Acta Oto-Laryngologica. 2015; Early Online, 1–7
ORIGINAL ARTICLE
Carnitine is associated with fatigue following chemoradiotherapy for head and neck cancer
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KAZUHIRA ENDO, AKIRA TSUJI, SATORU KONDO, NAOHIRO WAKISAKA, SHIGEYUKI MURONO & TOMOKAZU YOSHIZAKI Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
Abstract Conclusion: Longitudinal assessments of carnitine and fatigue in patients with head and neck squamous cell carcinoma suggest that cisplatin damages the carnitine system in patients undergoing chemoradiotherapy and that carnitine deficiency increases fatigue. Objectives: The purpose of this study was to monitor carnitine levels and fatigue in patients who received cisplatin-based CRT and, for comparison, in patients treated by surgery alone. Methods: To investigate the level of carnitine, mice were administered cisplatin. Next, a prospective analysis was performed to compare plasma carnitine levels before and after cisplatin-based chemoradiotherapy and to assess the relationship between carnitine levels and fatigue. Results: The plasma levels of total carnitine (TC), free carnitine (FC), and fatty acylcarnitine (AC) were significantly lower in mice receiving cisplatin compared with control mice. Mean total carnitine and free carnitine levels were significantly lower 2 weeks after chemoradiotherapy (total carnitine: Mean = 45.6, SD = 16.5, p = 0.01; free carnitine: Mean = 37.8, SD = 12.7, p = 0.02) than before chemoradiotherapy (total carnitine: Mean = 57.7, SD = 12.2; free carnitine: Mean = 48.1, SD = 11.6). There was a significant inverse correlation between carnitine levels and fatigue after chemoradiotherapy.
Keywords: Carnitine, cisplatin, head and neck squamous cell carcinoma
Introduction Fatigue is the most common side-effect of head and neck squamous cell carcinoma (HNSCC) and its treatments [1,2]. Sixty-five to 100% of cancer patients undergoing radiotherapy and 82–96% of those receiving chemotherapy suffer from fatigue during treatment [3,4]. This multi-faceted and subjective HNSCC-associated condition is influenced by physical, psychological, and biological factors. A biologic mechanism that contributes to fatigue involves abnormalities in adenosine triphosphate synthesis. The micronutrient carnitine transports long-chain fatty acids into mitochondria where they are converted to adenosine triphosphate [5,6]. Fatty acids released from adipocytes detach from coenzyme-A (CoA) and interact with carnitine to
form fatty acylcarnitine (AC) conjugates, which cross the inner mitochondrial membrane. Inside the mitochondria, the reverse reaction takes place: fatty acylCoA is reformed and free carnitine (FC) is released. FC can pass back across the mitochondrial membrane to be reused [6]. Carnitine deficiency may contribute to the development of cancer-related fatigue [7]. The chemotherapeutic agent cisplatin can reduce glomerular filtration and damage renal tubules [8]. Carnitine is absorbed by the proximal kidney tubules, and cisplatin may increase its clearance from the kidneys [9]. Dysfunction of the carnitine system may promote asthenia by impairing energy metabolism. Fatigue can lead to disablement and is often reported by cancer patients as one of their most severe and distressing symptoms. Despite this, cancerrelated fatigue has been largely ignored in the
Correspondence: Kazuhira Endo, MD, PhD, Division of Otolaryngology, Graduate School of Medicine, 13-1 Takara-machi, Kanazawa University, Kanazawa 920-8641, Japan. Tel: +81 76 265 2413. Fax: +81 76 234 4265. E-mail: [email protected]
(Received 6 January 2015; accepted 10 March 2015) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2015.1030769
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assessment of symptom severity and as a target for treatment and patients consider it a symptom to be endured. Alleviation of pain and suffering are important goals of cancer care, yet strategies to lessen and manage fatigue are limited. Corticosteroids have shown some positive effects in treating fatigue, but the data are incomplete and unconfirmed by comparative trials [10]. To our knowledge, no studies have evaluated fatigue and plasma carnitine levels in patients with HNSCC. We hypothesized that cisplatin-based chemoradiotherapy (CRT) decreases levels of carnitine, which contributes to fatigue. The purpose of this study was to monitor carnitine levels and fatigue in HNSCC patients who received cisplatin-based CRT and, for comparison, in patients treated by surgery alone.
Materials and methods Evaluation of plasma carnitine levels in mice treated with cisplatin Adult (8-week-old) F344/DuCrlCrlj wild-type mice (Charles River Japan Inc., Kanagawa, Japan) received a 5% glucose solution (control group) or cisplatin (Nippon Kayaku Co., Ltd, Tokyo, Japan) at doses of 2 mg/kg (6 mg/m2), 5 mg/kg (15 mg/m2), or 10 mg/kg (30 mg/m2). Each group included six mice. Cisplatin or vehicle was injected intravenously into the tail vein every week for 3 weeks. Animal procedures were performed in compliance with the guidelines of the Ethical Committee of the Laboratory for Animal Experiments, School of Medicine, Kanazawa University.
Patients Data for 36 patients (30 men and six women) histologically diagnosed with squamous cell carcinoma of the head and neck at Kanazawa University Hospital from April 2013 to April 2014 were analyzed. The present study was approved by the Investigational Review Board of Kanazawa University (no. 1389). All patients received written and oral information prior to the study. Informed consent was obtained from all participants before enrollment. Patients with a history of prior treatment for HNSCC were excluded from the study. Fourteen patients received surgery, and 22 patients received concomitant cisplatin-based chemoradiotherapy. The chemotherapy regimen consisted of 80 mg/m2 cisplatin on days 1, 21, and 42. Radiation was delivered at a conventional fraction size of 2 Gy, with a curative dose between 60 and 70 Gy.
