REVIEW URRENT C OPINION
The assessment and management of cancer cachexia: hypogonadism and hypermetabolism among supportive and palliative care patients Rony Dev
Purpose of review To update the healthcare providers on the potential contribution of increased basal metabolic rate, hypermetabolism, and low testosterone in the development of weight loss in cancer patients. Recent findings Cancer cachexia, the loss of skeletal muscle with or without the loss of fat, is a multifactorial syndrome. A wide variation in the frequency of hypermetabolism exists in cancer patients and can only be accurately identified by an indirect calorimeter. The frequency of hypermetabolism increases depending on the histology and stage of tumor, associated with the presence of an acute inflammatory response, and is often accompanied by weight loss. Hypogonadism, as a result of chemotherapy, radiation treatment, or the use of opioids to treat chronic pain, is frequently noted in male cancer patients and has been reported to be also associated with anorexia and weight loss. Summary Cancer patients may develop weight loss, cachexia, which can be distressing for both patients and their family. Treatments directed at reducing the basal metabolic rate and supplementation of testosterone in hypogonadic male patients may have the potential to improve lean body mass, but more research is needed. Keywords cancer cachexia, hypermetabolism, hypogonadism, palliative care, symptom management
INTRODUCTION In patients with cancer, malnutrition is a common occurrence and its frequency varies ranging from 8 to 84% [1]. In the past, cancer cachexia has been defined as a total involuntary weight loss of greater than 10% of preillness body weight [2]. Recently, in 2010, an international panel of experts have agreed to the following definition, ‘Cachexia is a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment’ [3]. The pathophysiology of cancer cachexia is complex and characterized by reduced nutritional intake, systemic inflammation, decreased muscle mass and strength, and symptoms of fatigue [4]. Researchers have highlighted that decreased nutritional intake alone does not fully account for weight loss [5], and unlike starvation, cancer cachexia is not reversed by adequate caloric supplementation [6].
Other metabolic derangements which may contribute to the development of cancer cachexia and potentially be targets for interventions to prevent or reverse weight loss include elevations of basal metabolic rate, hypermetabolism, and hypogonadism. The following review will highlight the recent studies examining the contribution of hypermetabolism and hypogonadism to cachexia in cancer patients and examine the interventions targeted at correcting these metabolic derangements in order to promote weight gain.
Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to Rony Dev, Unit 1414, Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA. Tel: +1 713 745 8146; fax: +1 713 792 6092; e-mail: rdev@mdander son.org Curr Opin Support Palliat Care 2014, 8:279–285 DOI:10.1097/SPC.0000000000000061
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KEY POINTS Elevated resting energy expenditure, hypermetabolism, and hypogonadism, in male patients, may contribute to the development of cancer cachexia. The frequency of hypermetabolism is variable in cancer patients and can only be accurately identified using measurements by indirect calorimetry. Hypermetabolism in cancer patients appears to be dependent on the histology and stage of tumor, the presence of an acute inflammatory response, and may decrease after patients receive chemotherapy or radiation treatment. In male cancer patients, hypogonadism, as a result of chemotherapy, radiation treatment, or opioid therapy for chronic pain, is also frequently noted and associated with anorexia and weight loss.
RESTING ENERGY EXPENDITURE AND HYPERMETABOLISM Hypermetabolism is a physiological state characterized by an increase in the body’s basal metabolic rate, resting energy expenditure (REE), which frequently occurs as a consequence of significant injury such as during a febrile state, infection, hyperthyroidism, severe burns, multiple traumas, and chronic exposure to steroids. Total energy expenditure (TEE) is the sum of several variables, including the thermic cost of nutritional intake, the energy required for physical activity, and the basal metabolic rate (REE) [7]. REE is believed to constitute the majority, 60–80%, of TEE [8] and is proportional to the lean body mass (LBM). Accurate assessments of energy requirements are utilized to provide caloric recommendations by the dieticians, prevent underfeeding, which can result in weight loss and cachexia, or overfeeding, which can lead to metabolic complications such as hyperglycemia, hepatic dysfunction, azotemia, and respiratory distress in critically ill patients [9]. Measurement of REE by indirect calorimetry is the most accurate method of determining the energy requirements [10], but is time consuming. Prediction equations, such as the Harris–Benedict equation, have been developed to estimate an individual’s REE; however, studies of the Harris–Benedict and other prediction equations report that they are not the best reference and may overestimate REE in healthy individuals [11]. In pancreatic cancer patients, a recent pilot study reported the limitations of prediction equations when compared with the actual measurements of REE by indirect calorimetry [12]. 280
