1 Division of HematologyOncology, Department of Medicine, 2 Division of Biostatistics, Indiana University School of Medicine and 3 Walther Cancer Institute, Indianapolis, IN, USA
* Correspondence to: Prof. L. H. Einhorn, Indiana Cancer Pavilion, 535 Barnhill Drive, Indianapolis, IN 46202, USA. Tel: 001-317-274-0920; Fax: 317-274-3646; Email: leinhorn{at}iupui.edu
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Abstract |
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Patients and methods: 174 patients with cancer, who had undergone treatment within the last six months, answered the questionnaires and the Brief Version Zung Self-Rating Depression Scale (BZSDS). Blood samples were drawn for hemoglobin, albumin, thyroid stimulating hormone (TSH), dehydroepiandrosterone-sulfate (DHEAS) and tumor necrosis factor-alpha (TNF- alpha). Testosterone levels were checked in male patients.
Results: Clinically significant fatigue with BFI 4 was present in 52.0% of patients. Measurement of laboratory parameters revealed the following: DHEAS levels <80 mcg/dl in males and <36 mcg/dl in females=54.1%; BZSDS scores
27=20.1%; testosterone levels <200 ng/dl=26.4% of male patients. Significant correlations were noted between BFI and FACT-F, albumin levels, hemoglobin levels and BZSDS scores. In addition, for male patients BFI correlated with DHEAS and testosterone levels. In multiple linear regression, hemoglobin, BZSDS scores and current opioid use were associated with response BFI. For male patients, DHEAS <80 mcg/dl, increased BZSDS and testosterone <200 ng/dl were associated with increased BFI.
Conclusion: Fatigue is common in this population and BFI correlates with more extensive measurements. Abnormalities such as decreased testosterone and DHEAS may lead to interventions that can be therapeutically exploited.
Key words: cancer, dehydroepiandrosterone, fatigue, testosterone
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Introduction |
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The pathogenesis of fatigue is not well understood. It has been correlated with anemia, psychological distress, nausea, dyspnea, hypoalbuminemia, disease burden, performance status and treatment modalities [57
]. Studies on biological correlates are very limited. Commonly checked laboratory parameters such as albumin and hemoglobin have been associated with fatigue. Anemia has been shown to be a major contributor to increased fatigue and declining quality of life in cancer populations [8
]. Treatment with epoietin-
has been shown to have positive impact on activity and energy levels in these patients [9
, 10
]. The role of depression in causing cancer fatigue is not very clear. The two are associated and commonly coexist [11
, 12
].
Other promising biological markers associated with fatigue which may have a role in pathogenesis include tumor necrosis factor- (TNF-
), hypothyroidism, dehydroepiandrosterone sulfate (DHEAS) and serum testosterone. TNF-
has been correlated with fatigue in non-cancer settings such as post-dialysis, chronic fatigue syndrome and parvovirus infections [13
15
]. Higher levels of soluble TNF receptor II have been associated with fatigue in breast cancer survivors [12
]. Anti-TNF therapy in a pilot study in patients with myelofibrosis with myeloid metaplasia helped relieve constitutional symptoms [16
]. DHEAS and testosterone have been implicated as potential biomarkers of fatigue in HIV populations and in Addison's disease [17
, 18
]. The pathophysiologic mechanisms by which these biomarkers are associated with fatigue are not clear. Also, their role in cancer-related fatigue is not defined.
In this study we evaluated the prevalence of fatigue in a diverse cancer patient population undergoing chemotherapy. We used broad entry criteria to assist with time and resource constraints, and also because we were looking for potential markers which cross different subgroups since the problem is so prevalent. Patients were screened for anemia, depression, hypoalbuminemia, hypothyroidism and TNF- levels, and for low levels of DHEAS and total testosterone. We used this exploratory study to test the association of these parameters with clinical fatigue. In addition, we were interested in generating hypotheses based on the findings that may have therapeutic implications.
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Patients and methods |
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Patients with prostate cancer were excluded since androgen levels were being screened, as were patients who were unable to give informed consent or to read and understand the self-reported questionnaires in English.
