CLINICAL REVIEW

Impaired sleep and rhythms in persons with cancer

Kathryn Leea,*, Maria Chob,1, Christine Miaskowskib,2, Marylin Doddb,3

aUniversity of California, San Francisco (UCSF) Box 0606, USAbUniversity of California, San Francisco (UCSF) Box 0610, USA

Dedicated to the memory of Dr. J. Christian Gillin, a dedicated and respected scholar and sleep researcher who lost his battle withesophageal cancer, 13 September 2003.

KEYWORDSBreast cancer; Prostate

cancer; Lung cancer;

Colorectal cancer;

Gynecological cancer;

Hematological cancer;

Bone marrow transplant;

Sleep; Insomnia; Fatigue

Summary This review includes research findings from sleep-related studies on specifictypes of cancers, on specific types of treatment protocols, and on persons with end-stage cancer regardless of treatment protocol. Since treatment protocols haveevolved in the past decade, literature since 1990 is emphasized. We conclude thatresearchers should design studies that attend to prior sleep history, gender, type ofcancer and treatment modalities, and the specific type of sleep problems experiencedover the course of diagnosis, treatment, and recovery. More research is also needed tounderstand sleep problems in children with cancer and sleep problems in familycaregivers. Research is also needed on effective pharmacological and non-pharmaco-logical interventions. Daytime functioning, daytime sleepiness, and altered circadianrhythms should be considered salient outcomes in addition to severity of cancer-related fatigue. Clinicians should consider whether a patient’s sleep problem has beenchronic and unrelated to cancer, or precipitated by diagnosis and treatment. Thespecific type of sleep problem should be ascertained so that appropriate interventionscan be prescribed. Appropriate interventions can include either pharmacologicalmedication or behavioral strategies, and each has the potential to promote restorativesleep and thereby improve the patient’s quality of life, daytime functioning, and well-being.q 2003 Elsevier Ltd. All rights reserved.

Introduction

The American Cancer Society estimates that a thirdof the United States (US) population will developcancer at some point in life, with about 80% of all

cancers diagnosed after 55 years of age.1 In males,prostate cancer is the leading type of cancer,followed by lung and colon. In females, breast canceris the leading type of cancer, followed by lung andcolon. Advances in treatment during the past decadehave reduced cancer mortality. Persons with cancernow live many years and cope with their prognosisand therapeutic regimen while maintaining theirsocial roles within the family and working commu-nity. The cost of cancer in the US is estimated at over$180 billion1 and these costs relate not only totreatment, but also lost productivity from poorhealth and side effects of treatment.

1087-0792/$ - see front matter q 2003 Elsevier Ltd. All rights reserved.doi:10.1016/j.smrv.2003.10.001

Sleep Medicine Reviews (2004) 8, 199–212

www.elsevier.com/locate/smrv

1 Tel.: þ415-476-4320; fax: þ415-476-8899.2 Tel.: þ415-476-9407; fax: þ415-476-8899.3 Tel.: þ415-476-4320; fax: þ415-476-8899.

*Corresponding author. Tel.: þ415-476-4442; fax: þ415-753-2161.

E-mail addresses: kathy.lee@nursing.ucsf.edu (K. Lee),macho@itsa.ucsf.edu (M. Cho), chris.miaskowski@nursing.ucsf.edu (C. Miaskowski), marylin.dodd@nursing.ucsf.edu (M. Dodd).

While cancer-related fatigue is a well-knownsymptom, its timecourse remainspoorly understood,and its relationship to impaired sleep is even lessunderstood. As Ancoli-Israel and colleagues2 pointout, poor sleep can be as major a factor in cancer-related fatigue as anemia or metabolic disorders. In alarge study of patients with various types of cancer,Davidson and colleagues3 reported that those whocomplained of insomnia also perceived poorerphysical and emotional health, problems concentrat-ing, and difficulty coping with stress.

Sleep is a physiological and behavioral activitynecessary for health and well-being. As seen in thestudies reviewed here, poor sleep can interferewith immune function, alter responses to stress,and impact daytime activities and quality oflife. Sleep occurs in a circadian pattern, withmost deep sleep (slow wave sleep, stages 3 and 4sleep, delta sleep) occurring during the first half ofthe night, and most rapid-eye-movement (REM)sleep occurring during the second half of the night.There are individuals who, because of their circa-dian rhythm patterns and chronotype, prefer earlybed times and wake times (early birds or larks), andthere are those who prefer later bed times andwake times (night owls). Those who sleep in phasewith their circadian rhythm obtain a better qualityof sleep, with minimal time to fall asleep and fewerawakenings, than those who sleep out of phase fromtheir circadian chronotype (such as shiftworkers orjet-lagged pilots and airline attendants).

Sleep disturbance, or insomnia, can includedifficulty falling asleep (taking more than 30 min),problems maintaining sleep (waking more thantwice during the night), awakening too early fromthe night’s sleep, or excessive daytime sleepiness.Those who have difficulty maintaining sleep may beso deprived of sleep that they have little troublefalling asleep, either at bedtime or during the day.Daytime sleepiness may be difficult for both thepatient and health care provider to distinguish fromfatigue. Since humans have a typical 24 h wake/sleep rhythm that allows them to function mostoptimally for their specific chronotype, this review isfocused on current knowledge of sleep and circadianrhythms in relation to cancer and its treatment.

The purpose of this review is to critically examineresearch on sleep in relation to cancer and itstreatments, suggest clinical practice guidelinesbased on current knowledge, and identify gaps inknowledge for future research efforts. Studiesinvolving specific types of cancers, specific treat-ments, and studies of personswithmetastatic cancerregardless of stage or treatment are included. Sincetreatment protocols have evolved in the pastdecade, literature since 1990 is emphasized

and studies were obtained by using key words thatincluded cancer and sleep or circadian rhythms.Studies of other symptoms, such as pain or fatigue,and studies of quality of life, were also examined formention of sleep or naps.

