Psychosomatics 2014:]:]]]–]]]
& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Original Research Reports Chronic Fatigue in Adult Survivors of Childhood Cancer: Associated Symptoms, Neuroendocrine Markers, and Autonomic Cardiovascular Responses Bernward Zeller, M.D., Ellen Ruud, M.D., Ph.D., Jon Havard Loge, M.D., Ph.D., Adriani Kanellopoulos, M.D., Hanne Hamre, M.D., Kristin Godang, B.Sc., Vegard Bruun Wyller, M.D., Ph.D.
Background: Chronic fatigue (CF) is a common late effect after childhood cancer. Objective: Based on findings among patients with the chronic fatigue syndrome (CFS), this study explored symptoms, neuroendocrine markers, and autonomic cardiovascular responses associated with CFS in childhood cancer survivors. Methods: Long-term survivors of childhood lymphoma and acute lymphoblastic leukemia reporting CF were compared with survivors without CF. Data included patient-reported outcomes, clinical examination, head-up tilt test, and neuroendocrine markers in the blood and the urine. Results: Of 102 included survivors, 15 were excluded from comparative analyses because of significant co-morbidity or pregnancy. Of the remaining 87 participants (median age 33.0 years, follow-up time 25.2 years), 35 had CF and 52 did not have CF. Compared with non-CF controls, CF cases reported a significantly (P o 0.01) higher frequency of
symptoms typical of the CFS (muscle or joint pain or both and feeling confused/disoriented) and symptoms of autonomic dysfunction (palpitations, feeling intermittently heat and cold, and watery diarrhea). CF cases and controls did not differ regarding autonomic cardiovascular responses to orthostatic stress, but the CF group had lower levels of plasma adrenocorticotrophic hormone (P ¼ 0.002) and higher levels of urine norepinephrine (P ¼ 0.017). Conclusions: Survivors with CF reported a high symptom-burden compared with controls. There were few differences between both the groups regarding biomarkers, but slight alterations of the hypothalamuspituitary-adrenal axis and sympathetic nervous activity were detected. CF in cancer survivors has features in common with the CFS, but further efforts are required to clarify the pathophysiology. (Psychosomatics 2014; ]:]]]–]]])
INTRODUCTION Chronic fatigue (CF) is a common late effect after cancer therapy,1–3 not only in cancer affecting adults but also in survivors of childhood cancer.4–8 Fatigue is a persistent, subjective experience of tiredness and lack of energy, which is not proportional to recent activities and interfers with usual functioning,2 and it is defined as chronic when it lasts for 6 months or more.9 CF in cancer survivors seems to have overlapping clinical features with the chronic fatigue syndrome (CFS).10,11 CFS is characterized by severe, unexplained, Psychosomatics ]:], ] 2014
Received November 22, 2013; revised November 22, 2013; accepted December 5, 2013. From Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway; National Resource Center for Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway; Department of Behavioral Sciences in Medicine, University of Oslo, Oslo, Norway ; Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway. Send correspondence and reprint requests to Bernward Zeller, M.D., Department of Pediatric Medicine, Oslo University Hospital, Mailbox 4950 Nydalen, N-0424 Oslo, Norway; e-mail: [email protected] & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
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Chronic Fatigue in Adult Survivors of Childhood Cancer long-lasting fatigue accompanied by pain, cognitive impairments, orthostatic intolerance, and other symptoms, resulting in substantial reduction of occupational, educational, social, and personal activities.9,12 The mechanisms of CFS remain relatively poorly understood. Viral infections,13 low-grade systemic inflammation,14 attenuation of the hypothalamuspituitary-adrenal (HPA) axis,15 and impairment of executive control functions16 are reported across adult patients with CFS. Altered autonomic cardiovascular control, eventually causing orthostatic hypotension or tachycardia or both, might also be involved in the pathophysiology.17–21 The autonomic alterations are characterized by enhanced sympathetic and attenuated parasympathetic cardiovascular nervous activity.22 Exploring whether symptoms and pathophysiologic characteristics of CFS apply to cancer survivors with CF may contribute to a better understanding of the latter condition and hopefully to developing preventive and therapeutic strategies. Some of the proposed pathophysiologic mechanisms for CF in cancer survivors are similar to those in CFS, including low-grade inflammation23 and alterations of the HPA axis.1 Autonomic alterations might also be a feature of CF in cancer survivors. This hypothesis has not been thoroughly investigated, but a few studies have described symptoms indicating functional autonomic disturbances,24 altered cardiovascular
FIGURE.
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autonomic responses during orthostatic challenges,25 and altered neuroendocrine levels in cancer survivors with CF.24,26 Thus, the aim of this study was to explore if clinical features and pathophysiologic mechanisms reported among patients with CFS are identifiable in adult childhood cancer survivors with CF, particularly focusing on autonomic symptoms, neuroendocrine markers and autonomic cardiovascular responses. Comparing survivors with and without CF, we hypothesized to find similar, but possibly less pronounced, symptom load and biomarker alterations in childhood cancer survivors with CF as reported in patients with CFS. METHODS Sample, Inclusion, and Previous Cancer Disease A flowchart of the study is shown in the Figure. The present study is the second part of a childhood cancer survivorship study including 290 adult survivors of childhood acute lymphoblastic leukemia (ALL) or lymphoma.4 Inclusion criteria in the first part were treatment at Oslo University Hospital (ALL) or whole of Norway (lymphomas), diagnosis between 1970 and 2002 at age r16 years (ALL) or r18 years (lymphoma), and at least 5 years observation time from diagnosis. In the present study (time point 2, TP2), survivors reporting CF in the original study (time
Study Flowchart. CF: Chronic Fatigue.
