Review. Hodgkin's disease: Quality of life in future trials. S. Kaasa, 1 H. Knobel, 1 J. Havard Loge 2 & M. Jensen Hjermstad 3

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1 Annals of Oncology (Suppl. ): S17-S Kluwer Academic Publishers. Printed in the Netherlands. Review Hodgkin's disease: Quality of life in future trials S. Kaasa, 1 H. Knobel, 1 J. Havard Loge 2 & M. Jensen Hjermstad 1 Unit for Applied Clinical Research, The Faculty of Medicine. The Norwegian University of Technolog v and Science, Trondheim; 2 Department of Behavioural Sciences in Medicine, University of Oslo, Department of Medical Oncology and Radiotherapy, The Norwegian Radium Hospital, Oslo, Norway Summary It is of great importance to collect data of objective as well as subjective morbidity in patients cured for Hodgkin's disease. Such information may be used when new treatment strategies are discussed, in patients information and communication, to establish rehabilitation programs and to identify individuals who may benefit from rehabilitation. Measurement of health related quality of life (HRQOL) may give important information on how the cancer and/or the treatment has influenced the patients. There is no gold standard instrument for measurement of HRQOL in cancer. However, it is a consensus to use multidimensional patients rated measures with a standard format and scoring procedure. SF-6, EORTC QLQ-C0 and FACT are widely used in Europe and North America. Domain specific instruments includes a more comprehensive evaluation of a specific domain, for example anxiety or fatigue. Fatigue seems to be a prevalent symptom in Hodgkin's disease survivors and might affect patients' ability to perform normal activities and will often reduce their quality of life. Fatigue is defined as a subjective feeling of tiredness and might be measured by standardised and validated instruments such as the Fatigue Questionnaire (FQ) and the Multi-Dimensional Fatigue Inventory (MFI-20). Clincal significance might be defined as a meaningful difference based on consensus by the patient, the doctor and the society. In oncology there is no agreement of how long a meaningful difference in survival should be. For HRQOL a difference between 7 to on a scale ranking from 0 to 0 has been regarded as clinical significant by some researchers. Another strategy to approach the issue of clinical significance is to use norms - estimates from the normal population - and/or reference estimates as guidelines. The long-term complication of the successful treatment of Hodgkin's disease reinforced the need for continued surveillance of treatment and related morbidities. Fatigue is a prevalent symptom and detailed diagnostic work-up is essential to identify patients with this problem. More knowledge about possible biological causes is required in order to understand fatigue and the impact on quality of life among Hodgkin's disease survivors. Key words: clinical significance, fatigue, health-related quality of life, Hodgkin's disease survivors Introduction In patients with Hodgkin's disease the cure rate has increased dramatically since combination chemotherapy has been introduced [1]. Modifications of the treatment schedules have resulted in overall better survival and reduced acute and late toxicity. In subcohorts of patients with advanced disease at diagnosis and/or unfavourable prognostic factors, more intensive chemotherapy may improve survival. Such treatment is known to be very toxic. The acute toxicity is well described, while the influence of the toxicity on subjective health is less well known. The primary treatment intention in these cohorts of patients is to improve the cure rate and/or survival. However, since prognostic factors for identifying those patients who may not benefit from this intensive treatment do not exist, some patients will be 'overtreated'. This is often seen in intensive oncological treatment. Therefore, it is necessary to collect detailed information about objective as well as subjective morbidity in order to give optimal treatment with a minimum of side effects. Such information may be used to modify the treatment schedule in order to optimise the cure rates and reduce the probability of late sequelae. Furthermore, information on morbidity may help clinicians to inform patients and to establish rehabilitation programs. The term Health Related Quality of Life (HRQOL) relates to patients' subjective experience of their life and living situation. In long-term cancer survivors, a wide range of physical, psychological and social limitations has been described [2-]. The WHO definition of health [] ('Health is not only the absence of infirmity and disease, but also a state of complete physical, mental and social well-being'), the Karnofsky Performance Status [6], and the research in the social sciences of social progress in the late 10s and 160s [7, ] have in a broad sense coloured the definition of HRQOL. HRQOL is defined as a multidimensional concept consisting of physical, social, and emotional (psychological) dimensions. These domains have been broken down further into subdimensions, such as physical concerns, functional ability, family well- Downloaded from