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CANCER AND RESTING ENERGY EXPENDITURE Hypermetabolism has been defined as measured REE (mREE) greater than 110% of predicted REE (pREE) based on the Harris–Benedict equation (some studies REE >115%), whereas a hypometabolic state has been defined as mREE less than 90% of pREE. Studies have reported a wide variation in the presence of hypermetabolism in cancer patients. In a study of 200 heterogeneous hospitalized cancer patients, predominantly gastrointestinal tumors, 26% of patients were hypermetabolic and 33% were hypometabolic [13]. Hypermetabolism was linked with a longer duration of disease, but not associated with age, height, weight, sex, nutritional status, or tumor burden [13]. In a study of 297 unselected cancer patients with solid tumors either with a local or distant lymph node involvement and a prognosis of greater than 6 months, roughly 49% of patients were classified as hypermetabolic and no difference was reported in the amount of caloric intake, including the proportion of dietary protein, carbohydrate, and fat, between hypermetabolic and normometabolic patients [14]. However, in hypermetabolic cancer patients, the mean dietary caloric intake was inadequate to maintain energy balance [14]. The authors of the study hypothesized that cancer cachexia may result from an ‘uncoupling of food intake to energy expenditure’. Other groups have also confirmed a significant proportion of cancer patients to have hypermetabolism [14,15] and noted it to be independent of the nutritional status. In addition, the effect of anticancer therapy on REE has also been studied and no effect was noted in a mixed population of cancer patients who received either chemotherapy or radiation treatment [16]. Recent studies examining mREE include a large study conducted in China which examined 714 newly diagnosed cancer patients – 150 esophageal, 154 gastric, 148 colorectal, 128 pancreatic, and 134 nonsmall cell lung cancer (NSCLC) – compared with 642 healthy control individuals and reported that all cancer types, with the exception of colorectal cancer, had significantly elevated mREE/pREE and mREE adjusted for fat-free mass (mREE/FFM) [17]. Also, cancer patients with stage IV disease, longer duration of disease, and history of weight loss had higher mREE and mREE/FFM, whereas presence of liver metastasis did not influence mREE [17]. In addition, all cancer types, with the exception of colorectal cancer, had increased oxidation of fats as opposed to carbohydrates, which was correlated with elevated mREE [17]. In 2012, researchers published a study of REE in patients with newly diagnosed urological cancers. Volume 8 Number 3 September 2014
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Of all the 122 cancer patients, 50% were noted to by hypermetabolic, and patients with kidney or adrenal cancer had significantly higher mREE/FFM than control individuals, whereas patients with bladder cancer showed no difference [18 ]. In the same study, cancer patients with stage IV disease had higher mREE/FFM, and early stages (I and II) had increased fat oxidation as opposed to carbohydrates, whereas late stages (III and IV) had increased utilization of carbohydrates [18 ].
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mREE [27 ]. The authors hypothesized that reduced energy intake in pancreatic cancer patients resulted in decreased REE.
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RESTING ENERGY EXPENDITURE IN GASTROINTESTINAL MALIGNANCIES In patients with various gastrointestinal malignancies, variable degrees of metabolism have been reported; pancreatic and hepatobiliary tumors being predominantly hypometabolic; gastric cancer patients predominantly hypermetabolic; and colorectal and esophageal malignancies were noted to be evenly distributed [19]. In a study of 101 colorectal cancer patients which evaluated mREE before and after the treatment, mREE was noted to be higher in the later stages (III and IV), poorly or undifferentiated histology, when there was poor response to radiotherapy and was not significantly affected by the nutritional variables [20]. On the other hand, a study of newly diagnosed population of patients with either gastric or colorectal cancer, compared with either healthy controls or patients with nonmalignant gastrointestinal cancer, reported mREE, percentage of hypermetabolism or hypometabolism, was not significantly different from the control individuals and did not differ with respect to weight loss (adjusted for FFM), cancer stage, or presence of liver metastasis [21]. In the studies examining patients with esophageal cancer, a various degree of hypermetabolism have also been noted [22–24]. Of note, black patients with esophageal cancer were noted to have lower mREE, but when corrected for body composition, FFM, no changes were noted in REE [22]. In a recent study of male patients newly diagnosed with esophageal cancer, mREE and mREE/FFM were significantly higher than healthy control individuals and was associated with weight loss, higher C-reactive protein (CRP) and IL-6 levels, and lower prealbumin and albumin levels [25 ]. In pancreatic cancer patients, research has shown elevated mREE, compared with a healthy control population, was significantly greater in patients with an acute-phase response (CRP >10 mg/l) [26]. However, in a recent study of 45 pancreatic cancer patients, when compared with 75 healthy individuals, reported significant decrease in energy intake, reduced body fat percentage and LBM, and lower &
RESTING ENERGY EXPENDITURE IN PATIENTS WITH LUNG CANCER AND HEAD AND NECK MALIGNANCIES In a study examining 33 matched patients with either small cell lung cancer (SCLC), NSCLC, or healthy controls, mREE when adjusted for FFM was significantly higher in SCLC than those with NSCLC, and both groups had elevated mREE when compared with healthy individuals [28]. Of note, in NSCLC, the FFM accounted for greater variation in mREE than fat mass, whereas SCLC patients’ mREE correlated to a less degree with FFM and more with fat mass, which the authors suggest a dependence on fat metabolism for SCLC patients [28]. Other groups have examined nonmetastatic (stages IA to IIIB) NSCLC and noted elevated mREE/FFM regardless of whether or not the patient had ongoing weight loss [29]. In addition, hypermetabolic NSCLC patients were reported to have decreased REE after surgical resection of the tumor [30]. In head and neck malignancies, preliminary studies showed conflicting results regarding REE. Before commencement of radiotherapy, one study reported increased mREE relative to what was predicted [31], whereas another group reported no difference [32]; however, both studies showed elevated mREE adjusted for FFM after radiation therapy. Alternatively, another group reported decreased mREE/FFM after radiation therapy for head and neck cancer patients [33]. In a recent study of 71 patients with recently diagnosed nonmetastatic head and neck cancer patients, mREE and mREE/FFM were not significantly different from that of matched control individuals, and decreased during and after radiotherapy [34 ]. It was also noted that the relative change in mREE adjusted for FFM initially decreased after the start of radiotherapy, recovered to some degree at the end of treatment and eventually decreased relative to the baseline [34 ]. The authors hypothesized that the initial decrease of mREE/FFM resulted from diminished caloric intake, the subsequent rise in mREE/ FFM because of inflammation as a result of mucositis, and eventually mREE was reduced compared with baseline several months after treatment. &
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TREATMENTS WHICH IMPACT RESTING ENERGY EXPENDITURE IN CANCER PATIENTS Effective treatment options for cancer patients with cachexia are limited. Interventions directed at
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decreasing REE in cancer patients have the potential to result in weight gain. Promising treatments which modulate REE include nonsteroidal antiinflammatory agents, polyunsaturated fatty acids, and beta-blockers. In a small preliminary study of 16 cachectic patients with pancreatic cancer, mREE was reported to be elevated when compared with matched healthy control individuals, and the administration of a 7-day course of ibuprofen (1200 mg) resulted in decreased CRP and decreased mREE compared with placebo [35]. Polyunsaturated fatty acids, fish oil, has also been studied and shown to stabilize REE resulting in weight gain [36], decrease mREE/FFM, and normalized the energy cost of feeding when incorporated in a nutritional supplement in pancreatic cancer patients with weight loss [37]. Propranolol has also been evaluated and treatment in conjunction with intralipid infusion resulted in decreased REE in elderly malnourished cancer patients [38]. Recently, a cyclooxygenase-2 inhibitor, celecoxib, has been reported to reduce mREE and improve the symptoms of cancer cachexia alone in a mixed population of advanced cancers [39], or in combination with other agents in patients with advanced gynecological cancers [40 ]. Of note, in these studies, REE was measured using a handheld indirect calorimeter which underestimates REE and may not be as accurate as traditional indirect calorimetry [41]. In summary, a wide variation in the frequency of hypermetabolism has been reported in patients with cancer. Prediction equations, such as Harris–Benedict equation, tend to be inaccurate and underestimate REE in cancer patients. REE fluctuates during the trajectory of illness in cancer patient and is more likely to be elevated, hypermetabolic, in certain types and advancing stages of cancers, associated with acute inflammatory response, and can decrease as a result of chemotherapy or radiation treatment. Hypermetabolism may lead to unmet caloric needs which can lead to weight loss or cachexia. Interventions, such as non-steroidal anti-inflammatory drugs or polyunsaturated fatty acids, have the potential to decrease REE and possibly prevent or reverse cachexia. The clinical utility of measuring REE is unclear but may identify cancer patients who are hypermetabolic and have no evidence of weight loss as potential patients at increased risk for weight loss, and eligible for interventions earlier in the disease trajectory in order to reduce REE and prevent cachexia. &
patients have been reported to be deficient in testosterone levels [42], which is significantly greater than the general male population. The cause of gonadal dysfunction in cancer patients can be secondary to a chronic inflammatory state, treatment with chemotherapy and radiotherapy, or as a side-effect of medications such as opioids, corticosteroids, and megestrol acetate. In patients with prostate cancer treated with androgen-deprivation therapy, treatment may result in side-effects including metabolic derangements, sexual side-effects, and alterations in body composition [43]. Side-effects of long-term hormonal blockade have been documented and include muscle atrophy, diminished strength, increased body fat, and osteoporosis [44]. In one study, hormonal ablation in male patients with prostate cancer resulted in loss of 2% LBM over 6 months [45]. Gonadal dysfunction can be classified as either primary or secondary. Primary hypogonadism is a consequence of testicular failure which may be due to chemotherapy or radiation treatment. Secondary hypogonadism is due to either hypothalamic or pituitary dysfunction and can result from chronic opioid use. In advanced cancer patients, it may be difficult to classify the underlying physiologic process causing low testosterone which may have multiple causes and be a combination of both primary and secondary causes.
SCREENING FOR HYPOGONADISM IN CANCER PATIENTS The lower limit of testosterone often differs depending on the laboratory reference values, ranging from 280 to 300 ng/dl (9.8–10.4 nmol/l). Screening for gonadal dysfunction can be challenging in frail cancer patients secondary to the variations in laboratory assays and reference values which differ by age. Also, testosterone measurements must be checked in the morning secondary to diurnal variation, levels may decrease by 70% at 8 p.m. [46], and must be repeated to confirm gonadal dysfunction. In patients with advanced cancer with poor sleeping patterns, testosterone values may not peak in the morning giving falsely low values. In addition, in chronic illnesses, such as cancer, sex-hormonebinding globulin will be increased and serum total testosterone values will be falsely elevated, and it may be prudent to screen cancer patients with free or bioavailable testosterone levels [47].