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Zeller et al. point 1, TP1) were invited back to a comprehensive study of fatigue-associated factors. Of 78 invited individuals with previous CF, 56 were willing to participate. A total of 53 were examined, while 3 individuals did not meet for the investigations. In addition, a sample of survivors without CF at TP1 (n ¼ 130) was invited to participate at TP2, matched with regard to diagnosis (ALL vs lymphoma), but otherwise randomly. A total of 67 were willing to participate, 3 were excluded owing to ongoing pregnancy, and 15 were not examined (because the planned number of controls was reached). Thus, 49 individuals not reporting CF in the original study attended the examinations at TP2. However, some survivors changed their fatigue status between TP1 and TP2 (“converters” in the Figure), and the current fatigue status at TP2 defined the CF cases (n ¼ 35) vs controls (n ¼ 52) in this study, regardless of previous fatigue status at TP1. Information on the previous cancer disease and treatment was retrieved from the patients’ medical records. Treatment of ALL and lymphoma in the relevant time period has been reported previously.4 Examinations Participants were instructed 2 days before the examination to not drink beverages containing alcohol or caffeine, not to take any drugs and not to use tobacco products. They were instructed to bring a urine sample collected on the morning of the investigation day. Participants met fasting in the morning, and all investigations were performed between 7:30 AM and 11:00 AM. Following a brief interview and physical examination, a stand-up test for orthostatic instability was carried out. Systolic, diastolic, and mean blood pressure (BP) and heart rate (HR) were recorded after 5 minutes of rest in supine position and repeated after 3 minutes of standing without support. Following application of an ointment containing the local anesthetic lidocaine (EMLA) on the skin in the elbows about an hour in advance, blood samples were drawn by antecubital venous puncture at approximately 8:00 AM after 5 minutes of resting in supine position. Blood tests included evaluation of adrenocorticotrophic hormone, cortisol, norepinephrine, and epinephrine. Urine analysis included evaluation of free cortisol to creatinine ratio, norepinephrine, and epinephrine. For technical details regarding analyses of Psychosomatics ]:], ] 2014
norepinephrine/epinephrine in the blood and the urine and free cortisol to creatinine ratio in the urine refer to the supplemental material. Head-up tilt (HUT) test was performed according to a previously described protocol,22 which has been proven feasible in studies among adolescents with CFS.27–29 The low tilt angle (201) is sufficient to demonstrate hemodynamic alterations among patients with CFS compared with controls, without precipitating syncope. The same investigator (B.Z.) performed the HUT test in all participants, in calm, silent surroundings with dimmed lights and at a room temperature of 211C–251C. Participants were positioned horizontally on a tilt table with foot-board support (Model 900-00, CNS-systems Medizintechnik, Graz, Austria) and were attached to the Task Force Monitor, (Model 3040i, CNSystems Medizintechnik, Graz, Austria), a combined hardware and software device for noninvasive continuous recording of cardiovascular variables.30 After five minutes of baseline recordings, they were head-up tilted 20° for 15 minutes, followed by another five minutes in the horizontal position. We obtained instantaneous HR from the R-R interval of the electrocardiogram. Continuous recording of arterial BP was obtained from photoplethysmography on the right middle finger.31 Impedance cardiography was used to obtain a continuous recording of the temporal derivate of the transthoracic impedance (dZ/dt).32 All recorded signals were transferred online to the computer of the Task Force Monitor, a running producer-developed software for data acquisition. For analysis of the HUT test data, we calculated medians of all variables in the 2 epochs from 270–30 seconds before tilt (baseline) and from 30–270 seconds after being tilted (Tilt). We report baseline values and delta values (Tilt minus baseline). For details concerning calculation of cardiovascular variables of the HUT test, refer to the supplemental material. Patient-Reported Outcomes Participants completed questionnaires that included the following: Chronic Fatigue “Caseness” We used the Fatigue Questionnaire,33,34 which measures the intensity of fatigue symptoms by www.psychosomaticsjournal.org
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Chronic Fatigue in Adult Survivors of Childhood Cancer 11 items, each with 4 response alternatives (each item was scored both in a standard Likert way—0, 1, 2, and 3—and a dichotomized way—0, 0, 1, and 1). CF “caseness” is defined by a dichotomized sum score Z4 and duration of symptoms for Z6 months.9 Some survivors identified as CF cases at TP1 converted to “no CF” and some without CF at TP1 converted to CF cases. In the present study, we compared patients with or without current CF at TP2, disregarding their previous CF status (Figure). Symptoms of CFS and Autonomic Symptoms Items addressing the frequency of common CFS symptoms, including the 8 accompanying symptoms of the Centers for Disease Control (CDC) case definition,9 were used. Each symptom has 5 response alternatives ranging from “never/rarely present” to “present all of the time,” rated on a 1–5 Likert scale. These questions were based on our clinical experience and have also proven feasible in previous studies from our institution.22,29 In the present study, items assessing symptoms asked for in the Fatigue Questionnaire were excluded. To assess symptoms of autonomic dysfunction, the questionnaire was supplemented with selected items from the Autonomic Symptom Profile inventory.35 Ethics All included survivors gave written informed consent before inclusion. The Regional Committee for Medical Research Ethics approved the study. Statistics Statistical analyses were performed using IBM SPSS Statistics 18 (SPSS Inc, Chicago, IL). Continuous and semi-continuous variables are described with mean ⫾ standard deviation or median (interquartile range), when appropriate. Categorical data are reported as proportions. To compare groups, the parametric t-test and the nonparametric Mann-Whitney-Wilcoxon test were used as appropriate for continuous variables. For categorical variables, we applied the Chi-square test. All tests were carried out 2-sided. A value of P o 0.05 was considered statistically significant. As this was an exploratory study, no adjustment for multiple testing was performed. 4
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RESULTS Following the examinations at TP2, 15 of 102 survivors were excluded from further analyses owing to major somatic conditions possibly explaining CF (5 secondary cancers, lung fibrosis, pituitary prolactinoma, cerebral infarctions with hemiplegia, paraplegia following injury to the spinal cord during cancer treatment, severe heart failure, hypopituitarism, recent cardiac infarction, recent removal of meningeomas with epilepsy, severe untreated hypertension, and ongoing pregnancy). Of the remaining 87 survivors, 35 reported current CF (cases) and 52 had no current CF (controls) at TP2 (Figure). Table 1 displays the demographics. Median age was 33.0 years (range: 20.5–53.1) and median follow-up time was 25.2 years (range: 11.3–39.9). Except for a slightly higher proportion of females in the CF group (P ¼ 0.047), there were no significant differences between cases and controls. In particular, the proportion of survivors being in full-time or part-time work was not different between cases and controls (72% vs 79%, P ¼ 0.484). Table 2 displays self-reported symptoms common to CFS and symptoms suggesting functional autonomic alterations. Survivors with CF reported significantly more headache, enlarged lymphatic nodes, muscular pain and joint pain, sensitivity toward sounds, nausea, and confusion or disorientation than controls. Furthermore, several of the autonomic symptoms were more frequent in the CF group (palpitations, intermittently feeling heat and cold, lightheadedness, and watery diarrhea). Results of the blood and urine analyses are shown in Table 3. The CF group had significantly lower plasma adrenocorticotrophic hormone values than controls. (median 2.6 vs 3.7 pmol/L, P ¼ 0.002). Plasma norepinephrine and epinephrine values did not differ between groups, but urine norepinephrine level was higher in the CF group (mean 200 vs 145 nmol/L, P ¼ 0.017). During the stand-up test, there was an increment of HR, systolic BP, and diastolic BP after standing up for all participants taken together, but we registered no significant differences between survivors with or without CF (data not shown). During the HUT test, cases and controls taken together showed the expected changes during the HUT (significant increase in HR, arterial BP, and total peripheral resistance index and decrease of Psychosomatics ]:], ] 2014
Zeller et al. TABLE 1.
Demographics of 87 Participants After Exclusion of Patients With Major Somatic Comorbidity or Pregnancy. Survivors With CF (CF Cases) Compared With Survivors Without CF (Controls). Number (%) When Not Indicated Otherwise. Significant P Values in Bold CF cases (n ¼ 35) Controls (n ¼ 52) P
Female gender
25 (71%)
26 (50%)
0.047
Diagnosis Lymphoma ALL
18 (51%) 17 (49%)
26 (50%) 26 (50%)
0.896
Age at investigation, years, median (range)
32.7 (22.7–50.7)
34.0 (20.5–53.1) 0.775
Follow-up time, years, median (range)*
24.4 (11.8–39.9)
25.6 (11.3–39.1) 0.856
Body mass index, kg/m2, median (range)
24.4 (18.7–40.0)
24.4 (16.0–37.8) 0.659
At present in paid 23/32 (72%) (full- or parttime) work Daily smoking 9/32 (28%)
37/47 (79%)
0.484
9/51 (18%)
0.260
functioned relatively well with a majority being in paid work. An important finding of our study is that survivors with CF experience symptoms common in CFS (but not assessed by the Fatigue Questionnaire) such as muscle and joint pain, nausea, and sensitivity toward light. They also experience symptoms of autonomic dysfunction, such as lightheadedness, palpitations, intermittent feelings of warmth and cold, and watery diarrhea. Although other associated symptoms, such as depression, anxiety, sleep disturbances, and cognitive problems, are well known from this patient group,6–8,36 we are the first to describe these specific symptoms in fatigued childhood cancer survivors. Our findings suggest substantial similarities between CFS and CF in childhood cancer survivors on the symptom level. Still, high levels of multiple somatic symptoms are not restricted to CFS but are also observed in other medically-unexplained conditions and in depression
TABLE 2.
