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Muscle protein anabolism in advanced cancer patients: response to protein and amino acids support, and to physical activity

  • S Antoun
    Correspondence
    Correspondence to: Dr Sami Antoun, Département Ambulatoire, Gustave-Roussy, Université Paris-Saclay, 114, rue Edouard Vaillant, 94800 Villejuif, France. Tel: +33-1 42114783; Fax: +33-1 42115202;
    Affiliations
    Département Ambulatoire, Gustave-Roussy, Université Paris-Saclay, Villejuif, France
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  • B Raynard
    Affiliations
    Département Interdisciplinaire de Soins de Support, Gustave Roussy, Université Paris-Saclay, Chevilly-Larue, France
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      ABSTRACT

      In the field of oncology, it is well recognized that a decrease in mass, density, strength, or function of skeletal muscle is associated to increased treatment toxicities and postoperative complications, as well as poor progression-free survival and overall survival. The ability of amino acids to stimulate protein synthesis in cancer patients is reduced. Considering nutritional intervention, this anabolic resistance could be in a part counteracted by increasing protein or by giving specific amino acids. In particular, Leucine might counteract this anabolic resistance not only by increasing substrate availability, but also by directly modulating the anabolic signal pathway. Few studies showed the possibility of increasing muscle protein synthesis by specific nutriments and/or by increasing amino acids or protein administration. In addition, whereas many studies provide evidence of a benefit of adapted physical activity in advanced cancer patients, it is difficult to specify the most appropriate type of exercise, and the optimum rhythm and intensity. Moreover, the benefits of physical activities and of protein support seem greater when it is started at the precachexia stage rather than at the cachexia stage, and their benefits are limited or nonexistent at the stage of refractory cachexia. Future approaches should integrate the combination of several complementary treatments in order to prevent (or improve) cachexia and/or sarcopenia in cancer patients.

      Keywords

       Key Message

      In cancer patients, the loss of muscle mass could be in part counteract by the association of adapted physical activity with the increase in protein intake and the administration of specific amino acids. The benefits seem greater when this association is administrated in the earlier stages of cachexia rather than in refractory cachexia stage.

      Introduction

      Nutrition-related disorders represent a serious and often under-recognized consequence of many cancer types. A combination of decreased food intake and metabolic abnormalities can lead to nutrition-related disorders, which in turn are associated with delayed recovery, as well as increased morbidity and mortality. Several recent studies have described this interaction between cancer and such metabolic and nutritional effects [
      • Blum D.
      • Stene G.B.
      • Solheim T.S.
      • et al.
      Validation of the consensus-definition for cancer cachexia and evaluation of a classification model–a study based on data from an international multicentre project (EPCRC-CSA).
      ,
      • Fearon K.
      • Strasser F.
      • Anker S.D.
      • et al.
      Definition and classification of cancer cachexia: an international consensus.
      ].
      Before the years 2000, nutritionists used to focus on weight loss, and the link between low body mass index (BMI) (or weight loss) on one hand, and outcomes on the other hand. However, focusing on weight is no longer considered the best purpose, since weight changes could be linked to water or to adipose tissue changes. During the past five years, a huge amount of studies about the association between skeletal muscle dysfunction and outcomes have identified skeletal muscle as the Holy Grail.
      The term of sarcopenia was originally used to define age-related skeletal muscle disorders; however, it is now used to describe skeletal muscle decline in many chronic diseases and in several other conditions such as starvation, denervation, immobilization, physical inactivity, and cancer [
      • Biolo G.
      • Cederholm T.
      • Muscaritoli M.
      Muscle contractile and metabolic dysfunction is a common feature of sarcopenia of aging and chronic diseases: from sarcopenic obesity to cachexia.
      ]. For oncologists, studies of the body composition of patients with cancer reveal that it is mainly the loss of skeletal muscle, which predicts risk of postoperative complications, chemotherapy toxicity, and mortality [
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      ,
      • Tan B.H.
      • Birdsell L.A.
      • Martin L.
      • et al.
      Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer.
      ], and they use the term of sarcopenia to define muscle mass loss.

