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Symposium 4: Hot topics in parenteral nutrition A review of the use of glutamine supplementation in the nutritional support of patients undergoing bone-marrow transplantation and traditional cancer therapy

Conference on ‘Malnutrition matters’

Published online by Cambridge University Press:  24 June 2009

Mark Crowther
Mark Crowther*
Affiliation:
Department of Haematology, Aberdeen Royal Infirmary, Foresterhill, AberdeenAB25 2ZD, UK
*
Corresponding author: Dr Mark Crowther, fax +44 1224 557014, email [email protected]
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Abstract

The relationship between glutamine and malignancy can be traced back to the 1950s and the requirement for glutamine for malignant-cell growth in culture. Later studies demonstrated an association between the rate of proliferation of the malignant cells and glutamine usage. The excessive use of glutamine by malignant cells was seen as an opportunity for the development of a treatment using glutamine analogues, but unfortunately excessive toxicity was observed during clinical studies. In animal models glutamine supplementation, initially thought to increase tumour growth, actually causes tumour regression as a result of improved immune clearance of the tumour and appears to reduce the severity of the side effects of chemo- and radiotherapy. This finding led to human studies in both traditional cancer therapy and bone-marrow transplantation, which are reviewed here. Unfortunately, the majority of the studies performed are small and have poor methodological reporting. There is clinical heterogeneity in terms of routes of administration, dosing schedules, chemotherapy regimens and diseases. Studies of glutamine in non-bone-marrow transplantation chemo- and/or radiotherapy treatment suggest a possible trend towards reductions in objective mucositis but no effect on subjective symptoms. There is no evidence for its effect on other clinical outcomes. For bone-marrow transplantation there appears to be some benefit from oral glutamine in reducing mucositis and graft v. host disease, while intravenous glutamine may reduce infections but at the expense of an increased relapse rate. Good-quality studies are required in this area.

Keywords

GlutamineCancerMalignancyChemotherapyComplications
Type
Research Article
Information
Proceedings of the Nutrition Society , Volume 68 , Issue 3 , August 2009 , pp. 269 - 273
Copyright
Copyright © The Author 2009

Starting in the test tube …

The 1950s brought great advances in cell-culture techniques such that mammalian cells could be continuously grown outside the body. The first immortal cell line used cervical cancer cells (HeLa cells)(Reference Scherer, Syverton and Gey1) and much work was done in finding the best culture mediums that allowed maximal cell growth. One nutrient that was found to be important and used avidly by the tumour cells was glutamine(Reference Eagle2). Scientists, now aware of a relationship between cancer and glutamine, investigated matters further.

It became apparent that the more rapidly growing, hence more aggressive, the tumour the more glutamine it metabolised(Reference Knox, Horowitz and Friedell3). Animal studies raised the possibility of a ‘glutamine trap’ in which the tumour consumes glutamine at a higher rate than other tissues and deficiency occurs(Reference Carrascosa, Martinez and Nunez de Castro4). This deficiency, it was thought, may have led to the cachexia and weight loss of malignancy. However, many of these studies used mouse and rat models of cancer in which the tumour was between 10% and 20% of the body weight of the animal, a much greater percentage than in human malignancies(Reference Chen, Salloum and Austgen5).

Glutamine supplementation: good or bad?

In animal models of cancer many researchers had thought that glutamine supplementation would cause increased tumour growth, as the amino acid appeared to be an important fuel for the tumour. Supplementation with glutamine actually causes tumour regression in some cases because glutamine is the preferred fuel of the body's tumour-killing cells, the natural killer cells(Reference Klimberg and McClellan6).

Glutamine was given to rats and mice after they had received chemo- and/or radiotherapy and it was found to reduce damage to the gut(Reference Fox, Kripke and De Paula7, Reference Klimberg, Salloum and Kasper8), hence reducing infections, which are a major cause of morbidity and mortality in patients with cancer.

Human studies

With the encouraging evidence from animal studies of decreased side effects of chemo- and radiotherapy and the suggestion that glutamine does not increase tumour size several studies of glutamine supplementation in human subjects were conducted.

The studies gave either oral or intravenous glutamine and the intravenous glutamine was given either with total parenteral nutrition or alone. The studies can be further divided into those in which patients received bone-marrow transplantation and those in which patients received traditional chemotherapy.

