Steroid myopathy and rehabilitation in patients with cancer

Abstract

Steroids are broadly used in oncology, despite known adverse events such as glucocorticosteroid-induced myopathy (SM). To date there are no accepted guidelines on the diagnosis and treatment of SM. The purpose of this review is to provide up-to-date information regarding SM with emphasis on neuro-oncology and hematopoietic stem cell transplant patients, given they are at high risk of experiencing SM following routine treatment with steroids. Our work is a combination of a comprehensive narrative review regarding etiology, pathogenesis, incidence, clinical presentation and treatment options for SM and a scoping review on the exercise therapy for SM. We have identified 24 in vivo studies of different exercise modalities in the settings of glucocorticosteroid treatment. Twenty of 24 studies demonstrated decreased muscle catabolism with exercise training. Both endurance and resistance exercises at mild to moderate intensity were beneficial. The value of high-intensity activities remains questionable as it may worsen muscle atrophy. Rehabilitation interventions, along with pharmacologic and dietary considerations, may be beneficial in preventing or reversing SM. Potential adverse events of some of these interventions and expected caveats in translating findings in preclinical models to human settings warrant caution and demand controlled clinical studies.

INTRODUCTION

Glucocorticosteroids (GCs) are widely used in oncology practice, employed in both antineoplastic and supportive treatments. GCs are used to manage a variety of conditions, such as brain or spinal cord edema, pain (neuropathic and somatic), dyspnea, fatigue, and vomiting.¹ Systemic GCs are the accepted primary therapy for acute and chronic graft-versus-host disease (GVHD), a dreaded complication of allogeneic hematopoietic stem cell transplant (alloHSCT).² Long-term, or high-dose, GCs may result in a variety of undesired side effects. Among them, steroid myopathy (SM), was first documented by Harvey Cushing in 1932 as a part of Cushing’s syndrome, a disorder stemming from high endogenous cortisol level exposure. Similar to Cushing’s syndrome, patients with SM typically have progressive, painless, and symmetric muscle weakness that frequently involves respiratory musculature. Repetitive cycles of weakness and subsequent sedentary behavior result in a positive feedback loop that leads to accelerated overall physical deconditioning, limiting overall mobility and participation in activities of daily living (ADLs), and ultimately decreasing quality of life.

To our knowledge there are no accepted guidelines on the diagnosis of SM. Furthermore, there is a lack of high-quality evidence-based medicine guidelines to inform management strategies. The purpose of this review is to provide information on the current literature about this condition and potential therapeutic options and rehabilitation strategies to treat SM. We cover the etiological and pathological findings of SM. We discuss the symptoms and current techniques to detect and monitor the onset and progression of SM. Furthermore, we discuss the clinical considerations of SM in vulnerable adult and pediatric patients who require GCs as a part of their cancer care, including those with brain tumors and recipients of alloHSCT and their complications such as GVHD. Finally, we go over potential treatment strategies and provide a unique in-depth review of the available literature on exercise therapy for SM.

METHODS

Our work is a comprehensive narrative review regarding etiology, pathogenesis, incidence, clinical presentation and treatment options for SM and a scoping review on exercise therapy for SM. The search was performed on PubMed and OVID databases looking for articles in English with no restrictions placed on country or publication date. Search terms included the following words and their combinations: steroid myopathy, glucocorticoid-induced myopathy, rehabilitation, exercise therapy, brain tumors, graft versus host disease, pediatric. Relevant articles were also found by scanning the references of found articles (backward search) and locating newer articles that included the original cited paper (forward search). For the scoping review on the exercise therapy we have identified 24 in vivo studies^3-26 of different exercise modalities in the settings of GC treatment, of which 19 were performed in rodent models and 5 in humans. Information concerning the type and number of participants, exercise mode and intensity, timing of GC administration and the type of steroid used, and study findings was extracted from the articles. For comparison purposes we calculated percent difference in outcome measures between control and exercise groups, based on each individual study. A summary of the different exercise interventions and findings are listed in Table 1. Finally, we determined evidence to support exercise programs for treatment and prevention of SM from the five human studies as per Melnyk and Fineout-Overholt.²⁷

TABLE 1.