      Impact of skeletal muscle decline on outcomes in cancer patients

      Cancer patients with low muscle mass have had a decrease in overall survival, an increase in chemotherapy toxicity and an increase in postoperative complications. The leading article by Prado et al. highlighted the interest of studying body composition parameters as prognostic factors [
      • Prado C.M.
      • Lieffers J.R.
      • McCargar L.J.
      • et al.
      Prevalence and clinical implications of sarcopenic obesity in patients with solid tumours of the respiratory and gastrointestinal tracts: a population-based study.
      ]. They showed that for obese colorectal and lung cancer patients, those with sarcopenia had an overall survival shortened by 10 months compared with those without sarcopenia. Subsequently, other studies have shown this link between sarcopenia and worse prognosis [
      • Tan B.H.
      • Birdsell L.A.
      • Martin L.
      • et al.
      Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer.
      ,
      • Martin L.
      • Birdsell L.
      • Macdonald N.
      • et al.
      Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index.
      ]. The study by Martin et al. is probably the most relevant one; the authors analyzed 1473 lung or gastro-intestinal cancer patients [
      • Martin L.
      • Birdsell L.
      • Macdonald N.
      • et al.
      Cancer cachexia in the age of obesity: skeletal muscle depletion is a powerful prognostic factor, independent of body mass index.
      ], and showed that high weight loss, low muscle mass, and low muscle density were independent prognostic of survival. Patients who exhibited all three characteristics survived 8.4 months, compared with 28.4 months in patients who had none of these characteristics.
      In addition to muscle mass, muscle density and muscle strength were also associated to mortality. Muscle function is the third component of muscle assessment and only few studies to date have shown a link between muscle function and survival in advanced cancer [
      • Kasymjanova G.
      • Correa J.A.
      • Kreisman H.
      • et al.
      Prognostic value of the six-minute walk in advanced non-small cell lung cancer.
      ,
      • Kilgour R.D.
      • Vigano A.
      • Trutschnigg B.
      • et al.
      Handgrip strength predicts survival and is associated with markers of clinical and functional outcomes in advanced cancer patients.
      ].
      The other interesting association is the link between sarcopenia and chemotherapy toxicity. The first study addressing this issue was that of Prado et al. in colorectal cancer patients [
      • Prado C.M.
      • Baracos V.E.
      • McCargar L.J.
      • et al.
      Body composition as an independent determinant of 5-fluorouracil-based chemotherapy toxicity.
      ], showing an impact of 5-fluorouracil dose per kg of lean body mass on the occurrence of dose-limiting toxicities (DLTs). This pivotal work has paved the way for to many other studies [
      • Antoun S.
      • Baracos V.E.
      • Birdsell L.
      • et al.
      Low body mass index and sarcopenia associated with dose-limiting toxicity of sorafenib in patients with renal cell carcinoma.
      ,
      • Mir O.
      • Coriat R.
      • Blanchet B.
      • et al.
      Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma.
      ,
      • Massicotte M.H.
      • Borget I.
      • Broutin S.
      • et al.
      Body composition variation and impact of low skeletal muscle mass in patients with advanced medullary thyroid carcinoma treated with vandetanib: results from a placebo-controlled study.
      ]. For example, among 40 patients with hepatocellular carcinoma treated with sorafenib, sarcopenic patients experienced more frequently DLT than nonsarcopenic patients (82% versus 31%; P = 0.005). The other interesting result is that, on day 28, median sorafenib area under the curve was significantly higher in sarcopenic patients (102.4 mg/l⋅h versus 53.7 mg/l⋅h; P = 0.013) [
      • Mir O.
      • Coriat R.
      • Blanchet B.
      • et al.
      Sarcopenia predicts early dose-limiting toxicities and pharmacokinetics of sorafenib in patients with hepatocellular carcinoma.
      ]. Another study showed similar results in advanced medullary thyroid carcinoma treated with vandetanib: patients with low skeletal muscle mass have a higher probability of DLT (73% versus 14%) and a higher vandetanib serum concentration (1037 ng/ml versus 745 ng/ml P = 0.04) [
      • Massicotte M.H.
      • Borget I.
      • Broutin S.
      • et al.
      Body composition variation and impact of low skeletal muscle mass in patients with advanced medullary thyroid carcinoma treated with vandetanib: results from a placebo-controlled study.
      ]. These articles raise the hypothesis that the mechanism of this toxicity could be an excessive dose of the chemotherapy, when adjusted to muscle mass.
      The last suspected relationship is between postoperative morbidity and sarcopenia. We have known for several years that there is a link between weight loss and postoperative complications. Because many studies have shown that sarcopenia alone is not the best predictor of postoperative complications, the concept of “frailty” including muscle function should be added to muscle mass assessment [
      • Huang D.D.
      • Wang S.L.
      • Zhuang C.L.
      • et al.
      Sarcopenia, as defined by low muscle mass, strength and physical performance, predicts complications after surgery for colorectal cancer.
      ,
      • Reisinger K.W.
      • van Vugt J.L.
      • Tegels J.J.
      • et al.
      Functional compromise reflected by sarcopenia, frailty, and nutritional depletion predicts adverse postoperative outcome after colorectal cancer surgery.
      ].

      Muscle anabolism is possible in cancer patients

      Beyond the demonstration of a link between skeletal muscle dysfunctions (loss of muscle mass; low skeletal muscle density and decrease in muscle function or strength) and outcomes, the main issue lies in the possibility to decrease, or to correct these muscles disorders.
      The use of computed tomography (CT)-scan image analysis has shown that muscle anabolism is possible, and that an increase in muscle mass can be observed during cancer treatment. Indeed, Tan et al. [
      • Tan B.H.
      • Birdsell L.A.
      • Martin L.
      • et al.
      Sarcopenia in an overweight or obese patient is an adverse prognostic factor in pancreatic cancer.
      ] surprisingly showed that even in pancreatic cancer patients, one-third had an increase in muscle mass, one-third had a stable muscle mass, and one-third had loss of muscle mass while all except one patient, lost adipose tissue.
      Prado et al. conducted a study based on CT images analysis for the loss and gain of muscle in a cohort of advanced cancer patients [
      • Prado C.M.
      • Sawyer M.B.
      • Ghosh S.
      • et al.
      Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential?.
      ]. They showed that 60.2% of patients gained or stabilized muscle mass, and especially those that were far from the date of death. The majority of instances of muscle gain (84.3%) occurred 3 months or more before death [
      • Prado C.M.
      • Sawyer M.B.
      • Ghosh S.
      • et al.
      Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential?.
      ]. The possible causes of muscle gain have been poorly studied. In the Prado et al. study [
      • Prado C.M.
      • Sawyer M.B.
      • Ghosh S.
      • et al.
      Central tenet of cancer cachexia therapy: do patients with advanced cancer have exploitable anabolic potential?.
      ], the review of medical charts of the top 5% with the quantitatively largest muscle gain showed that for 89% of them, the oncologist reported stable disease. The aforementioned studies are retrospective; however, they suggest that gaining or maintaining muscle mass is possible for cancer patients, and that tumor response is a principal factor of muscle gain.
      However, few data are available about the other potential factors (and more particularly nutritional factors) that could favor the positive net balance between protein synthesis and protein breakdown.
      Muscle protein anabolism results from the stimulations of synthesis or the suppression of proteolysis, with a combination maximizing the response. While it has been demonstrated in healthy humans that increasing food and protein intake stimulate protein synthesis, this is not necessarily the case during catabolic situations. The reduced protein synthetic response to food intake has been termed anabolic resistance (AR) and the question concerns the possibility to increase muscle protein synthesis (MPS), and to counteract this AR. Many interconnected and overlapping intracellular pathways regulates MPS [
      • Drummond M.J.
      • Dreyer H.C.
      • Fry C.S.
      • et al.
      Nutritional and contractile regulation of human skeletal muscle protein synthesis and mTORC1 signaling.
      ]. Amino acids (AAs), insulin, and contraction appear to converge and stimulate the mammalian target of rapamycin (mTOR) pathway, which has a pivotal role in controlling protein synthesis. The administration of specific AA could be interesting because in addition to be a substrate, they are one of the potentially modulator of the protein turn over. Many data demonstrate the capacity of Leucine to modulate protein metabolism by increasing substrate availability, increasing the secretion of anabolic hormones such as insulin, and directly modulating anabolic signaling pathways by stimulating protein synthesis and reducing protein breakdown [
      • Ham D.J.
      • Caldow M.K.
      • Lynch G.S.
      • Koopman R.
      Leucine as a treatment for muscle wasting: a critical review.
      ]. We will focus on the role of AA in promoting muscle anabolism with a special interest for Leucine and branched chain AA (BCAA).