Fatigue measurements Cancer-related fatigue was assessed using the Cancer Fatigue Scale (CFS) [11] and the Japanese version of the European Organization for Research and Treatment of Cancer (EORTC) (QLQ-C30, version 3.0) scale [12]. The CFS, developed in Japan in 2000, is a self-rating, 5-point (1 = ‘no’ to 5 = ‘very much’) Likertlike scale consisting of 15 items divided into physical (7 items), affective (4 items), and cognitive (4 items) sub-scales. The scores for each sub-scale range from 0–28 (physical), 0–16 (affective), and 0–16 (cognitive). Greater scores indicate more severe fatigue. The EORTC-QLQ-C30 is a widely used scale for cancer patients that consists of 30 items that generate 15 scores as follows: five scores for functional parameters (physical, role, cognitive, emotional, and social), three scores for symptoms (fatigue, pain, and nausea/vomiting), and six scores for additional symptoms (dyspnea, loss of appetite, insomnia, constipation, diarrhea, and financial difficulties). All items are scored on 4-point Likert scales ranging from 1 (‘not at all’) to 4 (‘very much’), with the exception of two items, which are scored on the global health status scale. All scores were linearly transformed such that they ranged from 0–100 in accordance with the guidelines of the EORTC Scoring Manual [12]. A higher score on a functional scale indicates better physical functioning, whereas a higher score on a symptom scale indicates worse physical functioning. All patients completed the CFS and the EORTCQLQ-C30 surveys before beginning treatment and 2 weeks after the end of surgery or CRT. Measurement of carnitine levels in plasma Carnitine levels in blood samples were measured four times in the CRT group, before treatment and 2 weeks after every chemotherapy cycle. In the surgery group, they were measured before and 2 weeks after surgery. All specimens were evaluated at BML, Inc. (Tokyo, Japan). Briefly, TC and FC was measured by tandem mass spectrometry and AC was calculated as the difference between TC and FC. Statistical analysis Carnitine levels before and after treatment were compared using two-tailed Student’s t-tests. Effects of carnitine levels on fatigue during treatment were determined via a correlation analysis. All statistical tests were 2-tailed with a p-value of < 0.05 considered statistically significant. Statistical analysis was performed using SPSS for Windows version 10.0 (SPSS, Inc., Chicago, IL).
Carnitine and fatigue after chemoradiotherapy 80
40
Total carnitine
3
Acylcarnitine
70
*
35 60 50
30
40 25 30 20
20
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Control
Control
CDDP CDDP CDDP 2 mg/kg 5 mg/kg 10 mg/kg 50.0
CDDP CDDP CDDP 2 mg/kg 5 mg/kg 10 mg/kg
Free carnitine
40.0 30.0 20.0 10.0 0.0 Control
CDDP CDDP CDDP 2 mg/kg 5 mg/kg 10 mg/kg
Figure 1. Carnitine levels in cisplatin-treated mice. Box-whisker plots showing changes in levels of total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) are presented. The central lines in each box denote median values, the lower and upper boundaries denote the 25th and 75th centiles, respectively, and the error bars denote the 10th and 90th centiles. Cisplatin decreased carnitine levels in a dose-dependent manner.
Results
Plasma carnitine levels in patients
Plasma carnitine levels in mice
To compare carnitine levels in patients before and after treatment, paired t-tests were performed. In the CRT group, mean TC and FC levels were significantly higher before chemotherapy (TC: Mean
The plasma levels of total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) were significantly lower in mice receiving cisplatin compared with control mice (Figure 1). Cisplatin reduced carnitine levels in a dose-dependent manner.
Table I. Demographic data of the patients. Surgery value (n = 14)
CRT value (n = 22)
56.4 years
62.1 years
Male
11
19
Female
3
3
nasal
3
0
oral
6
2
nasopharynx
0
4
oropharyx
0
2
hypopharyx
1
4
larynx
4
10
Characteristics
Patient demographics Thirty-six patients (30 men and six women) were enrolled in this prospective study. The main characteristics of these patients are summarized in (Table I). The age range was 20–78 years with a mean of 59.9 years and a median of 63.5 years. The surgery group (n = 14) consisted of 11 men and three women with a mean age of 56.4 years, and the CRT group (n = 22) consisted of 19 men and three women with a mean age of 62.1 years. The primary tumor sites in the surgery group were sinus (3), oral cavity (6), hypopharynx (1), and larynx (4). The primary tumor sites in the CRT group were oral cavity (2), nasopharynx (4), oropharynx (2), hypopharynx (4), and larynx (10).
Age Mean Gender
Tumor site
4
K. Endo et al. 100
Total carnitine
Acylcarnitine
20
#
80
15
60
10
40
5
20
0 Surgery
CRT
Surgery
Free carnitine
80
##
60
40
20
CRT
Surgery
Figure 2. Carnitine levels before and after chemotherapy or surgery. The central lines in each box denote median values, the lower and upper boundaries denote the 25th and 75th centiles, respectively, and the error bars denote the 10th and 90th centiles, respectively.
[M] = 57.7, standard deviation [SD] = 12.2; FC: M = 48.1, SD = 11.6) than 2 weeks after chemotherapy (TC: M = 45.6, SD = 16.5, p = 0.01; FC: M = 37.8, SD = 12.7, p = 0.02) (Figure 2). There were no significant differences in plasma carnitine levels in the surgery group before and after surgery.
65 60 Total carnitine
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CRT
55 50 45 40
Levels of TC decreased progressively during treatment with cisplatin-based CRT (Figure 3). Fatigue assessment The mean and SD values of the CFS and EORTC QLQ-30 scores for all patients in our study are listed in (Table II). In the surgery group, pre-treatment scores were significantly higher than post-treatment scores for physical functioning (p = 0.021) and role functioning (p = 0.013) and significantly lower for fatigue (p = 0.001) and insomnia (p = 0.025). In the CRT group, pre-treatment scores were significantly higher than post-treatment scores for physical functioning (p = 0.004) and role functioning (p = 0.010) and significantly lower for fatigue (p = 0.000), nausea/ vomiting (p = 0.008), appetite loss (p = 0.015), and diarrhea (p = 0.048). There were no statistically significant differences in the physical, affective, cognitive, or total fatigue CFS scores between pre- and post-treatments in either group.
35 Pre-treatment After 1st
After 2nd
After 3rd
Figure 3. Longitudinal changes in the levels of total carnitine in patients receiving cisplatin-based CRT. Data are shown as means, with error bars representing SEM.