Chemotherapy and radiotherapy

Traditional chemotherapy involves the administration of cytotoxic drugs that kill rapidly-dividing cells, which include malignant cells(Reference Gerson, Bhalla, Grant, Hoffman, Benz, Shattil, Furie and Cohen9). After administration there is a rest period during which the body recovers from the chemotherapy before more is given. Chemotherapy also damages rapidly-dividing normal cells, e.g. cells lining the gut, hair follicles and the bone marrow. It is the damage to the normal cells that leads to the side effects (mucositis from gut damage and increased infections from bone-marrow damage)(Reference Gerson, Bhalla, Grant, Hoffman, Benz, Shattil, Furie and Cohen9). Radiotherapy is the administration of radiation, usually in the form of ionising radiation, which as in chemotherapy damages rapidly-dividing cells(Reference Ng, Mauch, Hoffman, Benz, Shattil, Furie and Cohen10).

A brief search of PubMed has revealed nine randomised controlled trials that administered glutamine to patients receiving chemotherapy and/or radiotherapy(Reference Anderson, Schroeder and Skubitz11–Reference van Zaanen, van der Lelie and Timmer19). These studies are summarised in Table 1. Examination of one study(Reference Peterson, Jones and Petit18) led to concerns over the methodology of the study and consequently it will not be discussed further.

Table 1. Summary of randomised controlled studies of the administration of glutamine to patients receiving chemo- and/or radiotherapy

5-FU, 5-fluorouracil.

Considerable heterogeneity was found in the studies in relation to dosages and routes of administration of glutamine, malignancies and clinical outcomes. Unfortunately, the majority of the studies were small and had poor methodological reporting. Three studies report reduced mucositis with glutamine(Reference Anderson, Schroeder and Skubitz11–Reference Daniele, Perrone and Gallo13), while two report reduced subjective measures of mucositis (gut absorbtive capacity and endoscopic appearances) but no reduction in subjective symptoms of mucositis(Reference Decker-Baumann, Buhl and Frohmüller14, Reference Huang, Leung and Wang15). Three studies report no change in mucositis(Reference Jebb, Osborne and Maughant16, Reference Okuno, Woodhouse and Loprinzi17, Reference van Zaanen, van der Lelie and Timmer19). Neither of the two studies reporting infections(Reference Cerchietti, Navigante and Lutteral12, Reference van Zaanen, van der Lelie and Timmer19) demonstrates a difference in the number of infections.

Meta-analysis (Review Manager version 5.0 software; Cochrane Collaboration, Oxford, UK) was possible in two outcomes, which are reported as risk ratio and 95% CI. No significant difference was found between placebo and control when the presence of mucositis (objective measures risk ratio 0·94 (95% CI 0·65, 1·36) and subjective measures risk ratio 1·40 (95% CI 0·96, 2·05)) or severe mucositis (objective measures risk ratio 0·82 (95% CI 0·57, 1·18) and subjective measures risk ratio 1·12 (95% CI 0·68, 1·84)) was analysed. The forest plots are shown in Figs. 1 and 2.

Fig. 1. Meta-analysis of the presence of mucositis in patients undergoing non-bone-marrow transplantation chemo- and/or radiotherapy. M-H, Mantel-Haenszel; ←, →, values extend beyond range of values shown.

Fig. 2. Meta-analysis of the presence of severe mucositis in patients undergoing non-bone-marrow transplantation chemo- and/or radiotherapy. M-H, Mantel-Haenszel; ←, →, values extend beyond range of values shown.

Bone-marrow transplantation

The dose-limiting factor in giving chemotherapy is bone-marrow toxicity(Reference Hoffbrand, Pettit and Moss20). The harvesting of a patient's bone marrow, storing it while chemotherapy is administered and then re-infusing the marrow after the chemotherapy allows higher doses of chemotherapy to be given (autologous transplantation) as the bone marrow is spared from the effects of the chemotherapy. Using a donor's marrow (allogeneic transplantation) has the added advantage that the transplanted cells attack malignant cells (graft v. leukaemia effect) but this procedure can also be detrimental if the graft attacks normal tissues (graft v. host disease). Bone-marrow transplantation results in prolonged hospitalisation, infections and mucositis to a greater extent than traditional chemotherapy regimens(Reference Hoffbrand, Pettit and Moss20).