Etiology of sleep disturbances in personswith cancer

The etiology of sleep disturbance in persons withcancer is multi-dimensional in nature. In a recentreview of the literature on insomnia and cancer,Savard and Morin4 used Spielman and Glovinsky’sframework for categorizing etiologic factors aspredisposing, precipitating, or perpetuating. Pre-disposing factors for insomnia would include suchfactors as gender, age, and prior sleep history. Theprevalence of insomnia is higher among women andamong older persons in the general population, butoccurs in about 30% of the US population.5 Personswith cancer may already have sleep problems due topoor sleep hygiene or lifestyle issues, or may alreadybe diagnosed with a common sleep disorder such assleep apnea, narcolepsy, or restless legs syndrome.

Factors that are likely to precipitate sleepproblems include not only the type and stage of thecancer, but also pain and treatment side effects suchas nausea, vomiting, diarrhea, or urinary frequency.Hospitalization, or other changes in usual sleepingenvironment can also precipitate sleep disturbance.We are finding in our current study that getting upearlier than usual to commute to morning treatmentappointments can also be a precipitating factor.

Perpetuating factors include poor sleep hygienepractices and lifestyle habits such as poor nutrition,sedentary lifestyle, smoking, or lackofmoderation inalcohol and caffeine consumption. These perpetuat-ing factors are difficult to change during thecourse ofcancer treatment, and require education and coun-seling at a point when the patient is able to cope withmaking lifestyle changes. The focus of this review ison precipitating factors for sleep disturbances thatarise during diagnosis and treatment of cancer.

Prevalence of sleep problems in personswith cancer

The prevalence of sleep problems in persons withcancer is difficult to ascertain for many reasons.Epidemiologists often askabout frequency of ‘insom-nia’ without probing further about difficulty initiat-ing sleep, maintaining sleep, or daytime sleepiness.Smaller clinical studies often include many types

K. Lee et al.200

of cancer that vary not only by stage of disease andtime since diagnosis, but also include multipletreatment protocols with their associated sideeffects. Little is known about the prevalence ofsleep problems in US populations of cancer patients.A prevalence study of 1635 cancer patients referredto a pain clinic in Germany would indicate that themost frequent symptom is insomnia (59%), but of the15 symptoms listed, fatigue, the most commonproblem reported in US studies, was not on thelist.6 Two prevalence studies3,7 have been conductedin Canada and will be discussed here. Both werecross-sectional studies, andbothaskedabout specifictypes of insomnia. Differences in type of insomnia bytime since diagnosis or by type of treatment,however, was not a focus of their research.

Savard and colleagues7 used an investigator-developed questionnaire to estimate the prevalenceof insomnia in a sample of 300 Canadian women withbreast cancer. Most (55%) were Stage I, and only 9%were Stage III breast cancer. Their sample ranged inage from 28 to 90 years, and time since diagnosisranged from 2 months to 30 years. Almost half (48%)currently experienced sleep problems and 28%currently used sleep medication. There was norelationship between severity of impaired sleepand time since diagnosis, but the prevalent type ofinsomnia (initiation or maintenance) for thoserecently diagnosed was not compared with theprevalent type of insomnia for those who were livingmany years after diagnosis. While only 19% of thewomen reported, retrospectively, that they experi-enced insomnia prior to their cancer diagnosis, theirpreexisting sleep problems worsened, and 33% hadan onset of insomnia after diagnosis, with half ofthose indicating that the onset of their insomnia wasdirectly related to a cancer diagnosis. Furthermore,there was a four-fold increased risk of sleepproblems after diagnosis in the more highly edu-cated women who were living alone.

Most recently, Davidson and colleagues3 con-ducted a prevalence study on sleep problems in amore broadly representative sample of cancerpatients in the Canadian population. The responserate was 87% and there were 982 patients with sixdifferent types of cancer. The median time sincediagnosis was 34 months, with 41% diagnosed lessthan 2 years ago and 32% diagnosed 5 years or more.Types of treatment likewise varied between surgery,chemotherapy, radiation, and hormones. Patientscompleted a thorough sleep questionnaire while inclinic waiting rooms during the summer of 1996.Patients with more benign skin cancers served as acomparison group for those with breast, lung,gastrointestinal, genitourinary, or gynecologiccancer. When asked about the past 4 weeks, those

patients diagnosed in the past 6 months, regardlessof cancer type, had higher rates of excessive daytimesleepiness (37%) than those who had less recenttreatment (41 and 27%, respectively). Lung cancerpatients were diagnosed more recently, and weremore likely to take a sleep medication (40%) andexperience restless legs (47%) compared to othercancer types. Women with breast cancer were morelikely to report insomnia (38%) and menwith prostatecancer were least likely to report insomnia (18%).

Despite the type of cancer, insomnia was evidentin 45% of surgery patients, 35% of chemotherapypatients, and 39% of radiation therapy patients. Ofthe 300 patients with insomnia, 44% had difficultyfalling asleep and 76% had maintenance insomniawith several awakenings during the night. Theprevalence of daytime napping was not reported.Most (59%) had more than one type of insomnia andthe onset was at the time of diagnosis. Reasons forthe insomnia included: pain or discomfort, concernsabout family and finances, and physical effects of thecancer itself.3

This large Canadian sample did not includepatients with brain tumors, head and neck cancer,or rare tumors of the thyroid or pituitary gland.However, some patients had also received radiationto the head. Of interest from a circadian rhythmperspective was the finding that those who hadrecently received radiation to the head reportedmore daytime sleepiness and slept more than otherrecently treated cancer patients.3

As in the general US population, older age andfemale gender may be contributing factors in theprevalence of sleep problems also seen in cancerpatients. However, in samples that include varioustypes of cancer and treatment modalities, it wasthe younger cancer patient who was more likely toreport insomnia3,8 and men were more likely toreport insomnia (61%) than women (56%) in aGerman sample of cancer patients referred to apain clinic.6 In most studies of lung cancer or coloncancer, samples have not been large enough toexamine gender differences. No gender differencewas found in a study of over 200 chemotherapypatients with varying types of cancer,8 however,women with melanoma had more complaints ofsleep problems than men with melanoma.9

Impaired sleep in early-stage cancers

Breast cancer

Knobf10 was one of the first to document frequentnight awakenings in a small sample of women with

Impaired sleep and rhythms in persons with cancer 201

breast cancer. The 28 women were between 29 and75 years of age (mean 51.6 years) with Stage I–IIIdisease. Time since diagnosis and treatment rangedfrom 2 to 60 months and fatigue was related to poorsleep quality and more daytime sleep. In newlydiagnosed Stage I or II breast cancer patients ofsimilar age, Omne-Ponten and colleagues11 foundno differences in sleep disturbance for those whohad mastectomy compared to lumpectomy, but ahigher percentage (40–47%) experienced sleepdisturbance if they were employed or not part-nered. At 4 months after surgery, sleep disturbancewas more prevalent for women who also hadradiation therapy. By 1 year after surgery, therates were similar for both groups. While fatiguehas been found to be higher in women withcombination therapies compared to radiationtherapy only,12 no studies have compared sleepproblems by type of treatment for breast cancer.

