Fatigue in cancer patients treated with cytotoxic drugs

Transcription

1 J Oncol Pharm Practice (2006) 12: Fatigue in cancer patients treated with cytotoxic drugs Per Hartvig PharmD, PhD 1 Johan Aulin MSc in pharmacy 1,3 Matilda Hugerth MSc in pharmacy 3 Sofia Wallenberg MSc in pharmacy 3 Gunnar Wagenius MD, PhD 2 Study objectives. Cancer-related fatigue is a significant and distressing problem for the cancer patient, affecting their physical and psychosocial function negatively, and reducing their quality of life. The aims of this study were to assess frequency, severity, and the consequence of fatigue in cancer outpatients receiving cytotoxic drugs, using an existing international fatigue scale applied for Swedish use. Methods. The study used a non-randomized, prospective design to evaluate fatigue and its impact on quality of life in outpatients receiving cytotoxic drugs. Once a week, 147 cancer patients, in an outpatient ward for cytotoxic drug administration, filled out questionnaires containing 13 items from the Fatigue Symptom Inventory (FSI), and five additional questions. Results. Prevalence of fatigue was 92% in the week after all patients had received cytotoxic drugs, and patients were statistically significantly more fatigued during than before treatment. The degree of fatigue was highest the week after treatment, and declined over the following week. Other symptoms, especially depressed mood, showed a strong correlation with cancer and cytotoxic-induced fatigue. Lung and breast cancer patients experienced the highest degree of fatigue. Some cytotoxic drug regimens were, apart from the underlying disease, associated with high fatigue scores, eg, those with cyclophosphamide or gemcitabine. Patients not receiving first line treatment scored significantly higher fatigue with more influence on daily living. Conclusion. The study verified that fatigue is a common side effect, and affects quality of life negatively, even for outpatients receiving cytotoxic drugs. The clinical oncology pharmacist must inform patients that a severe tiredness, fatigue, may follow cytotoxic drug administration. J Oncol Pharm Practice (2006) 12: Key words: cytotoxic drugs; fatigue; quality of life; self-report; side effects INTRODUCTION Cancer-related fatigue (CRF) is a condition associated with a feeling of tiredness and lack of physical energy. From the 1 Hospital Pharmacy, University Hospital, Uppsala, Sweden 2 Department of Oncology, University Hospital, Uppsala, Sweden 3 Department of Pharmacokinetics and Drug Therapy, Uppsala University, Uppsala, Sweden Address correspondence and reprint requests to Per Hartvig, Adj. Professor, Hospital Pharmacy, University Hospital, SE , Uppsala, Sweden per.hartvig@apoteket.se It is, however, difficult to describe, and the definition in the literature varies. The National Comprehensive Cancer Network (NCCN) defined CRF as a persistent, subjective sense of tiredness related to cancer or cancer treatments that interferes with usual functioning. 1 Fatigue is one of many symptoms seen in cancer patients and both clinical experience and several clinical studies indicated that it was one of the most common unrelieved symptoms of cancer treatment. 2 The prevalence of CRF for patients undergoing cytotoxic drug therapy have been reported to be in the range 80100%. 3 The highest degree of 2006 SAGE Publications /

2 156 Hartvig et al.: Cytotoxic drug induced fatigue fatigue was often experienced shortly after cytotoxic drug treatment and then declined until the next treatment. 1,4,5 Fatigue also occurred in patients undergoing radiotherapy or biotherapy, eg, treatment with interferon or interleukin-2. Furthermore, CRF is a significant and distressing problem, affecting negatively the physical and psychosocial function of the cancer patient, 6 thus reducing their quality of life. 7 Fatigue may also affect treatment of the cancer by being a dose-limiting symptom. 8 Hence, improved control of CRF and other symptoms may increase tolerance towards cytotoxic drugs in cancer patients, resulting in a more effective treatment. Unfortunately, thus far, there is no generally effective treatment for fatigue. The clinical and scientific interest in CRF has grown in recent years. This could partly be due to a growing interest in patient s quality of life, and the fact that other symptoms of the disease, such as nausea and pain, are now relatively better controlled. 1 The mechanisms of fatigue are complex and poorly understood. 9 Many investigations have highlighted that fatigue is both multifactorial and multidimensional. 7,10,11 Biological, psychological, social and personal factors influence the onset, impact, expression, duration, and severity of the experience of fatigue. 