Fatigue and carnitine Pearson correlation coefficients were used to assess the relationship between fatigue and carnitine levels in
Carnitine and fatigue after chemoradiotherapy
5
Table II. Mean and SD values of functional assessment of CFS and EORTC QLQ for patients. Surgery Pre-treatment CFS
EORTC QLQ-C30
p-value#
Post-treatment 4.2 ± 4.0
Pre-treatment 3.9 ± 2.6
0.716
Post-treatment 6.4 ± 4.3
p-value# 0.064
Affective
8.5 ± 3.0
7.6 ± 3.6
0.656
9.1 ± 2.8
8.7 ± 2.6
0.624
Cognitive
1.9 ± 2.1
1.9 ± 2.5
0.743
2.4 ± 2.1
2.7 ± 1.6
0.462
15.5 ± 4.4
18.0 ± 5.9
0.123
89.1 ± 13.9
77.9 ± 17.6
0.004
# #
Total
14.7 ± 6.8
13.7 ± 7.7
0.508
Physical functioning
97.2 ± 6.0
92.2 ± 6.9
0.021
# #
Role functioning
96.9 ± 6.7
71.2 ± 28.0
0.013
Emotional functioning
75.0 ± 21.6
76.4 ± 28.1
0.772
86.8 ± 16.2
68.4 ± 25.4
0.010
80.6 ± 20.6
75.9 ± 17.6
0.282
Cognitive functioning
88.9 ± 13.0
88.9 ± 14.8
1.000
87.0 ± 15.7
78.7 ± 17.0
0.070
Social functioning
72.2 ± 27.8
72.2 ± 26.9
1.000
76.8 ± 25.7
73.1 ± 28.1
0.625
Global health status
68.8 ± 16.3
61.1 ± 28.9
0.283
54.2 ± 19.2
52.3 ± 25.4
0.744
Fatigue
16.7 ± 13.0
31.4 ± 9.3
0.001
19.8 ± 13.0
34.6 ± 12.0
0.000
#
0.0 ± 0.0
1.4 ± 4.8
0.339
0.9 ± 3.9
17.6 ± 22.5
0.008
#
Nausea/vomiting
#
13.9 ± 13.9
29.1 ± 28.5
0.067
19.4 ± 15.4
31.5 ± 21.3
0.061
Dypspea
5.6 ± 13.0
5.6 ± 13.0
1.000
13.0 ± 20.3
22.2 ± 25.6
0.205
Pain
Insominia
16.7 ± 22.5
44.4 ± 25.9
0.025
20.4 ± 23.3
37.0 ± 25.3
0.058
Appetite loss
11.1 ± 29.6
1.6 ± 0.7
0.658
16.7 ± 0.6
42.6 ± 31.9
0.015
Constipation
25.0 ± 32.2
27.8 ± 31.2
0.586
18.5 ± 17.0
27.8 ± 26.2
0.135
8.3 ± 15.1
11.1 ± 16.4
0.585
5.6 ± 12.8
14.8 ± 20.5
0.048
13.9 ± 17.2
22.2 ± 32.8
0.429
29.6 ± 25.2
35.1 ± 26.7
0.381
Diarrhea Financial difficulties
#
#
#
#paired t-test.
plasma after treatment. In the CRT group, there was a significant positive correlation between physical functioning and TC levels (r = 0.422, p = 0.04). However, A
there was no correlation between them in the surgery group (p = 0.98) (Figure 4). After treatment, patients who experienced greater fatigue had lower TC levels. B 80
CRT
Surgery
Total carnitine
80
Total carnitine
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4.4 ± 4.1
Physical
CRT
60
40
20
60
40
20 40
50
60 70 80 90 100 Physical functioning n = 22 r = 0.422, p = 0.04
40
50
60 70 80 90 100 Physical functioning n = 14 r = 0.318, p = 0.98
Figure 4. Carnitine levels and fatigue. (A) There was a significant positive correlation between physical functioning and plasma levels of total carnitine after treatment (r = 0.499, p = 0.04). (B) There was a negative correlation between total scores on the Cancer Fatigue Scale and total carnitine levels (r = 0.383, p = 0.03).
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Discussion Cisplatin-based CRT is recognized as one of the most effective current treatments for HNSCC. Patients with HNSCC experience a number of side-effects including mucositis, xerostomia, dermatitis, dysphagia, odynophagia, taste alteration, weight loss, and fatigue. Fatigue is defined as a general feeling of debilitating tiredness or loss of energy [13]. It contributes to difficulty in maintaining adequate nutrition and also remains a problem for cancer patients after treatment, adversely affecting QoL. Carnitine and its products have an important role in energy metabolism. Carnitine homeostasis is maintained by absorption, synthesis, and renal reabsorption. In humans, carnitine is produced in the liver and kidneys, stored in skeletal muscle, and excreted primarily in urine. This may explain why the carnitine system is dysfunctional when urinary excretion of carnitine is increased. Several anti-cancer drugs interfere with the carnitine network and increase urinary excretion of carnitine, resulting in impaired oxidation of long-chain fatty acids [14–16]. Cisplatin levels in the proximal tubular cells in the kidney are ~ 5-times higher than in circulating blood and accumulation of cisplatin in kidney tissue can cause nephrotoxicity and increase renal clearance of carnitine [6]. Nausea, vomiting, and anorexia associated with CRT may reduce the oral intake of foods high in carnitine, which could affect intracellular carnitine levels [17]. In addition, radiotherapy alone is an uncontrolled variable that could have an influence on fatigue and carnitine blood levels [18]. To our knowledge, this is the first study to evaluate the effects of cisplatin-based chemotherapy on carnitine levels and their relationship to fatigue in patients with HNSCC. We show that plasma carnitine levels decrease markedly in mice and patients treated with cisplatin. As reported by Hockenberry et al. [17], plasma carnitine levels in children increased after the first course of chemotherapy, suggesting that carnitine is released into the bloodstream to restore its levels. In our experience, plasma carnitine levels decrease over time with repeated exposure to cisplatin. For this reason, we monitored plasma carnitine levels 2 weeks after chemotherapy, as compared with 1 week after chemotherapy in the study of Hockenberry et al. [17]. Patients who undergo definitive CRT exhibit deteriorated physical and role functioning and increased fatigue, nausea/vomiting, appetite loss, and diarrhea. We show increased fatigue after surgery, although there is no significant differences in carnitine levels between pre- and post-treatment. Surgical stress response may be involved in pathogenesis of postoperative fatigue [19]. Current data suggest there is a