Impact of exercise on muscular function in steroid treatment settings.

	N	Mode	Intensity	Subject	Timing	Measure	Steroid	Resultρ
Horber 1985a4	12	Resistance	Exhaustion	Human	Ex after steroid	Strength†	Prednisone	+27X̄
Horber 1985b5	6	Resistance		Human	Ex after steroid	Strength†	Prednisone	+46X̄
Horber 19877	9	Resistance		Human	Ex after steroid	Strength†	Prednisone	+23X̄
Garrel 198810		Endurance	Moderate	Human	Ex before steroid	Protein breakdown	Prednisone	+13
Braith 19989	14	Resistance		Human	Ex after steroid	Strength†	Methylprednisolone, prednisone	+33X̄
Goldberg 19693		Overload		Rat	Simult	Muscle wt	Cortisone acetate	+31
Gardiner 19808	16	Resistance	Mild	Rat	Simult	Strength†	Triamcinolone	+26X̄
Hickson 198111	29	Endurance		Rat male	Ex before steroid	Muscle wt†	Cortisone acetate	Soleus +4–10 Plantaris +19–27 Gastroc +15–17
Seene 198222	20	Endurance		Rat	Ex before steroid	Myofibrillar protease activity	Dexamethasone	+32
Kurowski 19846	189	Overload		Rat	Simult	Muscle wt	Cortisone acetate	+27
Hickson 1984a12	61	Endurance		Rat female	Ex before steroid	Muscle wt†	Cortisone acetate	Gastroc + 8 Plantaris +11
Hickson 198614	24	Endurance		Rat female	Ex before steroid	Muscle wt†	Hydrocortisone acetate	Gastroc +25 Plantaris +33 Soleus +16
Hickson 1986b13		Overload		Rat	Ex before steroid	Muscle wt† plantaris	Cortisone acetate	0
Czerwinski 198724	36	Endurance		Rat	Ex before steroid	Muscle wt†	Cortisol acetate	Prevented 25% muscle loss in Gastroc and 60% muscle loss in plantaris
Czerwinski 198925	30–32	Endurance		Rat	Simult	Muscle wt† plantaris	Cortisol acetate	Prevented 30% of the muscle loss
Falduto 198919	12	Mixed endurance and sprints		Rat	Ex before steroid	Muscle wt† plantaris	Hydrocotisone	+29
Falduto 199017	14	Endurance		Rat	Simult	Muscle wt† plantaris	Cortisone acetate	+14
Falduto 199218		Mixed endurance and sprints		Rat	Ex after steroid	Muscle wt†	Cortisone acetate	Plantaris +20 Quadriceps +16
Falduto 1992b20	12	Mixed endurance and sprints		Rat	Ex before steroid	Muscle wt†	Cortisone acetate	Quadriceps +35 Soleus −0.7
Fimbel 199326	36	Endurance Sprinting		Rat	Ex before steroid	Muscle wt and protein content plantaris EDL, soleus, TA, Adductor longus	Hydrocortisone	−0.8 to 18%
Nakago 199923	10	Endurance	Mild	Rat	Simult	Fiber type cross section EDL, soleus	Hydrocortisone	+8
Ahtikoski 200421	36	Endurance Sprints		Rat	Simult	Muscle wt† EDL, Soleus, TA	Dexamethasone	All muscles showed improvement and after 10 days showed more improvement than after 3 days of exercise EDL: negative effect. TA: no change
Uchikawa 200816	32	Endurance	Moderate Strenuous	Rat	Simult	Muscle wt and muscle fiber cross sections	Triamcinolone	No change No change in muscle wt. Decrease in type I fibers in the Soleus and the type IIb fibers in the EDL∥
Barel 201015	15	Endurance		Rat	Ex before steroid	Running time capacity†	Dexamethasone	x TA = −0.1 Soleus +4 EDL +7

Abbreviations: Ex, exercise; EDL, extensor digitorum longus muscle; Ex before steroid, exercise started before steroid administration; Ex after steroid, steroid initiated before exercise, then concurrent administration of exercise and steroid; Gastroc, gastrocnemius muscle; N, number of participants in the study receiving a steroid and undergoing exercise and number of sedentary subjects receiving a steroid; Simult, simultaneous administration of steroid and exercise regimen; TA, tibialis anterior muscle; Timing, time at which steroids were administered.