ALL ¼ acute lymphoblastic leukemia. n
Patient-Reported Variables. Common CFS Symptoms and Selected Autonomic Symptoms. Reported as Mean (Total Range). Significant P Values in Bold
Time from cancer diagnosis to investigation.
Stroke index, cardiac index, and HR variability indices; data not shown). However, we found no differences in baseline cardiovascular variables between survivors with CF and controls, nor were there any differences in the response to mild orthostatic stress during the HUT test (Table 4).
DISCUSSION This study showed that adult survivors of childhood cancer suffering from CF had higher levels of symptoms commonly observed in patients with CFS, higher scores of autonomic symptoms, lower level of adrenocorticotrophic hormone in the plasma, and a higher level of norepinephrine in the urine as compared with survivors without CF. However, the groups did not differ regarding their cardiovascular response to orthostatic stress. Thus, CF in cancer survivors has features in common with the CFS. In spite of high levels of symptoms, most survivors with CF Psychosomatics ]:], ] 2014
Common CFS symptoms † Headache Sore throat Enlarged lymphatic nodes Muscular pain Joint pain Sensitivity toward sounds Sensitivity toward light Nausea Feeling confused or disoriented Autonomic symptoms Palpitations Pale and cold hands Feeling intermittently heat and cold Problems focusing or seeing clearly Lightheadedness Watery diarrhea Constipation
CF cases (n ¼ 35)
Controls* P (n ¼ 50)
2.57 1.51 1.31 3.20 2.97 2.11 1.51 2.11 1.94
1.94 1.34 1.08 2.20 1.78 1.54 1.18 1.50 1.12
(1–5) (1–5) (1–5) (1–5) (1–5) (1–5) (1–5) (1–5) (1–5)
(1–5) 0.031 (1–4) 0.306 (1–4) 0.021 (1–5) 0.004 (1–5) o0.001 (1–5) 0.039 (1–4) 0.057 (1–5) 0.032 (1–3) o0.001
2.23 (1–5) 1.26 (1–4) o0.001 2.00 (1–5) 1.80 (1–5) 0.432 2.26 (1–5) 1.44 (1–4) 0.004 2.11 (1–5) 1.64 (1–5)
0.076
2.69 (1–5) 2.00 (1–5) 0.022 1.80 (1–4) 1.27 (1–5) o0.001 0.054 1.50 (1–4) 1.20 (1–3)
CSF ¼ chronic fatigue syndrome. n
Answers missing in 2 controls. Except items included in the Fatigue Questionnaire (nonrelieving rest, postexertional malaise, problems of concentration and memory). †
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Chronic Fatigue in Adult Survivors of Childhood Cancer TABLE 3.
Results of Selected Blood and Urine Tests. Reported Median (Interquartile Range) Where Not Indicated Otherwise. Significant P Values in Bold Controls P CF cases (n ¼ 29–34)* (n ¼ 47–50)†
Blood ACTH (pmol/L) Cortisol (nmol/L): mean (SD) Norepinephrine (pmol/L) Epinephrine (pmol/L): mean (SD) Urine Cortisol to creatinine ratio Norepinephrine (nmol/L): mean (SD) Epinephrine (nmol/L)
2.6 (2.4) 418 (142) 1723 (1266)
3.7 (2.7) 440 (161)
0.002 0.525
1609 (1189) 0.772
300 (102)
296.1 (99)
0.857
6.4 (10.4)
5.8 (6.3)
0.894
200 (111)
145 (63)
0.017
18.0 (11)
15.0 (11)
0.193
ACTH ¼ adrenocorticotrophic hormone; SD ¼ standard deviation. n
Not available: 1 for cortisol, 2 for ACTH, 3 for norepinephrine and epinephrine, 4 for U- norepinephrine and U- epinephrine, 6 for cortisol to creatinine ratio. † Not available: 2 for cortisol, 3 for ACTH, U-norepinephrine and U-epinephrine, 5 for norepinephrine, epinephrine and cortisol to creatinine ratio.
TABLE 4.
disorders. In a previous article, we identified depression and anxiety as predictors of CF in this cohort.4 The limited sample size and the lack of prospectivelycollected data restrict the possibility to further elaborate on the symptom profile and a possible underlying “driver.” In CFS, altered cardiovascular responses during orthostatic stress are well documented.18,21,22,37 Terlou et al.25 investigated cardiovascular responses to orthostatic stress during stand-up tests in childhood cancer survivors. They found that orthostatic tachycardia developed in a significantly higher proportion of survivors compared with healthy controls. We explored cardiovascular responses by the stand-up test and by the HUT test and were not able to show differences between survivors with and without CF. A type II error is possible because of the relatively small sample size, but it does not seem likely, as significant findings of cardiovascular alterations in CFS and cancer-related fatigue have been reported in studies with similar sample sizes.22,25 There are several other possible explanations. Firstly, methodologic issues related to the applied orthostatic stress may play a role. During the stand-up test, 3 minutes of standing upright may be too short a time to evoke orthostatic intolerance. Terlou et al. used 10 minutes
Results of the Head-Up Tilt (HUT) Test. Measurements at Baseline (Supine Rest Before Tilt) and Delta Values (201 HUT Minus Baseline). Reported as Median (Interquartile Range) Where Not Indicated Otherwise Baseline
HR (beats/min) SBP (mm Hg) MBP (mm Hg) DBP (mm Hg) SI (ml/m2) CI (L/min/m2) TPRI (mm Hg/L/min/m2) LF norm (nu) HF norm (nu) LF/HF: mean (SD) SDNN (ms): mean (SD) pNN50 (%): mean (SD) r-MSSD (ms): mean (SD)
Delta (201 HUT—baseline)
CF cases (n ¼ 35)
Controls (n ¼ 52)
P
CF cases (n ¼ 35)
Controls (n ¼ 52)
P
64.7 108 82 70 44 2.8 9.4 46 54 1.12 44.7 12.3 38.3
63.6 108 83 71 46 2.86 8.5 50 50 0.88 55.2 26.3 48.3
0.371 0.838 0.720 0.896 0.454 0.518 0.103 0.427 0.427 0.716 0.396 0.299 0.716
1.1 3.3 3.4 3.9 3.4 0.2 0.9 5.3 5.2 0.2 2.8 2.5 5.2
1.8 3.1 2.9 2.6 3.9 0.2 0.7 3.8 3.8 0.1 0.1 2.5 6.6
0.264 0.894 0.527 0.142 0.658 0.929 0.429 0.548 0.559 0.451 0.243 0.723 0.359
(10.9) (11.7) (11.2) (10.4) (11.8) (0.66) (2.16) (19.6) (19.6) (1.20) (28.1) (35.1) (37.5)
(11.1) (11.4) (8.5) (7.7) (11.3) (0.75) (2.42) (17.2) (17.2) (1.19) (42.3) (39.1) (45.1)
(2.8) (4.0) (3.4) (3.6) (4.3) (0.3) (0.9) (12.0) (12.0) (0.7) (16.6) (11.9) (20.7)
(3.2) (4.0) (4.0) (4.2) (6.0) (0.4) (1.0) (11.2) (11.2) (0.8) (20.9) (11.8) (15.8)
CI ¼ cardiac index; DBP ¼ diastolic blood pressure; HF norm ¼ variability in the high-frequency region, normalized values; HR ¼ heart rate; LF/HF ¼ low-frequency absolute value/high-frequency absolute value; LF norm ¼ variability in the low-frequency region, normalized values; MBP ¼ mean blood pressure; ms ¼ milliseconds; nu ¼ normalized units; pNN50 ¼ proportion of successive R-R intervals with a difference greater than 50 ms; r-MSSD ¼ the square root of the mean square differences of successive R-R intervals; SBP ¼ systolic blood pressure; SD ¼ standard deviation; SDNN ¼ standard deviation of R-R intervals; SI ¼ Stroke index; TPRI ¼ total peripheral resistance index.