clear relationship between plasma levels of TC after chemotherapy and cancer-related fatigue, although no significant correlation was found between them after surgery. Chemotherapy-induced damage of the carnitine system may cause fatigue by impairing energy metabolism [6]. Tumor-induced cytokine production and host-produced pro-inflammatory cytokines may also contribute to fatigue [20]. Our results suggest that concomitant CRT damages the carnitine system in patients and that carnitine deficiency is one of the factors that increases fatigue. Moreover, carnitine deficiency may contribute to asthenia by impairing energy metabolism. L-carnitine supplementation to treat carnitine deficiency did not improve fatigue in patients with invasive malignancies and good performance status [21]. However, another study shows that L-carnitine supplementation has been shown to be beneficial in restoring normal plasma carnitine levels and relieving cancer-related fatigue in cancer cachexia [14]. We believe that the results of our study will support intervention planning to alleviate cancer-related fatigue in patients receiving CRT and, consequently, improve their quality-of-life. Conclusion Our longitudinal assessments of carnitine and fatigue in patients with HNSCC suggest that cisplatin damages the carnitine system in patients undergoing chemoradiotherapy and that carnitine deficiency increases fatigue. Our findings provide a basis for the design of future studies of carnitine supplementation to combat chemotherapy-induced fatigue. Further research is needed to understand the relationship between carnitine levels and fatigue in patients with HNSCC. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Babin E, Sigston E, Hitier M, Dehesdin D, Marie JP, Choussy O. Quality of life in head and neck cancers patients: predictive factors, functional and psychosocial outcome. Eur Arch Otorhinolaryngol 2008;265:265–70. [2] Sawada NO, de Paula JM, Sonobe HM, Zago MM, Guerrero GP, Nicolussi AC. Depression, fatigue, and health-related quality of life in head and neck cancer patients: a prospective pilot study. Support Care Cancer 2012;20: 2705–11. [3] Richardson A, Ream E. The experience of fatigue and other symptoms in patients receiving chemotherapy. Eur J Cancer Care 1996;5:24–30. [4] Schwartz AL, Nail LM, Chen S, Meek P, Barsevick AM, King ME, et al. Fatigue patterns observed in patients
Carnitine and fatigue after chemoradiotherapy
[5]
[6]
[7] [8]
Acta Otolaryngol Downloaded from informahealthcare.com by Kainan University on 04/07/15 For personal use only.
[9]
[10] [11]
[12]
[13]
receiving chemotherapy and radiotherapy. Cancer Invest 2000;18:11–19. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142C:77–85. Peluso G, Nicolai R, Reda E, Benatti P, Barbarisi A, Calvani M. Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system. J Cell Physiol 2000;182:339–50. Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol 1995;10:S8–24. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008;73:994–1007. Dodson WL, Sachan DS, Krauss S, Hanna W. Alterations of serum and urinary carnitine profiles in cancer patients: hypothesis of possible significance. J Am Coll Nutr 1989; 8:133–42. Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for evaluation and management. Oncologist 1999;4:1–10. Okuyama T, Akechi T, Kugaya A, Okamura H, Shima Y, Maruguchi M, et al. Development and validation of the cancer fatigue scale: a brief, three-dimensional, self-rating scale for assessment of fatigue in cancer patients. J Pain Symptom Manage 2000;19:5–14. Sprangers MA, Cull A, Bjordal K, Groenvold M, Aaronson NK. The european organization for research and treatment of cancer. Approach to quality of life assessment: guidelines for developing questionnaire modules. EORTC Study Group on Quality of Life. Qual Life Res 1993;2:287–95. Wagner LI, Cella D. Fatigue and cancer: causes, prevalence and treatment approaches. Br J Cancer 2004;91:822–8.
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[14] Graziano F, Bisonni R, Catalano V, Silva R, Rovidati S, Mencarini E, et al. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer 2002; 86:1854–7. [15] Waldner R, Laschan C, Lohninger A, Gessner M, Tuchler H, Huemer M, et al. Effects of doxorubicincontaining chemotherapy and a combination with L-carnitine on oxidative metabolism in patients with nonHodgkin lymphoma. J Cancer Res Clin Oncol 2006;132: 121–8. [16] Bianchi G, Vitali G, Caraceni A, Ravaglia S, Capri G, Cundari S, et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer 2005;41:1746–50. [17] Hockenberry MJ, Hooke MC, Gregurich M, McCarthy K. Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or doxorubicin. J Pediatr Hematol Oncol 2009;31:664–9. [18] Khan HA, Alhomida AS. A review of the logistic role of L-carnitine in the management of radiation toxicity and radiotherapy side effects. J Appl Toxicol 2011;31: 707–13. [19] Zargar-Shoshtari K, Hill AG. Postoperative fatigue: a review. World J Surg 2009;33:738–45. [20] McNeil C. Cancer fatigue: one drug fails but more are in the pipeline. J Natl Cancer Inst 2001;93:892–3. [21] Cruciani RA, Zhang JJ, Manola J, Cella D, Ansari B, Fisch MJ. L-carnitine supplementation for the management of fatigue in patients with cancer: an eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol 2012;30:3864–9.