      Role of total and specific amino acids in promoting muscle anabolism

      In cancer cachexia, muscle protein breakdown (MPB) produces AA needed for the inflammatory protein synthesis [
      • Lundholm K.
      • Edström S.
      • Ekman L.
      • et al.
      A comparative study of the influence of malignant tumor on host metabolism in mice and man.
      ]. It is more likely that the mechanisms involved in muscle wasting are more complex. Data concerning the relationship between AA administration and muscle protein anabolism are lacking. Scarce results are available from very disparate clinical studies, which concerned a wide variety of situations. Information are obtained both from very sophisticated protein kinetic studies and from clinical trials.

       Short-term interventions: AAs kinetic studies in cancer patients

      The studies that used isotopic tracer methodology explored the processes of MPS and MPB that are affected by the administration of AA. These sophisticated studies gave us information about the mechanisms which are involved, but it remains unknown whether repeated AA administration would translate into results similar to those observed after single administration. The translation of acute anabolic effects into gains of muscle mass and function has to be confirmed by long-term intervention trials. It is difficult to draw conclusion from these protein kinetic data, since only six studies, quite heterogeneous in terms of population and protocol, have been published. Three authors have focused on the global protein turn over [
      • Winter A.
      • MacAdams J.
      • Chevalier S.
      Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer cachexia.
      ,
      • van Dijk D.P.
      • van de Poll M.C.
      • Moses A.G.
      • et al.
      Effects of oral meal feeding on whole body protein breakdown and protein synthesis in cachectic pancreatic cancer patients.
      ,
      • Engelen M.P.
      • Safar A.M.
      • Bartter T.
      • et al.
      High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer.
      ], and three have studied muscle protein metabolism by including muscle biopsies in their assessment [
      • Williams J.P.
      • Phillips B.E.
      • Smith K.
      • et al.
      Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients.
      ,
      • Dillon E.L.
      • Volpi E.
      • Wolfe R.R.
      • et al.
      Amino acid metabolism and inflammatory burden in ovarian cancer patients undergoing intense oncological therapy.
      ,
      • Deutz N.E.
      • Safar A.
      • Schutzler S.
      • et al.
      Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food.
      ]. The interpretation of the results is also made difficult by the fact that the method of AA supplementation (parenteral administration or oral feeding), the amounts of AA, and the administration of specific AA (particularly BCAA), differ from one study to another. In addition, patients at different stages of tumor evolution were included, and there are growing evidences for a link between tumor evolution and a potential AR to AA administration. Tables 1 and 2 summarize the cancer type, the nutritional status, and the mechanisms that are involved when they are recorded [energy intake and systemic inflammatory parameters C-reactive protein (CRP)], the study design, the administration of specific AA, and the effects compared with a group control.
      Table 1Characteristics of patients and study design in amino acid kinetic studies: studies assessing the whole-body protein synthesis and the whole body protein balance
      Author (no. in treated group)Type of cancerNutritional status Systemic inflammation Energy intakeStudy design Perfusion versus oral intake AA versus AA + EAAResults
      • Winter (n = 10)
      • Clin Nutr 2012
      Non-small-cell lung
      • WL: 7.8%; BMI: 22.0 ± 0.9
      • CRP: 12.7
      • Energy intake: 1891 ± 76
      • Co: AA unknown
      • E: Protein 30 g
      • IV continuously 150 mn
      • Hyperinsulinemic-isoAA: PB ↓ Ca and Co, ↓ PB in Ca > ↓ PB in Co, PS unchanged in Ca and CO, net balance ↓ Ca > ↓ Co
      • Hyperinsulinemic-HyperAA: PB in Ca and Co unchanged
        PS ↑ in Ca and Co
        Net balance ↑ in Ca and Co (similar)
      • Engelen (n = 13)
      • Ann Oncol 2015
      Non-small-cell lung
      • WL: 8.4%; BMI: 26.5 ± 1
      • CRP: 9.8
      • Energy intake: 1944 ± 215
      • CaCo: AA 70 g (14 g EAA/non EAA)
      • CaE: AA 70 g (14 g EAA 50% Leu)
      • oral 5 mn 250  ml
      • PS and net balance ↑
      • CaE group > CaCo group (P < 0.001)
      • Van Dijk (n = 8)
      • JCSM 2015
      Pancreas
      • WL: 24.3%; BMI: 20.0
      • CRP: 8.3
      • Energy intake unknown
      • Co and Cancer: 480 ml
      • (caseine 50 g Leu 5, 25 g)
      • oral 4 h 480 ml
      • Baseline: PB in Ca > PB in Co, PS in Ca > PS in Co
      • Ingestion: PB ↓ Ca and Co
        PS in Ca equal to baseline, PS ↑ Co, net balance ↑ Ca and Co
      WL, weight loss (% of 6 months prior weight); BMI, body mass index (kg/m2); CRP, C-reactive protein (mg/L); energy intake kcal/day; Ca, cancer patients; Co, control group; E, experimental group; AAs, amino acids; EAA, essential AA; PB, protein breakdown; PS, protein synthesis.
      Table 2Characteristics of patients and study design in amino acid kinetic studies: studies assessing muscle protein synthesis and fractional synthetic rate (FSR)
      Author (no. in treated group)Type of cancerNutritional status Systemic inflammation Energy intakeStudy design Perfusion versus oral intake AA versus AA + EAAResults
      • Williams (n = 13)
      • Am J Clin Nutr 2012
      Colorectal
      • WL unknown; BMI 27.6 ± 1.1
      • CRP 8.8
      • Energy intake unknown
      IV continuous (bolus 30 mg/kg, continuous 102 mg/kg)
      • Muscle PS ↑ in Co; Muscle PS no change in Ca
      • Muscle PB ↑ in Co and Ca
      • Dillon (n = 6)
      • Clin Nutr 2007
      Ovarian
      • WL > 10%; BMI 22.0 ± 3
      • CRP normal
      • Energy intake unknown
      • Prot 40 g (EAA and non-EAA)
      • oral 540 ml 4 h
      Compared with basal: Muscle PS ↑, Muscle PB unchanged, net balance ↑ (from negative to zero)
      • Deutz (n = 10)
      • Clin Nutr 2011
      Colon lung
      • WL 2, 9% ± 2, 2; BMI 25.1 ± 3.3
      • CRP 28, 7
      • Energy intake unknown