2 1 Table 1 Content areas of the SF-6. Table 2. Content areas of the EORTC QLQ-C0. Quality of life domains Number of items Quality of life domains Physical functioning (PF) Role functioning-physical (RP) Bodily pain (BP) 2 General health (GH) Vitality (VT) Social functioning (SF) 2 Role functioning - emotional (RE) Mental health (MH) Reported health transition (HT) 1 being, emotional well-being, spirituality, treatment satisfaction, future orientation, sexuality/intimacy, social function, and occupational function. How to measure HRQOL Issues most likely to be affected by the cancer and/or the treatment should be included when selecting measures in clinical studies. Whenever possible, patients' selfreported data should be collected. Most researchers have therefore agreed upon the use of questionnaires. A series of methods has been developed and tested. Recommendations with regard to the use of measures have been given by several cooperative groups. These recommendations are partly based upon the content, the layout, the scoring procedure, and the development process of the various instruments. There is no gold standard instrument for measuring cancer-related HRQOL. However, it seems worthwhile to concentrate on as few measures as possible in cancer clinical trials in order to be able to compare data between studies. The methods should be multidimensional, with a standard format and scoring procedure, and should ideally be cross-culturally developed and validated. Furthermore, it may also be reasonable to choose measures used in earlier studies on similar populations. Generic instruments Functioning scale Physical Role Emotional Cognitive Social Global quality of life Symptom scales/items Fatigue Nausea and vomiting Pain Dyspnoea Sleep disturbance Appetite loss Constipation Diarrhoea Financial impact Total 0 Number of items within scales/ single items has now been translated and validated into more than 0 languages. The scale structure has been analysed in a multinational setting, and the experience from the IQOLA Project will soon be published in a supplement in the Journal of Clinical Epidemiology. Normative data are currently available for Italy, the US, the UK, Germany, Norway, and Sweden. Data are being collected in general population surveys in ten other countries for the purpose of norm-based interpretation. 1 Cancer-specific instruments In recent years, efforts have been made to design and validate cancer-specific instruments. The EORTC Core Quality of Life Questionnaire (EORTC QLQ-C0) [1] and the Functional Assessment of Cancer Therapy - General (FACT-G) [1] are the most recently developed, and are now widely used in Europe and in the US. One notes a tendency towards more frequent use of the QLQ- C0 in Europe, and the FACT-G in the US. Generic measures evaluate health and/or psychosocial related issues. Some of the generic measures, such as the SF-6 Health Survey (SF-6) [], the Nottingham Health Profile [], and Quality of Life Well-Being Scale [], may be used in cancer clinical trials. SF-6 SF-6 consists of a total of 6 items, and it is divided into eight scales and one single item (Table 1). This instrument is probably the most frequently used generic instrument in HRQOL surveys worldwide. The SF-6 has been translated and validated in the International Quality of Life Assessment (IQOLA) Project []. It EORTC QLQ-C0 The Core Quality of Life instrument encompasses 0 items. This instrument consists of six functioning scales, three symptom scales, and six single items (Table 2). 2 The reliability of the QLQ-C0 has been confirmed in several studies measuring its internal consistency [1-17] and, in one study, measuring the test/retest reliability [1]. The QLQ-C0 has been translated into 27 languages and has been found to be cross-culturally reliable and valid. A scoring manual is produced by the Study Group on Quality of Life, which includes information about various versions of the instrument, modules, scoring procedures, handling of missing data, etc. [1]. Downloaded from

3 1 Domain-specific instruments In addition to the generic and cancer-specific instruments, a series of instruments, the so-called domain-specific instruments, has been developed. This group of measures includes a more comprehensive evaluation of specific domains, such as anxiety, depression, activity of daily living, fatigue, etc. When health-related quality of life measures are used with patients with Hodgkin's disease, two domains seem particularly important of which to have additional information: anxiety/depression and fatigue. Fatigue Fatigue is usually defined as a subjective feeling of tiredness. In cancer patients, fatigue has most likely biological, behavioural, and psychological components, all of which may affect the degree, duration, and consequences of fatigue [21]. Various surveys indicate that fatigue in cancer patients [22, 2] and as fatigue