ORIGINAL ARTICLE
Carnitine is associated with fatigue following chemoradiotherapy for head and neck cancer
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KAZUHIRA ENDO, AKIRA TSUJI, SATORU KONDO, NAOHIRO WAKISAKA, SHIGEYUKI MURONO & TOMOKAZU YOSHIZAKI Division of Otolaryngology, Graduate School of Medicine, Kanazawa University, Kanazawa, Japan
Abstract Conclusion: Longitudinal assessments of carnitine and fatigue in patients with head and neck squamous cell carcinoma suggest that cisplatin damages the carnitine system in patients undergoing chemoradiotherapy and that carnitine deficiency increases fatigue. Objectives: The purpose of this study was to monitor carnitine levels and fatigue in patients who received cisplatin-based CRT and, for comparison, in patients treated by surgery alone. Methods: To investigate the level of carnitine, mice were administered cisplatin. Next, a prospective analysis was performed to compare plasma carnitine levels before and after cisplatin-based chemoradiotherapy and to assess the relationship between carnitine levels and fatigue. Results: The plasma levels of total carnitine (TC), free carnitine (FC), and fatty acylcarnitine (AC) were significantly lower in mice receiving cisplatin compared with control mice. Mean total carnitine and free carnitine levels were significantly lower 2 weeks after chemoradiotherapy (total carnitine: Mean = 45.6, SD = 16.5, p = 0.01; free carnitine: Mean = 37.8, SD = 12.7, p = 0.02) than before chemoradiotherapy (total carnitine: Mean = 57.7, SD = 12.2; free carnitine: Mean = 48.1, SD = 11.6). There was a significant inverse correlation between carnitine levels and fatigue after chemoradiotherapy.
Keywords: Carnitine, cisplatin, head and neck squamous cell carcinoma
Introduction Fatigue is the most common side-effect of head and neck squamous cell carcinoma (HNSCC) and its treatments [1,2]. Sixty-five to 100% of cancer patients undergoing radiotherapy and 82–96% of those receiving chemotherapy suffer from fatigue during treatment [3,4]. This multi-faceted and subjective HNSCC-associated condition is influenced by physical, psychological, and biological factors. A biologic mechanism that contributes to fatigue involves abnormalities in adenosine triphosphate synthesis. The micronutrient carnitine transports long-chain fatty acids into mitochondria where they are converted to adenosine triphosphate [5,6]. Fatty acids released from adipocytes detach from coenzyme-A (CoA) and interact with carnitine to
form fatty acylcarnitine (AC) conjugates, which cross the inner mitochondrial membrane. Inside the mitochondria, the reverse reaction takes place: fatty acylCoA is reformed and free carnitine (FC) is released. FC can pass back across the mitochondrial membrane to be reused [6]. Carnitine deficiency may contribute to the development of cancer-related fatigue [7]. The chemotherapeutic agent cisplatin can reduce glomerular filtration and damage renal tubules [8]. Carnitine is absorbed by the proximal kidney tubules, and cisplatin may increase its clearance from the kidneys [9]. Dysfunction of the carnitine system may promote asthenia by impairing energy metabolism. Fatigue can lead to disablement and is often reported by cancer patients as one of their most severe and distressing symptoms. Despite this, cancerrelated fatigue has been largely ignored in the
Correspondence: Kazuhira Endo, MD, PhD, Division of Otolaryngology, Graduate School of Medicine, 13-1 Takara-machi, Kanazawa University, Kanazawa 920-8641, Japan. Tel: +81 76 265 2413. Fax: +81 76 234 4265. E-mail: [email protected]
(Received 6 January 2015; accepted 10 March 2015) ISSN 0001-6489 print/ISSN 1651-2251 online 2015 Informa Healthcare DOI: 10.3109/00016489.2015.1030769
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K. Endo et al.
assessment of symptom severity and as a target for treatment and patients consider it a symptom to be endured. Alleviation of pain and suffering are important goals of cancer care, yet strategies to lessen and manage fatigue are limited. Corticosteroids have shown some positive effects in treating fatigue, but the data are incomplete and unconfirmed by comparative trials [10]. To our knowledge, no studies have evaluated fatigue and plasma carnitine levels in patients with HNSCC. We hypothesized that cisplatin-based chemoradiotherapy (CRT) decreases levels of carnitine, which contributes to fatigue. The purpose of this study was to monitor carnitine levels and fatigue in HNSCC patients who received cisplatin-based CRT and, for comparison, in patients treated by surgery alone.
Materials and methods Evaluation of plasma carnitine levels in mice treated with cisplatin Adult (8-week-old) F344/DuCrlCrlj wild-type mice (Charles River Japan Inc., Kanagawa, Japan) received a 5% glucose solution (control group) or cisplatin (Nippon Kayaku Co., Ltd, Tokyo, Japan) at doses of 2 mg/kg (6 mg/m2), 5 mg/kg (15 mg/m2), or 10 mg/kg (30 mg/m2). Each group included six mice. Cisplatin or vehicle was injected intravenously into the tail vein every week for 3 weeks. Animal procedures were performed in compliance with the guidelines of the Ethical Committee of the Laboratory for Animal Experiments, School of Medicine, Kanazawa University.
Patients Data for 36 patients (30 men and six women) histologically diagnosed with squamous cell carcinoma of the head and neck at Kanazawa University Hospital from April 2013 to April 2014 were analyzed. The present study was approved by the Investigational Review Board of Kanazawa University (no. 1389). All patients received written and oral information prior to the study. Informed consent was obtained from all participants before enrollment. Patients with a history of prior treatment for HNSCC were excluded from the study. Fourteen patients received surgery, and 22 patients received concomitant cisplatin-based chemoradiotherapy. The chemotherapy regimen consisted of 80 mg/m2 cisplatin on days 1, 21, and 42. Radiation was delivered at a conventional fraction size of 2 Gy, with a curative dose between 60 and 70 Gy.