      • CaCo: 24 g prot (Leu 2, 0)
      • CaE: 40.1 (leu 7, 5)
      • oral 30 mn
      • CaCo: FSR no change
      • CaE: FSR increase 40% (P = 0.027)
      WL, weight loss (% of 6 months prior weight); BMI, body mass index kg/m2; CRP, C-reactive protein (mg/l); energy intake kcal/day; Ca, cancer patients; Co, control group; E, experimental group; AA, amino acids; EAA, essential AA; PB, protein breakdown; PS, protein synthesis.
      Three studies assessed the whole-body protein synthesis and the whole body protein balance [
      • Winter A.
      • MacAdams J.
      • Chevalier S.
      Normal protein anabolic response to hyperaminoacidemia in insulin-resistant patients with lung cancer cachexia.
      ,
      • van Dijk D.P.
      • van de Poll M.C.
      • Moses A.G.
      • et al.
      Effects of oral meal feeding on whole body protein breakdown and protein synthesis in cachectic pancreatic cancer patients.
      ,
      • Engelen M.P.
      • Safar A.M.
      • Bartter T.
      • et al.
      High anabolic potential of essential amino acid mixtures in advanced nonsmall cell lung cancer.
      ] and showed that cancer patients have the potential for whole body protein anabolism, even under oncologic therapy, and regardless of tumor evolution, by increasing protein administration (containing or not essential AA). These results are consistent with the recommendations of Bozzetti and Bozzetti which are for patient with cancer cachexia, to perfuse solutions with high protein infusion and high proportion of BCAA [
      • Bozzetti F.
      • Bozzetti V.
      Is the intravenous supplementation of amino acid to cancer patients adequate? A critical appraisal of literature.
      ]. However, these studies have assessed the whole body protein turn over and not skeletal muscle protein anabolism, which is the key point of the nutritional support. The increase in whole body protein turn over could be associated to a reprioritization of nitrogen away from peripheral tissue (muscle) toward increased hepatic production of acute phase protein, as it was known and described since 1978 by Lundholm et al. [
      • Lundholm K.
      • Edström S.
      • Ekman L.
      • et al.
      A comparative study of the influence of malignant tumor on host metabolism in mice and man.
      ].
      The “gold standard” for the assessment of MPS is the measurement of the fractional synthetic rate by muscle biopsies. Given the difficulties to design such studies, few data are reported [
      • Williams J.P.
      • Phillips B.E.
      • Smith K.
      • et al.
      Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients.
      ,
      • Dillon E.L.
      • Volpi E.
      • Wolfe R.R.
      • et al.
      Amino acid metabolism and inflammatory burden in ovarian cancer patients undergoing intense oncological therapy.
      ,
      • Deutz N.E.
      • Safar A.
      • Schutzler S.
      • et al.
      Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food.
      ]. The interesting point in the series by Dillon et al., which was conducted in six ovarian cancer patients, is that these patients were still receiving chemotherapy and that they were not in a terminal stage of their cancer [
      • Williams J.P.
      • Phillips B.E.
      • Smith K.
      • et al.
      Effect of tumor burden and subsequent surgical resection on skeletal muscle mass and protein turnover in colorectal cancer patients.
      ]. The nutritional support was based on the infusion of high amounts of AA. Protein synthesis increased significantly from basal to AA support while protein breakdown remained unchanged. The study by Deutz et al. [
      • Dillon E.L.
      • Volpi E.
      • Wolfe R.R.
      • et al.
      Amino acid metabolism and inflammatory burden in ovarian cancer patients undergoing intense oncological therapy.
      ] highlights a few interesting points: (i) the experimental group not only received high amounts of protein as in Dillon et al. study, but also the addition of Leucine and fish oil. (ii) The study was conducted in cancer patients without or with a small amount of weight loss, and with a normal or overweight BMI. We can observe that early in cancer and before the observation of malnutrition, there was a resistance to muscle anabolism, as shown in the group who did not receive AA treatment. (iii) The main result was that after feeding MPS can be increased in these early stages of malnutrition and counteracts the AR. Finally, Williams et al. study showed different results in colorectal cancer patients [
      • Deutz N.E.
      • Safar A.
      • Schutzler S.
      • et al.
      Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food.
      ]: increases in MPS after feeding were evident in healthy control subjects; however, there was no change in fed protein synthesis before surgery when tumor has not yet been removed. After removal of the cancer, MPS had fully recovered in fed-state.
      Despite the differences in the results of these six studies, general conclusions can be drawn.
      • 1.
        Early in the tumor evolution with low or normal protein intake, there was a decrease in muscle protein anabolism (two over the three studies with muscle biopsies). This AR was well described in Deutz et al. study [
        • Deutz N.E.
        • Safar A.
        • Schutzler S.
        • et al.
        Muscle protein synthesis in cancer patients can be stimulated with a specially formulated medical food.
        ], and AR was observed early without or with a very low weight loss (about 2%).
      • 2.
        Patients had low inflammatory systemic syndrome (CRP levels were normal or near the normal values in five of the six studies), and energy intake was normal in all three studies in which this information was available. This may reflect the fact that patients were at an early stage of their disease, and one could assume that if muscle wasting is reversible, it could be at an early stage of the tumor evolution.
      • 3.
        With increasing protein intake, whether it contains Leucine or not, five over six studies showed the possibility of increasing the net balance protein. It was observed for the three studies that explored the whole protein turn over, and for two over three that explored the fractional synthetic rate by muscle biopsies.