HYPOGONADISM IN CANCER
SYMPTOM BURDEN IN CANCER PATIENTS WITH GONADAL DYSFUNCTION
Hypogonadism, low testosterone, is common in male cancer patients. Roughly two-thirds of cancer
In the studies of cancer patients, low testosterone has been shown to be associated with a variety of
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symptoms, including anorexia [48], mood abnormalities, and insomnia [49]. The symptom burden of low testosterone may result in decreased caloric intake, resulting in weight loss. In addition, low testosterone has been shown to be associated with evidence of chronic inflammation, weight loss, and poor performance status [50]. In a recent study of 131 consecutive mixed population of male cancer patients, low testosterone, total, free, and bioavailable, was significantly associated with fatigue, weight loss, poor performance status, opioid use, elevated CRP, and low albumin [51 ]. In a study of patients with unresectable pancreatic cancer, 73% of male patients were significantly more likely to be hypogonadic, when using calculated free testosterone values, compared with only 40% of healthy individuals; testosterone values also correlated inversely with the marker of inflammatory response and weight loss [52]. Of note, in both studies, hypogonadism was noted to be associated with a poorer prognosis. A recent review, however, reported no definitive relationship between nutrition and quality of life in advanced cancer patients with hypogonadism [53], and more studies are needed to examine the effect of low testosterone on caloric intake and body composition in patients with advanced cancer.
In addition, the physiological effects of testosterone and its bioactive metabolites, estrogen and dihydrotestosterone, are complex, and the relationship between these hormones and body composition needs further studies in cancer patients. In healthy patients, a study of the relative contributions of androgens and estrogens to body composition reported that LBM and muscle strength were androgen dependent, whereas fat mass correlated with estrogen levels [56 ]. Testosterone derivatives, oxandrolone and nandrolone, have been studied in patients with HIV and AIDs and chronic obstructive pulmonary disease, and reported improvements in body composition, increased LBM, but no placebocontrolled studies on cancer patients have been published in peer-reviewed journals. In summary, low testosterone is common in male patients with cancer and can be due to treatment with chemotherapy, radiation, or chronic opioid use. Hypogonadism is associated with increased symptom burden in cancer patients and accompanied by anorexia and weight loss. Replacement of testosterone in hypogonadic male patients with cancer has the potential to preserve or increase LBM and more research is needed.
TREATMENT OF HYPOGONADISM IN MALE CANCER PATIENTS
Cancer patients may develop weight loss, cachexia, which can be distressing for both patients and their family. Cancer cachexia, the loss of skeletal muscle with or without the loss of fat, is a multifactorial syndrome (Fig. 1). Elevated resting energy
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Currently, there are no clear guidelines for testosterone supplementation in hypogonadic patients with cancer. The Endocrine Society has made recommendations of testosterone supplementation in chronic illness such as HIV and chronic obstructive pulmonary disease on steroid therapy [54], but no guidelines exist for cancer patients. In addition, cancer patients often need opioid therapy to treat chronic pain which can result in low testosterone. Hypogonadic cancer patients receiving opioid therapy are potential candidates for supplementation with testosterone. Recently, a small prospective study has been conducted on the symptomatic benefits of replacing testosterone in male patients with advanced cancer with hypogonadism. The randomized placebo-controlled trial reported improvements in performance status at 4 weeks and decreased fatigue by day 72 in the group receiving testosterone replacement [55 ]; however, no effects on body composition were evaluated. Improvements in LBM and muscle strength may take several weeks to months to be realized, and studies screening cancer patients earlier in the disease trajectory with testosterone supplementation, if indicated, are needed to see the benefits with respect to body composition, LBM.
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CONCLUSION
Tumor
Host
Neurohormonal dysfunction Metabolic derangements Proinflammatory cytokines Basal metabolic rate
Testosterone Ghrelin Insulin Autonomic dysfunction
Cancer cachexia Lean body mass Body fat
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Symptom burden Functional status Survival Quality of life
Anorexia Fatigue Early satiety Depression Family distress
FIGURE 1. The underlying mechanisms of cancer cachexia.
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expenditure, hypermetabolism, as well as hypogonadism may contribute to the development of cancer cachexia. The frequency of hypermetabolism is variable in cancer patients and can only be accurately identified by measuring with an indirect calorimeter. Hypermetabolism appears to be dependent on the histology and stage of tumor, the presence of an acute inflammatory response, and may decrease after patients receive chemotherapy or radiation treatment. In male cancer patients, hypogonadism, as a result of chemotherapy, radiation treatment, or opioid therapy for chronic pain, is also frequently noted and associated with anorexia and weight loss. Treatments directed at reducing the basal metabolic rate and supplementation of testosterone in hypogonadic male patients may have the potential to improve LBM, but more research is needed. Acknowledgements Funding sources: None. Conflicts of interest There are no conflicts of interest.
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49. Rajagopal A, Vassilopoulou-Sellin R, Palmer JL, et al. Hypogonadism and sexual dysfunction in male cancer survivors receiving chronic opioid therapy. J Pain Symptom Manag 2003; 26:1055–1061. 50. Burney BO, Hayes TG, Smiechowska J, et al. Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cancer and relationship with cachexia. J Clin Endocrinol Metab 2012; 97:E700–E709. 51. Dev R, Hui D, Del Fabbro E, et al. Association between hypogonadism, & symptom burden, and survival in male patients with advanced cancer. Cancer 2014; 120:1586–1593. In a population of various advanced cancers, this study reports the association between total testosterone and free testosterone with symptoms and poor survival. 52. Skipworth RJ, Moses AG, Sangster K, et al. Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer. Support Care Cancer 2011; 19:391–401. 53. Vigano A, Piccioni M, Trutschnigg B, et al. Male hypogonadism associated with advanced cancer: a systematic review. Lancet Oncol 2010; 11:679– 684. 54. Bhasin S, Cunningham GR, Hayes FJ, et al. Testosterone therapy in men with androgen deficiency syndromes: an Endocrine Society Clinical Practice Guideline. J Clin Endocrinol Metab 2010; 95:2536–2559. 55. Del Fabbro E, Garcia JM, Dev R, et al. Testosterone replacement for fatigue in & hypogonadal ambulatory males with advanced cancer: a preliminary doubleblind placebo-controlled trial. Support Care Cancer 2013; 21:2599–2607. A small randomized controlled trial evaluating the symptomatic benefits of testosterone replacement in hypogonadic male cancer patients. 56. Finkelstein JS, Lee H, Burnett-Bowie SA, et al. Gonadal steroids and body && composition, strength, and sexual function in men. N Engl J Med 2013; 369:1011–1122. A novel study in healthy men which reported the effects of androgen and estrogen deficiency on body composition and sexual function.
