CHAPTER 32 ■ ■ ■ Fatigue William S. Breitbart and Yesne Alici INTRODUCTION Fatigue is a highly prevalent and distressing symptom of cancer, associated with decreased quality of life, as well as significant psychological and functional morbidity.1 ' Fatigue in cancer patients has been significantly associated with depression, hopelessness, and overall psychological distress.7 Fatigue has been shown to predict desire for hastened death among cancer patients.' Patients with cancer perceive fatigue as the most distressing symptom associated with cancer and its treatment, more distressing than pain, nausea, and vomiting.' As outlined in the National Comprehensive Cancer Network (NCCN) Practice Guidelines for Cancer-Related Fatigue,'Jt "fatigue most commonly occurs with other symptoms, such as pain, distress, anemia, and sleep disturbances," thus cancer patients presenting with fatigue should be screened for all these symptoms.*11 Despite its impact on patients and their caregivers, cancer-related fatigue is underrcportcd, underdiagnosed, and undertrcated.'10 As growing attention is given to symptom management and quality of life in cancer patients, clinicians treating such patients should be familiar with major issues in assessment and management of fatigue. This chapter reviews the definition, prevalence, and assessment of cancer-related fatigue, as well as evidence-based strategies for treatment. DEFINING CANCER-RELATED FATIGUE Fatigue is a poorly defined symptom that may involve physical, mental, and motivational components. Cancer-related fatigue is defined by the NCCN'10 practice guidelines as "a distressing, persistent, subjective sense of physical, emotional, and cognitive tiredness or exhaustion related to cancer or cancer treatment that is not proportional to recent activity and interferes with usual functioning." Cancer-related fatigue is more severe and more distressing than fatigue experienced by healthy individuals and is less likely to be relieved by rest."0 Recognizing the need for a standardized definition of fatigue, a group of expert clinicians* proposed a set of diagnostic criteria, which are included in the 10th edition of International classification of diseases (ICD-10) (Table 32-1). A standardized interview guide has been designed and validated for use In identifying patients with cancer-related fatigue.11 PREVALENCE OF FATIGUE The reported prevalence of cancer-related fatigue ranges from 4% to 100%, depending on the specific cancer population studied and the methods of assessment.1*" Fatigue is present at the time of diagnosis in approximately 50% of patients with cancer. In a study of 179 cancer patients, 23.5% of patients reported "severe fatigue" at the time of diagnosis, before the start of therapy." Fatigue occurs in up to 75% of patients with bone metastases, and approximately 60%-96% of patients undergoing treatment for cancer report fatigue.1* A national survey of 197 oncologists, 200 caregivers, and 419 cancer patients with various cancers, at various stages of illness, and treatment noted that more than 78% of patients experienced fatigue during the course of their disease and treatment. Thirty-two percent of patients experienced fatigue daily and 32% felt that fatigue significantly affected their daily routines. Sixty-one percent of patients said fatigue affected everyday life more than pain. Among the oncologists, 80% believed that fatigue was undertreatcd and that fatigue y„ . discussed between patients and oncologists.1 Chtrnoth therapy, and biologic and hormonal therapies have been^^' erbate fatigue.9 Women with early-stage breast cancer K f^10^ therapy have reported a 4% rate of fatigue, which increased four cycles of chemotherapy." Fatigue was estimated to be symptom in up to 67% of hospitalized and ambulatory pros patients."' A study in men with localized prostate cancersho • hJ?* fatigue rates increased from 4% to 25% after radiation treatai«!» a cross-sectional survey of 814 cancer patients receivingchem*1'' and/or radiotherapy, 80% of patients reported fatigue as a side cancer treatment. Female patients, younger and unemployed puT* and those with higher levels of depression and fatigue experienced fatigue." 1 Fatigue is a disruptive symptom months or even years after come!