding. No pericardial blocks or systematic cardiac shielding was used.35,36 Sixty-three patients (25 females and 38 males) received additional chemotherapy regimens containing bleomycin-anthracyclines or chlorambucil or both. Forty patients received doxorubicin, bleomycin, vincristine, and dacarbazine (ABVD) or epirubicin, bleomycin, vinblastine, and prednisone (EBVP). Chlorambucil, vinblastine, procarbazine and prednisone (ChlVPP) was administered to 50 patients, either alone (21 patients) or in combination (with ABVD/EBVP or epirubicin, bleomycin, vinblastine, and prednisone). Patients with risk factors for relapse or with bulky mediastinal diseases received four cycles of chemotherapy before radiation. Stage III and IV patients were treated with eight cycles of chemotherapy before radiotherapy.
Clinical Examination Cardiac sequelae were assessed with echocardiography, exercise testing and chest radiographs. Three types of cardiac sequelae were measured: valvular regurgitation, pericardial thickening, and coronary artery disease. The methods have been described in detail elsewhere.32,33 In brief, echocardiography was performed using standard ultrasonic techniques and acoustic windows. Cardiac dimensions were determined by M-mode echocardiography or a cross-sectional technique when appropriate. Valvular function was assessed using pulsed, continuous, and color Doppler echocardiography in at least three planes. Valvular regurgitation was semiquantitatively graded on a 0 to 3 scale (none, small, moderate, or severe), and regurgitation at more than grade 1 was defined as abnormal. For comparison, a reference group of healthy subjects was examined. Physical work capacity was examined by a symptom-limited, incremental bicycle workload test, with monitoring of ECG, blood pressure, and oxygen saturation. Pulmonary sequelae were evaluated with chest radiographs and lung function testing, including dynamic spirometry, determination of static lung volumes, and gas transfer.32,34 Registered variables included total lung capacity, forced vital capacity (FVC), forced vital capacity in 1 second (FEV1), and the lung’s transfer factor for carbon monoxide. The variables were expressed in absolute values and as percentages of predicted normal values, using the reference values recommended by the European Respiratory Society.37 Pulmonary sequelae were dichotomized into three subgroups: restrictive impairment (defined as total lung capacity and FVC < 80% of predicted), obstructive impairment (defined as FEV1 < 80% of predicted and FEV1-FVC ratio < 0.7), and gas transfer impairment (defined as lung’s transfer factor for carbon monoxide < 80% of predicted value). Chest radiographs were evaluated in a blinded manner by two independent observers, and fibrotic manifestations were classified as none, slight, moderate, or severe, according to predefined criteria.
Fatigue
Statistical Analysis Statistical procedures included two-sided t-tests (independent samples),  2 statistics (categorical variables), Pearsons’ one-way analysis of variance with Bonferroni’s correction for multiple comparisons, and logistic and linear multiple regression analysis. In the regression analysis, the explanatory variables were entered by a forward selection method. The level of significance was set at .05. In case of missing data in four or fewer items in the FQ, the missing values were replaced with the means of the corresponding known variables. Eight questionnaires lacked responses in four or fewer items. Mean TF was unchanged after the missing values were replaced. The data were analyzed using SPSS for Windows version 9.0 software (SPSS, Inc, Chicago, IL).
Fatigue Among HDSs The items and the frequencies of the endorsement are listed in Table 2. The frequency of the endorsement was similarly distributed among the physical fatigue items, except with a small deviation on item PF7 ("Do you feel weak?"). With the mental fatigue scale, items MF2 (Do you make slips of the tongue when speaking?) and MF3 (Do you find it more difficult to find the correct words?) were less frequently endorsed than the remaining items.