Data collection and study parameters
Information on the patient's disease, treatments, current medications and performance status was collected by a research nurse. Disease data included diagnosis, site and stage of disease. The Brief Fatigue Inventory (BFI), the Functional Assessment of Cancer Therapy-Fatigue (FACT-F) questionnaires and the Brief Zung Self-Reporting Depression Scale (BZSDS) were administered to all the patients. At the same visit, blood samples were drawn for determining hemoglobin, albumin, total testosterone levels, DHEAS, thyroid-stimulating hormone (TSH) and TNF- levels.
The BFI is a nine-item questionnaire that checks the patient's subjective report of fatigue severity. Patients rate each item based on how they feel currently and in the preceding week, using a 010 numerical scale. The mean of the nine items gives the total BFI score. The score is categorized as mild (03), moderate (46) or severe (710). It is a reliable (internally stable) test with low measurement error (=0.96) [19
]. BFI scores have been validated to results of the more detailed FACT-F scales in the past. Because of its abbreviated format, we opted to use BFI to screen for prevalence in order to reduce the burden on patients. FACT-F has been studied much more extensively as a fatigue measurement tool and is comprised of the FACT-General and the FACIT-F scale [20
, 21
]. FACT-General is a 33-item self-administered questionnaire covering the quality-of-life domains of physical, social, emotional and functional well-being, and the FACIT-F is a 13-item subscale which covers specific fatigue questions. Patients report their answers on a five-point scale for how true statements describe them in the past 7 days. After accounting for reverse-scored items, questions are summed across the subscales and added for a total score, with higher scores indicative of greater overall quality of life. We have incorporated FACT-F in clinical studies at our institution to serve as an alternative tool to BFI.
The BZSDS self-administered depression scale was developed from the widely used Zung Self-Rating Depression Scale [22]. It is an 11-item questionnaire focusing on depression. The sum of the 11 items, after correcting for the seven reverse-scored items, is converted into a score. Patients can be subdivided into groups based on the severity of their depressive symptoms. The different categories used based on the BZSDS scores are normal (021), mild depression (2226), moderate depression (2730) and severe depression (>31).
Data on performance status of the patients was collected using the Eastern Cooperative Group (ECOG) scales from 0 to 4. A score of 0 represented fully active predisease performance without restriction, a score of 1 represented ability to carry out light or sedentary work and a score of 2 reflected ability to perform self-care but not any work. A score of 3 reflected only limited self-care ability and confinement to bed or chair for >50% of waking hours, while a score of 4 represented complete disability and total confinement to bed or chair.
Laboratory tests and cytokine analysis
TNF- levels were determined using commercially available Quantikine Immunoassay kits (R&D Systems Inc., Minneapolis, MN). The blood samples were immediately frozen at temperatures below 20°C and the measurements were carried out according to the instructions of the manufacturer. The reference values for TNF-
for healthy volunteers were <4.71 pg/ml as quoted by the manufacturer. The intra-assay precision as reported by the manufacturer was tested in three samples of known concentration in replicates of 20. The CV% ranged from 8.8 to 5.3. The inter-assay precision in three samples of known concentration as evaluated in 40 separate assays had a CV% range of 16.710.8.
Other reference values used included hemoglobin <11 g/dl to define anemia for both males and females. This was believed to be a clinically useful cut-off as suggested by some studies [23, 24
] The Indiana University laboratory reference values were used to define albumin <3.5 g/dl as low and TSH was considered high if it was greater than the laboratory reference value of 4.2 µU/ml. DHEAS levels were considered low if they were <80 µg/dl in males or <36 µg/dl in females (our laboratory reference values). Total testosterone levels were checked in male patients and values <200 ng/dl were considered low.
Statistical analysis
A total of 175 patients were to be accrued to provide a sample size with >90% power by regression analysis and with a 5% significance level to detect a correlation of 0.25 between a covariate and a dependent variable. Pearson's correlation coefficients were calculated for continuous data. We present correlation between BFI and FACT-F to show the degree to which the scales are related in this sample. Multiple linear regression analysis was used to assess the association between the response variable BFI (scale 010) and multiple predictors. Statistical tests were two-sided at the 0.05 significance level. Analyses were performed using SAS version 8.02.
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Results |
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Correlates of age were also calculated. Age was negatively correlated with albumin and DHEAS (r=0.30, P <0.0001 and r=0.53, P <0.0001, respectively). Correlations with age were similar in male and female subgroups. In addition, there was a weak negative correlation between age and testosterone in males (r=0.23, P=0.032).