in general [2] is best studied as a multidimensional phenomenon. However, there seems to be no agreement as to how many or which dimensions to include in an instrument. The lack of one or two standardised measures hinders comparisons between the studies. Fatigue measures applied in published studies can be divided into owe- or multidimensional. One dimensional measures have been used most commonly. Such measures include self-constructed single variables, single variables in symptom scales or subscales in generic quality of life instruments such as the SF-6 or in disease-specific instruments - EORTC QLQ-C0. The most recently published one-dimensional instrument is a 1-item addendum to the FACT measurement system called the FACT-F [2]. Multi-dimensional fatigue instruments are available to a limited extent, and the following have been used in studies of cancer patients: Fatigue Questionnaire (FQ) [], The Multi-dimensional Fatigue /nventory (MFI- 20) [27], Piper Fatigue Self-report Scale (PFS) [2] and Fatigue Symptom Checklist (FSCL) [2]. Until now, no comparative studies between those instruments have been published, and there is no empirical data supporting a need for cancer-specific measures. Choosing an instrument for a specific study should reflect the research questions, characteristics of the sample, and the qualities of the measures. The FQ, the MFI-20, and the FACT-F are at present the instruments, which are the best documented. The instruments have not been validated externally due to the lack of any 'gold standard'. Validation has been performed indirectly as with other HRQOL-measures. To our knowledge, comparisons between these instruments have not been performed. Therefore, when comparing data on fatigue collected with different measures, interpretations must be done with caution. FQ was developed to measure fatigue in clinical and epidemiological studies. FQ in its present or previous Table Fatigue-instruments applied in measurements of fatigue among cancer patients. Instruments Characteristics References Unidimensional RFS Single item. VAS scale [22,2] VAFS Single item. VAS scale [] PBFFC 1 statements. response categories [1.] FACT-F 1 statements. response categories [2] Multidimensional FSCL 0 symptoms. subscales [. 6] PFS items, subscales [7] FQ items, 2 subscales [] MFI items, subscales [,0] Abbreviations: VAS - visual analog scale, RFS - Rhoten fatigue scale; VAFS - visual analog fatigue scale: PBFFC - Pearson Byars fatigue feeling checklist: FACT-F - functional assessment of cancer therapy - fatigue; FSCL - fatigue feeling checklist; PFS - Piper fatigue selfreport scale; FQ - fatigue questionnaire, MFI-20 - multidimensional fatigue inventory. versions has been used in population studies [0] and in one normstudy [1]. FQ measures fatigue two-dimensionally (physical and mental fatigue). MFI-20 has recently been developed and measures fatigue in five dimensions. In the MFI-20 the intercorrelations between the subscales were found to be high, and the authors themselves question the justifiability of all the subscales [2]. The FACT-F consists of thirteen items and measures physical fatigue-related symptoms (i.e., one-dimensionally). All these instruments have been validated, and reliability estimates have been found to be satisfactory. Fatigue seems to be an area of great interest in health care in general and in cancer and in Hodgkin's disease specifically. Taking into consideration the great interest and its clinical importance, further development of the construct fatigue, including investigation of the content seems to be necessary. Interpretation of data Interpretation of HRQOL data may be difficult. In order to use information in the decision-making process, both on the individual level and group level, the issue of clinical significance has to be addressed. Clinical significance is defined as a meaningful difference, for example after an intervention for a symptom. The outcome is often evaluated by the patient and guided by the doctor. On group level, a clinically significant difference is defined as a meaningful difference based on consensus by the patient, the doctor, and society. The challenge of clinical significance is a general problem in clinical research. For example, when comparing patients receiving combination chemotherapy to a group of patients receiving best supportive care, there is no agreement as to how great a clinical meaningful difference in survival should be. In order to determine the clinical significance on the Downloaded from