A systematic review of glutamine supplementation and bone-marrow transplantation has recently been completed(Reference Crowther, Avenell and Culligan21). Briefly, the search has produced seventeen(Reference Anderson, Ramsay and Shu22–Reference Blijlevens, Donnelly and Naber38) randomised controlled trials, of which seven used oral glutamine(Reference Anderson, Ramsay and Shu22–Reference Schloerb and Skikne28) and ten used intravenous glutamine(Reference Ziegler, Young and Benfell29–Reference Blijlevens, Donnelly and Naber38). Five studies investigated autologous transplantation(Reference Canovas, Leon-Sanz and Gomez24, Reference Jebb, Marcus and Elia26, Reference Sykorova, Horacek and Zak30, Reference Pytlik, Benes and Patorkova32, Reference Piccirillo, De Matteis and Laurenti33) while four investigated allogeneic transplantation(Reference Picardi, Selleri and Volpicelli27, Reference Ziegler, Young and Benfell29, Reference Masszi, Batai and Remenyl34, Reference Blijlevens, Donnelly and Naber38) and seven were mixed transplant types(Reference Anderson, Ramsay and Shu22, Reference Aquino, Harvey and Garvin23, Reference Coghlin Dickson, Wong and Negrin25, Reference Schloerb and Skikne28, Reference Schloerb and Amare31, Reference Gomez Candela, Castillo and de Cos35, Reference Brown, Goringe and Fegan37). Considerable heterogeneity was found in ages, dosing and underlying diseases.

Meta-analysis of these studies suggests a decrease in mucositis and graft v. host disease with oral glutamine but no effect with intravenous glutamine. There is also a reduction in infections with intravenous glutamine. There is, however, an increase in relapse with intravenous glutamine but this result was based on two small studies(Reference Sykorova, Horacek and Zak30, Reference Pytlik, Benes and Patorkova32) of patients undergoing autologous transplantation.

Conclusions

Glutamine and cancer have a long history but so far there is no clear evidence for glutamine supplementation following conventional chemotherapy. A similar conclusion has been reached by the Cochrane review in this area(Reference Worthington, Clarkson and Eden39). The problem has been that the majority of the studies performed have been small and have poor reporting of methodology. There have also been several different regimens of glutamine dosing and administration. The chemotherapy used and the tumours treated have also been different. There may therefore be a benefit in specific cancers and chemotherapy regimens.

There have been a larger number of studies performed with patients undergoing bone-marrow transplantation, but again many of these have been small and demonstrate poor methodological quality. There may be benefit for oral glutamine in reducing mucositis and graft v. host disease and for intravenous glutamine in reducing infections, but this outcome may be at the expense of increased relapse.

In both areas larger well-conducted and -reported randomised controlled trials are required.

Acknowledgements

The author declares no conflicts of interest. The author thanks Alison Avenell, Xueli Jia, Tania Lourenco and Romana Kucerova for help with data extraction and quality assessment. M. C. was employed as a Clinical Research Fellow by the Chief Scientist Office of the Scottish Government when this work was carried out.