Greenberg and colleagues13 studied 15 womenwith Stage I or II breast cancer who began radiationabout 5 weeks after lumpectomy. During the first 7weeks of treatment, self-reported sleep rangedfrom 7.5 to 8.2 h. There was no significant change inthe amount of sleep over time, but in this smallsample there was a trend for less sleep during thethird week and more sleep in the fourth and fifthweeks. It was interesting to note that fatiguepeaked at the end of the fourth week, but ‘fatigue’was assessed with a 10 cm scale with end anchorsranging from 1 (‘fit’) to 7 (‘increased need ofsleep’) and then 10 (‘pronounced need of sleep’).To understand the time course for these symptoms,measures that distinguish fatigue from sleepinesswould be useful in future research.

More recently, Berger and Farr14 studied 72women during breast cancer treatment. Aftersurgical recovery, women were monitored withwrist actigraphy for 4 days. There was no relation-ship between time since surgery and wake timeduring the night. Sixty of the 72 women were thenmonitored for 3 days at the midpoint of their firstthree cycles of chemotherapy. By the third cycle,they had more awakenings and longer wake timesduring the night, they were less active during theday, and they took more naps.

Andrykowski and colleagues15 studied 88 women 2years after treatment for breast cancer and com-pared them to 88 age-matched women with benignbreast problems. Using the Pittsburgh Sleep QualityIndex (PSQI), they found significantly poorer sleepquality in the breast cancer group (7.1 ^ 4.4)compared to the benign breast group (6.1 ^ 4.1).Poor sleep quality was primarily due to problemsfalling asleep rather than duration of sleep ordisturbances during sleep. Fortner and colleagues16

had similar levels of sleep disturbance (6.8 ^ 4.0) intheir sample of 72 women with breast cancerrecruited from an outpatient oncology clinic. Whilehigh, PSQI scores didnotdiffer from their comparisongroup of women recruited from a general medicalclinic (6.7 ^ 4.5). The only significantdifference wasincreased use of sleep medication among the womenwith breast cancer, in which 42% used a hypnotic inthe past month, and 21% used hypnotics more thantwice a week. The 29 women currently treated forbreast cancer reported more difficulty falling asleepand greater sleep disturbance in general, but thedifferences were not statistically significant com-pared to those in the pretreatment group ðn ¼ 19Þand post-treatment group ðn ¼ 23Þ:The small samplesizes in each group may have limited the power todetect any statistically significant difference in theirself-reports of sleep quality.

Reasons for disturbed sleep in women withbreast cancer have been documented in manystudies. Fortner and colleagues16 reported that50% had disturbed sleep due to need to void, 22%had pain, 10% stated they were coughing or snoring,and a few reported difficulty breathing (4%) or baddreams (3%). While only 4% complained of disturbedsleep due to feeling too cold, 17% reported beingtoo hot on three or more nights per week in the pastmonth.16 Use of hormone therapy and specificsymptoms of hot flashes or night sweats were notdiscussed. Bower and colleagues17 found thatbreast cancer survivors who experienced fatiguealso had a higher rate of bothersome hot flashes(60%) and night sweats (52%) compared to women inthe general population (55 and 40%, respectively).In a telephone survey with 114 breast cancersurvivors, Carpenter and Andrykowski18 found that68% had trouble sleeping, primarily due to meno-pausal symptoms such as hot flashes and nightsweats. About half the women were taking tamox-ifen hormone therapy. Interestingly, 18% ðn ¼ 21Þalso complained of ‘skin crawling’ but this symptomof restless legs was not discussed further.

Hormone therapy, such as tamoxifen, is oftenused as an adjunct to radiation or chemotherapy intreating estrogen-sensitive breast cancers. As aresult, estrogen insufficiency can become a pre-cipitating factor for sleep disturbance.19 There islimited research on how tamoxifen and its sideeffects of hot flashes and night sweats affect sleepin long-term breast cancer survivors. Stein andcolleagues20 studied 70 post-menopausal women4–6 weeks after starting either chemotherapy orradiation therapy. None of the chemotherapypatients were taking hormone therapy, and onlysix radiation therapy patients were taking tamox-ifen, but the two groups did not differ in their

K. Lee et al.202

experience with hot flashes. Those with hot flasheswere younger and had poorer sleep quality. Bergerand Higgenbotham21 used wrist actigraphy tomonitor sleep in 14 women between 32 and 69years of age during four cycles of chemotherapy.The ten women taking tamoxifen had more waketime at all four cycles, especially at the midpointand end of the third cycle. This finding, although ina small sample of younger women, is based on amore objective measure of sleep, and wouldindicate an effect that was not found in priorresearch using a single-item rating of difficultysleeping in older, post-menopausal women takingtamoxifen.22

The menstrual cycle itself may play a role insurvival after surgical treatment for breast cancer.Progesterone, a hormone secreted in high amountsfrom the ovary after ovulation, has been shown toinhibit cancer cell proliferation in-vitro, whileunopposed estrogen may exacerbate proliferation.Since natural killer cell activity is higher during theluteal phase of the menstrual cycle (post-ovulation,premenstrual) when progesterone levels are alsohigh, Senie and colleagues23 estimated the timeduring a woman’s menstrual cycle when breastcancer surgery was performed. Of the 283 womenwho underwent surgery, there were 98 recurrences(35%) during a 10 year period. After controlling fortumor size, family history and type of treatment,they still found that when the cancer was removedduring the luteal phase, there was a lower risk ofrecurrence (29%) compared to a risk of 42% duringthe follicular phase (preovulation when estrogen isunopposed). This finding supports data from animalmodels and other human studies,24 but objectiveindicators of menstrual cycle phase and measuresof estrogen and progesterone are needed in futureresearch on sleep disturbances in women withbreast cancer.