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Zeller et al. of upright standing, but they stated that even longer exposure to orthostatic stress may be required to evoke neurally-mediated hypotension. During the HUT test, the used tilt angle of only 201 may have been too low in the present patient group, although it was feasible in adolescents with CFS.22,28 Secondly, according to the findings of Terlou et al.,25 most childhood cancer survivors may have altered cardiovascular responses independent of their fatiguability. This may reduce potential differences between fatigued and nonfatigued survivors, thus explaining the lack of differences between these groups in our study. Lastly, in contrast to patients with CFS, most of the examined survivors with CF reported adequate daily functioning with similar proportions of cases and controls being in paid work. This may explain why there were no significant differences in cardiovascular responses between survivors with and without CF. We lacked CFS cases as a comparison group, which could have clarified some of these points. Studies of endocrine markers in CFS have indicated lower levels of cortisol in the plasma, urine, and saliva; altered circadian rhythms; and attenuated HPA axis responsiveness during stimuli that normally increase cortisol secretion.38,39 Similar results were reported in a study in breast cancer survivors.40 Increased resting levels of epinephrine and norepinephrine have been documented in CFS.27Increased levels of neuroendocrine markers in fatigued individuals were reported by 2 studies on breast cancer survivors. A study reported elevated norepinephrine levels before, during, and after a mental stressor.24 Another study found that higher neuroendocrine levels predicted the pain-depression-fatigue symptom cluster.26 Our findings of lower levels of adrenocorticotrophic hormone in the plasma and higher levels of norepinephrine in the urine are in accordance with these studies, suggesting slight inhibition of the HPA axis and enhanced sympathetic nervous activity also in childhood cancer survivors with CF. A strength of the study is the multimodal approach using both self-reported and objectively assessed variables. Further, the study sample included survivors of 2 of the most common childhood cancers. The sample was well defined, with exclusion of individuals with major somatic conditions that may have otherwise precluded meaningful analyses. The
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study is limited by its moderate sample size, leading to increased risk for type II errors. However, this should be compensated to some extent by the case-control design with similar distribution of diagnoses, gender, and age. We cannot rule out selection biases during the inclusion process. As we do not have information on fatigue severity of potential CF cases who declined participation or did not respond, the included CF cases may not be perfectly representative of all survivors with CF. Attrition analysis showed that included survivors were older than those not included (median 31.7 vs 28.6 years, P o 0.01), but there were no differences regarding gender, diagnosis, age at diagnosis, follow-up time, total anthracycline dose, or proportion having had radiotherapy. The relatively high number of statistical tests increases the risk of type I errors.
CONCLUSION The results of our study indicate that survivors with CF suffer from symptoms that characterize CFS as well as symptoms of autonomic dysfunction. Both the conditions also seem to have some pathophysiologic features in common (HPA axis attenuation and sympathetic enhancement), but the burden of disturbing symptoms was contrasted by relatively sparse findings regarding biomarkers. Orthostatic dysfunction is not a major feature in survivors suffering from CF. Taken together, CF in childhood cancer survivors seems to be a more heterogeneous and possibly less disabling condition than CFS. Further efforts are required to explore the pathophysiology in detail. Acknowledgments: This study has been financially supported by the Norwegian ExtraFoundation for Health and Rehabilitation and Simon Fougner Hartmann0 s Family Foundation. We want to thank Anna-Marie Thorndall Ryenbakken for study assistance, Kari Gjersum, Even Fagermoen, and Dag Sulheim for advice and practical help, and The Clinical Research Unit at Oslo University Hospital, Rikshospitalet, for practical assistance facilitating the study. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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17. Rowe PC, Lucas KE: Orthostatic intolerance in chronic fatigue syndrome. Am J Med 2007; 120(3):e13 18. Rowe PC, Bou-Holaigah I, Kan JS, Calkins H: Is neurally mediated hypotension an unrecognised cause of chronic fatigue? Lancet 1995; 345(8950):623–624 19. Hoad A, Spickett G, Elliott J, Newton J: Postural orthostatic tachycardia syndrome is an under-recognized condition in chronic fatigue syndrome. Q J Med 2008; 101(12): 961–965 20. Stewart JM: Autonomic nervous system dysfunction in adolescents with postural orthostatic tachycardia syndrome and chronic fatigue syndrome is characterized by attenuated vagal baroreflex and potentiated sympathetic vasomotion. Pediatr Res 2000; 48(2):218–226 21. Freeman R, Komaroff AL: Does the chronic fatigue syndrome involve the autonomic nervous system? Am J Med 1997; 102(4):357–364 22. Wyller VB, Due R, Saul JP, Amlie JP, Thaulow E: Usefulness of an abnormal cardiovascular response during low-grade head-up tilt-test for discriminating adolescents with chronic fatigue from healthy controls. Am J Cardiol 2007; 99(7):997–1001 23. Bower JE, Lamkin DM: Inflammation and cancer-related fatigue: mechanisms, contributing factors, and treatment implications. Brain Behav Immun 2013;(30 Suppl):48–57 24. Fagundes CP, Murray DM, Hwang BS, et al: Sympathetic and parasympathetic activity in cancer-related fatigue: more evidence for a physiological substrate in cancer survivors. Psychoneuroendocrinology 2011; 36(8):1137–1147 25. Terlou A, Ruble K, Stapert AF, Chang HC, Rowe PC, Schwartz CL: Orthostatic intolerance in survivors of childhood cancer. Eur J Cancer 2007; 43(18):2685–2690 26. Thornton LM, Andersen BL, Blakely WP: The pain, depression, and fatigue symptom cluster in advanced breast cancer: covariation with the hypothalamic-pituitaryadrenal axis and the sympathetic nervous system. Health Psychol 2010; 29(3):333–337 27. Wyller VB, Saul JP, Walloe L, Thaulow E: Sympathetic cardiovascular control during orthostatic stress and isometric exercise in adolescent chronic fatigue syndrome. Eur J Appl Physiol 2008; 102(6):623–632 28. Sulheim D, Hurum H, Helland IB, Thaulow E, Wyller VB: Adolescent chronic fatigue syndrome; a follow-up study displays concurrent improvement of circulatory abnormalities and clinical symptoms. Biopsychosoc Med 2012; 6:10 29. Wyller VB, Helland IB: Relationship between autonomic cardiovascular control, case definition, clinical symptoms, and functional disability in adolescent chronic fatigue syndrome: an exploratory study. Biopsychosoc Med 2013; 7(1):5 30. Fortin J, Habenbacher W, Heller A, et al: Non-invasive beat-to-beat cardiac output monitoring by an improved method of transthoracic bioimpedance measurement. Comput Biol Med 2006; 36(11):1185–1203 31. Parati G, Casadei R, Groppelli A, Di RM, Mancia G: Comparison of finger and intra-arterial blood pressure