References

1. Scherer, WF, Syverton, JT & Gey, GO (1953) Studies in the propagation of in vitro poliomyelitis viruses. J Exp Med 97, 695–720.CrossRefGoogle ScholarPubMed
2. Eagle, (1976) Media for animal cell culture. Methods Cell Sci 3, 517–520.Google Scholar
3. Knox, WE, Horowitz, ML & Friedell, GH (1969) The proportionality of glutaminase content to growth rate and morphology of rat neoplasms. Cancer Res 29, 669–680.Google ScholarPubMed
4. Carrascosa, JM, Martinez, P & Nunez de Castro, I (1984) Nitrogen movement between host and tumour in mice inoculated with Ehrlich ascitic tumour cells. Cancer Res 44, 3831–3835.Google Scholar
5. Chen, MK, Salloum, RM, Austgen, TR et al. (1991) Tumour regulation of hepatic glutamine metabolism. JPEN J Parenter Enteral Nutr 15, 159–164.CrossRefGoogle ScholarPubMed
6. Klimberg, VS & McClellan, JL (1996) Glutamine, cancer, and its therapy. Am J Surg 172, 418–424.CrossRefGoogle ScholarPubMed
7. Fox, AD, Kripke, SA, De Paula, J et al. (1988) Effect of a glutamine-supplemented enteral diet on methotrexate-induced enterocolitis. JPEN J Parenter Enteral Nutr 12, 325–331.CrossRefGoogle ScholarPubMed
8. Klimberg, VS, Salloum, RM, Kasper, M et al. (1990) Oral glutamine accelerates healing of the small intestine and improves outcome after whole abdominal radiation. Arch Surgery 125, 1040–1045.CrossRefGoogle ScholarPubMed
9. Gerson, SL, Bhalla, KN, Grant, S et al. (2005) Pharmacological and molecular mechanisms of antineoplastic agents for hematological malignancies. In Hematology. Basic Principles and Practice, 4th ed., pp. 955–1018 [Hoffman, R, Benz, E, Shattil, S, Furie, B and Cohen, H]. Philadelphia, PA: Elsevier.Google Scholar
10. Ng, AK & Mauch, PM (2005) Radiation therapy in the treatment of hematological malignancies. In Hematology. Basic Principles and Practice, 4th ed., pp. 1019–1028 [Hoffman, R, Benz, E, Shattil, S, Furie, B and Cohen, H]. Philadelphia, PA: Elsevier.Google Scholar
11. Anderson, PM, Schroeder, G & Skubitz, KM (1998) Oral glutamine reduces the duration and severity of stomatitis after cytotoxic cancer chemotherapy. Cancer 83, 1433–1439.3.0.CO;2-4>CrossRefGoogle ScholarPubMed
12. Cerchietti, LCA, Navigante, AH, Lutteral, MA et al. (2006) Double-blinded placebo-controlled study on intravenous L-alanyl-L-glutamine in the incidence of oral mucositis following chemoradiotherapy in patients with head-and-neck cancer. Int J Radiat Oncol Biol Phys 65, 1330–1337.CrossRefGoogle Scholar
13. Daniele, B, Perrone, F, Gallo, C et al. (2001) Oral glutamine in the prevention of flurouracil induced intestinal toxicity: a double blind, placebo controlled, randomised study. Gut 48, 28–33.CrossRefGoogle Scholar
14. Decker-Baumann, C, Buhl, K, Frohmüller, S et al. (1999) Reduction of chemotherapy-induced side-effects by parenteral glutamine supplementation in patients with metastatic colorectal cancer. Eur J Cancer 35, 202–207.CrossRefGoogle ScholarPubMed
15. Huang, EY, Leung, SW, Wang, CJ et al. (2000) Oral glutamine to alleviate radiation-induced oral mucositis: a pilot randomized study. Int J Radiat Oncol Biol Phys 48, 535–539.CrossRefGoogle Scholar
16. Jebb, SA, Osborne, RJ, Maughant, TS et al. (1994) 5-Fluorouracil and folinic acid induced mucositis: no effect of oral glutamine supplementation. Br J Cancer 70, 732–735.CrossRefGoogle ScholarPubMed
17. Okuno, SH, Woodhouse, CO, Loprinzi, CL et al. (1999) Phase III controlled evaluation of glutamine for decreasing stomatitis in patients receiving flurouracil (5-FU)-based chemotherapy. Am J Clin Oncol 22, 258–261.CrossRefGoogle Scholar
18. Peterson, DE, Jones, JB & Petit, RG (2006) Randomized, placebo-controlled study of saforis for prevention and treatment of oral mucositis in breast cancer patients receiving anthracycline-based chemotherapy. Cancer 109, 322–331.CrossRefGoogle Scholar
19. van Zaanen, HCT, van der Lelie, H, Timmer, JG et al. (1994) Parenteral glutamine dipeptide supplementation does not ameliorate chemotherapy-induced toxicity. Cancer 74, 2879–2884.3.0.CO;2-H>CrossRefGoogle Scholar
20. Hoffbrand, AV, Pettit, JE & Moss, PAH (2005) Essential Haematology, 4th ed., pp. 98–112. Oxford: Blackwell.Google Scholar
21. Crowther, M, Avenell, A & Culligan, DJ (2009) Systemic review and meta-analysis of studies of glutamine in haematopoietic stem cell transplantation. Bone Marrow Transplant (Epublication ahead of print version).CrossRefGoogle Scholar
22. Anderson, PM, Ramsay, NK, Shu, XO et al. (1998) Effect of low-dose oral glutamine on painful stomatitis during bone marrow transplantation. Bone Marrow Transplant 22, 339–344.CrossRefGoogle ScholarPubMed