Gynecological cancers

Very little research has been done on women whohave cancer of the cervix, uterus, or ovary. In alongitudinal study of women undergoing radiationtherapy for cervical cancer ðn ¼ 31Þ or uterinecancer ðn ¼ 18Þ; Christman and colleagues25 con-firmed the sleep problems noted in a previousstudy.26 About 30% had sleep problems, eitherdifficulty falling asleep or waking up during thenight, at initiation of therapy. The rate increasedover the course of treatment, and reached a peak ofabout 60% at the fourth or fifth week of radiation.When treatment was terminated, difficulty sleepingcontinued to be the second most problematicsymptom after fatigue.25

Savard and colleagues27 examined the associationbetween sleep quality and immune function in 91women with abnormal Papanicolaou smears whowere then referred for cervical biopsy. Althoughsleep variables were not described for those withand without a cervical cancer diagnosis, they didreport a high level of poor sleep in this sample oflargely low-income African American women. Whilerestful sleep was not related to immune measures,amount of sleep was related such that those whoreported getting sufficient sleep had significantlymore helper T cells and B cells, and fewer suppressorT cells. Since correlations were only modest ðr ¼

0:23 –0:27Þ for numbers and percentages of T cells,and only self-report Likert-type measures for restfuland sufficient sleep were used, findings from thisstudy need to be replicated before results can beconclusive. These findings, however, support pre-vious research associating insomnia with reducedimmune function.28

Prostate cancer

Studies of sleep in men with prostate cancer arerare. Prevalence study of Davidson and colleagues3

included 155 patients from a genitourinary clinic inCanada. Most were prostate cancer patients, butthere were also 14 men with cancer of the testis,kidney, or bladder. Their most prevalent problemswere feeling overly fatigued (40%), feeling overlysleepy (30%) and having restless legs (37%). Insom-nia occurred in about 18%, and very few used sleepmedication (15%). Sleep disordered breathing wasalso rarely reported (11%).

Greenberg and colleagues29 studied 15 menduring 9 weeks of radiation following a biopsy orprostate resection. Hours of sleep were recorded ona daily log and averaged each week. Interleukin-1(IL-1) levels were obtained at the end of each week.IL-1, the cytokine released from macrophages afterinjury, has been shown to increase deep, slow wavesleep (stages 3 and 4) in animal models.30 Self-reported sleep duration was longest during the lastweek of full volume radiation (sixth week). IL-1peaked for most of the men during the fourth weekand was correlated with hours of sleep ðr ¼ 0:64Þ;but not with other symptoms such as urinaryfrequency or dysuria.

Most recently, Lee and colleagues31 reported onchanges in sleep patterns for 50 prostate patients asthey went through 9 weeks of radiation therapy.Changes in sleep were assessed both objectivelywith wrist actigraphy and subjectively with theGeneral Sleep Disturbance Scale, a 21-item self-report instrument that asks about sleep during thepast week. Time in bed increased slightly over

Impaired sleep and rhythms in persons with cancer 203

the nine weeks, with a peak at the fourth week ofradiation. Total sleep time also peaked the fourthweek (397 ^ 60.4 min). Wake time during the nightsteadily increased from baseline to a peak(20 ^ 14.7%) at week six where it remained duringthe last week of radiation. Self-reported disturbedsleep also increased significantly from baseline tothe last week of treatment. Bladder irritation,frequent voiding, and hot flashes were the primaryreasons cited for awakenings during the night. Sleepdisturbances began to peak during the fourth week;fatigue peaked during the fifth week of radiationand remained high at the end of treatment. Thosewho took tamoxifen or other hormone therapieswere not analyzed separately.

Lung cancer

In the recent Canadian prevalence study by David-son and colleagues, patients with lung cancer hadthe highest rate of sleep problems.3 Of the 114 lungcancer patients who participated, 67% were maleand most were recently diagnosed. It was also thelung cancer patients who had the highest incidenceof restless legs (47%) and use of hypnotics (40%).Sleep disordered breathing was self-reported byonly 15%, and 34% reported sleeping more thanusual, but daytime sleep and sleepiness was notspecifically assessed.

Ginsburg and colleagues32 specifically studiedrecently diagnosed lung cancer patients. The 52Canadian men and women in their sample wereundergoing either radiotherapy or chemotherapyand the majority (52%) complained of insomnia.Only two had early morning awakenings, while sixhad excessive daytime sleepiness. Seven reportedprolonged wake periods during the night, whichthey attributed to anxiety, radiation treatment,medications, and depression.32

In a study of 69 women with lung cancerdiagnosed in the past 2 years, Sarna assessedsymptoms with a symptom distress scale. Pain andfatigue were the most prevalent sources of distress,but insomnia was reported by 31%.33 Although typeof insomnia could not be determined from measuresused in this study, findings support the relationshipbetween poor quality of life and symptoms of pain,fatigue, and insomnia in women recently diagnosedwith lung cancer.