The mean (± SD) fatigue scores among the HDSs were PF = 9.6 (± 4.0), MF = 5.0 (± 1.7), and TF = 14.6 (± 5.2). Twenty-four patients (26%) were classified as fatigue cases because they reported experiencing fatigue for 6 months or longer. In the univariate analysis of fatigue levels and cases, no statistically significant differences were found using sex, age, educational level, stage of disease, and stage of treatment as independent variables (data not presented). However, patients with stage I/IIB reported highest level of fatigue (mean PF, 11.1 [± 4.7]; mean MF, 5.5 [± 2.2]; mean TF, 16.6 [± 6.4]) as compared with the remaining patients, but the differences did not reach statistical significance. A trend was observed with regard to educational level. Thirty-seven percent of the HDSs with 10 or fewer years education were fatigue cases, compared with 27% of HDSs with higher levels of education and 19% among subjects with education at the university level (P = .07).
Fatigue and Cardiac Sequelae Among HDSs
Fatigue and Pulmonary Dysfunction
Fatigue and Work Capacity Mean maximal workload performed by the patients was 201 ± 50 watts (women, 159 ± 28 watts; men, 230 ± 41 watts; P < .00). There was a weak but significant correlation between PF and maximal workload (women, r = -.35, P = .03; men r = -.34, P = .01). Male HDSs who performed lower than mean maximal workload (n = 26) demonstrated higher levels of fatigue than male patients with higher physical performances (n = 28) (PF 10.7 v 8.5, P = .03; fatigue cases, 39% v 11%, P = .02). No differences were found among the female patients. HDSs with gas transfer impairment performed a significantly lower maximal workload than HDSs without pulmonary dysfunction (172 ± 43 watts v 213 ± 48 watts, P = .00). The differences were most pronounced between male patients with gas transfer impairment (n = 12) and without gas transfer impairment (n = 42) (mean max workload, 204 ± 38 watts v 237 ± 40 watts, P = .01). Thirteen of the 29 patients with gas transfer impairment stated the reason for discontinuing the exercise testing was dyspnea. Twelve of the 29 patients stopped testing because of tiredness. No differences in fatigue levels were found between these groups.
Fatigue and Thyroid Status
Predictors of PF and Fatigue Cases On the basis of knowledge about possible predictors of fatigue in the general population (age, sex), about predictors of fatigue in HDS demonstrated in previous studies (stage, substage), and on findings in our univariate analyses (physical performance, gas transfer impairments, and thyroid function, the latter entered as a dummy variable), these variables were entered as independent variables in a multivariate regression model. PF was entered as the dependent variable in a multiple linear regression model, and fatigue cases were entered as the dependent variable in a logistic regression model. Gas transfer impairment was the only statistically significant predictor of PF (beta = 2.28; 95% confidence interval, 0.57 to 4.00; P = .01) and of fatigue cases (beta = 1.60; odds ratio, 4.95; P = .002). The other variables were not entered into the equation.
The main finding of the present study is the association between fatigue and pulmonary dysfunction. Almost three times as many patients with gas transfer impairment (48%) were classified as fatigue cases as compared with the HDSs with no pulmonary dysfunction. When the other variables were controlled for, pulmonary dysfunction predicted both increased level of fatigue and fatigue cases. When one is interpreting differences between cohorts, the clinical significance level is just as important as the statistical significance level. There is an ongoing debate on this issue among scientists. In previous studies, a 10% to 15% difference was considered to be clinically meaningful.41 An estimate of 10.9 of PF for patients with pulmonary dysfunction and 8.9 for patients with no dysfunction is an approximately 20% difference and should be considered clinically meaningful. Furthermore, our group has published general population norms for the FQ.1 The age-adjusted score on PF was 7.7, which further supports the clinical significance of this finding. We are not aware of any study that has described an association between fatigue and pulmonary sequelae after cancer cure. In a single case study, one pediatric cancer patient reported fatigue after developing pulmonary fibrosis as a complication 2 years after nitrosurea therapy.42 Fatigue is a profound symptom in patients with sarcoidosis and pulmonary fibrosis.43 Furthermore, among patients with chronic lung diseases, such as chronic obstructive pulmonary disease (COPD), fatigue is reported to be a common symptom.44 The level of fatigue among the present patients seems to be similar to the level reported by patients with moderate to severe