11 The specific aims of the study were to study fatigue in cancer patients receiving cytotoxic drugs, the course of its severity over time, and to explore the correlation between fatigue in different subgroups with a variety of cancer types, treatments and side effects. A fatigue scale, translated for Swedish use, was developed from an existing international scale. METHOD Study design This longitudinal study was conducted at an outpatient ward for cytotoxic drug administration, in the Department of Oncology at the Uppsala University Hospital, Sweden. The Ethics Committee of the Faculty of Medicine, University of Uppsala, gave their approval for the study (No ). The study used a non-randomized, prospective design, to evaluate fatigue and the impact of fatigue on quality of life in consecutive cancer outpatients receiving cytotoxic drugs. Participating patients filled out a questionnaire at the end of every week. The first form was labelled Week 1, the second Week 2, the third Week 3 and so on. The first questionnaire for those patients who had never received cytotoxic drugs was called Baseline and was excluded in the general analyses. Study population Patients were selected systematically by the investigator with assistance from the caregivers. Inclusion of patients was made on three occasions October and November 2000 (study I: n/73); October and November 2003 (II: n /40); and February and March 2004 (III: n /34). In all, 147 patients were included. The two latter samples of patients were randomized to a simple exercise program for the relief of fatigue symptoms. 12 Inclusion criteria were: diagnoses of any cancer, receiving any kind of cytotoxic drug treatment, understanding Swedish, being fit enough to fill out the forms, and absence of severe psychiatric or mental disorders. Patients fulfilling the criteria were asked to participate and gave their consent. The gender of the patients, diagnosis, time elapsed since diagnosis, and disease status is given in Table 1. The cytotoxic drug treatment protocol, number of treatment cycles, and the length of each cycle were recorded from the patient records at the beginning of the study (Table 2). The patterns of CRF were studied separately for patients receiving treatment once every second and third to fourth week. A healthy population of 47 caregivers at the Department of Oncology, University Hospital of Uppsala, was used as a comparison group in 2000 to validate the instrument. They were asked to assess their fatigue on one occasion. Exclusion criteria for the healthy subjects were a history of cancer or cytotoxic drug treatment. The non-cancer group was only asked to respond to the original questions, No. 2 14, in the questionnaire. Age, gender and history of cancer or cytotoxic drug treatment were recorded for the non-cancer group as well. Instrument and data collection The Fatigue Symptom Inventory (FSI), 13 was chosen for assessment of CRF, as it was found easy and had relevant questions for the study. The English version of the instrument has previously been validated. 13 FSI was translated to Swedish and the translation was applied to healthy subjects for evaluation. In addition, comments from clinicians on the instruments were collected. The instrument was translated back to English to ensure that the Swedish translation was accurate. The instrument contained 13 question from FSI (question 214) and is shown in Appendix A. The first four items asked the respondent to rate the

3 Hartvig et al.: Cytotoxic drug induced fatigue 157 Table 1. Patient characteristics (n/147) Gender Males 47 (32%) Females 101 (68%) Diagnosis, site of tumor Breast 55 (38%) Gastrointestinal 44 (30%) Gynaecologic 20 (14%) Lymphoma 8 (6%) Prostate 7 (5%) Lung 7 (5%) Other sites 5 (3%) Time since diagnosis (months) (27%) (21%) (11%) /12 50 (41%) Cytotoxic drug regimen Cyclophosphamide, fluoruracil, epirubicin, FEC 28 (19%) Paclitaxel/docetaxel (alone or in combination) 25 (17%) Carboplatin (alone or in combination) 13 (9%) Fluorouracil (alone or in combination not FEC) 37 (25%) Gemcitabine 13 (9%) Irinotecan 5 (3%) Fluorouracil, methotrexate, cyclophosphamide; CMF 5 (3%) Vinorebine 5 (3%) Doxorubicin 4 (3%) Other cytotoxic drugs 12 (8%) Cycle at the beginning of the study First cycle 24 (16%) Second to fifth cycle 83 (56%) Sixth to ninth cycle 25 (17%) /Ninth cycle 15 (10%) Line of treatment First line treatment 93 (63%) Not first line treatment 54 (37%) intensity of fatigue at its worst, least and on mean, respectively, during the previous week, and their fatigue at the present moment, using an 11-point rating scale. The next seven items assessed the interference of fatigue symptoms with daily living. The respondents were asked to indicate to what extent fatigue interfered with their general activity, ability to take a bath and dress, work ability, ability to concentrate, relations, enjoyment of life and mood during the previous week, using the same 11-point rating scale. Two items assessed fatigue duration, eg, the number of days in the previous week that fatigue was experienced, and the severity of fatigue each day it was present. 