Silberfarb and colleagues34 compared the sleepof lung cancer and breast cancer patients with thesleep of gender- and age-matched healthy controlsand insomnia patients in a sleep laboratory environ-ment for three consecutive nights during theirnormal sleep time. Those with lung cancer were inbed longer and had poorer sleep than those with

breast cancer. The lung cancer patients complainedless about their sleep, but objective measuresindicated more fragmented sleep compared to theother groups. Lung cancer patients took twice aslong (63 min) to fall asleep compared to breastcancer patients (37 min) and healthy controls(26 min). Sleep efficiency (actual sleep as a func-tion of time spent trying to sleep) was 80% for lungcancer patients and 85% for breast cancer patients,compared to 90% for healthy controls. Both lung andbreast cancer patients had only 2–4% deep sleep,the type of sleep that is considered restorative,whereas 15–20% is a typical range for young healthymen and women. Both groups had a high rate ofperiodic leg movements during sleep (47%, 8/17lung cancer patients; 60%, 9/15 breast cancerpatients) compared to healthy (25%, 8/32) andinsomnia (22%, 7/32) subjects. Neither group hadsignificant sleep disordered breathing; in fact, noapnea was found in the lung cancer group and onlyone breast cancer patient had sleep apnea whilemonitored in the sleep laboratory. Findings fromthis laboratory study support self-report data insamples from Davidson and colleagues’ survey.3

Colon cancer and other gastrointestinalcancers

Davidson and colleagues3 also included a group of108 Canadian patients from a gastrointestinalcancer clinic. Most had colorectal cancer, but 10had other forms of gastrointestinal cancer, includ-ing esophagus, pancreas, and stomach. Comparedto the many other types of cancer in their sample,this group of gastrointestinal cancer patients hadthe lowest rates of sleep disordered breathing(7.4%), fatigue (40%) and restless legs (37%), andonly about 20% used a sleep medication. Portenoyand colleagues35 screened almost 400 outpatientsand found that pain was less prevalent in coloncancer (35%) compared to lung cancer (46%).Although there were differences in pain location,both groups were similar in that 55–57% reportedthat pain interfered with their sleep. Patients withgastrointestinal cancer are often diagnosed at laterstages of their disease and have a poorer prognosisthan breast or prostate cancer. Research shows thatthese patients are at risk for anxiety and depressionas long as 6 months after diagnosis.36 Since anxietyand depression can predispose, precipitate, orperpetuate complaints of insomnia, these symp-toms are important to clinically assess and treat.Due to the limited success in curing these types ofcancer, sleep problems are likely to become moreof an issue and palliative care should include use of

K. Lee et al.204

short-acting hypnotics as well as adequate painmanagement.

Head and neck cancers

Very little research has been done to characterizesleep problems experienced by patients with braintumors or cancer of the head, neck, or oral cavity.Radiation therapy to the head, face, or neck islikely to disrupt hypothalamic hormone secretionand pineal function to the extent that circadianrhythms would be altered and sleep/wake rhythmswould be affected. A ‘somnolence syndrome’ afterradiation to the head has been described in manyearly reports and can exist for up to 3 months aftertreatment is completed, or have an initial onsetmonths after treatment ends,37 but little has beendone to understand the mechanism or how circa-dian rhythms of wake and sleep might be affected.Davidson and colleagues3 did not include a sampleof patients with brain tumors or head and neckcancers in their large prevalence study, but 30patients who had received radiation to the headwere analyzed separately. It was this group whoreported excessive sleepiness and sleeping forlonger periods of time compared to those who didnot receive radiation to the head.

Harrison and colleagues38 asked 29 long-termsurvivors after radiation for tongue cancer tocomplete a survey about symptoms and quality oflife. Decreased energy was common (48%) anddistressful for 64%; pain was less common (43%)but more distressing (89%). Of the 41% withinsomnia, it was distressful for 78%. The 14 patientswith head or neck cancer in Munro and Potter’s39

study reported fatigue as the fourth most commonsymptom and inability to sleep as their seventhmost prevalent symptom.

Melanoma

One of the few longitudinal studies on sleep incancer patients involved 72 men and 72 women withmelanoma studied at 3 months after surgery andagain at 7 and 13 months.9 They were asked abouttheir sleep quality on a scale from 1 (very bad) to 5(very good) during the past 6 months. They werealso asked the frequency, from 0 (never) to 5 (everynight) with which they had sleep disturbances, felttired at work, had difficulty waking up in themorning, and did not feel rested. Since thicknessof a melanoma lesion is predictive of recurrenceand prognosis, the sample was dichotomized bythickness (.0.8 mm) and analyzed by group as wellas gender. Although the men had a significantlygreater mean thickness of their lesion (1.56 mm)

compared to women (1.09 mm), it was the womenwho reported a lower sleep quality and significantlymore sleep problems.

Hematological malignancies

Cancer-related fatigue has also been associatedwith disturbed sleep in patients with hematologicalcancers such as leukemia, lymphoma, and multiplemyeloma. Molassiotis40 included 91 patients whowere at least 6 months post-bone marrow trans-plant (mean 40 months) and 73 patients who wereat least 6 months post-chemotherapy (mean 39months). Difficulty sleeping was a significant pre-dictor of tiredness for chemotherapy patients butnot for bone marrow transplant patients.

In a convenience sample of 246 patients withleukemia or lymphoma,41 single-item scales wereused to rate symptom severity from 0 to 10, and theincidence of sleep problems was based on scoresgreater than 5. The most common complaint was‘waking up during the night’ (77%), followed by ‘notfeeling rested’ (60%) and ‘waking up too early’(59%). Fatigue was related to sleep disturbances,pain, opioid use, and gastrointestional symptoms.Most interesting was the finding that fatigue wasrelated to changes in sleep patterns rather thanduration of the night’s sleep; a finding that supportsprior studies of persons with other types of cancerbefore, during, and after radiation therapy.42,43 Inlight of epidemiological indications that sleepduration is associated with mortality,44 moreresearch is needed on objective measures ofsleep, including duration of daytime and nighttimesleep, as well as preexisting sleep patterns that maypredispose, precipitate, or perpetuate sleep dis-turbance long after cancer treatment has beencompleted.

Bone marrow transplantation

Bone marrow transplantation is becoming increas-ingly common and is used primarily in the treatmentof leukemias and lymphomas rather than solidtumors. Women undergoing autologous bone mar-row transplant for breast cancer completed asymptom distress measure from day of admissionuntil day of discharge; insomnia and fatigue weresecond only to loss of appetite in this sample.45

Andrykowski and colleagues46 followed a moreheterogeneous group of 138 adults for 18 monthsafter bone marrow transplant and found that sleepproblems did not diminish over time. There was no

Impaired sleep and rhythms in persons with cancer 205

difference in sleep problems between allogeneicand autologous transplant recipients despite use ofimmunosuppressants and corticosteroids in allo-geneic transplant patients. At the initial assess-ment, half (51%) reported problems with sleep, andsleep problems remained an issue 18 months laterfor 43% of the subjects, with 10% taking prescriptionor over-the-counter sleep medication three or moretimes per week. Those over 40 years of age at thetime of the transplant, women, and those whoreceived total body irradiation prior to the trans-plant were more likely to report sleep problems.