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childhood acute lymphoblastic leukemia and lymphoma. Pediatr Blood Cancer 2013; 60(5):849–855 De LF, Hargreaves J, Kakkar VV: Pathogenesis and management of delayed orthostatic hypotension in patients with chronic fatigue syndrome. Clin Auton Res 1997; 7(4): 185–190 Silverman MN, Heim CM, Nater UM, Marques AH, Sternberg EM: Neuroendocrine and immune contributors to fatigue. PM R 2010; 2(5):338–346 Cleare AJ: The HPA axis and the genesis of chronic fatigue syndrome. Trends Endocrinol Metab 2004; 15(2): 55–59 Bower JE, Ganz PA, Aziz N, Olmstead R, Irwin MR, Cole SW: Inflammatory responses to psychological stress in fatigued breast cancer survivors: relationship to glucocorticoids. Brain Behav Immun 2007; 21(3): 251–258
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& 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
Original Research Reports Chronic Fatigue in Adult Survivors of Childhood Cancer: Associated Symptoms, Neuroendocrine Markers, and Autonomic Cardiovascular Responses Bernward Zeller, M.D., Ellen Ruud, M.D., Ph.D., Jon Havard Loge, M.D., Ph.D., Adriani Kanellopoulos, M.D., Hanne Hamre, M.D., Kristin Godang, B.Sc., Vegard Bruun Wyller, M.D., Ph.D.
Background: Chronic fatigue (CF) is a common late effect after childhood cancer. Objective: Based on findings among patients with the chronic fatigue syndrome (CFS), this study explored symptoms, neuroendocrine markers, and autonomic cardiovascular responses associated with CFS in childhood cancer survivors. Methods: Long-term survivors of childhood lymphoma and acute lymphoblastic leukemia reporting CF were compared with survivors without CF. Data included patient-reported outcomes, clinical examination, head-up tilt test, and neuroendocrine markers in the blood and the urine. Results: Of 102 included survivors, 15 were excluded from comparative analyses because of significant co-morbidity or pregnancy. Of the remaining 87 participants (median age 33.0 years, follow-up time 25.2 years), 35 had CF and 52 did not have CF. Compared with non-CF controls, CF cases reported a significantly (P o 0.01) higher frequency of
symptoms typical of the CFS (muscle or joint pain or both and feeling confused/disoriented) and symptoms of autonomic dysfunction (palpitations, feeling intermittently heat and cold, and watery diarrhea). CF cases and controls did not differ regarding autonomic cardiovascular responses to orthostatic stress, but the CF group had lower levels of plasma adrenocorticotrophic hormone (P ¼ 0.002) and higher levels of urine norepinephrine (P ¼ 0.017). Conclusions: Survivors with CF reported a high symptom-burden compared with controls. There were few differences between both the groups regarding biomarkers, but slight alterations of the hypothalamuspituitary-adrenal axis and sympathetic nervous activity were detected. CF in cancer survivors has features in common with the CFS, but further efforts are required to clarify the pathophysiology. (Psychosomatics 2014; ]:]]]–]]])
INTRODUCTION Chronic fatigue (CF) is a common late effect after cancer therapy,1–3 not only in cancer affecting adults but also in survivors of childhood cancer.4–8 Fatigue is a persistent, subjective experience of tiredness and lack of energy, which is not proportional to recent activities and interfers with usual functioning,2 and it is defined as chronic when it lasts for 6 months or more.9 CF in cancer survivors seems to have overlapping clinical features with the chronic fatigue syndrome (CFS).10,11 CFS is characterized by severe, unexplained, Psychosomatics ]:], ] 2014
Received November 22, 2013; revised November 22, 2013; accepted December 5, 2013. From Department of Pediatric Medicine, Oslo University Hospital, Oslo, Norway; National Resource Center for Late Effects after Cancer Treatment, Department of Oncology, Oslo University Hospital, Oslo, Norway; Department of Behavioral Sciences in Medicine, University of Oslo, Oslo, Norway ; Section of Specialized Endocrinology, Department of Endocrinology, Oslo University Hospital, Oslo, Norway. Send correspondence and reprint requests to Bernward Zeller, M.D., Department of Pediatric Medicine, Oslo University Hospital, Mailbox 4950 Nydalen, N-0424 Oslo, Norway; e-mail: [email protected] & 2014 The Academy of Psychosomatic Medicine. Published by Elsevier Inc. All rights reserved.
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Chronic Fatigue in Adult Survivors of Childhood Cancer long-lasting fatigue accompanied by pain, cognitive impairments, orthostatic intolerance, and other symptoms, resulting in substantial reduction of occupational, educational, social, and personal activities.9,12 The mechanisms of CFS remain relatively poorly understood. Viral infections,13 low-grade systemic inflammation,14 attenuation of the hypothalamuspituitary-adrenal (HPA) axis,15 and impairment of executive control functions16 are reported across adult patients with CFS. Altered autonomic cardiovascular control, eventually causing orthostatic hypotension or tachycardia or both, might also be involved in the pathophysiology.17–21 The autonomic alterations are characterized by enhanced sympathetic and attenuated parasympathetic cardiovascular nervous activity.22 Exploring whether symptoms and pathophysiologic characteristics of CFS apply to cancer survivors with CF may contribute to a better understanding of the latter condition and hopefully to developing preventive and therapeutic strategies. Some of the proposed pathophysiologic mechanisms for CF in cancer survivors are similar to those in CFS, including low-grade inflammation23 and alterations of the HPA axis.1 Autonomic alterations might also be a feature of CF in cancer survivors. This hypothesis has not been thoroughly investigated, but a few studies have described symptoms indicating functional autonomic disturbances,24 altered cardiovascular
FIGURE.
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autonomic responses during orthostatic challenges,25 and altered neuroendocrine levels in cancer survivors with CF.24,26 Thus, the aim of this study was to explore if clinical features and pathophysiologic mechanisms reported among patients with CFS are identifiable in adult childhood cancer survivors with CF, particularly focusing on autonomic symptoms, neuroendocrine markers and autonomic cardiovascular responses. Comparing survivors with and without CF, we hypothesized to find similar, but possibly less pronounced, symptom load and biomarker alterations in childhood cancer survivors with CF as reported in patients with CFS. METHODS Sample, Inclusion, and Previous Cancer Disease A flowchart of the study is shown in the Figure. The present study is the second part of a childhood cancer survivorship study including 290 adult survivors of childhood acute lymphoblastic leukemia (ALL) or lymphoma.4 Inclusion criteria in the first part were treatment at Oslo University Hospital (ALL) or whole of Norway (lymphomas), diagnosis between 1970 and 2002 at age r16 years (ALL) or r18 years (lymphoma), and at least 5 years observation time from diagnosis. In the present study (time point 2, TP2), survivors reporting CF in the original study (time
Study Flowchart. CF: Chronic Fatigue.