       Branched chain amino acids: clinical trials

      Human interventional studies with specific AA administration are rare and few studies assessing muscle mass or muscle function have been published in cancer patients. BCAAs were the most frequently AA studied. May et al. [
      • May P.E.
      • Barber A.
      • D’Olimpio J.T.
      • et al.
      Reversal of cancer-related wasting using oral supplementation with a combination of β-hydroxy-β-methylbutyrate, arginine, and glutamine.
      ] studied patients who had weight loss of at least 5%. Patients received a control mixture of non-EAA or an experimental treatment containing β-hydroxyl-β-methylbutyrate, l-arginine, and glutamine. Up to 35% of patients withdrew before the evaluation at 4 weeks. A significant increase in fat-free mass (FFM) in the AA-supplemented group (1.1 kg) was observed, whereas the control patients lost 1.3 kg of FFM (P = 0.02). These results of FFM gain have given hope. Unfortunately, a more recent study with a similar design and much more patients did not find a similar positive effect of essential AA on FFM [
      • Berk L.
      • James J.
      • Schwartz A.
      • et al.
      A randomized, double-blind, placebo-controlled trial of a β-hydroxy-β-methylbutyrate, glutamine, and arginine mixture for the treatment of cancer cachexia (RTOG 0122).
      ], and there was no statistically significant difference in the 8-week lean body mass, weight, and quality of life scores.
      Importantly, in both studies, many patients withdrew before the end of the protocol. The lack of benefit of the nutritional support could be related to the status of progressive disease, and the treated patients could be in the situation of refractory cachexia, where any nutritional support is useless.
      Regarding the link between specific nutriment and tumor evolution independently from nutritional parameters, a number of small and diverse clinical trials, especially on hepatocellular carcinoma, investigated the benefit of BCAA supplementation on tumor evolution and cancer incidence. Despite the potential beneficial results, the role of specific nutriment supplementation remains to be clarified given the inconsistence of the findings, the heterogeneity of the patients, the small sample size, and the poor study design [
      • Choudry H.A.
      • Pan M.
      • Karinch A.M.
      • Souba WW.
      Branched-chain amino acid-enriched nutritional support in surgical and cancer patients.
      ,
      • Yoshiji H.
      • Noguchi R.
      • Ikenaka Y.
      • et al.
      Combination of branched-chain amino acid and angiotensin-converting enzyme inhibitor improves liver fibrosis progression in patients with cirrhosis.
      ,
      • Kawaguchi T.
      • Shiraishi K.
      • Ito T.
      • et al.
      Branched-chain amino acids prevent hepatocarcinogenesis and prolong survival of patients with cirrhosis.
      ].

       Other AAs: human cancer studies

      A recent review summarizes the observations on the role of AA in promoting protein anabolism in human cancer addressing the role of Arginine and Citrulline [
      • Chevalier S.
      • Winter A.
      Do patients with advanced cancer have any potential for protein anabolism in response to amino acid therapy?.
      ]. Experimental studies have shown that these two AA could be an alternative for muscle protein stimulator to BCAA [
      • Jonker R.
      • Engelen M.P.
      • Deutz NE.
      Role of specific dietary amino acids in clinical conditions.
      ]. Few human studies, most of them conducted for patients undergoing surgery, are available [
      • Jonker R.
      • Engelen M.P.
      • Deutz NE.
      Role of specific dietary amino acids in clinical conditions.
      ,
      • de Luis D.A.
      • Izaola O.
      • Terroba M.C.
      • et al.
      Effect of three different doses of arginine enhanced enteral nutrition on nutritional status and outcomes in well-nourished postsurgical cancer patients: a randomized single blinded prospective trial.
      ]. Therefore, despite the experimental data, there is little evidence to support a beneficial effect of Arginine and Citrulline as a treatment of muscle wasting.