13 The first question in the questionnaire, which does not originate from the FSI, was added to assess fatigue before any cytotoxic drugs were given to create a baseline result for each patient. The respondents experiences of pain, nausea, anxiety, mood depression, insomnia, diarrhoea or constipation during the last week were addressed in question No. 15. The respondents were also asked to answer questions (Nos. 16 and 17) about exercise and nutritional intake the previous day. The last question (No. 18) was open-ended. Statistical analysis Data were transferred from written documents to a database file (Excel). The results were first analysed with descriptive methods: mean, number, frequency and distribution were studied. In a multivariable test, X-variables were defined as all demographic and medical variables, including presence or absence of pain, nausea, anxiety, depression, insomnia, diarrhoea or constipation. Y-variables were defined as question 2 14 in the questionnaire (fatigue and interference scores). The Sign test, MannWhitney U-test, and Kruskal Wallis ANOVA test were used to perform statistical analyses. These tests do not assume that data follow a normal distribution; they are so called non-parametric tests. The Sign test was used to verify the difference between fatigue before treatment and during treatment. Differences between subgroups with different demographic and medical variables at Week 1 and Week 2 were detected with Mann Whitney U-test (two subgroups in each analysis), and KruskalWallis ANOVA-test (more than two Table 2. Differences in fatigue rating FSI between the non-cancer group and the cancer group from the three studies (I III) before treatment and 1 week after treatment Non-cancer group Before treatment Mean Week 1 Mean Week 2 Mean fatigue (standard deviation) 2.83 (1.78) I: 2.46 (2.84) 3.01 (1.99)* 3.38 (1.99)* II: 2.36 (1.76) 3.24 (2,13) 2.53 (1.94) III: 2.29 (1.99) 2.52 (2.0) 2.02 (1.71) No. of days fatigued during the week (standard deviation) 1.33 (1.48) Not measured 2.36 (2.26)** 2.83 (2.30)** *Statistically significantly higher than before treatment (the Sign test). **Statistically significantly higher than in the non-cancer group (Mann Whitney U-test).

4 158 Hartvig et al.: Cytotoxic drug induced fatigue subgroups in each analysis). Statistically significant results were defined as P 5/0.05. RESULTS Patient characteristics A total of 180 patients were screened for inclusion, and of these 147 (82%) agreed to participate in the study. Reasons for not participating were mostly that participation took too much time. Seven patients (5%) failed to return the questionnaires. The ages of the patients varied between 26 and 79 years, with a distribution of 100 females and 47 males. The sample was diverse with respect to type, stage of disease and cytotoxic drugs regime (Table 1). Prevalence and intensity of CRF Prevalence of CRF was defined as the percentage of patients not reporting 0 for mean fatigue. The prevalence of fatigue was 85% at Week 1. Females had a higher prevalence (91%) than males (71%). The prevalence in the total population had increased to 92% by Week 2, when all patients had received cytotoxic drugs. The prevalence of fatigue before any treatment for cancer was 57%. The intensity of fatigue measured as mean FSI score was significant less before treatment compared to after cytotoxic drugs, 3.019/1.99 and 2.469/2.84, respectively (Table 2). The mean fatigue score in the three study groups given cytotoxic drug treatment are shown in Table 2. Non-cancer subjects compared with cancer patients before and during treatment There were 47 subjects in the non-cancer group. Their mean age was 449/10 years, 23% were male, and 77% were female. The non-cancer subjects had higher scores for fatigue, but lower scores for other variables compared with the first sample of cancer patients at Week 2, and for most variables at Week 1. Statistically significant differences were obvious in the non-cancer and cancer patient groups at Week 2 for number of days fatigued, severity and duration of fatigue each day, fatigue right now, least fatigue, interference with general activity (question 6), interference with ability to dress or bath (question 7), and interference with ability to work (question 8). For questions on the number of days fatigued, least fatigued and interference with ability to dress and bath (question 