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The assessment and management of cancer cachexia: hypogonadism and hypermetabolism among supportive and palliative care patients Rony Dev
Purpose of review To update the healthcare providers on the potential contribution of increased basal metabolic rate, hypermetabolism, and low testosterone in the development of weight loss in cancer patients. Recent findings Cancer cachexia, the loss of skeletal muscle with or without the loss of fat, is a multifactorial syndrome. A wide variation in the frequency of hypermetabolism exists in cancer patients and can only be accurately identified by an indirect calorimeter. The frequency of hypermetabolism increases depending on the histology and stage of tumor, associated with the presence of an acute inflammatory response, and is often accompanied by weight loss. Hypogonadism, as a result of chemotherapy, radiation treatment, or the use of opioids to treat chronic pain, is frequently noted in male cancer patients and has been reported to be also associated with anorexia and weight loss. Summary Cancer patients may develop weight loss, cachexia, which can be distressing for both patients and their family. Treatments directed at reducing the basal metabolic rate and supplementation of testosterone in hypogonadic male patients may have the potential to improve lean body mass, but more research is needed. Keywords cancer cachexia, hypermetabolism, hypogonadism, palliative care, symptom management
INTRODUCTION In patients with cancer, malnutrition is a common occurrence and its frequency varies ranging from 8 to 84% [1]. In the past, cancer cachexia has been defined as a total involuntary weight loss of greater than 10% of preillness body weight [2]. Recently, in 2010, an international panel of experts have agreed to the following definition, ‘Cachexia is a multifactorial syndrome defined by an ongoing loss of skeletal muscle mass (with or without loss of fat mass) that cannot be fully reversed by conventional nutritional support and leads to progressive functional impairment’ [3]. The pathophysiology of cancer cachexia is complex and characterized by reduced nutritional intake, systemic inflammation, decreased muscle mass and strength, and symptoms of fatigue [4]. Researchers have highlighted that decreased nutritional intake alone does not fully account for weight loss [5], and unlike starvation, cancer cachexia is not reversed by adequate caloric supplementation [6].
Other metabolic derangements which may contribute to the development of cancer cachexia and potentially be targets for interventions to prevent or reverse weight loss include elevations of basal metabolic rate, hypermetabolism, and hypogonadism. The following review will highlight the recent studies examining the contribution of hypermetabolism and hypogonadism to cachexia in cancer patients and examine the interventions targeted at correcting these metabolic derangements in order to promote weight gain.
Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA Correspondence to Rony Dev, Unit 1414, Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, Texas, USA. Tel: +1 713 745 8146; fax: +1 713 792 6092; e-mail: rdev@mdander son.org Curr Opin Support Palliat Care 2014, 8:279–285 DOI:10.1097/SPC.0000000000000061
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KEY POINTS Elevated resting energy expenditure, hypermetabolism, and hypogonadism, in male patients, may contribute to the development of cancer cachexia. The frequency of hypermetabolism is variable in cancer patients and can only be accurately identified using measurements by indirect calorimetry. Hypermetabolism in cancer patients appears to be dependent on the histology and stage of tumor, the presence of an acute inflammatory response, and may decrease after patients receive chemotherapy or radiation treatment. In male cancer patients, hypogonadism, as a result of chemotherapy, radiation treatment, or opioid therapy for chronic pain, is also frequently noted and associated with anorexia and weight loss.