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Zeller et al. point 1, TP1) were invited back to a comprehensive study of fatigue-associated factors. Of 78 invited individuals with previous CF, 56 were willing to participate. A total of 53 were examined, while 3 individuals did not meet for the investigations. In addition, a sample of survivors without CF at TP1 (n ¼ 130) was invited to participate at TP2, matched with regard to diagnosis (ALL vs lymphoma), but otherwise randomly. A total of 67 were willing to participate, 3 were excluded owing to ongoing pregnancy, and 15 were not examined (because the planned number of controls was reached). Thus, 49 individuals not reporting CF in the original study attended the examinations at TP2. However, some survivors changed their fatigue status between TP1 and TP2 (“converters” in the Figure), and the current fatigue status at TP2 defined the CF cases (n ¼ 35) vs controls (n ¼ 52) in this study, regardless of previous fatigue status at TP1. Information on the previous cancer disease and treatment was retrieved from the patients’ medical records. Treatment of ALL and lymphoma in the relevant time period has been reported previously.4 Examinations Participants were instructed 2 days before the examination to not drink beverages containing alcohol or caffeine, not to take any drugs and not to use tobacco products. They were instructed to bring a urine sample collected on the morning of the investigation day. Participants met fasting in the morning, and all investigations were performed between 7:30 AM and 11:00 AM. Following a brief interview and physical examination, a stand-up test for orthostatic instability was carried out. Systolic, diastolic, and mean blood pressure (BP) and heart rate (HR) were recorded after 5 minutes of rest in supine position and repeated after 3 minutes of standing without support. Following application of an ointment containing the local anesthetic lidocaine (EMLA) on the skin in the elbows about an hour in advance, blood samples were drawn by antecubital venous puncture at approximately 8:00 AM after 5 minutes of resting in supine position. Blood tests included evaluation of adrenocorticotrophic hormone, cortisol, norepinephrine, and epinephrine. Urine analysis included evaluation of free cortisol to creatinine ratio, norepinephrine, and epinephrine. For technical details regarding analyses of Psychosomatics ]:], ] 2014
norepinephrine/epinephrine in the blood and the urine and free cortisol to creatinine ratio in the urine refer to the supplemental material. Head-up tilt (HUT) test was performed according to a previously described protocol,22 which has been proven feasible in studies among adolescents with CFS.27–29 The low tilt angle (201) is sufficient to demonstrate hemodynamic alterations among patients with CFS compared with controls, without precipitating syncope. The same investigator (B.Z.) performed the HUT test in all participants, in calm, silent surroundings with dimmed lights and at a room temperature of 211C–251C. Participants were positioned horizontally on a tilt table with foot-board support (Model 900-00, CNS-systems Medizintechnik, Graz, Austria) and were attached to the Task Force Monitor, (Model 3040i, CNSystems Medizintechnik, Graz, Austria), a combined hardware and software device for noninvasive continuous recording of cardiovascular variables.30 After five minutes of baseline recordings, they were head-up tilted 20° for 15 minutes, followed by another five minutes in the horizontal position. We obtained instantaneous HR from the R-R interval of the electrocardiogram. Continuous recording of arterial BP was obtained from photoplethysmography on the right middle finger.31 Impedance cardiography was used to obtain a continuous recording of the temporal derivate of the transthoracic impedance (dZ/dt).32 All recorded signals were transferred online to the computer of the Task Force Monitor, a running producer-developed software for data acquisition. For analysis of the HUT test data, we calculated medians of all variables in the 2 epochs from 270–30 seconds before tilt (baseline) and from 30–270 seconds after being tilted (Tilt). We report baseline values and delta values (Tilt minus baseline). For details concerning calculation of cardiovascular variables of the HUT test, refer to the supplemental material. Patient-Reported Outcomes Participants completed questionnaires that included the following: Chronic Fatigue “Caseness” We used the Fatigue Questionnaire,33,34 which measures the intensity of fatigue symptoms by www.psychosomaticsjournal.org
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Chronic Fatigue in Adult Survivors of Childhood Cancer 11 items, each with 4 response alternatives (each item was scored both in a standard Likert way—0, 1, 2, and 3—and a dichotomized way—0, 0, 1, and 1). CF “caseness” is defined by a dichotomized sum score Z4 and duration of symptoms for Z6 months.9 Some survivors identified as CF cases at TP1 converted to “no CF” and some without CF at TP1 converted to CF cases. In the present study, we compared patients with or without current CF at TP2, disregarding their previous CF status (Figure). Symptoms of CFS and Autonomic Symptoms Items addressing the frequency of common CFS symptoms, including the 8 accompanying symptoms of the Centers for Disease Control (CDC) case definition,9 were used. Each symptom has 5 response alternatives ranging from “never/rarely present” to “present all of the time,” rated on a 1–5 Likert scale. These questions were based on our clinical experience and have also proven feasible in previous studies from our institution.22,29 In the present study, items assessing symptoms asked for in the Fatigue Questionnaire were excluded. To assess symptoms of autonomic dysfunction, the questionnaire was supplemented with selected items from the Autonomic Symptom Profile inventory.35 Ethics All included survivors gave written informed consent before inclusion. The Regional Committee for Medical Research Ethics approved the study. Statistics Statistical analyses were performed using IBM SPSS Statistics 18 (SPSS Inc, Chicago, IL). Continuous and semi-continuous variables are described with mean ⫾ standard deviation or median (interquartile range), when appropriate. Categorical data are reported as proportions. To compare groups, the parametric t-test and the nonparametric Mann-Whitney-Wilcoxon test were used as appropriate for continuous variables. For categorical variables, we applied the Chi-square test. All tests were carried out 2-sided. A value of P o 0.05 was considered statistically significant. As this was an exploratory study, no adjustment for multiple testing was performed. 4
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RESULTS Following the examinations at TP2, 15 of 102 survivors were excluded from further analyses owing to major somatic conditions possibly explaining CF (5 secondary cancers, lung fibrosis, pituitary prolactinoma, cerebral infarctions with hemiplegia, paraplegia following injury to the spinal cord during cancer treatment, severe heart failure, hypopituitarism, recent cardiac infarction, recent removal of meningeomas with epilepsy, severe untreated hypertension, and ongoing pregnancy). Of the remaining 87 survivors, 35 reported current CF (cases) and 52 had no current CF (controls) at TP2 (Figure). Table 1 displays the demographics. Median age was 33.0 years (range: 20.5–53.1) and median follow-up time was 25.2 years (range: 11.3–39.9). Except for a slightly higher proportion of females in the CF group (P ¼ 0.047), there were no significant differences between cases and controls. In particular, the proportion of survivors being in full-time or part-time work was not different between cases and controls (72% vs 79%, P ¼ 0.484). Table 2 displays self-reported symptoms common to CFS and symptoms suggesting functional autonomic alterations. Survivors with CF reported significantly more headache, enlarged lymphatic nodes, muscular pain and joint pain, sensitivity toward sounds, nausea, and confusion or disorientation than controls. Furthermore, several of the autonomic symptoms were more frequent in the CF group (palpitations, intermittently feeling heat and cold, lightheadedness, and watery diarrhea). Results of the blood and urine analyses are shown in Table 3. The CF group had significantly lower plasma adrenocorticotrophic hormone values than controls. (median 2.6 vs 3.7 pmol/L, P ¼ 0.002). Plasma norepinephrine and epinephrine values did not differ between groups, but urine norepinephrine level was higher in the CF group (mean 200 vs 145 nmol/L, P ¼ 0.017). During the stand-up test, there was an increment of HR, systolic BP, and diastolic BP after standing up for all participants taken together, but we registered no significant differences between survivors with or without CF (data not shown). During the HUT test, cases and controls taken together showed the expected changes during the HUT (significant increase in HR, arterial BP, and total peripheral resistance index and decrease of Psychosomatics ]:], ] 2014
Zeller et al. TABLE 1.