7), the differences were statistically significant also at Week 1 (MannWhitney U-test). A comparison of the mean fatigue between the different groups is shown in Table 2. Change in fatigue ratings over time Fatigue increased in the weeks following cytotoxic drug treatment and then declined before the next treatment (Figure 1). There was a discrepancy between Week 1, when most patients, except those with a cycle length of 7 days (n /6), were not receiving cytotoxic drugs, and Week 2, when all patients were receiving cytotoxic drugs. This was a general trend, but due to the different intervals between cytotoxic drugs administered to the patients, results from the questionnaires of each study week is not given. Correlation with demographic and clinical variables Non-significant relationships (KruskalWallis ANOVA test) were recorded between the following variables and the fatigue and interference scores at Week 1 : age (P/0.10), gender, diagnosis, time since diagnosis, and disease status measured as Karnofsky performance status. A gender difference of fatigue scores became statistically significant for Week 2. Females showed higher mean fatigue than males (3.869/1.94 compared with 2.279/1.67). There was no consistent trend in the differences between age groups, ie, that a higher age would be associated with higher fatigue. Regarding differences between diagnoses of the first patient sample, lung cancer patients seemed to experience the highest degree of fatigue after treatment, followed by breast, gynaecologic and gastro- Average fatigue Week Treatment every 2nd week Treatment every 3rd week Figure 1. The mean fatigue experienced by patients receiving cytotoxic drugs every second week (Week 2, 4, 6 and 8) and every third week (Week 2 and 5) 5 6 7

5 Hartvig et al.: Cytotoxic drug induced fatigue 159 Table 3. Mean (SD) fatigue reported by patients with different diagnoses in study I Lymphoma (n/6) Prostate (n/3) Gynecologic (n/6) GI (n/16) Breast (n/30) Lung (n/3) Before treatment 4.33 (3.01) 2.00 (3.46) 4.17 (3.54) 2.33 (3.01) 2.33 (2.89) 1.0 (1.73) Week (1.47) 2.00 (3.47) 3.33 (1.61) 2.94 (2.80) 3.30 (1.86) 3.67 (1.53) Week (0.71) 1.67 (1.53) 3.33 (2.40) 2.57 (1.65) 4.35 (1.66) 5.00 (2.00) intestinal, lymphoma and prostate cancer patients ( Week 2 ), as illustrated in Table 3 (Figure 2). The difference in fatigue score between the diagnoses with the highest number of patients, eg, breast, gynaecologic and gastrointestinal cancer patients, was statistically significant, while there was no difference between all the diagnoses (P/0.06). Patients with lymphoma, prostate and gynaecological cancer experienced less fatigue at Week 2 than before treatment (Table 3). Influence of the cytotoxic drug treatment Analysis of separate treatments yielded that the highest mean fatigue at Week 2 was experienced by patients from the first sample, who received in decreasing order: gemcitabine, cyclophosphamide, fluorouracil in combination, epirubicin (FEC), docetaxel, carboplatin and fluorouracil (Figure 3). However, the number of patients in each subgroup was too small in many of the separate treatment groups and, therefore, they had to be excluded from the statistical analyses. The difference between treatments was not statistically significant at the P 5/ 0.05 level. There was no statistically significant correlation (KruskalWallis ANOVA test) between fatigue and the number of cytotoxic drugs cycles the patients had undergone at the start of the study. However, patients who received first line treatment had lower scores than the patients who had already tried first line treatment unsuccessfully. These differences were significant for mean fatigue, most fatigue and interference with general activity (question 6) at Week 2 (Mann Whitney U-test). Influence of other symptoms and side effects Statistically significant correlation (MannWhitney U-test) were found at Week 1 and Week 2 between fatigue ratings and pain, nausea, anxiety, depression and insomnia, whereas the correlation was not statistically significant with diarrhoea and constipation (Table 5). Patients with the former symptoms (pain, nausea, anxiety, depression and insomnia) had higher fatigue scores. The prevalence of the symptoms is shown in Table 4. Responses to the open-ended question A total of 59 answers, relating to fatigue, were given to the open-ended question, by 33 patients. Several patients pointed out a distinction between the tiredness they were feeling during the treatment and Fatigue Week Diagnosis ±Std. Dev. ±Std. Err. Mean Figure 2. Box-plot of the fatigue scores at Week 2 for cancer patients with different diagnosis. 0/lymphoma (n/2), 1/prostate (n/3), 2/lung (n/3), 3/gynaecologic (n/9), 4/gastrointestinal (n/14) and 5/breast (n/18).