COPD.29,45 In comparison with the general population, the level of fatigue among HDSs with lung complications equalled the level reported by subjects within the general population with the poorest somatic health.1 One reason for the high frequency of gas transfer impairment in HDSs may be the development of interstitial fibrosis. The chest x-rays support this assumption in that 76% (23 of 29) of the patients with gas transfer impairment had paramedian or apical fibrosis. Clinically, the cardinal symptom of fibrosis is dyspnea. Dyspnea limits the exercise tolerance in HDSs with pulmonary-restrictive defects and in patients with severe COPD.46,47 Fatigue is usually not measured or asked about. However, it has recently been shown that patients with COPD, asthma, and pulmonal hypertension could not distinguish between dyspnea and fatigue.48 Fatigue and dyspnea may occur at the same time or at different times in different people but may be symptoms of the same disease.4 From a clinical perspective, the present findings underscore the importance of measuring subjective symptoms together with objective variables in the follow-up of HDSs. Measurement of fatigue is feasible and inexpensive. Second, measuring fatigue is also a prerequisite for evaluation of therapeutic interventions for conditions with fatigue symptoms. The prevalence of thyroid dysfunction in the present study is in the upper levels of what other studies of HDSs have reported. Seventy percent of the sample had a subclinical or clinical hypothyroidism, with or without thyroid hormone replacement therapy, compared with 31% to 78% reported in other studies.12,22,49,50 In contrast to the common perception about fatigue as a major symptom of hypothyroidism and thyroid dysfunction, we did not find any strong association between fatigue and thyroid dysfunction. However, patients with substituted hypothyroidism were more fatigued than those with thyroid dysfunction. This finding might be explained by several factors. The thyroid dysfunction may be of less severity and with minor or nonspecific symptoms among the untreated patients compared with the treated patients. In some definitions of hypothyroidism, subclinical hypothyroidism is described by the absence of hypothyroid symptoms.30 This finding may also imply that fatigue symptoms in HDSs might be diagnosed as hypothyroidism and treated accordingly. Despite replacement therapy, the patients still experience fatigue. This situation often arises in clinical practice. Limited knowledge exists about pathophysiologic conditions that contribute to subjective fatigue among patients with hypothyroidism.51 Further, the HDSs with hypothyroidism may not be appropriately substituted despite acceptable thyroxin serum levels. It has been indicated that in some cases subclinical hypothyroidism is caused by immunologic changes. In such patients thyroxin treatment would probably not help.30,52 Finally, the small sample size and subgroups should be considered, and significant differences may be difficult to demonstrate. Our data indicate that hypothyroidism alone plays a minor role in the perception of the subjective feeling of fatigue. However, we can not conclude that thyroid dysfunction and fatigue in HDSs are not related. It must be kept in mind that the substituted group reported the highest level of fatigue. Further empirical studies, preferably with a prospective design, are needed. In the present study, we demonstrated that long-term heart sequelae were of minor importance in explaining fatigue. The levels of fatigue in HDSs with cardiac sequelae did not differ from levels in those without cardiac sequelae. Functionally, they were comparable to levels in those with no signs of injury. This finding is consistent with reports from other studies. Despite a high frequency of cardiac sequelae among HDSs, cardiac function is interpreted to be minimally impaired.15,32 A small group of HDSs with coronary artery disease reported high levels of fatigue. They reported a 30% greater level of fatigue as compared to those in the general population with poorest health.1 They also demonstrated impaired physical performance compared with the remaining cardiac cases. In the multivariate analysis, cardiac and combined cardiopulmonary sequelae were not predictors of fatigue in HDSs, in contrast to gas transfer impairments. This observation may strengthen the assumption that pulmonary dysfunction is more strongly associated with fatigue in HDSs than the other organ injuries. Apart from coronary artery disease, most of the cardiac lesions after treatment for HD do not impair cardiac function for many years. Therapy-induced cardiac damage, however, is not reversible. In some cases, the cardiac lesions will progress over time, be symptomatic, and may then induce fatigue. The moderate correlation between