Demographics of 87 Participants After Exclusion of Patients With Major Somatic Comorbidity or Pregnancy. Survivors With CF (CF Cases) Compared With Survivors Without CF (Controls). Number (%) When Not Indicated Otherwise. Significant P Values in Bold CF cases (n ¼ 35) Controls (n ¼ 52) P
Female gender
25 (71%)
26 (50%)
0.047
Diagnosis Lymphoma ALL
18 (51%) 17 (49%)
26 (50%) 26 (50%)
0.896
Age at investigation, years, median (range)
32.7 (22.7–50.7)
34.0 (20.5–53.1) 0.775
Follow-up time, years, median (range)*
24.4 (11.8–39.9)
25.6 (11.3–39.1) 0.856
Body mass index, kg/m2, median (range)
24.4 (18.7–40.0)
24.4 (16.0–37.8) 0.659
At present in paid 23/32 (72%) (full- or parttime) work Daily smoking 9/32 (28%)
37/47 (79%)
0.484
9/51 (18%)
0.260
functioned relatively well with a majority being in paid work. An important finding of our study is that survivors with CF experience symptoms common in CFS (but not assessed by the Fatigue Questionnaire) such as muscle and joint pain, nausea, and sensitivity toward light. They also experience symptoms of autonomic dysfunction, such as lightheadedness, palpitations, intermittent feelings of warmth and cold, and watery diarrhea. Although other associated symptoms, such as depression, anxiety, sleep disturbances, and cognitive problems, are well known from this patient group,6–8,36 we are the first to describe these specific symptoms in fatigued childhood cancer survivors. Our findings suggest substantial similarities between CFS and CF in childhood cancer survivors on the symptom level. Still, high levels of multiple somatic symptoms are not restricted to CFS but are also observed in other medically-unexplained conditions and in depression
TABLE 2.
ALL ¼ acute lymphoblastic leukemia. n
Patient-Reported Variables. Common CFS Symptoms and Selected Autonomic Symptoms. Reported as Mean (Total Range). Significant P Values in Bold
Time from cancer diagnosis to investigation.
Stroke index, cardiac index, and HR variability indices; data not shown). However, we found no differences in baseline cardiovascular variables between survivors with CF and controls, nor were there any differences in the response to mild orthostatic stress during the HUT test (Table 4).
DISCUSSION This study showed that adult survivors of childhood cancer suffering from CF had higher levels of symptoms commonly observed in patients with CFS, higher scores of autonomic symptoms, lower level of adrenocorticotrophic hormone in the plasma, and a higher level of norepinephrine in the urine as compared with survivors without CF. However, the groups did not differ regarding their cardiovascular response to orthostatic stress. Thus, CF in cancer survivors has features in common with the CFS. In spite of high levels of symptoms, most survivors with CF Psychosomatics ]:], ] 2014
Common CFS symptoms † Headache Sore throat Enlarged lymphatic nodes Muscular pain Joint pain Sensitivity toward sounds Sensitivity toward light Nausea Feeling confused or disoriented Autonomic symptoms Palpitations Pale and cold hands Feeling intermittently heat and cold Problems focusing or seeing clearly Lightheadedness Watery diarrhea Constipation
CF cases (n ¼ 35)
Controls* P (n ¼ 50)
2.57 1.51 1.31 3.20 2.97 2.11 1.51 2.11 1.94
1.94 1.34 1.08 2.20 1.78 1.54 1.18 1.50 1.12
(1–5) (1–5) (1–5) (1–5) (1–5) (1–5) (1–5) (1–5) (1–5)
(1–5) 0.031 (1–4) 0.306 (1–4) 0.021 (1–5) 0.004 (1–5) o0.001 (1–5) 0.039 (1–4) 0.057 (1–5) 0.032 (1–3) o0.001
2.23 (1–5) 1.26 (1–4) o0.001 2.00 (1–5) 1.80 (1–5) 0.432 2.26 (1–5) 1.44 (1–4) 0.004 2.11 (1–5) 1.64 (1–5)
0.076
2.69 (1–5) 2.00 (1–5) 0.022 1.80 (1–4) 1.27 (1–5) o0.001 0.054 1.50 (1–4) 1.20 (1–3)
CSF ¼ chronic fatigue syndrome. n
Answers missing in 2 controls. Except items included in the Fatigue Questionnaire (nonrelieving rest, postexertional malaise, problems of concentration and memory). †
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Chronic Fatigue in Adult Survivors of Childhood Cancer TABLE 3.
Results of Selected Blood and Urine Tests. Reported Median (Interquartile Range) Where Not Indicated Otherwise. Significant P Values in Bold Controls P CF cases (n ¼ 29–34)* (n ¼ 47–50)†
Blood ACTH (pmol/L) Cortisol (nmol/L): mean (SD) Norepinephrine (pmol/L) Epinephrine (pmol/L): mean (SD) Urine Cortisol to creatinine ratio Norepinephrine (nmol/L): mean (SD) Epinephrine (nmol/L)
2.6 (2.4) 418 (142) 1723 (1266)
3.7 (2.7) 440 (161)
0.002 0.525
1609 (1189) 0.772
300 (102)
296.1 (99)
0.857
6.4 (10.4)
5.8 (6.3)
0.894
200 (111)
145 (63)
0.017
18.0 (11)
15.0 (11)
0.193
ACTH ¼ adrenocorticotrophic hormone; SD ¼ standard deviation. n
Not available: 1 for cortisol, 2 for ACTH, 3 for norepinephrine and epinephrine, 4 for U- norepinephrine and U- epinephrine, 6 for cortisol to creatinine ratio. † Not available: 2 for cortisol, 3 for ACTH, U-norepinephrine and U-epinephrine, 5 for norepinephrine, epinephrine and cortisol to creatinine ratio.