6 160 Hartvig et al.: Cytotoxic drug induced fatigue Fatigue Week Treatment ±Std. Dev. ±Std. Err. Mean Figure 3. Box-plot of the fatigue scores at Week 2 for cancer patients receiving different treatments. 1/cyclophosphamide, fluorouracil and epirubicin (FEC) (n/8), 2/fluorouracil (Flv) (n/7), 3/carboplatin (n/2), 5/docetaxel (n/7), and 8/gemcitabine (n/3). course of disease, compared with before, eg, abnormal (tiredness) compared with before. Another patient described a change in the onset of fatigue: I now become tired suddenly. My energy used to run out gradually instead of all at once. Physical fatigue was described as, eg, The muscle weakness in my arms is marked and I am physically worn out. Several patients suggested that nausea, pain, anxiety, loss of appetite and other symptoms had an impact on their CRF. DISCUSSION The present study in outpatients receiving cytotoxic drugs has verified that fatigue is a common side effect, and negatively affects the quality of life for cancer patients. However, the result was probably an underestimation of the fatigue problem in the total cancer population, since only the least ill patients, outpatients, were asked to assess their fatigue. There are several different definitions of fatigue and no universal one is available. Some studies have shown that patients with cancer experience CRF as something distinguishably different from any tiredness they have experienced before the cancer disease. 14 Stone et al., 2 suggested that there are two distinct meanings of the term fatigue: one objective decrement in physical or mental performance together with a subjective feeling of weariness together with a perception of decreased capacity for physical and mental work. 2 Often, only the subjective feeling of tiredness and lack of physical energy is meant. 11 A further description by Piper, 15 defined fatigue as: a subjective feeling of tiredness that is influenced by cardiac rhythm. It can vary in unpleasantness, duration and intensity. When acute, it serves a protective function; when it becomes unusual, excessive or constant (chronic), it no longer serves this function and may lead to an aversion to activity with the desire to escape. 10,15 Fatigue has also been defined as an abnormal condition that persists for 2 or more weeks and occurs on most days. 14 Common features may include reduced motivation and interest in activities, exhaustion, apathy, generalized weakness, sleep ab- Table 4. Prevalence of other symptoms (from study I and III) during the first week of study Pain 28 Nausea 20 Anxiety 23 Depressed mood 31 Insomnia 35 Diarrhoea 17 Constipation 22 Table 5. The prevalence of other symptoms at Week 1 and 2 Week 1 Week 2 Pain 20; 29% 40; 33% Nausea 45; 19% 17; 31% Anxiety 34; 26% 39; 29% Depression 42; 26% 37; 33% Insomnia 29; 44% 33; 53% Diarrhoea 10; 14% 17; 22% Constipation 27; 17% 24; 24%

7 Hartvig et al.: Cytotoxic drug induced fatigue 161 normalities, irritability and sadness. 14 A more commonly used definition stresses that the subjective fatigue is perceived as unusual, abnormal or excessive whole body tiredness disproportionate to, or unrelated to, activity or exertion. 16 Ream and Richardson, 17 have suggested a similar definition of fatigue: A subjective, unpleasant symptom which incorporates total body feelings ranging from tiredness to exhaustion creating an unrelenting overall condition which interfered with the individuals ability to function to their normal capacity. The most common way to measure subjective fatigue is to use self-report scales. The answer may be given on a verbal rating scale (not at all, a little, quite a bit, very much), a numeric rating scale (05), or a visual analogue scale, VAS, ie, a line that represents different degrees of fatigue. 9 Some of the older scales only measure the intensity of fatigue (one-dimensional). Examples of widely used onedimensional scales are the Rhoten Fatigue Scale, 18 the Profile of Mood States (POMS), 19 and the Fatigue Severity Scale. 20 The multidimensional scales, besides assessing the intensity of fatigue, also try to assess the quality of the symptoms. 11,1928 Dimensions included in multidimensional scales are, for example, physical, emotional and cognitive fatigue. Since fatigue is now considered a multidimensional symptom, most of the recent studies have used multidimensional scales. However, the number of items has generally been too many and one of the less complex scales was chosen for this study. The present study used the FSI, which is a three-dimensional scale measuring intensity, duration and impact of fatigue on quality of life. 13 The results of the present study confirm the prediction that cytotoxic drug treatment, together with other factors, significantly contribute to fatigue in cancer patients. Evidence to support this hypothesis was given by the fact that the degree of fatigue was distinctively higher at Week 2, when every patient had received cytotoxic drugs compared to Week 1, when all but six patients did not receive cytotoxic drugs. Patients also claimed to be more fatigued during treatment than before treatment. Further support was that fatigue was highest the week after treatment and in concordance to studies by Schwartz et al. 14 There seemed to be a correlation between fatigue and diagnosis. The results need to be interpreted with caution in some of the groups, since the number of patients was small. Lung cancer patients experienced the highest degree of fatigue, which was consistent with earlier studies. 