Fatigue measurements Cancer-related fatigue was assessed using the Cancer Fatigue Scale (CFS) [11] and the Japanese version of the European Organization for Research and Treatment of Cancer (EORTC) (QLQ-C30, version 3.0) scale [12]. The CFS, developed in Japan in 2000, is a self-rating, 5-point (1 = ‘no’ to 5 = ‘very much’) Likertlike scale consisting of 15 items divided into physical (7 items), affective (4 items), and cognitive (4 items) sub-scales. The scores for each sub-scale range from 0–28 (physical), 0–16 (affective), and 0–16 (cognitive). Greater scores indicate more severe fatigue. The EORTC-QLQ-C30 is a widely used scale for cancer patients that consists of 30 items that generate 15 scores as follows: five scores for functional parameters (physical, role, cognitive, emotional, and social), three scores for symptoms (fatigue, pain, and nausea/vomiting), and six scores for additional symptoms (dyspnea, loss of appetite, insomnia, constipation, diarrhea, and financial difficulties). All items are scored on 4-point Likert scales ranging from 1 (‘not at all’) to 4 (‘very much’), with the exception of two items, which are scored on the global health status scale. All scores were linearly transformed such that they ranged from 0–100 in accordance with the guidelines of the EORTC Scoring Manual [12]. A higher score on a functional scale indicates better physical functioning, whereas a higher score on a symptom scale indicates worse physical functioning. All patients completed the CFS and the EORTCQLQ-C30 surveys before beginning treatment and 2 weeks after the end of surgery or CRT. Measurement of carnitine levels in plasma Carnitine levels in blood samples were measured four times in the CRT group, before treatment and 2 weeks after every chemotherapy cycle. In the surgery group, they were measured before and 2 weeks after surgery. All specimens were evaluated at BML, Inc. (Tokyo, Japan). Briefly, TC and FC was measured by tandem mass spectrometry and AC was calculated as the difference between TC and FC. Statistical analysis Carnitine levels before and after treatment were compared using two-tailed Student’s t-tests. Effects of carnitine levels on fatigue during treatment were determined via a correlation analysis. All statistical tests were 2-tailed with a p-value of < 0.05 considered statistically significant. Statistical analysis was performed using SPSS for Windows version 10.0 (SPSS, Inc., Chicago, IL).
Carnitine and fatigue after chemoradiotherapy 80
40
Total carnitine
3
Acylcarnitine
70
*
35 60 50
30
40 25 30 20
20
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Control
Control
CDDP CDDP CDDP 2 mg/kg 5 mg/kg 10 mg/kg 50.0
CDDP CDDP CDDP 2 mg/kg 5 mg/kg 10 mg/kg
Free carnitine
40.0 30.0 20.0 10.0 0.0 Control
CDDP CDDP CDDP 2 mg/kg 5 mg/kg 10 mg/kg
Figure 1. Carnitine levels in cisplatin-treated mice. Box-whisker plots showing changes in levels of total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) are presented. The central lines in each box denote median values, the lower and upper boundaries denote the 25th and 75th centiles, respectively, and the error bars denote the 10th and 90th centiles. Cisplatin decreased carnitine levels in a dose-dependent manner.
Results
Plasma carnitine levels in patients
Plasma carnitine levels in mice
To compare carnitine levels in patients before and after treatment, paired t-tests were performed. In the CRT group, mean TC and FC levels were significantly higher before chemotherapy (TC: Mean
The plasma levels of total carnitine (TC), free carnitine (FC), and acylcarnitine (AC) were significantly lower in mice receiving cisplatin compared with control mice (Figure 1). Cisplatin reduced carnitine levels in a dose-dependent manner.
Table I. Demographic data of the patients. Surgery value (n = 14)
CRT value (n = 22)
56.4 years
62.1 years
Male
11
19
Female
3
3
nasal
3
0
oral
6
2
nasopharynx
0
4
oropharyx
0
2
hypopharyx
1
4
larynx
4
10
Characteristics
Patient demographics Thirty-six patients (30 men and six women) were enrolled in this prospective study. The main characteristics of these patients are summarized in (Table I). The age range was 20–78 years with a mean of 59.9 years and a median of 63.5 years. The surgery group (n = 14) consisted of 11 men and three women with a mean age of 56.4 years, and the CRT group (n = 22) consisted of 19 men and three women with a mean age of 62.1 years. The primary tumor sites in the surgery group were sinus (3), oral cavity (6), hypopharynx (1), and larynx (4). The primary tumor sites in the CRT group were oral cavity (2), nasopharynx (4), oropharynx (2), hypopharynx (4), and larynx (10).
Age Mean Gender
Tumor site
4
K. Endo et al. 100
Total carnitine
Acylcarnitine
20
#
80
15
60
10
40
5
20
0 Surgery
CRT
Surgery
Free carnitine
80
##
60
40
20
CRT
Surgery
Figure 2. Carnitine levels before and after chemotherapy or surgery. The central lines in each box denote median values, the lower and upper boundaries denote the 25th and 75th centiles, respectively, and the error bars denote the 10th and 90th centiles, respectively.
[M] = 57.7, standard deviation [SD] = 12.2; FC: M = 48.1, SD = 11.6) than 2 weeks after chemotherapy (TC: M = 45.6, SD = 16.5, p = 0.01; FC: M = 37.8, SD = 12.7, p = 0.02) (Figure 2). There were no significant differences in plasma carnitine levels in the surgery group before and after surgery.
65 60 Total carnitine
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CRT
55 50 45 40
Levels of TC decreased progressively during treatment with cisplatin-based CRT (Figure 3). Fatigue assessment The mean and SD values of the CFS and EORTC QLQ-30 scores for all patients in our study are listed in (Table II). In the surgery group, pre-treatment scores were significantly higher than post-treatment scores for physical functioning (p = 0.021) and role functioning (p = 0.013) and significantly lower for fatigue (p = 0.001) and insomnia (p = 0.025). In the CRT group, pre-treatment scores were significantly higher than post-treatment scores for physical functioning (p = 0.004) and role functioning (p = 0.010) and significantly lower for fatigue (p = 0.000), nausea/ vomiting (p = 0.008), appetite loss (p = 0.015), and diarrhea (p = 0.048). There were no statistically significant differences in the physical, affective, cognitive, or total fatigue CFS scores between pre- and post-treatments in either group.
35 Pre-treatment After 1st
After 2nd
After 3rd
Figure 3. Longitudinal changes in the levels of total carnitine in patients receiving cisplatin-based CRT. Data are shown as means, with error bars representing SEM.