RESTING ENERGY EXPENDITURE AND HYPERMETABOLISM Hypermetabolism is a physiological state characterized by an increase in the body’s basal metabolic rate, resting energy expenditure (REE), which frequently occurs as a consequence of significant injury such as during a febrile state, infection, hyperthyroidism, severe burns, multiple traumas, and chronic exposure to steroids. Total energy expenditure (TEE) is the sum of several variables, including the thermic cost of nutritional intake, the energy required for physical activity, and the basal metabolic rate (REE) [7]. REE is believed to constitute the majority, 60–80%, of TEE [8] and is proportional to the lean body mass (LBM). Accurate assessments of energy requirements are utilized to provide caloric recommendations by the dieticians, prevent underfeeding, which can result in weight loss and cachexia, or overfeeding, which can lead to metabolic complications such as hyperglycemia, hepatic dysfunction, azotemia, and respiratory distress in critically ill patients [9]. Measurement of REE by indirect calorimetry is the most accurate method of determining the energy requirements [10], but is time consuming. Prediction equations, such as the Harris–Benedict equation, have been developed to estimate an individual’s REE; however, studies of the Harris–Benedict and other prediction equations report that they are not the best reference and may overestimate REE in healthy individuals [11]. In pancreatic cancer patients, a recent pilot study reported the limitations of prediction equations when compared with the actual measurements of REE by indirect calorimetry [12]. 280
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CANCER AND RESTING ENERGY EXPENDITURE Hypermetabolism has been defined as measured REE (mREE) greater than 110% of predicted REE (pREE) based on the Harris–Benedict equation (some studies REE >115%), whereas a hypometabolic state has been defined as mREE less than 90% of pREE. Studies have reported a wide variation in the presence of hypermetabolism in cancer patients. In a study of 200 heterogeneous hospitalized cancer patients, predominantly gastrointestinal tumors, 26% of patients were hypermetabolic and 33% were hypometabolic [13]. Hypermetabolism was linked with a longer duration of disease, but not associated with age, height, weight, sex, nutritional status, or tumor burden [13]. In a study of 297 unselected cancer patients with solid tumors either with a local or distant lymph node involvement and a prognosis of greater than 6 months, roughly 49% of patients were classified as hypermetabolic and no difference was reported in the amount of caloric intake, including the proportion of dietary protein, carbohydrate, and fat, between hypermetabolic and normometabolic patients [14]. However, in hypermetabolic cancer patients, the mean dietary caloric intake was inadequate to maintain energy balance [14]. The authors of the study hypothesized that cancer cachexia may result from an ‘uncoupling of food intake to energy expenditure’. Other groups have also confirmed a significant proportion of cancer patients to have hypermetabolism [14,15] and noted it to be independent of the nutritional status. In addition, the effect of anticancer therapy on REE has also been studied and no effect was noted in a mixed population of cancer patients who received either chemotherapy or radiation treatment [16]. Recent studies examining mREE include a large study conducted in China which examined 714 newly diagnosed cancer patients – 150 esophageal, 154 gastric, 148 colorectal, 128 pancreatic, and 134 nonsmall cell lung cancer (NSCLC) – compared with 642 healthy control individuals and reported that all cancer types, with the exception of colorectal cancer, had significantly elevated mREE/pREE and mREE adjusted for fat-free mass (mREE/FFM) [17]. Also, cancer patients with stage IV disease, longer duration of disease, and history of weight loss had higher mREE and mREE/FFM, whereas presence of liver metastasis did not influence mREE [17]. In addition, all cancer types, with the exception of colorectal cancer, had increased oxidation of fats as opposed to carbohydrates, which was correlated with elevated mREE [17]. In 2012, researchers published a study of REE in patients with newly diagnosed urological cancers. Volume 8 Number 3 September 2014
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Of all the 122 cancer patients, 50% were noted to by hypermetabolic, and patients with kidney or adrenal cancer had significantly higher mREE/FFM than control individuals, whereas patients with bladder cancer showed no difference [18 ]. In the same study, cancer patients with stage IV disease had higher mREE/FFM, and early stages (I and II) had increased fat oxidation as opposed to carbohydrates, whereas late stages (III and IV) had increased utilization of carbohydrates [18 ].
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mREE [27 ]. The authors hypothesized that reduced energy intake in pancreatic cancer patients resulted in decreased REE.
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RESTING ENERGY EXPENDITURE IN GASTROINTESTINAL MALIGNANCIES In patients with various gastrointestinal malignancies, variable degrees of metabolism have been reported; pancreatic and hepatobiliary tumors being predominantly hypometabolic; gastric cancer patients predominantly hypermetabolic; and colorectal and esophageal malignancies were noted to be evenly distributed [19]. In a study of 101 colorectal cancer patients which evaluated mREE before and after the treatment, mREE was noted to be higher in the later stages (III and IV), poorly or undifferentiated histology, when there was poor response to radiotherapy and was not significantly affected by the nutritional variables [20]. On the other hand, a study of newly diagnosed population of patients with either gastric or colorectal cancer, compared with either healthy controls or patients with nonmalignant gastrointestinal cancer, reported mREE, percentage of hypermetabolism or hypometabolism, was not significantly different from the control individuals and did not differ with respect to weight loss (adjusted for FFM), cancer stage, or presence of liver metastasis [21]. In the studies examining patients with esophageal cancer, a various degree of hypermetabolism have also been noted [22–24]. Of note, black patients with esophageal cancer were noted to have lower mREE, but when corrected for body composition, FFM, no changes were noted in REE [22]. In a recent study of male patients newly diagnosed with esophageal cancer, mREE and mREE/FFM were significantly higher than healthy control individuals and was associated with weight loss, higher C-reactive protein (CRP) and IL-6 levels, and lower prealbumin and albumin levels [25 ]. In pancreatic cancer patients, research has shown elevated mREE, compared with a healthy control population, was significantly greater in patients with an acute-phase response (CRP >10 mg/l) [26]. However, in a recent study of 45 pancreatic cancer patients, when compared with 75 healthy individuals, reported significant decrease in energy intake, reduced body fat percentage and LBM, and lower &