11,15,16 Patients with prostate, lymphoma and gynaecological cancer stated that they experienced less fatigue before treatment than during treatment. The few lymphoma cancer patients became less fatigued during treatment, which verified a clinical impression of a general condition improvement in these patients. For the gynaecological patients, it is not expected that they were less tired during treatment than before, although they still experienced rather high fatigue as a group. This result, which could be due to regression of their tumours, needs further investigation. Patients with ovarian cancer should also be separated from patients with cervix cancer, since a study indicated that patients with ovarian cancer experienced high CRF, while patients with cervix cancer experienced low fatigue. 16 One unexpected finding was that females seemed to experience a higher degree of fatigue than males. There are many factors that contribute to the subjective fatigue. The contribution of each factor may vary between patients and in the individual patients over the course of illness and treatment. The degree of fatigue also differed between cancer diagnoses. Furthermore, both the underlying cancer disease and the cytotoxic drug treatment may cause fatigue and are, therefore, hard to separate, since they coexist. Cytotoxic drugs have been proven to cause fatigue, but thus far, no relationship between different cytotoxic drugs regimes and the degree of fatigue has been truly established. 29 One study, with a small number of patients in different treatment groups, showed greater fatigue for subjects receiving bolus and continuous cytotoxic drugs, as in the 5-flourouracil protocol or the epirubicin, cisplatin and 5- flourouracil protocol, than for subjects receiving a short-term infusion every 21 days. 30 Among the cytotoxic drug courses analysed in the present study, gemcitabine and FEC seemed to be associated with the highest degree of fatigue, while fluorouracil alone correlated with a lower degree. In the case of gemcitabine, it was only used as first line treatment for lung cancer, and as second line treatment for other diagnoses. Therefore, patients receiving second line treatment and those with lung cancer rated higher fatigue in this study. The higher fatigue scores for patients not receiving first line treatment should be analysed in light of a more severe disease and a greater psychological stress in these patients. Symptoms, such as weight loss, cachexia, anorexia, muscle wasting, atrophy, protein degradation, increased metabolism and energy expenditure, are often seen in cancer patients and are also a possible causes of CRF. 21 The non-specific inflammatory

8 162 Hartvig et al.: Cytotoxic drug induced fatigue response to the tumour leads to alterations in the cytokine metabolism, for example, increased production of interleukin, interferon and tumour necrosis factor. Cytokines are known to cause many of the symptoms mentioned above. 5 One study with 15 patients found a correlation between interleukin-1 (IL-1) and fatigue, while another study did not find such a relationship. 2 Inactivity due to fatigue, decreased food intake, pain or psychosocial factors may cause further fatigue. The same holds true for decreased food intake, which may be caused by fatigue, inactivity, loss of appetite, anorexia or nausea. The symptoms mentioned above, eg, weight loss, cachexia and muscle wasting may also be a result of inactivity and compromised nutritional status, and may lead to further inactivity and decreased food intake. 21 The cause and effect are tightly connected, resulting in a negative spiral. Several mental factors, such as depression, anxiety and stress, may also contribute to CRF. Depression, depressed mood and anxiety are common in cancer patients. Depression has been shown to correlate with fatigue. 31 Similar factors, such as mental stress and depression, may also lead to changes in nutrition and, thereby, fatigue caused by secondary physiological factors. 5 The present study showed that the strongest correlation to fatigue were other cancerrelated symptoms and cytotoxic drugs-related side effects. Pain, nausea, anxiety, depression and insomnia were correlated to CRF according to univariate analyses, while pain, nausea, depression, anxiety and constipation were the most important variables, according to the multivariate analysis. Depressed mood was most important, as observed in earlier studies, in which pain, emotional upset, nausea and sleeping problems were also associated with fatigue. 