      The role of physical activity

      The potential antitumor effect of physical activity (exercise) is still debated, but is supported by several experimental models [
      • Penna F.
      • Busquets S.
      • Pin F.
      • et al.
      Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise.
      ,
      • Lira F.S.1
      • Yamashita A.S.
      • Rosa J.C.
      • et al.
      Hypothalamic inflammation is reversed by endurance training in anorectic-cachectic rats.
      ,
      • Puppa M.J.
      • White J.P.
      • Velázquez K.T.
      • et al.
      The effect of exercise on IL-6-induced cachexia in the Apc (Min/+) mouse.
      ]. We will herein focus on the direct effects of exercise on muscle in cancer cachexia models.
      Physical activity has an anti-inflammatory effect in tumor cachexia models. This effect is intimately linked to increase not only in interleukin 6 (IL-6) synthesis but also in IL-6 receptor, alpha, and in soluble tumor necrosis factor (sTNFr)-1 and 2. These cytokines have an anti-inflammatory effect in muscle, in particular not only by reducing catabolizing effect of TNFα and IL-1 (by direct antagonism and reduction of their synthesis), but also by participating in induction of interleukin 10 (IL-10) production, also powerful anti-inflammatory in muscle [
      • Lira F.S.
      • Yamashita A.S.
      • Rosa J.C.
      • et al.
      Exercise training decreases adipose tissue inflammation in cachectic rats.
      ]. IL-6 and IL-10 would also contribute to decreased macrophage activation in muscle. Anti-inflammatory cytokines are also involved in the reduction of TNFα-induced insulin resistance, by increasing the expression of GLUT4 via the activation of AMP kinase. They also contribute to the reduction of TNFα-induced lipolysis. The increase in the production of GLUT4 could activate the transcription factor MEF2 and thus stimulate myogenesis and therefore the regeneration and increase of muscle volume. Increased oxidation of lipids by the liver under repeated exercise would contribute to the improvement of insulin resistance [
      • Gould D.W.
      • Lahart I.
      • Carmichael A.R.
      • et al.
      Cancer cachexia prevention via physical exercise: molecular mechanisms.
      ].
      Through PGC-1α4 pathway, exercise, and in particular repeated exercise, inhibits FOXO on one side and NFκB on the other, further contributing to limiting muscle proteolysis related to tumor disease. PGC-1α4 is also one of the actors, in the same way as the production of GH at the hypothalamic level, stimulation of IGF1 production. This activates mTOR and thus inhibits ubiquitin-proteasome-dependent proteolysis via Atrogin1 and MuRF1. Physical activity could also intervene on muscular homeostasis by positively regulating autophagy [
      • Lira F.S.
      • Neto J.C.
      • Seelaender M.
      Exercise training as treatment in cancer cachexia.
      ]. Exercise could also have an anti-proteolytic effect during cancer cachexia, by positively regulating enzyme activities involved in elimination of reactive oxygen species in muscle, including SOD and GPx, and by increasing production and glutathione activity. Finally, prolonged physical activity could block the inhibitory effect of myostatin on muscle regeneration, with repeated stimulation of motor plate.
      The effect of physical activity on appetite in tumor-bearing animals is variable in the literature. The rate of proinflammatory cytokines (TNFα, IL-1) is decreased in hypothalamus of animals subjected to intense and regular exercise but without effect on oral intakes [
      • Pigna E.
      • Berardi E.
      • Aulino P.
      • et al.
      Aerobic exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer.
      ]. However, several studies have shown a positive effect of (intense) exercise on the ingesta of cachectic mice [
      • Daneryd P.L.
      • Hafström L.R.
      • Karlberg IH.
      Effects of spontaneous physical exercise on experimental cancer anorexia and cachexia.
      ,
      • Jee H.
      • Chang J.E.
      • Yang EJ.
      Positive prehabilitative effect of intense treadmill exercise for ameliorating cancer cachexia symptoms in a mouse model.
      ].
      Finally, some authors suggest that repeated physical activity could reduce total energy expenditure by regulating resting energy expenditure via its anti-inflammatory effect.

       Benefits in the preclinical setting

      The models of tumor-bearing animals—almost exclusively murine—showing a benefit of exercise on muscle mass or muscle strength are finally few. However, in these studies, physical activity has a positive impact on total weight gain (independent of tumor weight) and on muscle mass [
      • Donatto F.F.
      • Neves R.X.
      • Rosa F.O.
      • et al.
      Resistance exercise modulates lipid plasma profile and cytokine content in the adipose tissue of tumour-bearing rats.
      ,
      • Daneryd P.
      • Hafström L.
      • Svanberg E.
      • Karlberg I.
      Insulin sensitivity, hormonal levels and skeletal muscle protein metabolism in tumour-bearing exercising rats.
      ,
      • al-Majid S.
      • McCarthy DO.
      Resistance exercise training attenuates wasting of the extensor digitorum longus muscle in mice bearing the colon-26 adenocarcinoma.
      ,
      • Hojman P.
      • Fjelbye J.
      • Zerahn B.
      • et al.
      Voluntary exercise prevents cisplatin-induced muscle wasting during chemotherapy in mice.
      ]. In some published models, physical activity (or electrical muscle stimulation) was even able to partially reverse sarcopenia [
      • al-Majid S.
      • McCarthy DO.
      Resistance exercise training attenuates wasting of the extensor digitorum longus muscle in mice bearing the colon-26 adenocarcinoma.
      ]. In other models, it was able to prevent cachexia, and thus improve the survival of mice [
      • Pigna E.
      • Berardi E.
      • Aulino P.
      • et al.
      Aerobic exercise and pharmacological treatments counteract cachexia by modulating autophagy in colon cancer.
      ]. Regular exercise during cisplatin chemotherapy seems to limit its adverse effects on the muscle [
      • Khamoui A.V.
      • Park B.S.
      • Kim D.H.
      • et al.
      Aerobic and resistance training dependent skeletal muscle plasticity in the colon-26 murine model of cancer cachexia.
      ].
      Repetitive physical exercise in cachectic mice can therefore improve muscle strength [
      • Penna F.
      • Busquets S.
      • Pin F.
      • et al.
      Combined approach to counteract experimental cancer cachexia: eicosapentaenoic acid and training exercise.
      ,
      • Gould D.W.
      • Lahart I.
      • Carmichael A.R.
      • et al.
      Cancer cachexia prevention via physical exercise: molecular mechanisms.
      ]. Jee et al. have even shown improvement in behavioral tests (equivalent to a quality of life assessment) in cachectic mice subjected to repeated physical exercise [
      • Jee H.
      • Chang J.E.
      • Yang EJ.
      Positive prehabilitative effect of intense treadmill exercise for ameliorating cancer cachexia symptoms in a mouse model.
      ].