TABLE 4.
disorders. In a previous article, we identified depression and anxiety as predictors of CF in this cohort.4 The limited sample size and the lack of prospectivelycollected data restrict the possibility to further elaborate on the symptom profile and a possible underlying “driver.” In CFS, altered cardiovascular responses during orthostatic stress are well documented.18,21,22,37 Terlou et al.25 investigated cardiovascular responses to orthostatic stress during stand-up tests in childhood cancer survivors. They found that orthostatic tachycardia developed in a significantly higher proportion of survivors compared with healthy controls. We explored cardiovascular responses by the stand-up test and by the HUT test and were not able to show differences between survivors with and without CF. A type II error is possible because of the relatively small sample size, but it does not seem likely, as significant findings of cardiovascular alterations in CFS and cancer-related fatigue have been reported in studies with similar sample sizes.22,25 There are several other possible explanations. Firstly, methodologic issues related to the applied orthostatic stress may play a role. During the stand-up test, 3 minutes of standing upright may be too short a time to evoke orthostatic intolerance. Terlou et al. used 10 minutes
Results of the Head-Up Tilt (HUT) Test. Measurements at Baseline (Supine Rest Before Tilt) and Delta Values (201 HUT Minus Baseline). Reported as Median (Interquartile Range) Where Not Indicated Otherwise Baseline
HR (beats/min) SBP (mm Hg) MBP (mm Hg) DBP (mm Hg) SI (ml/m2) CI (L/min/m2) TPRI (mm Hg/L/min/m2) LF norm (nu) HF norm (nu) LF/HF: mean (SD) SDNN (ms): mean (SD) pNN50 (%): mean (SD) r-MSSD (ms): mean (SD)
Delta (201 HUT—baseline)
CF cases (n ¼ 35)
Controls (n ¼ 52)
P
CF cases (n ¼ 35)
Controls (n ¼ 52)
P
64.7 108 82 70 44 2.8 9.4 46 54 1.12 44.7 12.3 38.3
63.6 108 83 71 46 2.86 8.5 50 50 0.88 55.2 26.3 48.3
0.371 0.838 0.720 0.896 0.454 0.518 0.103 0.427 0.427 0.716 0.396 0.299 0.716
1.1 3.3 3.4 3.9 3.4 0.2 0.9 5.3 5.2 0.2 2.8 2.5 5.2
1.8 3.1 2.9 2.6 3.9 0.2 0.7 3.8 3.8 0.1 0.1 2.5 6.6
0.264 0.894 0.527 0.142 0.658 0.929 0.429 0.548 0.559 0.451 0.243 0.723 0.359
(10.9) (11.7) (11.2) (10.4) (11.8) (0.66) (2.16) (19.6) (19.6) (1.20) (28.1) (35.1) (37.5)
(11.1) (11.4) (8.5) (7.7) (11.3) (0.75) (2.42) (17.2) (17.2) (1.19) (42.3) (39.1) (45.1)
(2.8) (4.0) (3.4) (3.6) (4.3) (0.3) (0.9) (12.0) (12.0) (0.7) (16.6) (11.9) (20.7)
(3.2) (4.0) (4.0) (4.2) (6.0) (0.4) (1.0) (11.2) (11.2) (0.8) (20.9) (11.8) (15.8)
CI ¼ cardiac index; DBP ¼ diastolic blood pressure; HF norm ¼ variability in the high-frequency region, normalized values; HR ¼ heart rate; LF/HF ¼ low-frequency absolute value/high-frequency absolute value; LF norm ¼ variability in the low-frequency region, normalized values; MBP ¼ mean blood pressure; ms ¼ milliseconds; nu ¼ normalized units; pNN50 ¼ proportion of successive R-R intervals with a difference greater than 50 ms; r-MSSD ¼ the square root of the mean square differences of successive R-R intervals; SBP ¼ systolic blood pressure; SD ¼ standard deviation; SDNN ¼ standard deviation of R-R intervals; SI ¼ Stroke index; TPRI ¼ total peripheral resistance index.
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Zeller et al. of upright standing, but they stated that even longer exposure to orthostatic stress may be required to evoke neurally-mediated hypotension. During the HUT test, the used tilt angle of only 201 may have been too low in the present patient group, although it was feasible in adolescents with CFS.22,28 Secondly, according to the findings of Terlou et al.,25 most childhood cancer survivors may have altered cardiovascular responses independent of their fatiguability. This may reduce potential differences between fatigued and nonfatigued survivors, thus explaining the lack of differences between these groups in our study. Lastly, in contrast to patients with CFS, most of the examined survivors with CF reported adequate daily functioning with similar proportions of cases and controls being in paid work. This may explain why there were no significant differences in cardiovascular responses between survivors with and without CF. We lacked CFS cases as a comparison group, which could have clarified some of these points. Studies of endocrine markers in CFS have indicated lower levels of cortisol in the plasma, urine, and saliva; altered circadian rhythms; and attenuated HPA axis responsiveness during stimuli that normally increase cortisol secretion.38,39 Similar results were reported in a study in breast cancer survivors.40 Increased resting levels of epinephrine and norepinephrine have been documented in CFS.27Increased levels of neuroendocrine markers in fatigued individuals were reported by 2 studies on breast cancer survivors. A study reported elevated norepinephrine levels before, during, and after a mental stressor.24 Another study found that higher neuroendocrine levels predicted the pain-depression-fatigue symptom cluster.26 Our findings of lower levels of adrenocorticotrophic hormone in the plasma and higher levels of norepinephrine in the urine are in accordance with these studies, suggesting slight inhibition of the HPA axis and enhanced sympathetic nervous activity also in childhood cancer survivors with CF. A strength of the study is the multimodal approach using both self-reported and objectively assessed variables. Further, the study sample included survivors of 2 of the most common childhood cancers. The sample was well defined, with exclusion of individuals with major somatic conditions that may have otherwise precluded meaningful analyses. The
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study is limited by its moderate sample size, leading to increased risk for type II errors. However, this should be compensated to some extent by the case-control design with similar distribution of diagnoses, gender, and age. We cannot rule out selection biases during the inclusion process. As we do not have information on fatigue severity of potential CF cases who declined participation or did not respond, the included CF cases may not be perfectly representative of all survivors with CF. Attrition analysis showed that included survivors were older than those not included (median 31.7 vs 28.6 years, P o 0.01), but there were no differences regarding gender, diagnosis, age at diagnosis, follow-up time, total anthracycline dose, or proportion having had radiotherapy. The relatively high number of statistical tests increases the risk of type I errors.
CONCLUSION The results of our study indicate that survivors with CF suffer from symptoms that characterize CFS as well as symptoms of autonomic dysfunction. Both the conditions also seem to have some pathophysiologic features in common (HPA axis attenuation and sympathetic enhancement), but the burden of disturbing symptoms was contrasted by relatively sparse findings regarding biomarkers. Orthostatic dysfunction is not a major feature in survivors suffering from CF. Taken together, CF in childhood cancer survivors seems to be a more heterogeneous and possibly less disabling condition than CFS. Further efforts are required to explore the pathophysiology in detail. Acknowledgments: This study has been financially supported by the Norwegian ExtraFoundation for Health and Rehabilitation and Simon Fougner Hartmann0 s Family Foundation. We want to thank Anna-Marie Thorndall Ryenbakken for study assistance, Kari Gjersum, Even Fagermoen, and Dag Sulheim for advice and practical help, and The Clinical Research Unit at Oslo University Hospital, Rikshospitalet, for practical assistance facilitating the study. Disclosure: The authors disclosed no proprietary or commercial interest in any product mentioned or concept discussed in this article.
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