4,31 It was obvious that cancer-related symptoms and fatigue correlated to each other, but there is dilemma in trying to separate the cause and effect, since many of these symptoms also could be a result of fatigue. However, this result was confounded by diagnosis. GI-cancer and prostate cancer, which is associated with low fatigue ratings, were more common among the males, in contrast to the breast cancer diagnosis where high fatigue was present. Lower fatigue scores were generally reported compared to similar studies on fatigue. In a study, the mean fatigue among 54 females undergoing adjuvant breast cancer treatment was 4.0, and the number of days fatigued was A possible explanation for the lower scores for number of days fatigued in the present study, except for the differences in diagnoses, could be the translation of the word fatigue. In Sweden and many other non- English speaking countries, there is no word for fatigue. Fatigue, therefore, has to be translated to a related term. In all questions, except for number 13 (number of days fatigued) and number 14 (how much each day), the word tiredness was used. In these two questions, the term abnormal tiredness was used. The problem with lack of a terminology for fatigue was also reflected in the result of the comparison between non-cancer subjects and cancer patients. The difference between the two groups was greater for number of days fatigued than for the mean fatigue experienced during the last week. Even if the difference in fatigue between noncancer subjects and cancer patients undergoing treatment was not as great as one might expect, there is a difference in the origin of the fatigue between these groups. In healthy individuals, fatigue is a protective response to physical or psychological stress, and might be a more agreeable form of tiredness. This was also demonstrated by the noncancer subjects scores on impact of fatigue on their quality of life, which were much lower than for cancer patients undergoing treatment. The scores for fatigue were lower for cancer patients before treatment then in the non-cancer group. The difficulty in demonstrating that healthy individuals experience less fatigue than cancer patients without treatment has been pointed out. 20 The explanation was similar to the one above, ie, that the quality of tiredness might be more distressing in disease than in health. The Swedish translation of FSI seemed to be rather well accepted. Translation of the Swedish version back to English did not reveal any major differences between the two versions. A further limitation was the uncertainty if the noncancer group was representative of the general population. The mean age in the comparison group was lower and there were more females in the comparison group compared with the cancer patient group. Further, the first item in the questionnaire, that asks the respondent to assess fatigue before cytotoxic drugs treatment, created an artificial baseline for the patients. This baseline might have a lower validity than a true baseline, since it might be hard to recall the level of fatigue before treatment. It does, however, have some advantages, since it points out the problem of assessing a subjective feeling and compares the results between different individuals. The non-cancer subjects had higher scores than the cancer subjects claimed to have before treatment. This is probably due to patients frames of references

9 Hartvig et al.: Cytotoxic drug induced fatigue 163 have changed, since they became ill and experienced the abnormal tiredness. An interesting finding is that in one of the subgroups throughout the study period, patients experiencing the highest fatigue scores also had the highest scores on fatigue ratings before treatment. In conclusion, most patients with cancer suffered from fatigue, which was aggravated by cytotoxic drug treatment. Fatigue was shown to be a major problem for these patients, although the study had limitations with respect to inclusion of only outpatients with only few diagnoses and inclusion of only a few cytotoxic drugs regimens and variable further adjuvant treatment. Prior surgical or radiation treatment, which also may cause fatigue, was not possible to record. The fatigue symptoms should be acknowledged by the nursing staff. The oncology pharmacist must inform patients about fatigue and that treatment may increase suffering. Cancer-related fatigue probably has multifactorial causes and simultaneous symptoms must be considered. Depressed mood, pain, anxiety, nausea and insomnia, which correlate with the fatigue, should be treated favorably and individually, in order to decrease fatigue. Only a few interventions have been evaluated so far, and most were exercise interventions. 