4 EORTC QLQ-C0, a subjective significant questionnaire was used []. The questionnaire asks the patients about perceived changes in physical, emotional and social functioning, and in global quality of life. Patients' scorings on the QLQ-C0 were compared to the rating on the subjective significant questionnaire. For patients who indicated 'little' change, either for better or worse, the mean change in scores was about -, for a moderate change about -20, and for very much change greater than 20 []. These numbers can be used as guidelines when interpreting quality of life data and also when sample sizes are required to be calculated in clinical trials. Other methods may also be used, such as anchoring patients' scorings to norms and comparing patients scores to different subcohorts of normal populations. Reference data Values representing the general population are often absent for HRQOL measures. Reference data from random draws from the Norwegian population are presented here. Such data may be used as a guideline when interpreting scores in different patient populations. EORTC QLQ-C0 Reference data of the EORTC QLQ-C0 have been established through a population survey of 000 Norwegian inhabitants []. The participants who were randomly drawn from the Norwegian Population Registry received a questionnaire packet consisting of the EORTC QLQ- C0 (+) and a form asking about sociodemographic data, and past or present illness or health. An excellent response rate of 6% was achieved. There was a low amount of missing data, only 1.%, but more missing data were seen with increasing age. The sensitivity of the questionnaire was shown by the clear discrimination in scores between age and gender groups. Clinical validity was shown by the distinct differences according to age and sociodemographic characteristics. The mean scores for all scales and items divided by gender and ten-year age groups are listed in Table. SF-6 For the SF-6, reference data from the general population are available in many different countries. As part of the Norwegian follow-up study of long-term Hodgkin Disease Survivors (HDS), normative data for the SF-6 was collected by approaching 00 Norwegians aged 1-, representative of the general Norwegian population (Table ). We received 22 completed questionnaires (67%) []. Both the response rate and the data quality declined with increasing age. In all scales except in the General Health scale, women reported poorer health than men. All the physical health scales were strongly influenced by age, with decreasing subjective health with increasing age. While the mental health scales were influenced by marital status, educational status affected all scales, but least in the mental scales. In future comparisons, differences in social status between the samples must therefore receive special attention in addition to adjustment for age and gender. Fatigue questionnaire Population norms for interpretation of fatigue measurements have been lacking. A random sample of 00 Norwegians aged 1- years was therefore approached by mail [1]. We received 22 responses (67%). The sum score of all the responses (each scored 0, 1, 2, ) is designated total fatigue (TF). The FQ also allows for case definition which demands substantial fatigue of duration six months or longer. The survey also included variables on sociodemographic status and health, and the normative data for physical, mental and total fatigue, and fatigue cases are presented in Table 6. Use of norms Similar findings were found for the HRQOL measures and fatigue questionnaire with respect to gender and age. Thefindingscan be summarised as follows: Men reported better functioning on all scales compared to women. Age seemed to influence the scores for both genders, with a gradual decline in mean scores for all functioning scales except emotional, and more symptomatology with increasing age. This may be a natural process and should be taken into consideration when interpretation and comparisons of HRQOL and fatigue are performed. It is not recommended to compare data directly between studies using different HRQOL measures. However, the norm-based data presented here, stratified on gender and age, may serve as a guide for comparison of data collected with different instruments in various studies. Known group comparison In the general population, data on self reported illness was collected (Table 7). The subjects in the fatigue norm study were asked if they had (currently or previously) one offivediseases or if they had some type of present health problem (nine items). (2%) reported a past or present disease (hypertension: (17%), cardiac failure: (%), cancer: 0 (%), cardiac infarction: 67 (%), diabetes: 2 (2%)). Twelve hundred forty-six (%) stated they had a present health problem, most commonly back pain (n - 02, 22%) and chronic allergy («= 2, 1%). Based on the responses to these 1 items, the sample was divided into four categories: no disease or current health problem, disease but no current health problem. Downloaded from

5 Q-C0 General population. Male Female All (n = 16) 1-2 (;i = 20) 0- (7/ = 22) 0- (7i = 12) 0- (n = 1) 60-6 (n= ) >70 (n = 1) All (n = ) 1-2 (n = 1) 0- (7i = 1) 0- (7/ = 17) 0- (7i = 1) 60-6 (n = 12) >70 (71=171) ". new tes better function. tes more symptoms. ral population. Female ^ 2 years ( = 2) 0- years ( = 2) 0- years (7, =21) 0- years ( = 17) 60-6 years ( = ) > 70 years (71 = 0) All (il = 0) ^ 2 years (71 = 2700) 0- years ( = 21) 0- years (» = 220) 0- years ( = 1) 60-6 years (7i = physical functioning; RP - role limitations, physical; RE - role limitations, emotional; BP - bodily pain; SF - social functioning; MH - mental health; VT - vitality; GH -- gen Downloaded from

