E D I T O R I A L

See referenced original article on pages 37782.

Address for reprints: John C. Ruckdeschel, M.D.,Karmanos Cancer Institute, Executive Ofce, 4100John R, Detroit, MI 48201; Fax: (313) 993-7165;E-mail: ruckdeschel@karmanos.org

Received September 13, 2004; accepted Septem-ber 20, 2004.

Fatigue Is Becoming anExhausting ProblemJohn C. Ruckdeschel, M.D.

Karmanos Cancer Institute, Detroit, Michigan.

Over the past quarter of a century, we have learned how to managethe infectious complications of chemotherapy and the disablingnausea and emesis that was such a feature of the early platinum era.What we have been left with, however, is profound fatigue as one ofthe major complaints of patients on chemotherapy. Brown and col-leagues from Scotland have given us an intriguing study that sought tosort out many of the issues related to fatigue, but, like any goodreport, proposes more questions than it answers.1

Those authors examined a population of 38 patients with ad-vanced lung cancer who were not on therapy and 15 age-matched andgender-matched normal controls. They included measures of de-pression, anxiety, inammation, physical function, anemia, and per-formance status. Physical function was operationalized as either gripstrength or chair-rise time to make it somewhat less subjective. Notsurprisingly, the cancer patients were more fatigued, more depressed,had poorer physical function and performance status, and had ele-vations of several markers of inammation. In a multivariate analysisof the relation to fatigue, only performance status, a weakness score,and the anxiety and depression scores were correlated signicantly.Brown et al. concluded that physical functioning was poorer withincreasing fatigue and that fatigue was related to performance statusand psychological distress and not to weight loss or anemia.1

The failure to use chemotherapy in lung cancer (therapeuticnihilism) and the failure of nonsmall cell lung carcinoma to causesignicant anemia on its own removed the impact of anemia from thetrial by Brown et al. and, no doubt, led to the lack of a correlation withfatigue. This helps us sort out the other contributory factors butmakes the results less universal.

Indeed, because there is such an extraordinarily lucrative marketin the therapy of anemia, our focus on fatigue has been skewed in thisdirection. What this trial conrms is that, even absent signicantanemia, there is signicant fatigue.

The trial is not without its problems, however, not the least ofwhich is the relatively small number of patients studied. There is onlya sparse description of the cancer patients, with only a series ofaverage scores with wide standard deviations presented. The attemptto use chair-rise time as a surrogate for physical function is notunreasonable; however, lacking a description of the numbers of pa-tients with painful bone metastases or other conditions that may limitmobility, we are left to wonder about the ability to generalize thisnding.

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2004 American Cancer SocietyDOI 10.1002/cncr.20770Published online 22 November 2004 in Wiley InterScience (www.interscience.wiley.com).

What is most unclear is the sequence of events.Does diminished physical functioning predate andcontribute to fatigue, or does it always follow fatigue?If fatigue is the rst step, then focusing on the psy-chological distress, anemia, and other contributors tofatigue should be more productive. If diminishedphysical functioning antedates fatigue, then focusingon the behavioral and inammatory factors that maylead to diminished physical activity would be moreproductive. The ability of aerobic exercise programs toovercome fatigue suggests that there are elements ofphysical functioning that are important in the laterdevelopment of fatigue.2,3 Conversely, both fatigueand diminished physical activity may be secondary toan earlier event or series of events, including, forexample, depression.

An array of possible antecedent events, includingabnormalities of energy metabolism,4 neurophysio-logic changes in muscle,5 chronic stress responses,68

anxiety and depressive disorders,911 specic treat-ments,1214 concomitant systemic diseases,15 and hy-pothalamic-pituitary axis dysfunction,68 have beenproposed and discussed extensively.16 What is lackingto date is the ability to assess whether these changescause the later fatigue or whether they merely areassociated with its development.

I have long had a certain amount of skepticismabout the mind-body connection and its relation tocancer.17 However, there is some intriguing and, atrst glance, unrelated data that suggest there is asystemic affect that precedes the development of theclinical fatigue syndromes we are accustomed to see-ing. In the middle 1980s, the Lung Cancer StudyGroup took a relatively unsophisticated look at qualityof life in patients with early-stage, resected lung can-cer.18 That group found that a simple quality-of-lifequestionnaire administered to patients with early-stage lung cancer prior to any intervention wasstrongly predictive of survival. Several different groupshave corroborated this nding in a number of differ-ent malignancies.1921 The Lung Cancer Study Groupreport was all the more signicant, because this nd-ing was noted in a group of patients with early-stagedisease who had not yet had any of the confoundingeffects of therapy. What is it that these patients sensethat causes them to report a lower quality of lifeafter controlling for disease stage, age, gender, andperformance status? Is it a product of tumor growthand metabolism, such as proteolysis-inducing fac-tor,2224 that leads to a catabolic state that can besensed but cannot be articulated well?

Depression has long been associated with cancer,although the evidence is strongest that the depressionis reactive or secondary to the cancer diagnosis rather

than etiologic for the cancer itself. A broad meta-analysis of cancer and depression showed that, over-all, 24% (range, 1542%) of cancer patients were de-pressed without regard to tumor type, disease stage, ordisease status.9 This may have been an underestimate,particularly for a disease like lung cancer, in whichtherapeutic nihilism is rampant, and patients oftenare given little or no hope of cure or lasting remission.The current study by Brown et al. is compatible withthe concept that depression precedes fatigue, in thatall of the patients studied were end-stage lung cancerpatients who were receiving no therapy, and depres-sion was one of the signicant correlates.

What is needed is a study of these events withphysical, behavioral, biologic, and hematologic mea-sures taken serially over time. One problem will bewhich measures to choose; however, hopefully, a con-sensus could be reached. More important is the pop-ulation to study. It should be a population-basedstudy using individuals without cancer at the onset. Itis possible that much of these data reside in existingpopulations and serum samples, such as the WomensHealth Initiative or the Framingham Heart Study.