Impaired sleep and rhythms in late-stagecancers

Very little sleep and circadian rhythm research hasfocused on late stage or terminal phases of cancer.In Longman and colleagues’47 study of women withstages I–IV breast cancer, only 15% had late stage IVcancer or metastasis. Results were not presented bystage of disease, but the primary complaint offatigue was related to poor quality of life. In 39patients with advanced pancreatic cancer, thepredominant symptom was pain (82%), but 54%had sleep problems and 46% complained of fati-gue.48 In 157 patients with advanced lung cancer(stage III or IV), those with fatigue had significantlyhigher scores for self-report sleep problems thanthose without fatigue.49

Geels and colleagues50 described changes insymptoms after every third cycle of palliativechemotherapy to reduce pain in women withmetastatic breast cancer. Trouble sleeping waspresent at baseline for 68%, and 89% felt tired.Insomnia improved for 55%, remained the same for28%, and worsened for 17%, while lethargy stayedthe same for 33% and became worse for 30% of thewomen. Medication use was not discussed and itwas unclear whether the type of insomnia may havechanged over time.

Miaskowski and Lee51 used wrist actigraphy tomonitor sleep in 24 adults receiving palliativeradiation treatment for bone metastasis. Comparedto the average sleep efficiencies documented in thelaboratory setting for lung cancer (80%) and breastcancer (85%) patients,34 this sample had poor sleep(70.7 ^ 22.4%) indicating that patients were awake,on average, 30% of the night in their homeenvironment. Palliative radiation treatment isoffered to provide symptom relief, particularly forpain, yet sleep was more disturbed for those whowere nearing completion of treatment than thosewho were beginning treatment. Naps were prevalent

(82%), but the amount of daytime sleep recorded byactigraphy was unrelated to nighttime awakening orperception of fatigue.

Impaired sleep and rhythms in childrenwith cancer

No studies were found that directly examined sleepor circadian rhythms in children with cancer. Lewinand Dahl52 discussed the importance of adequatesleep and pain management for children’s healthand well-being, but studies of symptoms in childrenwith cancer, specifically pain and fatigue, rarelyincluded sleep measures. In focus groups withchildren at various times after their cancer diag-nosis, lack of sleep in the hospital environment, orchanges in schedules and sleep patterns, werefrequently mentioned as causes of their fatigue.53

Adolescents also described fears that kept themawake at night, and changing their normal sleepingposition to accommodate intravenous needleplacement. Both young children and adolescentsfound naps helpful in reducing fatigue.53 Likeadults, it may be difficult for children with cancerto distinguish between fatigue and daytime sleepi-ness, since much of the discussion in the focusgroups was about their sleep problems rather thanfatigue.

Impaired sleep and rhythms in familycaregivers of cancer patients

Much of today’s treatment protocols for cancer areconducted in outpatient clinics, which shifts theburden of care from health care professionals tofamily caregivers. Sleep disturbances are commonin older women who are primary caregivers forspouses with dementia or for elderly familymembers in general.54,55 However, there is littleresearch on family caregivers’ sleep and quality oflife, during early stages of cancer or during laterstages of palliative care when 24 h palliative care isrequired. Carter and Chang56 interviewed 51 menand women caring for a family member withadvanced cancer and their mean score was11.3 ^ 4.37 on the PSQI. Scores above 5 areindicative of sleep disturbance, but these care-givers were reluctant to take any form of hypnoticto improve their sleep because of caregivingresponsibilities. Studies on caregivers and theirneeds for support and information about caring forfamily members with cancer are reviewed else-where57 but sleep disturbances are not addressed.

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Sleep problems in children with cancer can haveobvious effects on the sleep of parents and otherfamily caregivers. Interviews with 31 parentsprovide vivid commentary on the experience ofcaring for a child in pain.58 The entire experiencemay bring families closer together, but disruptsfamily life in many ways. Sleep deprivation due tocaregiving at night, difficulty falling asleepbecause of worries, and lack of restful sleepresulting in daytime fatigue were issues reportedby parents.58

The role of circadian rhythms in cancertreatment outcomes

Few studies have examined the influence ofsleep/wake patterns or circadian rhythms oncancer therapy outcomes. Researchers have stu-died how circadian timing can be used to optimizeanti-neoplastic effects and minimize toxicity tonormal tissues. Much of the earlier work involvedanimal models,59 and little has been done withhumans. Hrushesky60 studied 31 women withadvanced ovarian cancer and found that thosewho received adriamycin in the morning andcisplatin in the evening had fewer side effects.Those who received evening adriamycin and morn-ing cisplatin had more treatment delays due to sideeffects and required more frequent adjustments todecrease their chemotherapy dosage. These find-ings were confirmed by Levi and colleagues in morecarefully controlled clinical trials involving largegroups of patients with metastatic colorectalcancer.61 –63

Others have studied chemotherapy-inducedgranulocytopenia in women with ovarian cancerand found that timing of Granulocyte Colony-Stimulating Factor (G-CSF) administration, eitherat 700 or 1900 h, had similar peaks in plasma levels12 h64 after administration. Plasma levels of G-CSFare typically lower in the morning compared toafternoon and evening, and previous studies ofmice injected with G-CSF at 700 h had higherleukocyte counts than mice injected at 1900 h. The10 women who received the morning dose hadslightly better outcomes than the 10 women whoreceived G-CSF at 1900 h, but the difference wasnot statistically significant in this small sample.64