Multiple linear regression analysis
Multiple linear regression analysis was used to analyze the association between BFI and factors BZSDS, TSH, albumin, hemoglobin, time since last chemotherapy (>28 days compared with <29 days), days since last radiation therapy (>28 days compared with <29 days), current opioid use and age. In selecting these factors we used not only biological variables of interest as per the study, but also added other relevant clinical factors which were felt to be influencing fatigue. These included the timing of chemotherapy and radiation therapy with respect to the point time when BFI was measured, as well as age and the current use of opioids. The full model was reduced using stepwise elimination to include only factors with P-values <0.10 (Table 3). In the reduced model, increased BFI scores were associated with current opioid use (P=0.007), higher BZSDS scores (ß = 0.17, P <0.0001) and lower hemoglobin levels (ß=0.21, P=0.027).
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Discussion |
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The pathogenesis of fatigue has been extremely difficult to elucidate and undoubtedly reflects the multiple etiologies that contribute to its development in cancer patients. One limitation of our study is the heterogeneous population as it includes patients with different stages of solid cancers receiving adjuvant therapies, treatments for unresectable disease and metastatic disease, as well as hematological malignancies. Another obvious limitation of this study is its cross-sectional design. Symptoms of fatigue are likely to vary over the course of time and treatment. Whether the various laboratory parameters studied are epiphenomena or play roles in pathogenesis is unclear. Even for variables such as depression which have been better studied, the causeeffect relationship is not clear. In a large placebo-controlled trial conducted to look at the effect of paroxetine on fatigue and depression in cancer patients, an effect on fatigue separate from the antidepressant effect was not found [11]. This suggested that modulation of serotonin may not be a primary mechanism of fatigue related to cancer treatment.
Some of the specific findings of the study included the association between opioid use and fatigue. Since we did not collect pain scores, it is unclear whether this is a reflection of a pain fatigue syndrome, advanced underlying disease or the use of the opioid drugs itself. In addition, chronic use of long-acting opioids has been associated with hypogonadism [25], which again points to the many potential confounding factors in studying the etiology of cancer-related fatigue.
In our present study, we generate hypotheses of correlation between fatigue and potential biological markers. Inflammatory cytokines such as TNF- have previously been hypothesized to contribute to fatigue symptoms. Our current study failed to show any association between BFI scores and TNF-
levels in this heterogeneous population. A recent study of breast cancer patients receiving paclitaxel therapy explored the association between fatigue and influenza-like symptoms experienced by the patients and various cytokines [26
]. While TNF-
levels did not correlate with the symptoms, plasma levels of interleukins 6, 8 and 10 were transiently increased with treatments and correlated with symptoms.
An important finding was that DHEAS and testosterone levels appeared to be promising markers of fatigue in male patients. It is unclear whether the finding that DHEAS was associated with fatigue in males but not in females reflect different pathophysiologic mechanisms or is confounded by other variables. For example, more females (23%) than males (17.2%) had a moderatesevere depression score on the BZSDS. Also, more females (24.7%) than males (18.4%) had a hemoglobin <11 g/dl. Low DHEAS levels have been associated with fatigue in chronic fatigue syndrome and HIV populations [18, 19
]. Controlled trials in Addison's disease have shown that DHEA supplementation helps to improve fatigue and mood [27
, 28
]. With respect to testosterone levels in males, most of our knowledge is based on testosterone replacement studies in non-cancer populations. Patients with known testosterone deficiency and hypogonadism have demonstrated increased muscle mass, bone mineral density, hemoglobin, sexual function and well-being with testosterone supplementation [29
, 30
]. Age-related decline in testicular function may occur with associated symptoms and often responds to testosterone supplementation as well. In the HIV population, testosterone treatment has been effective for the short-term treatment of symptomatic clinical hypogonadism, including low energy [31
]. Very few studies have looked at its effect on cancer patients. Beneficial effects of nandrolone decanoate, an anabolic steroid, were studied in two trials of patients with advanced cancer without any exclusion criteria based on testosterone levels [32
, 33
]. They showed that treatment resulted in less severe weight loss, increase in muscle mass and decreased requirement of transfusions. In another placebo-controlled trial of testosterone replacement in men with mild testosterone deficiency following cytotoxic therapy, physical fatigue scores showed significant improvement [34
]. All 35 patients in this trial were survivors of hematological malignancies with no evidence of cancer recurrence. The effects of oxandrolone, an oral anabolic steroid, were reported in cancer-related weight loss. Improvements in weight, body cell mass, performance status and quality of life were reported in 37 patients initially. Updated results in 131 patients were reported and confirmed the significant weight gain and body cell mass findings [35
]. We believe that these data for non-cancer populations combined with our study findings suggest that low levels of DHEAS and testosterone levels in males have an association with fatigue and provide a reasonable rationale for testing hormone replacement therapy in this select cancer patient population. We have initiated a phase II trial of testosterone supplementation in male cancer patients with low testosterone levels and moderatesevere fatigue. Further study is essential to enhance our understanding of this disabling syndrome and to provide therapeutic relief to our patients.