fatigue and impaired physical performance strengthens the assumption that fatigue among HDSs has a physical component. This is in contrast to several studies, which have demonstrated normal muscle strength and endurance in patients with chronic fatigue.53 The effect of physical performance on fatigue disappeared in the multivariate analysis when gas transfer impairment was controlled for. This implies that the effect of physical performance is mainly due to gas transfer impairment. The finding in our study concerning an association between educational level and fatigue is supported by the findings in the study of fatigue in the general population.1 We do not know what this means. It might be related to differences in class-based type of employment, to a trend toward higher morbidity, especially in subjective health, among people with lower educational levels and lower status jobs, or to coping skills in response to severe life events. It might also be related to the response style in questionnaire surveys. The present study has some limitations. The data were collected at two different times. We have, however, no reason to believe that the perception of fatigue among HDSs would change. Loge et al31 did not find any effect of time since diagnosis on fatigue in the complete cohort of HDSs. Second, we regard the late medical complications as chronic. Presumably, any changes in the severity of the sequelae would be a progression rather than a regression. Furthermore, the sample size is small for investigating differences between subgroups. The risk of making type II errors must be considered. The relationship between impaired exercise capacity and fatigue is not optimally investigated. A treadmill exercise testing of aerobic capacity while measuring peak oxygen uptake, blood gas level, and lung function, including spirometry and gas transfer factor, would evaluate more sensitive associations between fatigue and the severity of pulmonary dysfunction.54 With respect to thyroid status, we have no data on the thyroid hormone levels nor the symptoms before the replacement therapy was initiated in the patients with hypothyroidism. How to measure fatigue in general and in cancer patients in particular is currently under debate. The FQ was constructed for use in clinical and epidemiologic studies and has gained widespread use.38,40 However, few of the studies of cancer-related fatigue have used the FQ. Recently, some cancer-specific fatigue instruments have been developed. Few of the instruments have been compared, and no agreement has yet been reached on a common instrument. The scoring procedure used in the FQ, asking how patients assess their symptoms of the last month as compared with earlier, might introduce an underreporting bias regarding fatigue symptoms. A more common scoring procedure, ie, simply asking about the intensity or frequency of present symptoms, is, in our opinion, preferable. While late complications in cancer patients in complete remission are mainly associated with treatment, the causal relations of subjective health-related late complications like fatigue are poorly understood. Treatment-related late effects seem to be of a certain importance in explaining fatigue in this cohort. Improvement in treatment procedures may reduce the late pulmonary and thyroid complications. The standard treatment procedures for HD have been changed for both radiotherapy and chemotherapy. The radiation doses and the size of the radiation field have been reduced. The lung shields have been improved and the involved field has become the standard radiation therapy, replacing the mantle field. Today the standard maximum doses are 30 Gy (35 Gy in cases of rest tumors), 10 Gy less than the subjects in the present study received. With regard to the chemotherapy regimen, mechlorethamine/vincristine/procarbazine/prednisone–like regimens and ChlVPP have been abandoned, except for ChlVPP, which is preferred in cases of relapse. ABVD is the standard regimen as the primary chemotherapy. Today, patients with limited disease receive less chemotherapy than in the past, but in cases of advanced disease and relapses, treatment has become more intensive. Whether these changes in treatment strategies have any influence on fatigue in the survivors should be assessed in future studies. More research is needed to better understand the phenomenon of fatigue in HDSs. In the follow-up of HDSs, our findings indicate that physicians should not only focus on organic examination but also systematically investigate subjective phenomena, such as fatigue. The FQ could be useful as a first screening tool or a guide for communication between the patient and the physician.
Supported by a fellowship grant from Janssen-Cilag AS, Oslo, Norway.
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ABSTRACT
INTRODUCTION