^†Other anthropometric or biochemical measurements (muscle cross-section area, muscle/fat ratio, etc).

^X̄Averaged values.

^∥Exact values not reported, unable to calculate % change.

^ρCalculated percent difference between control and exercise groups, based on each individual study.

Steroid myopathy: Etiology and pathogenesis

GCs are a class of steroid hormones that exert a variety of systemic effects mostly through modulation of immune and metabolic functions in target cells. GCs bind to cytoplasmic glucocorticoid receptors (GCRs) and translocate to the nucleus, where they regulate target gene expression. GCRs have been functionally linked to the etiology of SM in preclinical settings, as GCR antagonist treatment prevents the onset of SM.²⁸ Mechanistically, SM is caused by a combination of catabolic and anti-anabolic effects of GCs on myofibers. GCs activate cellular proteolysis in target cells via the ubiquitin proteasome and the lysosomal systems, leading to muscle breakdown.^29,30 The antianabolic effects of GCs occur via a concomitant reduction of substrate availability (inhibition of transport of amino acids into the muscle cells) and direct inhibition of synthetic pathways such as mTOR/S6 kinase 1 pathway.³¹ GCs also induce the expression of myostatin, a negative regulator of skeletal muscle mass,³² and they also inhibit insulin-like growth factor 1 (IGF1)-stimulated protein synthesis.³³ Preclinical data show that muscle IGF1 overexpression and myostatin gene deletion in genetically-engineered models prevents SM, further supporting the implication of GCs in the etiology of SM.^34,35

Physiologically, SM leads to a preferential atrophy of type II muscle fibers, whereas type I fibers are affected to a lesser extent.^3,36-38 For instance, a study by Minetto et al. collected longitudinal biopsies from dominant vastus lateralis muscles in five healthy men before and after a 7-day course of dexamethasone (8 mg/day) and showed that even a short-term steroid treatment led to atrophy, decreased specific force, and decreased myosin concentration of both type I and type II fibers, although type II fibers were more profoundly affected.³⁷

Type I and type II fibers are evenly distributed in both proximal and distal extremity muscles (with the exception of some static muscles such as tibialis anterior, soleus, and abductor pollicis brevis).³⁹ Despite common clinical presentation of proximal weakness, qualitative and epidemiologic evidence suggests that SM affects both proximal and distal muscles.^40,41 The apparent predilection of SM for proximal muscle groups may be due to the limitations in the current diagnostic tools for SM and thus may reflect that proximal muscle defects are easier to detect clinically.

Incidence and risk factors

The reported incidence of SM in adult patients with cancer varies from 10% to 28%⁴² based on retrospective studies. Some prospective studies have reported up to a 60% incidence of proximal muscle weakness in upper and lower extremities and a 53% incidence of neck flexor weakness following GC treatment, with 67% of patients experiencing a substantial decline in respiratory function and 40% reporting weaknesses interfering with activities of daily living.¹ Similarly, in pediatric populations the incidence of SM ranges from “rare”⁴³ to 60% of patients, depending on the study⁴⁴; however, data in pediatric oncology patients are lacking.