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Acknowledgements |
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Notes |
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Received for publication February 1, 2005. Revision received April 13, 2005. Accepted for publication April 14, 2005.
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References |
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![]() ![]() ![]() ![]() ![]() ![]() ![]() |
---|
2. Morrow GR, Andrews PL, Hickok JT et al. Fatigue associated with cancer and its treatment. Support Care Cancer 2002; 10: 389398.[CrossRef][ISI][Medline]
3. Vogelzang NJ. The Fatigue Coalition: patient, caregivers and oncologists perceptions of cancer related fatigue. Semin Hematol 1997; 34: 412.[ISI][Medline]
4. Groopman JE. Fatigue in Cancer and HIV/AIDS. Oncology 1998; 12: 335344.[Medline]
5. Wang XS, Giralt AS, Mendoza TR et al. Clinical factors associated with cancer-related fatigue in patients being treated for eukemia and non-Hodgkin's lymphoma. J Clin Oncol 2002; 20: 13191328.
6. Okuyama T, Akechi T, Shima Y et al. Factors correlated with fatigue in terminally ill cancer patientsa longitudinal study. Proc Am Soc Clin Oncol 2001; 20: 299b (Abstr 2949).
7. Hwang SS, Chang VT, Corpion C et al. A preliminary study of clinical predictors for lack of energy in patients with advanced cancer. Proc Am Soc Clin Oncol 1997; 16: 70a (Abstr 241).
8. Holzer B, Kemmler G, Greil R et al. The impact of hemoglobin levels on fatigue and quality of life in cancer patients. Ann. Oncol 2002; 13: 965973.
9. Glaspy J, Bukowski R, Steinberg D et al. Impact of therapy with epoetin alfa on clinical outcomes in patients with non-myeloid malignancies during cancer chemotherapy in community oncology practice. J Clin Oncol 1997; 15: 12181234.
10. Demetri G, Kris M, Wade J, Degos L, Cella D. Quality of life benefit in chemotherapy patients treated with epoeitin alpha is independent of disease response or tumor type: results from a prospective Community Oncology study. J Clin Oncol 1998; 16: 34123425.
11. Morrow GR, Hickok JT, Raubertas RF et al. Effect of an SSRI antidepressant on fatigue and depression in seven hundred thirty-eight cancer patients treated with chemotherapy: a URCC CCOP Study. Proc Am Soc Clin Oncol 2001; 20: 384a (Abstr 1531).
12. Bower JE, Ganz PA, Aziz N, Fahey JL. Fatigue and proinflammatory cytokine activity in breast cancer survivors. Psychosom Med 2002; 64: 604611.
13. Dreisbach AW, Hendrickson T, Beezhold D et al. Elevated levels of tumor necrosis factor alpha in postdialysis fatigue. Int J Artif Organs 1998; 21: 8386.[ISI][Medline]
14. Patarca R, Klimas NG, Lugtendorf S et al. Dysregulated expression of tumor necrosis factor in chronic fatigue syndrome: interrelations with cellular sources and patterns of soluble immune mediator expression. Clin Inf Dis 1994; 18: S147S153.[ISI][Medline]
15. Kerr JR, Barah F, Mattey DL et al. Circulating tumor necrosis factor alpha and interferon gamma are detectable during acute and convalescent parvovirus B19 infection and are associated with prolonged and chronic fatigue. J Gen Virol 2001; 82: 30113019.
16. Steensma DP, Mesa RA, Li CY et al. Etanercept, a soluble tumor necrosis factor receptor, palliates constitutional symptoms in patients with myelofibrosis with myeloid mataplasia: results of a pilot study. Blood 2002; 99: 22522254.