* tion of cancer treatment, which ranges from 17% to 53% in diftna prevalence studies depending on the diagnostic criteria used to ifa fatigue.10JU(UI A systematic review of fatigue among breast cancerb vivors concluded that survivors experienced significant fatigue up to! years after completion of adjuvant chemotherapy." Fatigue is most common among cancer patients in palliative ort« tings reported by 84%-100% of patients in palliative care units."*'1 As evidenced by the prevalence studies, fatigue is a common sysf torn in cancer patients and survivors of cancer, from diagnosis thrasi all stages of treatment and beyond. PATHOPHYSIOLOGY OF FATIGUE The exact mechanisms involved in the cancer-related fatigue a unknown. Studies have focused on understanding factors that contrfei to fatigue, including the cancer itself, cancer-related treatments, tea* variety of physical and psychological co-morbidities (e.g., anerru*^ depression, anxiety, cachexia, sleep disturbances, and irofflowW)?-Production of cytokines, abnormal accumulation of muscle meU » changes in neuromuscular function, abnormalities in ^""''"'Z!^-phate synthesis, serotonin dysrcgulation, disruption of the lamic-pituitary-adrenal axis, modulation of the circadian vagal nerve activation have been proposed as possible mech,i(iJj|fj the development of fatigue.25"27 The role of cytokines in fat'g^^ researchers to consider cytokine-antagonist drugs, such as ^B sis factor (TNF) receptor etanercept, TNF-a antagonist trau improve tolerability of chemotherapy regimens and Pot"V j^iN fatigue and cachexia in cancer patients.'2'-30 Genetic vana^ been implicated to play a role in the development of fat!gu^^ifbi** cer patients. Advanced colorectal cancer patients with two of the DPYD gene were significantly less likely than "-^V^ng V* a form of the gene known as DPYD'S to report fatigue l^,^,^ ment with a chemotherapy regimen of 5-fiuorouraci, oxaliplatin.31 . K ;s und'^ The pathogenesis of fatigue among cancer »urvtv» fr5uin". most likely multifactorial.'"7 A study comparing sJgoi*£ji with and without fatigue (n = 20 In each group) n«i ^sf t>T^ higher levels of interleukin-1 receptor antagonist, sot^^un^ and higher numbers of T lymphocytes among """^ m*P* with fatigue suggesting a chronic inflammatory p T-cell compartment In this group of patients. TflWe 33-t. lCD-i fATIGUE 237 ^<^i^fd« following symptoms l^vTt^^^--^l^^^^i fatigue A-5 JWtoncof the symptoms^ (Al) significant E*^^"^*^^- Sicnificant fatigue, diminished energy, «r increased neM, V duHn& *"^I^^77~T- * JSmplaints of generalized weakness or limb heavl" t0 di5P'°Portiona, , P ,hc PMt momh' 1 anyrecen« change in actiVtyl Al- Slgn o ComK'""""" o—--■-------------"i Diminished concentration or attention JJ Decrease motivation or interest to engage in usual activity *' In<:omnia or hypersomnia * activities f6 Experience of sleep as unrefreshing or nonrestorative V7 Perceived need to struggle to overcome inactivity Marked emotional reactivity (eg, sadness, frustration ■ ■ . J,. Difficulty completing daily tasks attributed to feeling^VatiZ ^ to f",ing ^tigued AiO. Perceived problems with short-term memory ,a»gued A9 UHlKuuj ™H aiinuuted to AIO. Perceived problems with short-term memory »11, Postexertional malaise lasting several hours ____inmc roiisp rlinirallv cinnifif->nt ___ Clhc" Jor^der, or delirium.__^P^h,atr,c disorders, such as major depression, somati.tion disorder, soma.o- sovrce: Adapted from' Cella D, Peterman A, PassikS, Jacobsen P. Breitbart w~d----_._ I998J2J69-377. W ProS™ 'oward guidelines for the managenvnt of fatigue. Oncology (MUistan Park). All I'osiw""""* --" '-""S s<->crai nours symptoms cause clinically significant distress or impair™ t • ■Thereisevidencefromthch^ Ml___are not nrimaH.v .___________* ^ W» « * -sequence S ASSESSMENT OF FATIGUE ■ All cancer patients should be screened for fatigue at their initial visit, at regular intervals during and following cancer treatment, and as clinically indicated.'"5 The NCCN practice guidelines on cancer-related fatigue recommend the use of numerical self-report scales or verbal scales to assess the severity of fatigue. As fatigue is a symptom that is perceived by the patient, like pain, it is most accurately described by self-report. If the severity is measured as moderate or severe (a score of 4 or more on a scale of 0 to 10 with higher numbers indicating increased severity) a focused history