Studies have shown that prednisone doses above 40 mg/day are associated with the onset of SM; however, lower doses have been reported to cause SM. For instance, a study of 60 adult patients with asthma treated with different GC doses showed that only 2.9% (1/35) of patients within the group taking <30 mg/day of prednisone had hip flexor weakness detected by Cybex dynamometer testing, as opposed to 48% (12/25) of patients taking ⩾40 mg/day of prednisone.⁴⁵

Given that SM incidence rises with cumulative GC exposure, certain conditions that increase the exposure to GCs, or that require the use of fluorinated GCs or strict treatment duration, are nonmodifiable SM risks.^1,41,45,46 Among the oncologic population, patients with central nervous system (CNS) tumors, hematologic malignancies and those requiring alloHSCT are at an increased risk for developing steroid myopathy as GC are almost inevitably a part of the treatment course.

Serum albumin concentration <2.5 g/dL is associated with increased frequency of prednisone side effects, including SM,⁴⁷ likely due to the steroid-binding properties of albumin, thus suggesting that nutritional optimization is a potential mitigation strategy for patients with SM. Alternatively, a recent study showed that patients with brain tumor who received phenytoin alongside GC had a lower risk of SM,⁴⁶ likely explained by the fact that the antiepileptic drug reduced oral bioavailability of dexamethasone from 84% to 33%.⁴⁸ One important modifiable SM risk factor is inactivity, which promotes skeletal muscle protein breakdown when combined with hypercortisolemia.⁴⁹

Clinical presentation and disease course

The SM symptoms range from subtle proximal strength deficit or isolated respiratory compromise to severe global weakness, involving all muscle groups.¹ SM develops in acute and chronic forms; whereas acute SM is rare and occurs within days, typically after high-dose GC exposure,⁵⁰ chronic SM following prolonged GC administration is more common.⁵¹

There are discrepancies in the reported time course for SM. For example, Dropcho et al. reported that among 216 patients with primary brain tumors who received dexamethasone for >14 days, clinical SM developed in 10.6% of patients, with symptoms appearing between weeks 9 and 12 for two thirds of these patients.⁴⁶ In contrast, Batchelor et al. found that the majority of patients developed proximal and respiratory weakness within 15 days of treatment,¹ likely due to higher GC exposure than in the study by Dropcho et al.

SM resolves after steroid discontinuation and improves with GC dose reduction⁴⁶; however, the symptom trajectories are poorly studied. Among the few longitudinal studies in SM following GC dose reduction, Batchelor et al. described improvement or resolution of the proximal muscle weakness and respiratory impairment in patients followed for more than 3 months off steroids.¹

GC-induced musculature changes may precede clinical symptoms, thus opening opportunities for early detection and monitoring of SM. For instance, Martucci et al. used quantitative ultrasound to compare the musculature of 20 patients with brain tumors and 30 healthy controls, where they showed that patients exposed to dexamethasone for a mean of 3.3 (±1.7) months at an average dose of 10.25 (±5.5) mg per day had significantly increased fatty muscle infiltration relative to the control group despite normal clinical examination.⁴⁰

Steroid myopathy in primary and metastatic CNS tumors

GCs are routinely used in patients with primary or metastatic CNS tumors to reduce peritumoral edema through modulation of tumor vascular permeability, the associated neurologic complications of local inflammation, and the side effects of radiation therapy. Dexamethasone has been a preferred agent because of its minimal mineralocorticoid effects, long half-life, and reduced tendency to induce psychosis.⁵² GC treatment length and dose depends on symptomatology, tumor histology, the timing of surgery and/or radiation therapy. For example, postsurgical taper may take as little as 3 days, whereas the majority of postradiation GC treatment may last up to 4 weeks.⁴²

A prospective study in 15 adult patients with solid tumor CNS metastases, treated with dexamethasone for epidural spinal cord compression (10 patients), brain metastases (4 patients), or brachial plexopathy (1 patient), showed that 9/15 patients (60%) developed proximal arm and leg muscle weakness and 8 patients (53.3%) developed neck flexor weakness; SM symptoms appeared 15 days following dexamethasone treatment in 8 patients, whereas one patient developed symptoms 20 weeks later. Respiratory muscle weakness was also observed on serial measurements in 8 patients, correlating with limb weakness, usually arising during the third week of treatment. In this cohort, the risk of myopathy was associated with the cumulative steroid dose but not with the average daily dose of dexamethasone or the total treatment duration.¹ A separate study reported that prolonged exposure to steroids increased incidence of SM in patients with primary brain tumors.⁴⁶

In addition to SM, worsening weakness in patients with CNS tumors can be secondary to primary disease progression, paraneoplastic syndromes, or cancer-associated inflammatory myopathies.