6 12 7 Total fatigue, physical fatigue, mental fatigue and percentage fatigue cases in relation to health condition in the general population (mean scores after adjustment for age and gender by ANCOVA). Health condition Total fatigue Physical fatigue Mental fatigue Percentage of cases < ^ No disease/current health problem (n = 6) Past or current present diseased = ) Current health problem (n = 2) Disease and current health problem (n = ) Women Men Cases in percentage of each group's total. 2" o ~ no disease but current health problem, and disease and current health problem. This type of data may be used to interpret differences between disease cohorts and samples from the general population (see below) by comparing disease groups to the different norm groups depending upon self-reported disease and/or health problems. V = ON r-j - r-l \d -^ -- ws HRQOL and fatigue in Hodgkin's disease survivors O. O O- < w O = ^ II o ^ O\ ^ n m 00 o We have reported a high incidence of various long-term self-reported medical problems among HDS treated at the Norwegian Radium Hospital We also found high levels of anxiety and fatigue among those HDS [6, 7]. Other studies of subjective health among long-term HDS have demonstrated lacking return of energy or fatigue [, ], reduced cognitive functioning [], increased levels of psychological distress [0], reduced physical functioning [, 1], and restrictions in role functioning [, 1]. Since HRQOL was measured differently in these studies, direct comparisons of the results become difficult. Comparisons are also limited by characteristics of the samples. In one study the HDS had been recruited for clinical trials, and in another they had been treated for advanced disease. In two of the studies the samples were relatively small (< 0 subjects), and only two of the studies included comparison groups. Consequently, the published studies of HRQOL among long-term HDS strongly indicate that HRQOL is affected many years after curative treatment, although the severity of this, and which dimensions are most affected, are not clarified. O V = q ^f ^ oo i HDS, HRQOL, and fatigue in Norway u _ 0. 2 r- In a cross-sectional study, fatigue among the HDS (aged 1-7 years) treated at the Norwegian Radium Hospital from 171 to was assessed by the Fatigue Downloaded from

7 1 Questionnaire (FQ), and the results were compared to normative data from 221 controls of the same age [7]. The controls were representative of the general Norwegian population [1]. The level of fatigue was significantly higher among the HDS than among the normal controls (1. versus.2; P < 0.001) [7]. In order to interpret the level of fatigue in HDS, the controls were divided into four subgroups by their health conditions. Fatigue caseness was defined by substantial fatigue lasting six months or longer. Cases were significantly more frequent among the HDS (men: 2%, women: 27%) than among the controls (men: %, women: %; P < 0.001). Biological correlates In most questionnaires fatigue and vitality are included as separate domains [, 1, 2]. Many cancer patients experience fatigue as a serious health problem leading to intervals with sick leaves or in the end, to a permanent pension at young age [7, ]. Similar findings have been seen in patients suffering from AIDS [1], systemic lupus erythematosus (SLE) [0], and multiple sclerosis (MS) [2]. The pathogenesis behind the symptom fatigue is unclear [61]. The probable causes are multiple, consisting of psychological and/or biological factors [21-2, ]. Furthermore, it may vary between diseases [60]. A better understanding of the mechanism may be used to develop treatment strategies for specific groups suffering from fatigue. Organic morbidity including heart and/or lung failure, permanent changes in the endocrine or immune system, and neurologic impairments may cause fatigue. This type of morbidity may be treatment and/or disease correlated [22,, 62]. There is no data showing a clear empirical connection between biological factors and fatigue reported among patients. The immunodeficiency caused by Hodgkin's disease itself and/or the mutilation related to the therapy may increase the level of cytokines [2-]. In other diseases such as SLE and MS, an increased level of IL-1 has been observed with increased level of fatigue [0, 2]. In HIVpatients changes in the levels of IL-1, TNF, and IFN-y have been observed, and it is suggested to be a possible explanation for fatigue among these patients [1]. It is proposed that cytokines may act as 'neurokines' and affect the central nervous system [2]. In the central nervous system IL-1 is produced by astroglial cells or by neurons, or it may gain access to the brain through a lacking blood brain barrier in the region of preoptic nucleus of the hypothalamus. Cytokines react on neurons and their axons ramify widely through the brain including the limbic cortex, brainstem, and lateral