Fatigue and carnitine Pearson correlation coefficients were used to assess the relationship between fatigue and carnitine levels in
Carnitine and fatigue after chemoradiotherapy
5
Table II. Mean and SD values of functional assessment of CFS and EORTC QLQ for patients. Surgery Pre-treatment CFS
EORTC QLQ-C30
p-value#
Post-treatment 4.2 ± 4.0
Pre-treatment 3.9 ± 2.6
0.716
Post-treatment 6.4 ± 4.3
p-value# 0.064
Affective
8.5 ± 3.0
7.6 ± 3.6
0.656
9.1 ± 2.8
8.7 ± 2.6
0.624
Cognitive
1.9 ± 2.1
1.9 ± 2.5
0.743
2.4 ± 2.1
2.7 ± 1.6
0.462
15.5 ± 4.4
18.0 ± 5.9
0.123
89.1 ± 13.9
77.9 ± 17.6
0.004
# #
Total
14.7 ± 6.8
13.7 ± 7.7
0.508
Physical functioning
97.2 ± 6.0
92.2 ± 6.9
0.021
# #
Role functioning
96.9 ± 6.7
71.2 ± 28.0
0.013
Emotional functioning
75.0 ± 21.6
76.4 ± 28.1
0.772
86.8 ± 16.2
68.4 ± 25.4
0.010
80.6 ± 20.6
75.9 ± 17.6
0.282
Cognitive functioning
88.9 ± 13.0
88.9 ± 14.8
1.000
87.0 ± 15.7
78.7 ± 17.0
0.070
Social functioning
72.2 ± 27.8
72.2 ± 26.9
1.000
76.8 ± 25.7
73.1 ± 28.1
0.625
Global health status
68.8 ± 16.3
61.1 ± 28.9
0.283
54.2 ± 19.2
52.3 ± 25.4
0.744
Fatigue
16.7 ± 13.0
31.4 ± 9.3
0.001
19.8 ± 13.0
34.6 ± 12.0
0.000
#
0.0 ± 0.0
1.4 ± 4.8
0.339
0.9 ± 3.9
17.6 ± 22.5
0.008
#
Nausea/vomiting
#
13.9 ± 13.9
29.1 ± 28.5
0.067
19.4 ± 15.4
31.5 ± 21.3
0.061
Dypspea
5.6 ± 13.0
5.6 ± 13.0
1.000
13.0 ± 20.3
22.2 ± 25.6
0.205
Pain
Insominia
16.7 ± 22.5
44.4 ± 25.9
0.025
20.4 ± 23.3
37.0 ± 25.3
0.058
Appetite loss
11.1 ± 29.6
1.6 ± 0.7
0.658
16.7 ± 0.6
42.6 ± 31.9
0.015
Constipation
25.0 ± 32.2
27.8 ± 31.2
0.586
18.5 ± 17.0
27.8 ± 26.2
0.135
8.3 ± 15.1
11.1 ± 16.4
0.585
5.6 ± 12.8
14.8 ± 20.5
0.048
13.9 ± 17.2
22.2 ± 32.8
0.429
29.6 ± 25.2
35.1 ± 26.7
0.381
Diarrhea Financial difficulties
#
#
#
#paired t-test.
plasma after treatment. In the CRT group, there was a significant positive correlation between physical functioning and TC levels (r = 0.422, p = 0.04). However, A
there was no correlation between them in the surgery group (p = 0.98) (Figure 4). After treatment, patients who experienced greater fatigue had lower TC levels. B 80
CRT
Surgery
Total carnitine
80
Total carnitine
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4.4 ± 4.1
Physical
CRT
60
40
20
60
40
20 40
50
60 70 80 90 100 Physical functioning n = 22 r = 0.422, p = 0.04
40
50
60 70 80 90 100 Physical functioning n = 14 r = 0.318, p = 0.98
Figure 4. Carnitine levels and fatigue. (A) There was a significant positive correlation between physical functioning and plasma levels of total carnitine after treatment (r = 0.499, p = 0.04). (B) There was a negative correlation between total scores on the Cancer Fatigue Scale and total carnitine levels (r = 0.383, p = 0.03).
6
K. Endo et al.
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Discussion Cisplatin-based CRT is recognized as one of the most effective current treatments for HNSCC. Patients with HNSCC experience a number of side-effects including mucositis, xerostomia, dermatitis, dysphagia, odynophagia, taste alteration, weight loss, and fatigue. Fatigue is defined as a general feeling of debilitating tiredness or loss of energy [13]. It contributes to difficulty in maintaining adequate nutrition and also remains a problem for cancer patients after treatment, adversely affecting QoL. Carnitine and its products have an important role in energy metabolism. Carnitine homeostasis is maintained by absorption, synthesis, and renal reabsorption. In humans, carnitine is produced in the liver and kidneys, stored in skeletal muscle, and excreted primarily in urine. This may explain why the carnitine system is dysfunctional when urinary excretion of carnitine is increased. Several anti-cancer drugs interfere with the carnitine network and increase urinary excretion of carnitine, resulting in impaired oxidation of long-chain fatty acids [14–16]. Cisplatin levels in the proximal tubular cells in the kidney are ~ 5-times higher than in circulating blood and accumulation of cisplatin in kidney tissue can cause nephrotoxicity and increase renal clearance of carnitine [6]. Nausea, vomiting, and anorexia associated with CRT may reduce the oral intake of foods high in carnitine, which could affect intracellular carnitine levels [17]. In addition, radiotherapy alone is an uncontrolled variable that could have an influence on fatigue and carnitine blood levels [18]. To our knowledge, this is the first study to evaluate the effects of cisplatin-based chemotherapy on carnitine levels and their relationship to fatigue in patients with HNSCC. We show that plasma carnitine levels decrease markedly in mice and patients treated with cisplatin. As reported by Hockenberry et al. [17], plasma carnitine levels in children increased after the first course of chemotherapy, suggesting that carnitine is released into the bloodstream to restore its levels. In our experience, plasma carnitine levels decrease over time with repeated exposure to cisplatin. For this reason, we monitored plasma carnitine levels 2 weeks after chemotherapy, as compared with 1 week after chemotherapy in the study of Hockenberry et al. [17]. Patients who undergo definitive CRT exhibit deteriorated physical and role functioning and increased fatigue, nausea/vomiting, appetite loss, and diarrhea. We show increased fatigue after surgery, although there is no significant differences in carnitine levels between pre- and post-treatment. Surgical stress response may be involved in pathogenesis of postoperative fatigue [19]. Current data suggest there is a
clear relationship between plasma levels of TC after chemotherapy and cancer-related fatigue, although no significant correlation was found between them after surgery. Chemotherapy-induced damage of the carnitine system may cause fatigue by impairing energy metabolism [6]. Tumor-induced cytokine production and host-produced pro-inflammatory cytokines may also contribute to fatigue [20]. Our results suggest that concomitant CRT damages the carnitine system in patients and that carnitine deficiency is one of the factors that increases fatigue. Moreover, carnitine deficiency may contribute to asthenia by impairing energy metabolism. L-carnitine supplementation to treat carnitine deficiency did not improve fatigue in patients with invasive malignancies and good performance status [21]. However, another study shows that L-carnitine supplementation has been shown to be beneficial in restoring normal plasma carnitine levels and relieving cancer-related fatigue in cancer cachexia [14]. We believe that the results of our study will support intervention planning to alleviate cancer-related fatigue in patients receiving CRT and, consequently, improve their quality-of-life. Conclusion Our longitudinal assessments of carnitine and fatigue in patients with HNSCC suggest that cisplatin damages the carnitine system in patients undergoing chemoradiotherapy and that carnitine deficiency increases fatigue. Our findings provide a basis for the design of future studies of carnitine supplementation to combat chemotherapy-induced fatigue. Further research is needed to understand the relationship between carnitine levels and fatigue in patients with HNSCC. Declaration of interest: The authors report no conflicts of interest. The authors alone are responsible for the content and writing of the paper.