and physical examination; evaluation of the pattern, onset, and duration of fatigue; associated symptoms; and interference with norma! functioning is recommended.910 Description of patient behavior by family members and other caregivers is an important part of assessment among children and elderly patients. Precipitating factors, such as acute physical and psychological stresses should be identified, as should perpetuating factors such as physical inactivity and ongoing psychological or social stresses. Age specifications have been included in the NCCN practice guidelines for screening fatigue and assessing We severity of it highlighting the importance and variability of fatigue across the lifespan.*'0 assessment of etiologies. The etiologies of fatigue are complex and ^fied, including tumor by-products, opioids or other drugs (such as ^depressants, p-blockers, benzodiazepines, antihistamines), hypogonadism, hypothyroidism, cachexia, anemia, malnutrition, pain, myop-*■* nausea, hormonal therapy, chemotherapy, radiation therapy, bone E^^plantation, and treatment with biological response rnodi-?(Table »-2) ».w"3 Potentially reversible causes of fatigue (such as shl?u?°tiona] stress, sleep disturbance, anemia, hypouhyro.Jsm 58* identified and t»*ed, ™d nonessential centrally acting drugs Pres"iption drugs, over-the-counter medications, and sup S£ms jhould be eliminated."0 Clinicians should consider|4eP° Jl°f dePressi°» due to its high prevalence in patients With ameer 3?d? tre«ment.^ If anemia is the main cause of **^J* C,ic °Uld determi"<= the necessity of a transfusion in severd^ymp C lPatie^- Clinical trials have shown that patients wit*.anemia ^ergy and less fatigue after erythropoietin tretfM* cCand COnditi0"" ^ as cardiac, pulmonary, rena. hep.g "jo St al cnCUrol°8ic dysfunction, and infections should bend^jj S» h T? of fali§ue- Several chemotherapy agents and ndiat Si becn associa«d with endocrine abnormal JJ^JJJ ^ i2:mnand hp^nadism.- Ass«smc^nu^n (we g ^ »luid-electrolyte imbalances) and activity icvci Table 32-2. Etiologies of cancer-related fatigue Preexisting conditions -Congestive heart failure, chronic obstructive pulmonary disease Direct effects of cancer, "tumor burden" Effects of cancer treatment -Surgery, radiation therapy, chemotherapy, hiological therapies Psychological factors -Depression, anxiety Immobility Sleep disturbances (insomnia, excessive daytime sedation with or without narcolepsy, restless leg syndrome, obstructive sleep apnea) Cancer-related symptoms -Pain, nausea Conditions related to cancer or its treatment -Anemia, dehydration, malnutrition, infections, electrolyte abnormalities, cytokine production, myopathy Medications and drugs -Opioid analgesics, psychotropic agents, (5-blockers, alcohol important elements of assessment.'10 Anemia, polypharmacy cognitive impairment, malnutrition, and cachexia are the most likely etiologies of fatigue in palliative care settings.17 Assessment Instruments. Fatigue is not only difficult to define but , AHit to assess and quantify Nonetheless, reliable and valid tools also difficult to assess 4 1 ^ and research pro. for assessment an cruc al for p ^ ^ ^ g.ess. Va^usstandarJ^^rep ^ ^ mMJU„ ^d^entaUy the context of cancer. d . conCeptions of fatigue, different aspects or <™J^inhibi,orS ^^-norepinephrine uptake inhibitors Vtnliföine Puloxttine .Vorpintphrine-dopamine ' ^uptake inhibitor Bupropion a.2Uagonist/5-HT2/5HT3 antagonist Mirtazapine Starting dose «ncer-related fatigue 2.5-5 mg daily or twice daily 2.5-5 mg daily or twice daily ,.iiifi^-f,rC"fl0tmS agtntS 50-100 mg daily $0 10-20 mg/day 10-20 mg/day 10-20 mg/day 5-10 mg/day 25-50 mg/day 37.5-75 mg/day 20-30 mg/day 75 mg/day 7.5-15 mg/day 10-60 mg/day 10-40 mg/day 10-40 mg/day 5-20 mg/day 25-200 mg/day 37.5-225 mg/day 20-60 mg/day 75-450 mg/day 7.5-45 mg/day Longer-acting form? are available Capsule form! can be sprinkled on food Longer-acting formulations are available Capsule forms can be sprinkled on food Favorable side-effect profile Well-tolerated Citalopram, escitalopram, and sertraline have the least drug-drug interactions ■ Well-tolerated Monitor blood pressure regularly Doses higher than 300 mg a day should be administered twice daily to minimize the risk of seizures Most helpful in patients with insomnia and anorexia aibieviatios: 5HT, 5-hydroxytryptamine. 