       Benefits in clinical trials

      On 1 September 2017, using clinicaltrial.gov, we identified three ongoing trials concerning the effect of physical activity or muscular stimulation, associated or not with other therapies (relaxation techniques, omega-3 fatty acids, etc.) on sarcopenia and/or cancer cachexia (NCT03151291, NCT02293239, NCT02330926). Two additional tests have been completed but have not yet been published (NCT01136083, NCT0090492).
      In a recently published study, a multimodal strategy combining oral nutritional supplements enriched with omega-3, anti-COX2 and physical activity, despite a poor compliance at 6 weeks, found stabilization of weight and muscle mass in experimental group compared with control group [
      • Solheim T.S.
      • Laird B.J.A.
      • Balstad T.R.
      • et al.
      A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer.
      ]. Neither muscle strength nor fatigue score was enhanced by multimodal treatment.
      In a recent meta-analysis, the effect of physical activity on fatigue in cancer patients was as effective at both metastatic and nonmetastatic stages, and appeared to be equivalent, or even more effective (to the same extent as psychotherapy or relaxation) than medication management [
      • Mustian K.M.
      • Alfano C.M.
      • Heckler C.
      • et al.
      Comparison of pharmaceutical, psychological, and exercise treatments for cancer-related fatigue: a meta-analysis.
      ]. However, the last Cochrane meta-analysis specifically focusing on the effect of physical activity on cancer and cachectic patients concluded that there was insufficient data to determine its safety and efficacy in this context [
      • Grande A.J.
      • Silva V.
      • Maddocks M.
      Exercise for cancer cachexia in adults: executive summary of a cochrane collaboration systematic review.
      ].
      In sarcopenic cancer patients (head and neck, prostate, lymphoma), or probably sarcopenic but not cachectic, regular physical activity during treatment improves muscle mass and strength, fatigue, and quality of life [
      • Galvão D.A.
      • Taaffe D.R.
      • Spry N.
      • et al.
      Combined resistance and aerobic exercise program reverses muscle loss in men undergoing androgen suppression therapy for prostate cancer without bone metastases: a randomized controlled trial.
      ,
      • Nedergaard A.
      • Dalgas U.
      • Primdahl H.
      • et al.
      Collagen fragment biomarkers as serological biomarkers of lean body mass—a biomarker pilot study from the DAHANCA25B cohort and matched controls.
      ,
      • Lønbro S.
      • Dalgas U.
      • Primdahl H.
      • et al.
      Progressive resistance training rebuilds lean body mass in head and neck cancer patients after radiotherapy—results from the randomized DAHANCA 25B trial.
      ,
      • Lønbro S.
      • Dalgas U.
      • Primdahl H.
      • et al.
      Lean body mass and muscle function in head and neck cancer patients and healthy individuals—results from the DAHANCA 25 study.
      ,
      • Adamsen L.
      • Quist M.
      • Andersen C.
      • et al.
      Effect of a multimodal high intensity exercise intervention in cancer patients undergoing chemotherapy: randomised controlled trial.
      ,
      • Courneya K.S.
      • Sellar C.M.
      • Stevinson C.
      • et al.
      Randomized controlled trial of the effects of aerobic exercise on physical functioning and quality of life in lymphoma patients.
      ,
      • Courneya K.S.
      • Jones L.W.
      • Peddle C.J.
      • et al.
      Effects of aerobic exercise training in anemic cancer patients receiving darbepoetin alfa: a randomized controlled trial.
      ].
      Several uncontrolled prospective studies have shown positive effects of physical activity in patients with advanced cancer of function or muscle strength [
      • Litterini A.J.1
      • Fieler V.K.
      • Cavanaugh J.T.
      • Lee JQ.
      Differential effects of cardiovascular and resistance exercise on functional mobility in individuals with advanced cancer: a randomized trial.
      ,
      • van den Dungen I.A.
      • Verhagen C.A.
      • van der Graaf W.T.
      • et al.
      Feasibility and impact of a physical exercise program in patients with advanced cancer: a pilot study.
      ,
      • Chasen M.R.
      • Feldstain A.
      • Gravelle D.
      • et al.
      An interprofessional palliative care oncology rehabilitation program: effects on function and predictors of program completion.
      ], functional status or nutritional status and fatigue or quality of life [
      • Chasen M.R.
      • Feldstain A.
      • Gravelle D.
      • et al.
      An interprofessional palliative care oncology rehabilitation program: effects on function and predictors of program completion.
      ,
      • Temel J.S.
      • Greer J.A.
      • Goldberg S.
      • et al.
      A structured exercise program for patients with advanced non-small cell lung cancer.
      ]. A randomized controlled trial in patients identified as cachectic showed a stabilization of muscle function (hand grip test and 6-minute walk test) in patients undergoing a physical activity, endurance and aerobic program, of 8 weeks with 2 sessions per week [
      • Oldervoll L.M.
      • Loge J.H.
      • Lydersen S.
      • et al.
      Physical exercise for cancer patients with advanced disease: a randomized controlled trial.
      ]. However, 35.5% of randomized patients “physical activity” group (22.6% in control group) did not follow the initially planned program. Indeed, the follow-up (or adherence) of physical activity programs in patients with locally advanced or metastatic cancer is debated. A compliance rate between 50 and 65% was found in other studies [
      • Solheim T.S.
      • Laird B.J.A.
      • Balstad T.R.
      • et al.
      A randomized phase II feasibility trial of a multimodal intervention for the management of cachexia in lung and pancreatic cancer.
      ,
      • van den Dungen I.A.
      • Verhagen C.A.
      • van der Graaf W.T.
      • et al.
      Feasibility and impact of a physical exercise program in patients with advanced cancer: a pilot study.
      ,
      • Temel J.S.
      • Greer J.A.
      • Goldberg S.
      • et al.
      A structured exercise program for patients with advanced non-small cell lung cancer.
      ,
      • Glare P.
      • Jongs W.
      • Zafiropoulos B.
      Establishing a cancer nutrition rehabilitation program (CNRP) for ambulatory patients attending an Australian cancer center.
      ]. In a survey of advanced cancer patients, 100% felt they were physically able to follow an adapted physical activity (APA) program, but only two-thirds had undertaken to do so [
      • Maddocks M.
      • Armstrong S.
      • Wilcock A.
      Exercise as a supportive therapy in incurable cancer: exploring patient preferences.
      ]. In the study by Chasen et al., the only independent predictor of good adherence to an APA program in patients with advanced cancer was low CRP, suggesting the lack of interest in APA in patients with severe or refractory cachexia [
      • Chasen M.R.
      • Feldstain A.
      • Gravelle D.
      • et al.
      An interprofessional palliative care oncology rehabilitation program: effects on function and predictors of program completion.
      ].
      APA associated with other therapies may be more effective in cachectic or precachectic patients. In the study by Pyszora et al., a physiotherapy program including physical exercise (compared with standard care) twice daily for 12 days in 60 patients with an average Karnofsky performance status (KPS) of 47% significantly improved the fatigue score (Brief Fatigue Inventory) and several symptoms, including anorexia, included in the Edmonton Symptom Assessment Scale [
      • Pyszora A.
      • Budzyński J.
      • Wójcik A.
      • et al.
      Physiotherapy programme reduces fatigue in patients with advanced cancer receiving palliative care: randomized controlled trial.
      ]. Several studies combining physical activity with dietary advice (with or without nutritional supplements) have improved nutritional status, appetite or ingesta [
      • Glare P.
      • Jongs W.
      • Zafiropoulos B.
      Establishing a cancer nutrition rehabilitation program (CNRP) for ambulatory patients attending an Australian cancer center.
      ,
      • Del Fabbro E.
      • Hui D.
      • Dalal S.
      • et al.
      Clinical outcomes and contributors to weight loss in a cancer cachexia clinic.
      ,
      • Kapoor N.
      • Naufahu J.
      • Tewfik S.
      • et al.
      A prospective randomized controlled trial to study the impact of a nutrition-sensitive intervention on adult women with cancer cachexia undergoing palliative care in India.
      ], or quality of life [
      • Kapoor N.
      • Naufahu J.
      • Tewfik S.
      • et al.
      A prospective randomized controlled trial to study the impact of a nutrition-sensitive intervention on adult women with cancer cachexia undergoing palliative care in India.
      ].