8,12,17 One conclusion was that: The best way to treat fatigue may be to take into consideration and treat all of the components that contribute to it. 5 Important aspects of interventions to consider are treatment of cancer-related symptoms, adequate nutrition, patient education, and psychosocial intervention. REFERENCES 1 Patrick DL, Ferketich SL, Frame PS, et al. National Institutes of Health State-of-the-Science Conference Statement: symptom management in cancer: pain, depression, and fatigue, July 1517, J Nat Cancer Inst 2003; 95: Simon A, Zittoun R. Fatigue in cancer patients. Curr Opin Oncol 1999; 11: Ream E, Richardson A. From therapy to practice: designing interventions to reduce fatigue in patients with cancer. Oncol Nurs Forum 1999; 26: Irvine D, Vincent L, Graydon J, et al. The prevalence and correlates of fatigue in patients receiving treatment with chemotherapy drugs and radiotherapy. Cancer Nurs 1994; 17: Kalman D. Nutritional aspects of cancer-related fatigue. J Am Diet Assoc 1997; 97: Rhodes V, Watson PM, Hanson BM. Patients description of the influence of tiredness and weakness on self-care abilities. Cancer Nurs 1988; 11: Aistars J. Fatigue in the cancer patient: a conceptual approach to a clinical problem. Oncol Nurs Forum 1987; 14: Dimeo F, Stieglitz RD, Novelli-Fischer U, Fetscher S, Keul J. Effects of physical activity on the fatigue and psychological status of cancer patients during cytotoxic drugs. Cancer 1999; 85: Richardson A. Measuring fatigue in patients with cancer. Support Care Cancer 1998; 6: Piper B, Lindsey AM, Dodd M. Fatigue mechanisms in cancer patients: developing nursing theory. Oncol Nurs Forum 1987; 14: Richardson A. Fatigue in cancer patients: a review of the literature. Eur J Cancer Care 1995; 4: Hartvig P, Aulin J, Wallenberg S, et al. Physical exercise for cytotoxic drug induced fatigue. J Oncol Pharm Pract (submitted / ). 13 Hann D, Jacobsen PB, Azzarello LM. Measurement of fatigue in cancer patients: development and validation of the fatigue symptom inventory. Qual Life Res 1998; 7: Schwartz A, Nail LM, Chen S, et al. Fatigue patterns observed in patients receiving chemotherapy drugs and radiotherapy. Cancer Invest 2000; 18: Piper B. Fatigue and cancer: inevitable companions? Support Care Cancer 1993; 1: Cella D, Peterman A, Passik S, et al. Progress toward guidelines for the management of fatigue. Oncology 1998; 12: Ream E, Richardson A. Fatigue: a concept analysis. Int J Nurs Stud 1996; 33: Rhoten D. Fatigue and the postsurgical patient, In Norris C ed. Concept clarification in nursing. Aspen, 1982: Krupp L, LaRocca NG, Muir-Nash J, et al. The Fatigue Severity Scale. Arch Neurol 1989; 46: Chalder T, Berelowitz G, Pawlikowska T, et al. Development of a fatigue scale. J Psych Res 1992; 37: Glaus A. Fatigue in patients with cancer. Analysis and assessment. Recent results. Cancer Res 1998; 145: I XI, Kogi K, Saito Y, Mitsuhashi T. Validity of three components of subjective fatigue feelings. J Sci Lab 1970; 46: Yellen S, Cella DF, Webster K, et al. Measuring fatigue and other anaemia-related symptoms with the functional assessment of cancer therapy. J Pain Symptom Manage 1997; 13: Smets E, Garssen B, Bonke B, et al. The multidimensional fatigue inventory (MFI) psychometric qualities of an

10 164 Hartvig et al.: Cytotoxic drug induced fatigue instrument to assess fatigue. J Psych Res 1995; 39: Stein K, Martin SC, Hann DM, et al. A multidimensional measure of fatigue for use with cancer patients. Cancer Pract 1998; 6: Piper BF. Piper fatigue scale for clinical testing. Oncol Nurs Forum 1990; 17: Piper B, Dibble SL, Dodd MJ, et al. The revised Piper Fatigue Scale: psychometric evaluation in women with breast cancer. Oncol Nurs Forum 1998: 25: Schwartz A. The Schwartz cancer fatigue scale: testing reliability and validity. Oncol Nurs Forum 1998; 25: Richardson A. The experience of fatigue and other symptoms in patients receiving chemotherapy. Eur J Cancer Care 1996; 5: Richardson A, Ream E, Wilson-Barnett J. Fatigue in patients receiving chemotherapy: patterns of change. Cancer Nurs 1998; 21: Smets E, Garssen B, Cull A, et al. Application of the multidimensional fatigue inventory (MFI-20) in cancer patients receiving radiotherapy. Br J Cancer 1996; 73: Jacobsen P, Hann DM, Azzarello LM, et al. Fatigue in women receiving adjuvant chemotherapy for breast cancer: characteristics, course and correlates. J Pain Symptom Manage 1999; 18: APPENDIX A The Fatigue Inventory Scale 1) Rate Your level of fatigue on the day You felt most fatigued during the past week. 2) Rate Your level of fatigue on the day You felt least fatigued during the past week. 3) Rate Your level of fatigue on the mean in the last week. 4) Rate Your level of fatigue right now. 5) Rate how much, in the past week, fatigue interfered with Your general level of activity. 6) Rate how much, in the past week, fatigue interfered with Your ability to bath and dress Yourself. 7) Rate how much, in the past week, fatigue interfered with Your normal work activity (includes both work outside the home and housework). 8) Rate how much, in the past week, fatigue interfered with Your ability to concentrate. 9) Rate how much, in the past week, fatigue interfered with Your relation with other people. 10) Rate how much, in the past week, fatigue interfered with Your enjoyment of life. 11) Rate how much, in the past week, fatigue interfered with Your mood. 12) Indicate how many days, in the past week, You felt fatigued for any part on the day. 13) Rate how much of the day, on the mean You felt fatigue in the past week. 14) Do you want to add anything that describes Your current fatigue or general situation?