hypothalamus. This implies that cytokines may act like a modulator of neural functions as they are modulators of the immune system [2, ]. Chronic cardiac dysfunction in HDS has been found after irradiation and may be due to pathology in peri- Female Male No disease or current health problem B Past or present disease Current health problems Disease and current health problems E Hodgkin's disease survivors Figure I. Fatigue cases in Hodgkin/s disease survivors and controls with different health conditions. cardial, myocardial, valvular, conduction system, or coronary arteries [, ]. In chronic heart failure, fatigue is a cardinal symptom limiting physical activity even in low level exercise leading to the build-up of products of anaerobe metabolism within skeletal muscle, leading to reduced physical capacity []. Furthermore, reduced lung function has been observed in several cohorts with HDS [6]. Pathology in the lung, in the heart muscle, and, as an indirect consequence, in the skeletal muscle, may lead to fatigue. A frequent complication following radiotherapy among patients with HD is hypothyroidism, although mostly a subclinical manifestation. Also, the risk of Graves'disease, and benign and malignant thyroid nodularity in HD after irradiation is found to be elevated [7]. The frequency and severity of gonadal dysfunction appears to be higher among HDS compared with longtime survivors of non Hodgkin's disease []. It is probably related to the intensive radiation therapy and the relatively higher dosis of procarbazine in the combination chemotherapy in HD. A link between endocrine dysfunction and fatigue among HDS is not empirical documented. The long-term complications of the successful treatment of Hodgkin's disease reinforce the need for continued surveillance of treatment- (and disease-) related morbidities. Fatigue is a prevalent symptom in a series of diseases, and detailed diagnostic work-up is essential to identify patients with this problem. More knowledge about possible biological causes is required in order to understand fatigue and the impact on quality of life among HDS. Downloaded from

8 1 How to measure quality of life in future trials Most of the studies published so far regarding Hodgkin's disease have used cross-sectional designs measuring HRQOL at a given point of time after treatment. In order to improve the understanding of patients' HRQOL, prospective data will give a better insight into the nature of the disease and/or the treatment's influence on patients' lives. Such information may be used to guide the doctor/patient communication, to develop support programs, and to better understand late sequelae after disease and/or treatment. Since the prevalence of Hodgkin's disease is low, multinational collaborations seem to be of great importance. Standardisation of instruments will improve the possibility of comparing data between studies. SF-6 and the EORTC QLQ-C0 are now frequently used instruments, both in HDS and other cancer cohorts. Both instruments have been shown to be valid and feasible for use in both cross-sectional and prospective studies. Disease-specific instruments supplementing the EORTC QLQ-C0 may be necessary to use in some studies, depending upon the study question. Fatigue seems to be of specific importance in Hodgkin's disease; whether this is the case for other cancer diagnoses is not clarified. Investigations comparing HDS with other cancer diagnoses, such as testicular cancer, breast cancer etc., may give an answer as to whether fatigue is specific in Hodgkin's disease or a general symptom after cancer cure. In order to improve cancer fatigue, a better biological understanding of the phenomenon seems necessary. By using standardised questionnaires of the fatigue construct, primarily in a prospective design combined with measures of biological changes, new knowledge may be gained. It seems logical to look for changes in the immune system, including measuring cytokines, and in the endocrine system, including measurements of thyroid function. Furthermore, such investigations should probably be supplemented by measures of cognitive behaviour and psychological reactions. Conclusion and recommendations HRQOL measures including fatigue have given important information about survivors of HDS. International collaboration is necessary in order to obtain sufficiently large samples in prospective studies. Notes 1. To request copies of published or pre-publication IQOLA Project translations, or to request permission to translate the SF-6 in other languages, contact Barbara Gandek, IQOLA Project Director. Health Assessment LAB, 70 Washington Street. XEMC # Boston. MA 021. USA. Fax: (617) 66-. Additional information about the SF-6 Health Survey can be found at 2. To request permission to use the questionnaire and to receive the scoring manual, contact EORTC Data Center, Quality of Life Unit. Avenue E. Mounier -B, 00 Brussel, Belgium, Tel Fax References 1. Sutcliffe SB. Wringley PFM, Peto J et al. 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