Several molecular targeted agents, including bevacizumab and corticorelin acetate have been used as a treatment for peritumoral edema in patients with cerebral tumors; the reduction in brain tumor-associated cerebral edema in turn eventually enables the reduction in the dose of GCs.^53,54 In a study by Recht and colleagues, patients receiving corticorelin acetate demonstrated an improvement in myopathy and were less likely to develop signs of Cushing syndrome.⁵⁴

Steroid myopathy in patients with GVHD

AlloHSCT is a common treatment for hematologic malignancies, severe aplastic anemia, inherited bone marrow failure syndromes and immunodeficiencies. One of the major complications of alloHSCT is GVHD, which carries a high risk of morbidity and mortality. GVHD occurs when donor immune cells recognize host tissues as foreign. Depending on the time of onset, clinical presentation, and histopathological features, GVHD can be acute (aGVHD) or chronic (cGVHD). About half of the patients undergoing alloHSCT develop aGVHD and 20%–50% develop cGVHD.⁵⁵

The standard first-line treatment for GVHD includes high-dose systemic GCs.² Approximately 35%–50% of aGvHD cases⁵⁶ and 40%–50% of cGVHD cases⁵⁷ become refractory to systemic steroid therapy, thus requiring protracted GC taper that may help control GVHD but that in turn may lead to GC-related toxicities.

Our literature search revealed a single study focusing on SM in patients with GVHD, a retrospective analysis in a cohort of patients with acute myeloid leukemia or myelodysplastic syndrome with grade ≯2 aGVHD following alloHSCT. In this study, 70 patients were treated with 2 mg/kg of methylprednisolone and survived at least 100 days post transplant. As defined by manual muscle testing and Functional Independence Measure scores, 41% of patients developed SM (38% moderate, 3% severe).⁵⁸ To our knowledge, SM has not been studied in pediatric patients with GVHD to date.

Differential diagnosis of SM in patients with GVHD includes GVHD-related and GVHD-independent inflammatory myopathies such as polymyositis, dermatomyositis, inclusion body myositis, and immune-mediated necrotizing myopathy. Workup may include blood work (including serum creatine kinase levels, antinuclear antibodies, extractable nuclear antigens, and myositis panel), electromyography, and muscle biopsy. Based on the 2014 National Institutes of Health consensus criteria, muscle biopsies should be considered in the absence of other manifestations of GVHD in order to determine the cause of myopathy.⁵⁹ Inflammatory myopathy may be due to GVHD or to autoimmunity,⁶⁰ and histological diagnosis may be challenging as both autoimmune and GVHD myositis present muscle-infiltrated CD4+ T cells.⁶¹ However, unlike autoimmune disease settings, GVHD-related myopathy results from donor lymphocyte infiltration rather than native host cell immune responses.