In animal research, light exposure can be con-trolled and all subjects would be homogeneous intheir peak and nadir rhythms of G-CSF or otherphysiological parameters. Although the 20 womenwith ovarian cancer were in randomly assignedgroups, there was no consideration of how their

baseline circadian rhythm chronotype might influ-ence results.64

In a multi-site study of patients with metastasisfrom colorectal cancer, Levi and colleagues63

randomized subjects to receive either a constantrate of infusion over time, or administration thatconsidered circadian timing. Only 29% of the 93patients who received a constant rate of infusionresponded to treatment, and treatment failureaveraged 4.9 months. In contrast, the response totherapy was 51% in 93 patients on a chronotherapyregimen and time to treatment failure was longer(6.4 months). Fewer patients on a chronotherapyschedule had mucosal toxicity (15 vs. 76%) orfunctional impairment due to neuropathy (16 vs.31%). The drug regimen was best tolerated when5-fluorouracil and folinic acid was given at 400 hand oxaliplatin was given at 1600 h. These resultsreplicate their earlier study in which a smallconvenience sample of patients on constantinfusion developed mucositis at a higher ratethan patients on chronotherapy.65

Mormont and Levi66 provide an excellent reviewof both animal and human research on circadianrhythms and cancer. In addition to circadiantiming for optimal chemotherapy, this group hasalso conducted large studies to ascertain theinfluence that an individual’s circadian rhythmhas on treatment outcomes. In one study, patientswith metastasis from colorectal cancer weremonitored with wrist actigraphy for 3 days beforeinitiating chemotherapy to establish the ampli-tude of their activity rhythm.67 Those with higheramplitudes had a five-fold increase in rate ofsurvival at 2 years, less fatigue, and better qualityof life.68 In another group of ambulatory cancerpatients, they found that those with higheramplitudes in their activity rhythm had lesssleep disturbance.69

Similar findings are also noted for women withmetastatic breast cancer. Sephton and colleagues(70) obtained salivary cortisol samples four timeseach day for 3 days to assess the circadian rhythmamplitude as a predictor of 7-year survival rates.Dampened or flat amplitudes in cortisol rhythmwere associated with fewer circulating naturalkiller (NK) cells and suppressed NK activity, withmetastasis to the bone or viscera rather than tothe chest, and with more self-reported nightawakenings. A dampened cortisol rhythm was alsopredictive of earlier mortality.70 Taken together,these studies indicate that prognosis and quality oflife may be more positive for those who manifestrobust circadian rhythms and maintain consistencyin their daily sleep and wake activities.

Impaired sleep and rhythms in persons with cancer 207

Interventions to improve sleepfor cancer patients

Pharmacological sleep aids

After a cancer diagnosis, patients receive a multi-tude of medications to either treat their cancer orreduce side effects of therapy. Medications forsleep may be under-prescribed in cancer patients,71

perhaps because of fear of side effects, addiction,or drug interactions. There are no recent data, butrates of hypnotic prescriptions for hospitalizedcancer patients were similar for men and womenregardless of age,72 and consistent at 43–44%between 1977 and 1987.71

Engstrom and colleagues73 conducted a tele-phone survey with 150 patients at various stagesof treatment for breast or lung cancer. Although44% had a problem with sleep on most nights inthe past month, they reported that health careproviders never asked about their sleep. Thepatients considered their sleep problem to be ofa lower priority than the cancer treatment itself,and also did not bother to discuss it with theirhealth care provider. These findings are similar toa previous report on breast cancer and lymphomapatients.74

Many health care providers, however, are con-cerned about overall well-being of their patients,and prescribe a hypnotic for potential sleepproblems precipitated by anxiety or depression atthe time of initial cancer diagnosis. This may be amore common practice for those patients predis-posed to sleep problems, such as the elderly, orthose diagnosed at advanced stages. Since hypno-tics may be less effective after a few weeks ofcontinued use, patients should be informed that theprescription is indicated for short-term use, andwill probably be most helpful during the peak periodof treatment or during painful procedures.

Patients may be reluctant to take yet anothermedication, fear addiction, feel they cannot affordto fill the prescription, or poorly tolerate sideeffects that accompany many hypnotics. As withfatigue, patients may wrongly assume that theirinsomnia is also a problem to endure rather thanbother to discuss treatment options with theirhealth care provider.75 Educating patients withcancer about the restorative function of sleep,health risks and compromised immune systemassociated with lack of sleep76,77 and impairedphysical and cognitive functioning associated withsleep loss78 would allow them to make an informeddecision about taking hypnotics, particularly atpeak periods of discomfort during their treatment.

Non-pharmacological interventions for sleepin cancer patients

If sleep problems continue after cancer treat-ment is terminated, longer-term non-pharmaco-logical therapy should be explored with thepatient. Perpetuating factors should be evalu-ated, since these factors often include poor sleephygiene and lifestyle habits that can be improvedwith education and cognitive/behavioral inter-ventions. Without consultation with their healthcare provider, however, patients often useineffective self-care strategies or over-the-coun-ter remedies that could interfere with the cancertreatment itself.

To cope with cancer-related fatigue duringchemotherapy, patients often try a variety ofineffective self-care strategies.79 Primary strat-egies included resting, napping, and earlier bedtime. Nutritional strategies were rarely considered,but a ‘soothing’ drink was one such strategy.Patients may use alcohol as a soothing drink toinduce sleep without realizing that it can interferewith sleep maintenance. Sleep onset may be morerapid, but fragmented and restless sleep occurslater in the night once the alcohol wears off. Sleepypatients may self-medicate with caffeine beveragesduring the day, and may continue into the eveningwhen stimulant effects from a soothing hot drinkwould delay sleep onset. Green tea, a popularhealth-promoting herbal drink often recommendedfor cancer patients, has high levels of caffeine butcan be purchased in a decaffeinated form forevening consumption.

Many studies on the effectiveness of cognitive/behavioral therapies for insomnia have been con-ducted with conclusive evidence of long-termbenefits and patient satisfaction.80,81 However,these studies typically excluded adults with anytype of medical problem such as cancer, andexcluded children altogether. Davidson and col-leagues82 have recently reported promising resultsafter a six-week group intervention program invol-ving cognitive/behavioral strategies for insomnia incancer patients. The sample was primarily womenand consisted of only a very small group from a largepotential pool of patients, but self-report dataindicated significant improvement in their sleepafter 1 and 2 months of monitoring.