17. Scott LV, Salahuddin F, Cooney J et al. Differences in adrenal steroid profile in chronic fatigue syndrome, in depression and in health. J Affect Disord 1999; 54: 129137.[CrossRef][ISI][Medline]
18. Rabkin JG, Ferrando SJ, Wagner GJ, Rabkin R. DHEA treatment for HIV+ patients: effects on mood, androgenic and anabolic parameters. Psychoneuroendocrinology 2000; 25: 5368.[CrossRef][ISI][Medline]
19. Mendonza T, Wang S, Cleeland C, Morrissey M. The rapid assessment of fatigue severity in cancer patients: use of the Brief Fatigue Inventory. Cancer 1999; 85: 11861196.[CrossRef][ISI][Medline]
20. Cella DF, Tulsky DS, Gray G et al. The Functional Assessment of Cancer Therapy (FACT) scale: development and validation of the general measure. J Clin Oncol 1993; 11: 570579.
21. Brady MJ, Cella D, Fei M et al. Reliability and validity of the Functional Assessment of Cancer Therapy-Breast Quality of Life Instrument. J Clin Oncol 1997; 15: 974986.
22. Dugan W, McDonald MV, Passik SD, Rosenfeld BD, Theobald D, Edgerton S. Use of the Zung Self-Rating Depression Scale in cancer patients: feasibility as a screen tool. Psychooncology 1998; 7: 483493.[CrossRef][ISI][Medline]
23. Cleeland CS, Demetri GD, Glaspy J et al. Identifying hemoglobin level for optimal quality of life: results of an incremental analysis. Proc Am Soc Clin Oncol 1999; 18: 574a (Abstr 2215).
24. Yellen SB, Cella DF, Webster K, Blendowski C, Kaplan E. Measuring fatigue and other anemia-related symptoms with the Functional Assessment of Cancer Therapy (FACT) measurement system. J Pain Symptom Manage 1997; 13: 6374.[CrossRef][ISI][Medline]
25. Daniell HW. Hypogonadism in men consuming sustained-action oral opioids. J Pain 2002; 3: 377384.[CrossRef][ISI][Medline]
26. Pusztai L, Mendoza TR, Reuben JM et al. Changes in plasma level of inflammatory cytokines in response to paclitaxel chemotherapy. Cytokine 2004; 25: 94102.[CrossRef][ISI][Medline]
27. Hunt PJ, Gurnell EM, Huppert FA et al. Improvement in mood and fatigue after DHEA replacement in Addison's disease in a randomized, double blind trial. J Clin Endocrinol Metab 2000; 85: 46504656.
28. Arlt W, Callies F, van Vlijmen JC et al. DHEA replacement in females with adrenal insufficiency. N Engl J Med 1999; 341: 10131020.
29. Petak SM, Baskin HJ, Bergman DA et al. AACE clinical practice guidelines for the evaluation and treatment of hypogonadism in adult male patients. Endocr Pract 1996; 2: 440453.
30. Snyder PJ, Peachey H, Berlin JA et al. Effects of testosterone replacement in hypogonadal men. J Clin Endocrinol Metab 2000; 85: 26702677.
31. Rabkin JG, Wagner GJ, Rabkin R. A double-blind, placebo-controlled trial of testosterone therapy of HIV-Positive men with hypogonadal symptoms. Arch Gen Psychiatry 2000; 57: 141147.
32. Chelebowski RW, Herrold J, Ali I et al. Influence of nandrolone decanoate on weight loss in advanced non-small cell lung cancer. Cancer 1986; 58: 183186.[ISI][Medline]
33. Spiers AS, DeVita SF, Allar MJ et al. Beneficial effects of an anabolic steroid during cytotoxic chemotherapy for metastatic cancer. J Med 1981; 12: 433445.[Medline]
34. Howell SJ, Radford JA, Adams JE et al. Randomized placebo-controlled trial of testosterone replacement in men with mild Leydig cell insufficiency following cytotoxic chemotherapy. Clin Endocrinol 2001; 55: 315324.[CrossRef][ISI][Medline]
35. Von Roenn JH, Tchekmedyian S, Hoffman RM, Chang CY, Ottery FD. Safety of oxandrolone in cancer-related weight loss. Proc Am Soc Clin Oncol 2003; 22: 749 (Abstr 3013).
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