Unique considerations and side effects of glucocorticosteroids in children

Children are susceptible to similar systemic effects of GCs as adults including SM, however additionally in the pediatric population GCs may affect growth,⁶² cognition, mood, attention, behavior, memory, and sleep patterns.⁶³ A study comparing neurobehavioral effects on children of different ages receiving GCs as part of their treatment for acute lymphocytic leukemia (ALL) demonstrated that children younger than 5 years old appear more susceptible to those side effects than older children.⁶⁴ In regard to development, it is known that HSCT recipients functionally fare worse than children that do not require HSCT.⁶⁵ Although HSCT recipients have more complicated courses that could involve additional treatments such as total body irradiation they are also often prescribed GCs. The exact contribution of GCs in affecting development compared to the rest of the medications and interventions in the treatment protocol is not specifically known and warrants further research. A clinician evaluating children for SM should also be aware of their risk for impaired peak bone mass, fracture risk, and avascular necrosis. As with adults, GCs negatively affect both bone cell lineage and calcium metabolism.^62,63 Osteopenia has been seen in children with prednisolone doses less than 0.16 mg/kg/day. The incidence of fracture during ALL treatment is reported to be as high as 39% with a median time of 15 months from diagnosis for first fracture. Risk factors for fractures and decreased bone mineralization include older age, pubertal age, the male gender, and dexamethasone use.⁶² Aforementioned side effects could be contributing to functional decline caused by SM and therefore are important to address alongside treating SM. Literature on exercise therapy for SM in the pediatric population is lacking. Anecdotal evidence suggests that exercise may reverse SM in children, although recovery may take up to a year⁴³ and may not be complete.⁴⁴

Objective findings and diagnostic tools

SM diagnosis is typically based on the onset of painless proximal muscle weakness and a history of treatment with GCs. Self-reported weakness, decrease in observable muscle size, and measurable decreased strength are usually the first findings. No definitive diagnostic test or set of clinical criteria have been developed, although there are tools useful in both clinical and research settings.

Stationary and hand-held dynamometers objectively assess muscle strength in both clinical and research settings. Hand-held dynamometers, which are simple and reliable, are increasingly used in adults and children in recent years. Normative data for isometric strength are available for healthy adults and children. A study by Minetto et al. suggests that systematic incorporation of dynamometers into routine patient examinations is useful for diagnosis and monitoring of the myopathic process; however, the use of dynamometry in this population has yet to be validated in independent studies.⁶⁶

Laboratory findings in SM include normal aldolase, serum glutamic-oxaloacetic transaminase, lactate dehydrogenase,^45,67 normal or decreased creatinine phosphokinase (CPK) and myoglobin, and increased urinary 3-methylhistidine/creatinine ratio.⁶⁸ These observed findings can be explained by increased muscle protein degradation (resulting in increased 3-methylhistidine/creatinine ratio) and decreased muscle protein synthesis (which in turn reduces the circulating levels of CPK and myoglobin).⁶⁹ Elevated serum CPK can help differentiate between SM and an inflammatory myopathy. Serial urinary creatine excretion may also be of value in diagnosis of SM, although its use remains experimental.⁶⁸

Muscle biopsy is not routinely used in SM given that it is invasive and nonspecific, and it is thus generally reserved for suspected inflammatory myopathy cases. However, muscle biopsy may discern between atrophy of type II and, to a lesser degree, type I muscle fibers, in the absence of overt necrosis or inflammation.³⁷ Ultrastructural analyses of muscle biopsies include thickening of the sarcolemmal and the capillary basement membranes, disorganization of muscle fibers, myosin loss, and pronounced mitochondrial damage.^37,70 Similar biopsy findings are seen in other conditions such as aging, neuropathic processes, and muscle wasting of chronic origin.⁷¹

Nerve conduction and needle electromyography (EMG) are normal in most patients with SM, in line with the fact that needle EMG tests mostly type I muscle fiber function, which are recruited first in a voluntary muscle contraction (unlike type II fibers, which are the ones primarily affected by SM). Research studies using surface EMG demonstrated that the muscle fiber conduction velocity (MFCV) decreases following short-term GC administration. That can be attributed to a decreased muscle fiber diameter and to a suppressive effect of GCs on sarcolemmal excitability.⁷² Fiber diameter largely determines MFCV; thus, its decline is observed across different muscle-wasting conditions such as immobilization, aging, and neuromuscular disorders. For that reason, slowing MFCV is not specific for SM and is not recommended for diagnostic purposes.⁷¹