23. Aquino, VM, Harvey, AR, Garvin, JH et al. (2005) A double-blind randomized placebo-controlled study of oral glutamine in the prevention of mucositis in children undergoing hematopoietic stem cell transplantation: a pediatric blood and marrow transplant consortium study. Bone Marrow Transplant 36, 611–616.CrossRefGoogle ScholarPubMed
24. Canovas, G, Leon-Sanz, M, Gomez, P et al. (2000) Oral glutamine supplements in autologous hematopoietic transplant: Impact on gastrointestinal toxicity and plasma protein levels. Haematologica 85, 1229–1230.Google ScholarPubMed
25. Coghlin Dickson, TM, Wong, RM, Negrin, RS et al. (2000) Effect of oral glutamine supplementation during bone marrow transplantation. JPEN 24, 61–66.CrossRefGoogle ScholarPubMed
26. Jebb, SA, Marcus, R & Elia, M (1995) A pilot study of oral glutamine supplementation in patients receiving bone marrow transplants. Clin Nutr 14, 162–165.CrossRefGoogle ScholarPubMed
27. Picardi, M, Selleri, C, Volpicelli, M et al. (2001) Effect of early administration of high-dose oral glutamine in allogeneic bone marrow transplanted patients. Bone Marrow Transplant 27, 338.Google Scholar
28. Schloerb, PR & Skikne, BS (1999) Oral and parenteral glutamine in bone marrow transplantation: a randomized, double-blind study. JPEN J Parenter Enteral Nutr 23, 117–122.CrossRefGoogle ScholarPubMed
29. Ziegler, TR, Young, LS, Benfell, K et al. (1992) Clinical and metabolic efficacy of glutamine-supplemented parenteral nutrition after bone marrow transplantation. A randomized, double-blind, controlled study. Ann Intern Med 116, 821–828.CrossRefGoogle ScholarPubMed
30. Sykorova, A, Horacek, J, Zak, P et al. (2005) A randomized, double blind comparative study of prophylactic parenteral nutritional support with or without glutamine in autologous stem cell transplantation for hematological malignancies –three years' follow-up. Neoplasma 52, 476–482.Google ScholarPubMed
31. Schloerb, PR & Amare, M (1993) Total parenteral nutrition with glutamine in bone marrow transplantation and other clinical applications (a randomized, double-blind study). JPEN J Parenter Enteral Nutr 17, 407–413.CrossRefGoogle ScholarPubMed
32. Pytlik, R, Benes, P, Patorkova, M et al. (2002) Standardized parenteral alanyl-glutamine dipeptide supplementation is not beneficial in autologous transplant patients: a randomized, double-blind, placebo controlled study. Bone Marrow Transplant 30, 953–961.CrossRefGoogle Scholar
33. Piccirillo, N, De Matteis, S, Laurenti, L et al. (2003) Glutamine-enriched parenteral nutrition after autologous peripheral blood stem cell transplantation: effects on immune reconstitution and mucositis. Haematologica 88, 192–200.Google ScholarPubMed
34. Masszi, T, Batai, A, Remenyl, P et al. (2000) ABMT patients benefit from glutamine supplementation of total parenteral nutrition. Bone Marrow Transplant 25, S240.Google Scholar
35. Gomez Candela, C, Castillo, R, de Cos, AI et al. (2006) Efectos de la glutamina parenteral en pacientes sometidos a trasplante de médula ósea. (Effects of parenteral glutamine in patients submitted to bone marrow transplantation). Nutr Hosp 21, 13–21.Google Scholar
36. da Gama Torres, HO, Vilela, EG, da Cunha, AS et al. (2008) Efficacy of glutamine-supplemented parenteral nutrition on short-term survival following allo-SCT: a randomized study. Bone Marrow Transplant 41, 1021–1027.CrossRefGoogle ScholarPubMed
37. Brown, SA, Goringe, A, Fegan, C et al. (1998) Parenteral glutamine protects hepatic function during bone marrow transplantation. Bone Marrow Transplant 22, 281–284.CrossRefGoogle ScholarPubMed
38. Blijlevens, NM, Donnelly, JP, Naber, AH et al. (2005) A randomised, double-blinded, placebo-controlled, pilot study of parenteral glutamine for allogeneic stem cell transplant patients. Support Care Cancer 13, 790–796.CrossRefGoogle ScholarPubMed
39. Worthington, HV, Clarkson, JE & Eden, TOB (2007) Interventions for preventing oral mucositis for patients with cancer receiving treatment. Cochrane Database of Systematic Reviews, issue 4. CD000978. Chichester, West Sussex: John Wiley and Sons Ltd.Google Scholar
Figure 0

Table 1. Summary of randomised controlled studies of the administration of glutamine to patients receiving chemo- and/or radiotherapy

Figure 1

Fig. 1. Meta-analysis of the presence of mucositis in patients undergoing non-bone-marrow transplantation chemo- and/or radiotherapy. M-H, Mantel-Haenszel; ←, →, values extend beyond range of values shown.

Figure 2

Fig. 2. Meta-analysis of the presence of severe mucositis in patients undergoing non-bone-marrow transplantation chemo- and/or radiotherapy. M-H, Mantel-Haenszel; ←, →, values extend beyond range of values shown.