References [1] Babin E, Sigston E, Hitier M, Dehesdin D, Marie JP, Choussy O. Quality of life in head and neck cancers patients: predictive factors, functional and psychosocial outcome. Eur Arch Otorhinolaryngol 2008;265:265–70. [2] Sawada NO, de Paula JM, Sonobe HM, Zago MM, Guerrero GP, Nicolussi AC. Depression, fatigue, and health-related quality of life in head and neck cancer patients: a prospective pilot study. Support Care Cancer 2012;20: 2705–11. [3] Richardson A, Ream E. The experience of fatigue and other symptoms in patients receiving chemotherapy. Eur J Cancer Care 1996;5:24–30. [4] Schwartz AL, Nail LM, Chen S, Meek P, Barsevick AM, King ME, et al. Fatigue patterns observed in patients
Carnitine and fatigue after chemoradiotherapy
[5]
[6]
[7] [8]
Acta Otolaryngol Downloaded from informahealthcare.com by Kainan University on 04/07/15 For personal use only.
[9]
[10] [11]
[12]
[13]
receiving chemotherapy and radiotherapy. Cancer Invest 2000;18:11–19. Longo N, Amat di San Filippo C, Pasquali M. Disorders of carnitine transport and the carnitine cycle. Am J Med Genet C Semin Med Genet 2006;142C:77–85. Peluso G, Nicolai R, Reda E, Benatti P, Barbarisi A, Calvani M. Cancer and anticancer therapy-induced modifications on metabolism mediated by carnitine system. J Cell Physiol 2000;182:339–50. Pons R, De Vivo DC. Primary and secondary carnitine deficiency syndromes. J Child Neurol 1995;10:S8–24. Pabla N, Dong Z. Cisplatin nephrotoxicity: mechanisms and renoprotective strategies. Kidney Int 2008;73:994–1007. Dodson WL, Sachan DS, Krauss S, Hanna W. Alterations of serum and urinary carnitine profiles in cancer patients: hypothesis of possible significance. J Am Coll Nutr 1989; 8:133–42. Portenoy RK, Itri LM. Cancer-related fatigue: guidelines for evaluation and management. Oncologist 1999;4:1–10. Okuyama T, Akechi T, Kugaya A, Okamura H, Shima Y, Maruguchi M, et al. Development and validation of the cancer fatigue scale: a brief, three-dimensional, self-rating scale for assessment of fatigue in cancer patients. J Pain Symptom Manage 2000;19:5–14. Sprangers MA, Cull A, Bjordal K, Groenvold M, Aaronson NK. The european organization for research and treatment of cancer. Approach to quality of life assessment: guidelines for developing questionnaire modules. EORTC Study Group on Quality of Life. Qual Life Res 1993;2:287–95. Wagner LI, Cella D. Fatigue and cancer: causes, prevalence and treatment approaches. Br J Cancer 2004;91:822–8.
7
[14] Graziano F, Bisonni R, Catalano V, Silva R, Rovidati S, Mencarini E, et al. Potential role of levocarnitine supplementation for the treatment of chemotherapy-induced fatigue in non-anaemic cancer patients. Br J Cancer 2002; 86:1854–7. [15] Waldner R, Laschan C, Lohninger A, Gessner M, Tuchler H, Huemer M, et al. Effects of doxorubicincontaining chemotherapy and a combination with L-carnitine on oxidative metabolism in patients with nonHodgkin lymphoma. J Cancer Res Clin Oncol 2006;132: 121–8. [16] Bianchi G, Vitali G, Caraceni A, Ravaglia S, Capri G, Cundari S, et al. Symptomatic and neurophysiological responses of paclitaxel- or cisplatin-induced neuropathy to oral acetyl-L-carnitine. Eur J Cancer 2005;41:1746–50. [17] Hockenberry MJ, Hooke MC, Gregurich M, McCarthy K. Carnitine plasma levels and fatigue in children/adolescents receiving cisplatin, ifosfamide, or doxorubicin. J Pediatr Hematol Oncol 2009;31:664–9. [18] Khan HA, Alhomida AS. A review of the logistic role of L-carnitine in the management of radiation toxicity and radiotherapy side effects. J Appl Toxicol 2011;31: 707–13. [19] Zargar-Shoshtari K, Hill AG. Postoperative fatigue: a review. World J Surg 2009;33:738–45. [20] McNeil C. Cancer fatigue: one drug fails but more are in the pipeline. J Natl Cancer Inst 2001;93:892–3. [21] Cruciani RA, Zhang JJ, Manola J, Cella D, Ansari B, Fisch MJ. L-carnitine supplementation for the management of fatigue in patients with cancer: an eastern cooperative oncology group phase III, randomized, double-blind, placebo-controlled trial. J Clin Oncol 2012;30:3864–9.