In clinical studies, cross-sectional computed tomography⁷³ and dual x-ray absorptiometry⁷⁴ have been used for quantifying muscle mass and volume changes. Likewise, ultrasound techniques also open opportunities for assessing muscle volume and quality. For example, quantitative ultrasound was used by Martucci et al. to identify changes in the muscle quality of patients treated with GCs, given that increasing echo intensity generally reflects signs of muscle degradation, including increased deposition of endomysial fat, development of connective tissue, and myofiber atrophy, although the contribution of each factor could not be fully discerned. In the study by Martucci et al., echo intensity was significantly higher in steroid-treated patients compared to controls across different anatomical regions, with the greatest differences seen in tibialis anterior. Moreover, increased duration of GC therapy correlated with the variation in muscle echo intensity.⁴⁰ Another study found a correlation between echo intensity and thickness of peripheral muscles (evaluated based on ultrasonographic B-mode images), and functional muscle assessments (handgrip strength, walking speed) in patients with active and remittent Cushing disease. That study concluded that the echo intensity of vastus lateralis, tibialis anterior, and medial gastrocnemius was significantly higher in patients with active disease compared to patients with remission.⁷⁵ Overall, those results suggest that quantitative ultrasound can identify changes in the muscles of patients treated with GCs and that approach could be a valuable tool to evaluate SM onset and progression.

The landscape of SM treatment strategies

There are no widely accepted pharmacological approaches to prevent or treat SM. In general, GC treatment duration and dose should be minimized to prevent the onset and magnitude of adverse effects, and these should be reassessed and treated promptly. Whenever possible, switching from fluorinated to nonfluorinated GCs should be considered, because fluorinated GCs (such as triamcinolone, betamethasone, dexamethasone) are more likely to lead to myopathy than nonfluorinated preparations (prednisone, prednisolone, hydrocortisone).⁷⁶

SM treatment strategies and dietary interventions

Clinical and preclinical studies^74,77 have shown improvements in muscle strength following administration of anabolic steroids in patients with SM. Oxandrolone is currently approved by the Food and Drug Administration as adjunctive therapy to offset the protein catabolism associated with prolonged administration of corticosteroids. Although the molecular mechanisms underlying anabolic steroid-induced muscular improvement are not completely understood, some studies suggest that androgens stimulate IGF-1 expression.⁷⁸

Crawford et al. conducted a double-blind clinical trial testing two androgens in 51 male patients with SM, treated with an average daily prednisone dose of 12.6 ± 2.2 mg. The participants were randomized to testosterone (200 mg mixed esters), nandrolone decanoate (200 mg) or placebo, given every fourth night by intramuscular injection during a total of 12 months.⁷⁴ That study focused on male participants because GCs decrease serum testosterone in men, which in turn was shown to worsen myopathy. In that study, androgen treatment significantly increased muscle mass and strength, suggesting that that approach could be a promising strategy for the treatment of SM in male patients. To our knowledge there are no studies of anabolic steroids for treatment of SM in pediatric populations; however, anabolic steroids are indicated in children for short stature in Turner syndrome, delayed puberty in males, or weight loss associated with burns and HIV^79-82 and should therefore be carefully examined to see if anabolic steroid treatment could benefit pediatric patients with SM.

Dietary modulation approaches could be potential interventional strategies to treat SM. Protein-rich diet is a potential approach for preventing and treating SM. Branched-chain amino acids (BCAAs) and glutamine supplementation have been studied only in pre-clinical settings, which showed that BCAAs (and in particular, leucine) stimulate protein synthesis³⁸; however, steroids inhibit the cellular import of amino acids and therefore the efficacy of this intervention remains questionable. Additionally, dietary supplementation with creatine (a naturally occurring nonprotein amino acid that plays an important role in maintaining energy availability in muscle) mitigates muscle mass loss in an animal model of SM.³¹ About half of the daily need of creatine is obtained from the diet, and the remaining portion is synthesized primarily in the liver and kidneys.⁸³ In humans, creatine is an agent widely used to improve athletic performance, and given its safety and efficacy profile,⁸³ creatine should be investigated in the management of SM.