Relaxation training, as one component of cogni-tive/behavioral therapy, may be effective for cancerpatients with sleep problems. Compared to routinecare, those who received relaxation training reducedself-reported sleep onset time from an average of 2 hto30 min.83 Total sleep time also increased, and they

K. Lee et al.208

felt more rested upon awakening. The effects ofrelaxation training were still evident after 3months.83

Non-pharmacological intervention studies forsleep problems are far less common in theliterature than studies to relieve cancer-relatedfatigue. Yet, adequate and restful sleep duringthe night may be one intervention to reducedaytime fatigue. Sleep outcome measures wereseldom included in intervention trials for cancer-related fatigue, although daytime sleepiness maybe difficult to distinguish from daytime fatiguewith existing subjective or objective measures.There is also current debate about whether napswould be more helpful than exercise in relievingcancer-related fatigue.21,84 Aerobic exercise hasbeen shown to reduce anxiety and depression inwomen with breast cancer, but sleep outcomeswere not included even though anxiety anddepression can influence sleep.85 Mock86 com-pared women who exercised with women who didnot exercise during radiation treatment for breastcancer and found a positive relationship betweenamount of self-reported walking and quality ofsleep. Others have also described positive resultswith the exercise programs for patients after bonemarrow transplantation87 or chemotherapy.88

Conclusions

As patients receive improved cancer therapies toeliminate the malignancy or to control tumorgrowth, issues related to longer-term quality oflife and sense of well-being emerge. Both patientsand their health care providers should be aware ofhow sleep disturbances can influence quality of liferelated to daytime sleepiness and fatigue. Sleepproblems may or may not be discussed with theoncologist treating the cancer, and patients eithertake an over-the-counter sleep aid that mayinteract with prescribed therapy, or they are leftto their own ineffective self-care strategies.Patients, their families, and health care providersrequire a better knowledge base for assessing andtreating sleep problems.

In keeping with Spielman and Glovinsky’s89

framework, clinical interventions should beaimed at recognizing any predisposing risk factors,such as a history of sleep problems prior to thecancer diagnosis, younger patients, or employedsingle women. Most studies indicate that sleepproblems in cancer patients are precipitated bydiagnosis and treatment, and hypnotics would be

indicated when patients are receiving the peakdoses of their chemotherapy or radiation. Inaddition, adequate evaluation and managementof precipitating factors that include pain, anxiety,or depression would be important in assuringadequate sleep, particularly in advanced stagesof disease.

Pharmacological therapy may be very appro-priate for short-term complaints, but relaxationtraining, exercise programs, and many other typesof non-pharmacologic interventions are bettertolerated by patients, and may be ideally suitedto reducing the distress associated with insomniaprecipitated by cancer diagnosis and treatmentwithout interfering with chemotherapy or otherdrug regimens. Cognitive-behavioral interventions,whether conducted with groups or with individ-uals, may help patients with insomnia perpetuatedlong after their initial cancer treatment hasended.

Most of the literature on sleep and cancerconsists of patients earlier in their cancer diagnosisand treatment, rather than in later stages ofdisease or during palliative care. There is very littleresearch on sleep problems in children with cancer,and very little on sleep problems in family care-givers. Studies on cytokine levels during diagnosisand treatment are needed to further understandthe relationship between immune function andsleep quality in persons with cancer.

While little research has been done on men withprostate cancer, there is a great deal of research onwomen with breast cancer. Most of the research onbreast cancer supports the higher rate of sleepdisturbance and fatigue in women, but a fewstudies indicated no significant difference fromthe general population, and further research isneeded to understand specific type of insomniaexperienced over the course of treatment andrecovery, how cancer treatment protocols altersleep patterns and the consequences of thesealterations, and what role circadian rhythms haveover the course of diagnosis, treatment, andrecovery.

What is known about circadian rhythms andimplications for both cancer treatment and long-term survival is limited to only a few publishedstudies and limited to only a few types of cancer.The role of circadian rhythms in predisposing,precipitating, and perpetuating sleep problemsduring treatment and long term survival is as poorlyunderstood as how cancer treatment optionsreduce quality of life by disrupting circadianrhythms and sleep-wake rhythms.

Impaired sleep and rhythms in persons with cancer 209

Practice points

† Cancer-related fatigue can be a directresult of the patient’s sleep disturbanceand it may be difficult for patients todistinguish fatigue from daytimesleepiness.

† Insomnia can be either difficulty fallingasleep, difficulty maintaining sleep, ordaytime sleepiness and appropriatetreatment should be targeted at the type ofinsomnia complaint.

† Because of the complex medication regimenfor treatment of cancer, non-pharmacological interventions may be moreeffective for long-term management ofinsomnia.

† Because of the poor prognosis in late stagecancer, short-acting hypnotics andadequate pain management may be moreeffective for management of sleepproblems.

† The high rate of restless legs in certaincancer populations may be associated withdifficulty falling asleep, and warrants an in-depth clinical assessment of anemia and lowiron levels.

Research agenda

† Further research is necessary to delineatethe specific type of insomnia (initiation,maintenance, or daytime sleepiness)experienced by patients during early stagesof cancer. More attention to predisposing,precipitating and perpetuating factorsassociated with the insomnia is needed toprovide clues to potential interventions forimproving sleep. Research questions couldincludea. To what extent is initiation insomnia

related to the experience of restless legs?b. To what extent does stress and worry

about the diagnosis interfere with sleeponset?

c. To what extent is the sleep problemassociated with pain and ineffective painmanagement?

d. Does prior history of insomnia have aneffect on outcomes of cancer treatment?

† Randomized clinical trials are needed totest non-pharmacological interventions inthe treatment of insomnia during the courseof chemotherapy or radiation treatment.

† More studies are needed to testeffectiveness of circadian timing foradministration of cancer treatment.

† Studies of patients who receive radiationtherapy to areas of the brain involved inmaintaining circadian rhythms are neededto better understand sleep and rhythmdisturbances.

† Non-invasive measures of circadian rhythmsare needed to help establish the role ofrhythm in insomnia as well as prognosis andlong-term survival.

† Studies of family members providing late-stage cancer care are needed to betterunderstand and treat their sleep problems.

Acknowledgements

Grant Support: NIH Grants #R01 NR04835 (CMiaskowski, P.I.), #R01 CA83316 (M. Dodd, P.I.),and #2 T32 NR07088 (K. Lee, P.I.).

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