RESTING ENERGY EXPENDITURE IN PATIENTS WITH LUNG CANCER AND HEAD AND NECK MALIGNANCIES In a study examining 33 matched patients with either small cell lung cancer (SCLC), NSCLC, or healthy controls, mREE when adjusted for FFM was significantly higher in SCLC than those with NSCLC, and both groups had elevated mREE when compared with healthy individuals [28]. Of note, in NSCLC, the FFM accounted for greater variation in mREE than fat mass, whereas SCLC patients’ mREE correlated to a less degree with FFM and more with fat mass, which the authors suggest a dependence on fat metabolism for SCLC patients [28]. Other groups have examined nonmetastatic (stages IA to IIIB) NSCLC and noted elevated mREE/FFM regardless of whether or not the patient had ongoing weight loss [29]. In addition, hypermetabolic NSCLC patients were reported to have decreased REE after surgical resection of the tumor [30]. In head and neck malignancies, preliminary studies showed conflicting results regarding REE. Before commencement of radiotherapy, one study reported increased mREE relative to what was predicted [31], whereas another group reported no difference [32]; however, both studies showed elevated mREE adjusted for FFM after radiation therapy. Alternatively, another group reported decreased mREE/FFM after radiation therapy for head and neck cancer patients [33]. In a recent study of 71 patients with recently diagnosed nonmetastatic head and neck cancer patients, mREE and mREE/FFM were not significantly different from that of matched control individuals, and decreased during and after radiotherapy [34 ]. It was also noted that the relative change in mREE adjusted for FFM initially decreased after the start of radiotherapy, recovered to some degree at the end of treatment and eventually decreased relative to the baseline [34 ]. The authors hypothesized that the initial decrease of mREE/FFM resulted from diminished caloric intake, the subsequent rise in mREE/ FFM because of inflammation as a result of mucositis, and eventually mREE was reduced compared with baseline several months after treatment. &
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TREATMENTS WHICH IMPACT RESTING ENERGY EXPENDITURE IN CANCER PATIENTS Effective treatment options for cancer patients with cachexia are limited. Interventions directed at
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decreasing REE in cancer patients have the potential to result in weight gain. Promising treatments which modulate REE include nonsteroidal antiinflammatory agents, polyunsaturated fatty acids, and beta-blockers. In a small preliminary study of 16 cachectic patients with pancreatic cancer, mREE was reported to be elevated when compared with matched healthy control individuals, and the administration of a 7-day course of ibuprofen (1200 mg) resulted in decreased CRP and decreased mREE compared with placebo [35]. Polyunsaturated fatty acids, fish oil, has also been studied and shown to stabilize REE resulting in weight gain [36], decrease mREE/FFM, and normalized the energy cost of feeding when incorporated in a nutritional supplement in pancreatic cancer patients with weight loss [37]. Propranolol has also been evaluated and treatment in conjunction with intralipid infusion resulted in decreased REE in elderly malnourished cancer patients [38]. Recently, a cyclooxygenase-2 inhibitor, celecoxib, has been reported to reduce mREE and improve the symptoms of cancer cachexia alone in a mixed population of advanced cancers [39], or in combination with other agents in patients with advanced gynecological cancers [40 ]. Of note, in these studies, REE was measured using a handheld indirect calorimeter which underestimates REE and may not be as accurate as traditional indirect calorimetry [41]. In summary, a wide variation in the frequency of hypermetabolism has been reported in patients with cancer. Prediction equations, such as Harris–Benedict equation, tend to be inaccurate and underestimate REE in cancer patients. REE fluctuates during the trajectory of illness in cancer patient and is more likely to be elevated, hypermetabolic, in certain types and advancing stages of cancers, associated with acute inflammatory response, and can decrease as a result of chemotherapy or radiation treatment. Hypermetabolism may lead to unmet caloric needs which can lead to weight loss or cachexia. Interventions, such as non-steroidal anti-inflammatory drugs or polyunsaturated fatty acids, have the potential to decrease REE and possibly prevent or reverse cachexia. The clinical utility of measuring REE is unclear but may identify cancer patients who are hypermetabolic and have no evidence of weight loss as potential patients at increased risk for weight loss, and eligible for interventions earlier in the disease trajectory in order to reduce REE and prevent cachexia. &
patients have been reported to be deficient in testosterone levels [42], which is significantly greater than the general male population. The cause of gonadal dysfunction in cancer patients can be secondary to a chronic inflammatory state, treatment with chemotherapy and radiotherapy, or as a side-effect of medications such as opioids, corticosteroids, and megestrol acetate. In patients with prostate cancer treated with androgen-deprivation therapy, treatment may result in side-effects including metabolic derangements, sexual side-effects, and alterations in body composition [43]. Side-effects of long-term hormonal blockade have been documented and include muscle atrophy, diminished strength, increased body fat, and osteoporosis [44]. In one study, hormonal ablation in male patients with prostate cancer resulted in loss of 2% LBM over 6 months [45]. Gonadal dysfunction can be classified as either primary or secondary. Primary hypogonadism is a consequence of testicular failure which may be due to chemotherapy or radiation treatment. Secondary hypogonadism is due to either hypothalamic or pituitary dysfunction and can result from chronic opioid use. In advanced cancer patients, it may be difficult to classify the underlying physiologic process causing low testosterone which may have multiple causes and be a combination of both primary and secondary causes.