Rehabilitation and exercise

Exercise decreases the catabolic effects of steroids and may mitigate strength losses following the administration of steroids.⁸⁴ Therapeutic exercise tolerance in oncologic patients is often limited: besides the underlying health conditions following specific cancer diagnoses, the severity of the symptoms and treatment time constraints hinder patient engagement. There are two equally important considerations when designing restorative interventions for SM: first, the mitigation of modifiable risk factors and compounding problems (such as inactivity, pain, poor sleep, and malnutrition); second, the personalized approach to exercise prescription, taking into account current patient abilities, the potential need of assistive devices, caregiver engagement, and environmental factors such as safe exercise space availability.

Exercise mode

Our search has identified 24 in vivo studies^3-26 of different exercise modalities in the settings of GC treatment, of which 19 were performed in rodent models and 5 in humans. We calculated percent difference in outcome measures between control and exercise groups, based on each individual study. A summary of the different exercise interventions and findings are listed in Table 1. In brief, 20 of these studies demonstrated decreased muscle catabolism,^{3-12,14,15,17-20,22-25} 1¹³ showed no effect, and 1²⁶ found overall negative results with exercise training. Two studies showed different results based on the type of training that was used. Ahtikoski et al. studied the effect of exercise training on muscle mass in rats treated with dexamethasone and demonstrated that endurance training attenuated the decrease in muscle mass, whereas uphill sprint running enhanced the effects of dexamethasone.²¹ Uchikawa et al. did not demonstrate significant changes in muscle weight with exercise training as compared to sedentary rats receiving steroids but did show a decline in type 1 muscle fiber cross-sectional area in the soleus muscle and type IIb fiber cross-sectional area in the extensor digitorum longus with strenuous exercise.¹⁶

An executive summary of the key findings and considerations for these studies follows:

1. Both endurance and resistance exercises were beneficial^{3-12,14,15,17-20,22-25} in mitigating SM symptoms.

2. Intensity of the exercise in human studies varied, demonstrating positive outcomes with both moderate level activity¹⁰ and with exercise to exhaustion.^4,5,7 In the animal models results were inconclusive, with some evidence suggesting that strenuous exercise as well as regimens that included sprinting may worsen muscular atrophy.^16,21

3. Duration of the exercise therapy among the human studies varied from 50 days to 6 months demonstrating positive effects in each study. The discrepancies between lifespan in humans versus preclinical models might hinder direct translation to humans, and thus findings from preclinical studies should be carefully examined in controlled clinical trials.

4. Related to the preceding, most preclinical studies are difficult to translate to human pediatric settings, given the sexual maturation differences between preclinical models and humans, further highlighting the need for studies in pediatric SM.

5. Evidence to support exercise programs for treatment of SM from the five human studies was classified by level as per Melnyk and Fineout-Overholt²⁷ (seven levels of evidence with 1 being the strongest). Level 2 evidence exists to support resistance exercise program to reverse SM based on study by Braith et al.⁹ Level 3 evidence exists to support the preventative role of endurance exercise programs of moderate intensity on GC-induced protein waste.¹⁰

CONCLUSIONS

SM is a serious debilitating condition that substantially impairs patients’ performance status and quality of life. In adult patients with cancer, SM is associated with decreased tolerance to cancer treatment, thus compromising their oncologic care.⁸⁵ Pharmacologic, dietary, and physical interventions may be beneficial in preventing or reversing SM, although the potential adverse effects of some of these interventions, as well as the expected caveats in translating findings in preclinical models to human settings, warrant caution and demand controlled clinical studies in adult and pediatric patients. Strong level of evidence exists to support resistance training program to mitigate SM in adult patients. Whereas exercises at mild to moderate intensity are beneficial, the value of high-intensity activities (which may increase atrophy) remains questionable. In the pediatric population, a better understanding of the trajectory of SM and a response to exercise is crucial for developing targeted treatment strategies. Finally, early detection and treatment of SM with exercise therapy may help mitigate functional loss, positively affecting the survival and quality of life of these groups of vulnerable patients.