      Conclusions

      In cancer patients, we can express that a decrease in mass, density, strength, or function of skeletal muscle is linked to a decrease in survival, and associated with poor outcome. Muscle wasting is associated to chemotherapy toxicities, progression free survival, overall survival, and postoperative complications. The question of the possibility in increasing muscle mass or minimizing skeletal muscle disorders is still open. In physiologic conditions, skeletal muscle is characterized by a protein breakdown in the fasting state and MPS in the postprandial state. The net balance at the end of the day is a stable muscle mass. In cancer patients, the ability of AA to stimulate protein synthesis is reduced. Considering nutritional intervention, this AR could be in a part counteracted by increasing protein, AA quantity and administration of specific AA specialty Leucine. Leucine, by increasing substrate availability and by directly modulating the anabolic signal pathway, might counteract this AR. Few well designed and sophisticated kinetic studies, showed the possibility of increasing MPS by specific nutriments and/or by increasing amino acids or protein administration.
      However, the translation of acute anabolic effects into gains of muscle mass and function have to be confirmed. Further research is needed in order to validate the hypothesis of Deutz and Wolf that there are no upper limits to the anabolic response to protein or amino acid intake [
      • Deutz N.E.
      • Wolfe RR.
      Is there a maximal anabolic response to protein intake with a meal?.
      ].
      As far as exercise is concerned, while many studies provide evidence of a benefit of APA in advanced cancer patients, it is difficult to specify the most appropriate type of exercise and the optimum rhythm and intensity. It is likely that the benefits of physical activity are greater when it is started at the precachexia stage rather than at the cachexia stage, and its benefit is limited or nonexistent (in addition to not be feasible) at the stage of refractory cachexia. Finally, future approaches should integrate the combination of several complementary treatments in order to prevent or improve cachexia and/or sarcopenia.

      Acknowledgement

      The authors wish to thank Dr Olivier Mir for his support to this work.

      Funding

      This supplement was made possible by funding support from Helsinn. Helsinn did not have any influence on the content and all items are subject to independent peer-review.

      Disclosure

      SA has acted as board member for Chugai; BR has received honoraria from Fresenius Kabi France as member of the NUTRICANCER2012 advisory board.

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