'Aviiiable in liquid formulations. Table 32-4. Psychotropic medication trials for the treatment of cancer-related fatigue Sample Mähylphtmdate Sanillctal. 2001M Vvaraetal. 2002M Patients with advanced cancer Prospective, open-label design (n = 11) Patients with advanced cancer Prospective, open-label study (n = 16) att*etal.2002" Patients with melanoma al. 2003« receiving interferon Prospective, open-label study (n = 12) Patients with advanced cancer. Prospective open-label (n = 30) Jntenxntion Remits Comments Methylphenidate 10 mg twice daily Methylphenidate 5-30 mg/day, mean duration of treatment 8 days Exercise and methylphenidat 20 mg/day e Patient-controlled methylphenidate 5 mg every 2 hours with a maximum of 4 caps in a day Decreased fatigue in 9 out of 11 patients, with sedation and pain improving in some patients Decreased fatigue scores (p = 0.01) Decreased fatigue scores Decrease in fatigue, depression well-being and overall More than half of the patients experienced side effects, such as insomnia, agitation, anorexia, nausea, vomiting, and dry mouth Two patients dropped out due to insomnia Visual analog scale was used for assessment of fatigue Unclear whether the positive effect was due to exercise or meth-ylphenidate or both None of the patients discontinued the medication (Continued) 239 Sample Hanna et al. 2006*' Brueraetal. 2006™ - Roth et al. 2006" D-methylphenidate Lower et al. 2005" Butler et al. 200773 Mar Fan et al. 20087< Modafinil Morrow et al. 20057» Kaieita et al. 2006'° Patients with breast cancer, who were cancer free longer than 6 months but less than 5 years. Open-label, phase II study (n = 37) Patients with advanced cancer (n = 52 in medication arm, n = 53 in placebo arm). Randomized, double-blind, placebo-controlled trial Ambulatory* patients with prostate cancer Randomized, placebo-controlled, phase III trial (n = 15 in the placebo arm, n = 14 in the medication arm) Adult patients with cancer, 2 months after chemotherapy Randomized, placebo-controlled, phase III trial (n = 75 placebo, n = 77 medication arm) Adult patients with primary or metastatic brain rumors on radiation therapy Double-blind, randomized, placebo-controlled trial (n=34 in each arm) Women with breast cancer undergoing adjuvant chemotherapy Randomized, double-blind, placebo-controlled trial (n - 29 on medication, n = 28 on placebo) Women with breast cancer, 2 years after treatment Prospective, open-label study (n = 51) Adult patients with brain tumor. Phase III, open-label trial (n = 30) Table 3^-4. Continued Intervention Methylphenidate 5 mg twice daily for 6 w«ks Patient-controlled methylphenidate (5 mg every 2 hours up to 4 caps a day) versus placebo for a total of 7 days Methylphenidate versus placebo D-metfiylphenidate 10-50 mg/d for more than 2 weeks D-threo-methylphenidate 15 mg twice daily for 4-12 weeks D-methylphenidate up to 10 twice daily for 20-140 days ■ Results 54% of the patients responded with a decrease in BFI score of more than 2 points Fatigue scores improved both in placebo and medication arm on day 8 13 patients taking placebo and 8 patients taking methylphenidate completed the study 73% of the patients in the methylphenidate arm, 23% of the patients in the placebo arm showed improvement in fatigue scores Medication was found to be more effective compared to placebo in improving fatigue Prophylactic use of d-threo-methylphenidate did not result in improvement of fatigue scores or quality of life There were no significant differences between the FACT-F scores of the randomized groups Modafinil 200 mg/day for a month 16%*thep„. °Pcn-labti Ph. Modafinil, mean dose 225 mg/day at week 8,258 mg/day at week 12 Preliminary^ the study■ ^ ****** ^roppedoutdueta cardiacsideeff^ Final data analysis been published, ytt 86% reported improvement in fatigue Well-tolerated; mean fatigue score change at week 8 and 12 was significantly higher in the intervention arm Researchers conduded that therapeutic rather than prophylactic d-methylphcnidite was recommended for patients undergoing brain RT who devdop fatigue or cognitive dysfunction Greater number of ptW discontinued studydn? inthed-MPHamtte the placebo arm, on the other hand cqd numbers in each p«T required dose redact** for presumed d-MPn toxicity Final data analysis Jj5^ been published)* open-label <*[C ^ P^^T^ this,*st£« 