SCREENING FOR HYPOGONADISM IN CANCER PATIENTS The lower limit of testosterone often differs depending on the laboratory reference values, ranging from 280 to 300 ng/dl (9.8–10.4 nmol/l). Screening for gonadal dysfunction can be challenging in frail cancer patients secondary to the variations in laboratory assays and reference values which differ by age. Also, testosterone measurements must be checked in the morning secondary to diurnal variation, levels may decrease by 70% at 8 p.m. [46], and must be repeated to confirm gonadal dysfunction. In patients with advanced cancer with poor sleeping patterns, testosterone values may not peak in the morning giving falsely low values. In addition, in chronic illnesses, such as cancer, sex-hormonebinding globulin will be increased and serum total testosterone values will be falsely elevated, and it may be prudent to screen cancer patients with free or bioavailable testosterone levels [47].
HYPOGONADISM IN CANCER
SYMPTOM BURDEN IN CANCER PATIENTS WITH GONADAL DYSFUNCTION
Hypogonadism, low testosterone, is common in male cancer patients. Roughly two-thirds of cancer
In the studies of cancer patients, low testosterone has been shown to be associated with a variety of
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symptoms, including anorexia [48], mood abnormalities, and insomnia [49]. The symptom burden of low testosterone may result in decreased caloric intake, resulting in weight loss. In addition, low testosterone has been shown to be associated with evidence of chronic inflammation, weight loss, and poor performance status [50]. In a recent study of 131 consecutive mixed population of male cancer patients, low testosterone, total, free, and bioavailable, was significantly associated with fatigue, weight loss, poor performance status, opioid use, elevated CRP, and low albumin [51 ]. In a study of patients with unresectable pancreatic cancer, 73% of male patients were significantly more likely to be hypogonadic, when using calculated free testosterone values, compared with only 40% of healthy individuals; testosterone values also correlated inversely with the marker of inflammatory response and weight loss [52]. Of note, in both studies, hypogonadism was noted to be associated with a poorer prognosis. A recent review, however, reported no definitive relationship between nutrition and quality of life in advanced cancer patients with hypogonadism [53], and more studies are needed to examine the effect of low testosterone on caloric intake and body composition in patients with advanced cancer.
In addition, the physiological effects of testosterone and its bioactive metabolites, estrogen and dihydrotestosterone, are complex, and the relationship between these hormones and body composition needs further studies in cancer patients. In healthy patients, a study of the relative contributions of androgens and estrogens to body composition reported that LBM and muscle strength were androgen dependent, whereas fat mass correlated with estrogen levels [56 ]. Testosterone derivatives, oxandrolone and nandrolone, have been studied in patients with HIV and AIDs and chronic obstructive pulmonary disease, and reported improvements in body composition, increased LBM, but no placebocontrolled studies on cancer patients have been published in peer-reviewed journals. In summary, low testosterone is common in male patients with cancer and can be due to treatment with chemotherapy, radiation, or chronic opioid use. Hypogonadism is associated with increased symptom burden in cancer patients and accompanied by anorexia and weight loss. Replacement of testosterone in hypogonadic male patients with cancer has the potential to preserve or increase LBM and more research is needed.
TREATMENT OF HYPOGONADISM IN MALE CANCER PATIENTS
Cancer patients may develop weight loss, cachexia, which can be distressing for both patients and their family. Cancer cachexia, the loss of skeletal muscle with or without the loss of fat, is a multifactorial syndrome (Fig. 1). Elevated resting energy
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Currently, there are no clear guidelines for testosterone supplementation in hypogonadic patients with cancer. The Endocrine Society has made recommendations of testosterone supplementation in chronic illness such as HIV and chronic obstructive pulmonary disease on steroid therapy [54], but no guidelines exist for cancer patients. In addition, cancer patients often need opioid therapy to treat chronic pain which can result in low testosterone. Hypogonadic cancer patients receiving opioid therapy are potential candidates for supplementation with testosterone. Recently, a small prospective study has been conducted on the symptomatic benefits of replacing testosterone in male patients with advanced cancer with hypogonadism. The randomized placebo-controlled trial reported improvements in performance status at 4 weeks and decreased fatigue by day 72 in the group receiving testosterone replacement [55 ]; however, no effects on body composition were evaluated. Improvements in LBM and muscle strength may take several weeks to months to be realized, and studies screening cancer patients earlier in the disease trajectory with testosterone supplementation, if indicated, are needed to see the benefits with respect to body composition, LBM.
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CONCLUSION
Tumor
Host
Neurohormonal dysfunction Metabolic derangements Proinflammatory cytokines Basal metabolic rate
Testosterone Ghrelin Insulin Autonomic dysfunction
Cancer cachexia Lean body mass Body fat
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Symptom burden Functional status Survival Quality of life
Anorexia Fatigue Early satiety Depression Family distress
FIGURE 1. The underlying mechanisms of cancer cachexia.
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expenditure, hypermetabolism, as well as hypogonadism may contribute to the development of cancer cachexia. The frequency of hypermetabolism is variable in cancer patients and can only be accurately identified by measuring with an indirect calorimeter. Hypermetabolism appears to be dependent on the histology and stage of tumor, the presence of an acute inflammatory response, and may decrease after patients receive chemotherapy or radiation treatment. In male cancer patients, hypogonadism, as a result of chemotherapy, radiation treatment, or opioid therapy for chronic pain, is also frequently noted and associated with anorexia and weight loss. Treatments directed at reducing the basal metabolic rate and supplementation of testosterone in hypogonadic male patients may have the potential to improve LBM, but more research is needed. Acknowledgements Funding sources: None. Conflicts of interest There are no conflicts of interest.
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