Although there is no question that agents thatstimulate erythropoiesis are useful in combating someof the symptoms of fatigue,25 it equally is clear thatanemia is not the mechanism for all cases of fatigue.We need to move our exploration of the early events inthe development of fatigue far earlier in the pathwaythat leads to clinical fatigue. If we are fortunate andthere is a common pathway by which multiple eventsrelated to the tumor or its treatment can cause fatigue,then addressing that pathway will be more productivethan trying to treat empirically.

REFERENCES1. Brown DJF, McMillan DC, Milroy R. The correlation be-

tween fatigue, physical function, the systemic inammatoryresponse, and psychological distress in patients with ad-vanced lung cancer. Cancer. 2005;103:377382.

2. Windsor PM, Nicol KF, Potter J. A randomized, controlledtrial of aerobic exercise for treatment-related fatigue in menreceiving radical external beam radiotherapy for localizedprostate carcinoma. Cancer. 2004;101:550557.

3. Dimeo FC, Stieglitz RD, Novelli-Fischer U, Fetscher S, KeulJ. Effects of physical activity on the fatigue and psychologicstatus of cancer patients during chemotherapy. Cancer.1999;85:22732277.

4. Gibney E, Jennings G, Jebb SA, Murgatroyd PR, Elia M.Measurement of total energy expenditure in patients withlung cancer and validation of the bicarbonate-urea methodagainst whole-body indirect calorimetry [abstract]. ProcNutr Soc. 1997;56:226A.

5. Westerblad H. Recent advances in the understanding ofskeletal muscle fatigue. Curr Opin Rheumatol. 2002;14:648652.

214 CANCER January 15, 2005 / Volume 103 / Number 2

6. Checkley S. The neuroendocrinology of depression andchronic stress. Br Med Bull. 1996:52:597617.

7. Scott LV, Dinan TG. The neuroendocrinology of chronicfatigue syndrome: focus on the hypothalamic-pituitary-ad-renal axis. Funct Neurol. 1999;14:311.

8. Inui A. Cancer anorexia-cachexia syndrome: are neuropep-tides the key? Cancer Res. 1999;59:44934501.

9. McDaniel JS, Musselman DL, Porter MR, et al. Depression inpatients with cancer: diagnosis, biology, and treatment.Arch Gen Psychiatr. 1995;52:8999.

10. Loge JH, Abrahamsen AF, Ekeberg O , et al. Fatigue andpsychiatric morbidity among Hodgkins disease survivors. JPain Symptom Manage. 2000;19:9199.

11. Hopwood P, Stephens RJ. Depression in patients with lungcancer: prevalence and risk factors derived from quality-of-life data. J Clin Oncol. 2000;18:893903.

12. Smets EM, Garssen B, Schuster-Uitterhoeve AL, de Haes JC.Fatigue in cancer patients. Br J Cancer. 1993;68:220224.

13. Stone P, Richards M, Hardy J. Fatigue in patients with can-cer. Eur J Cancer. 1998;34:16701676.

14. Fobair P, Hoppe RT, Bloom J, et al. Psychosocial problemsamong survivors of Hodgkins disease. J Clin Oncol. 1986;4:805814.

15. Mock V, Atkinson A, Barsevick A, et al. NCCN clinical prac-tice guidelines for cancer-related fatigue. Version 1.2003[monograph online]. Available from URL: http://www.-nccn.org/physician_gls/index.html [accessed June 1, 2003].

16. Stasi R, Abriani L, Beccaglia P, Terzoli E, Amadori S. Cancer-related fatigue: evolving concepts in evaluation and treat-ment. Cancer. 2003;98:17861801.

17. Ruckdeschel JC, Blanchard C, Albrecht T. Psychosocial on-

cology research: where we have been, where we are goingand why we wont get there. Cancer. 1994;74:14581463.

18. Ruckdeschel JC, Piantadosi S. Quality-of-life assessment inlung surgery for bronchogenic carcinoma. Lung CancerStudy Group. Theor Surg. 1991;6:201205.

19. Chang VT, Thaler HT, Polyak TA, Kornblith AB, Lepore JM,Portenoy RK. Quality of life and survival: the role of multi-dimensional symptom assessment. Cancer. 1998;83:173179.

20. Coates A, Gebski V, Signorini D, et al. Prognostic value ofquality-of-life scores during chemotherapy for advancedbreast cancer. J Clin Oncol. 1992;10:18331838.

21. Ganz PA, Lee JJ, Siau J. Quality of life assessment. An inde-pendent prognostic variable for survival in lung cancer.Cancer. 1991;67:31313135.

22. Todorov P, Cariuk P, McDevitt T, Coles B, Fearon K, TisdaleM. Characterisation of a cancer cachectic factor. Nature.1996;379:739742.

23. Lorite MJ, Smith HJ, Arnold JA, Morris A, Thomson MG, Tis-dale MJ. Activation of ATP-ubiquitin-dependent proteolysis inskeletal muscle in vivo and murine myoblasts in vitro by aproteolysis-inducing factor. Br J Cancer. 2001;85:297302.

24. Cabal-ManzanoR,BhargavaP, Torres-DuarteA,Marshall J, Bhar-gava P, Wainer IW. Proteolysis-inducing factor is expressed intumours of patients with gastrointestinal cancers and correlateswith weight loss. Br J Cancer. 2001;84:15991601.

25. Seidenfeld J, Piper M, Flamm C, et al. Epoetin treatment ofanemia associated with cancer therapy: a systematic reviewand meta-analysis of controlled clinical trials. J Natl CancerInst. 2001;93:12041214.

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