5" analysis^ "l published 240 etal.200551 CAmetal.20O4M Mossctal.2006* Brum et aL 2003* SwetiL 2006"" 2007" ■ Patients with malignant melanoma Doublc-randomizcd controlled trial (n = 40) Patients with breast cancer receiving chemotherapy Randomized, double-blind, placebo-controlled trial (n = 479) Patients with breast cancer undergoing chemotherapy, Randomized, double-blind, placebo-controlled trial (n = 94) Patients with advanced stage cancer (n = 189) without major depressive disorder Randomized, double-blind, placebo-controlled trial Adult patients with cancer Open-label, prospective design (n = 15). Adult patients with cancer Prospective, case series (n = 21) Adult patients with cancer Open-label trial (n=27) Adult patients with brain tumor Open-label, phase II trial (n = 34). Adult patients with advanced cancer Randomized, double-blind, placebo-controlled trial with donepezil (n = 47) versus placebo (n = 56) oflnf r rethe start ^Interferon therapy Paroxetine 20 mg/dav versus placebo for 8 weeks Paroxetine 20 mg/day versus placebo ■ Serial ine 50 mg/day (n = 95) versus placebo (n = 94) ■ Bupropion sustained release 100-150 mg/day Bupropion sustained release 100-300 mg/day No significant difference 7« detected in fatigue improvement between Pl=«bo and paroxetine arms No significant difference was observed in fatigue scores between the placebo and paroxetine arms No significant difference was observed in depression, anxiety, fatigue, and overall well-being Donepezil 5mg/day for 7 days Donepezil 5 mg/day for 24 weeks - ■ Donepezil 5 mg/day for 7 days ■ 13 patients reported improvement in fatigue Well-tolerated; both depressed and nondepressed patients reported improvement in their fatigue All of the 20 patients who completed the trial showed significant improvement in fatigue Fatigue subscale of the Profile of Mood States scale showed improvement short of statistical significance, "trend toward significance" as noted by the researchers There was no significant difference in fatigue scores between the donepezil and placebo groups ■ ■ ■ Risk of depression was significantly reduced in the paroxetine arm There was a significant difference between groups in the mean level of depression Paroxetine was effective in treating depression, but not cancer-related fatigue Sertraline was kept at the starting dose throughout the study duration of 8 weeks Small sample size, open-label design Small sample size. Placebo-controlled studies arc needed to confirm the results 7 patients dropped out. Open-label design limits the significance of positive results Improvement in cognitive functioning and health-related quality of life were observed Improvement in sedation observed both in the placebo and donepezil arms Open-label phase of the study with donepezil showed sustained improvement in fatigue scores %t ^ BFi. brief fatlgue Jummfi d.MpH) d^ethviphenldtte hydrochloride. FAC S^^teUted fatigue. While open-label studies with psy-^Colt? Sh0wn improvements in cancer-related toff* t&$W6* rando«^ed trials have found a remarkable placebo ^JfiJ? Palients <" well as improved fatigue scores with , .A nniE Administration (FDA) approved the use of The Food *«d modaf.nil in adult patient* w»th exces- ^efulness-promot ng agem obstructive sleep apnea, and £ve sleepiness«oca d *Qna P ^ ^ ( «t^PW» t^gS&H*as an adjunct trcatI,,ent p i ■ presumably enhance, .ctivtty th ejjjj JbeIomBininai.ry nucleus multiple sclerosis- and has been tudtfd«. JJ»J triflls.^ Well-related fatigue with tapnwment of fcto.e in ope^ ^ designed, randomized, control ed dmical "^"^^ faligue. clarify the role of modafinil in the treatment ^ AtftiVNOMtt. The phenomenological s.m an ties an fty of a bidirectional relationship between J'S"^^ canccr. led clinicians to consider antidepressants In the treatment ""SHE of antidepressant use are no, dear in^cer-related fatigue in the absence of a depressive mood disorder Researchhas su^ettSTcornmon pathophysiological mechanism such as serotonm insufficient in the development of both fatigue and depre^on^ Studies have examined the role of paroxetine,"** s rtrahnc, and bupropion-" in the treatment of cancer-related fatigue. Paroxetine and sertraline" were effective in improving fatigue among cancer patients with co-morbid depressive symptoms. Bupropion was found to be effective and well-tolerated in both depressed and nondeprcssed canccr patients in open-label trials"" However controlled studies are required to determine whether the effect of bupropion on fatigue is independent of its antidepressant effects. Underlying depression treated with selective serotonin-reuptake inhibitors (SSRJs) is generally better tolerated than tricyclic antidepressants in patients with cancer. Medications should be initiated at lower doses and drug-drug interactions should be carefully monitored among patients with cancer-related fatigue.5" Corticosteroids. Corticosteroids have been used in the treatment of cancer-related fatigue, In a survey among Swedish palliative care physicians, 40% of the clinicians reported using corticosteroids to treat fatigue, and 80% reported "very "or "some effect" of corticosteroids on fatigue.** Bruera and colleagues in their prospective, randomized, double-blind study observed that 40 palliative care patients who received a 2-week treatment with methylprednisolone demonstrated an increase in activity that became nonsignificant after 4 weeks of treatment." This study suggests that the positive effects of corticosteroids in the treatment of fatigue may be transient. It is important to note that corticosteroids may have detrimental side effects such as muscle wasting with long-term use. Megestrol acetate, Megestrol acetate, a progestational agent, which has been found to improve appetite in canccr-retated cachexia, may have a role in the treatment of cancer-related fatigue. A double-blind crossover study comparing megestrol acetate (160 mg 3 times daily for 10 days) to placebo in the treatment of cachexia among patients with advanced cancer (n = 84, total number of patients) has shown significant improvement m overall fatigue scores measured by the PFS M The effects of megestrol acetate on fatigue are not dear but probably involve anticv-tokine and corticosteroid-type effects.*" L-carnitinc. L-carnitine is a cofactor that binds free lons-chain fattv ids to transport them a™« ____. ? . " ratt> -carnitine --— mi\j 1 i 1( supplements improved fatigue and deoressinn in » t ^«rwim^carniunedefid^ cancer-related fatieue |S Alth™gh the use of L-carnitine in ^f^tS^SSS&S^ "Potation shows ffiXi'aiisrinhibitor * ofdonepe.ilj" ** ^rfSS^feft"? "I blind randomiz.ed^onS SS^ffl A between donepezil and placebo in il!!!^ t0,show anV difference ents " patients.' m ,mpr0Vi"ß f«ÜB»e among cancer Other medications. Amantadine an antiinflucnza a • *r«-u used in Parkinsons disease and as an a.li? w''h a Off for chronic hepatitis C.^Jgj;^ in the treatment of fatigue associated with mul,ip]e ^ u h« not been studied in cancer-related fatigue.** Jg^ljS „flamltory drugs, select ve cydooxygerjase 2 inhih oxb). monoclonal antibodies (e.g., mfl.ximab), cyu^S^ nd bradykinin antagonists have been considered „ Potcm a >■' for cancer-related fatigue through their direct and indi antagonistic effects.50" CONCLUSIONS Fatigue is highly prevalent among patients with cancer, and . elated with decreased quality of life. Fatigue should be assessed, monitored, and treated promptly for all age J**.^ stages of canccr, before, during, and following treatment J.' ?4 by the NCCN Practice Guidelines on cancer-related fatiguet*?^ nonpharmacologic and pharmacologic treatment options' ^ able for management of fatigue. Increased physical activity J** types of psychosocial interventions, dietary management, and'?'15 hygiene are well-supported by research in the treatment' of f P Psychostimulants and antidepressants have been studied the in the treatment of cancer-related fatigue. Psychostimulant* at?? tolerated and appear to have a role in the improvement of J despite a large placebo effect. Antidepressants are most effective patients with underlying depression. Activating antidepressant* sJ'3 bupropion may be more effective in the treatment of fatigue symPt0'» However, it is important to emphasize that more research is n«d«U evaluate the efficacy of pharmacologic interventions, as current rti dencc falls short of pros-iding sufficient evidence to recommend rrudi cations for treating cancer-related fatigue. REFERENCES 1. Curt GA, Breitbart \V, Cella D, et al. Impact of cancer-relattd fctpu on the lives of patients: new findings from the Fatigue Coalition. OmalerLi 2000;5:353-360. 2. 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