Eda K, Uzer K, Murat T, Cenk U. The effects of enteral glutamine on radiotherapy induced dermatitis in breast cancer. Clin Nutr. 2016;35:436-439.
The study aimed to assess occurrence/severity/progression of radiation dermatitis with and without oral glutamine intervention.
The study included 40 patients with breast carcinoma who had undergone either modified radical mastectomy (MRM) or breast-conserving surgery followed by radiotherapy. The majority of the patients received supraclavicular field radiotherapy in addition to either whole breast (n=30) or thoracic wall (n=10) radiotherapy. Eighteen of those in the treatment group and 20 of those in the placebo group underwent chemotherapy. Whether chemotherapy was administered before or after radiation was not detailed. Average age of subjects was 50.3 y in the treatment group and 46 y in the placebo group.
Study Medication and Dosage
Patients were randomized to receive either 15 g of glutamine per day (divided into 5 g doses 3 times daily) or placebo. The glutamine solution was prepared by mixing glutamine in 250 ml of water at room temperature. The placebo group received a solution of the same volume containing glucose and matching the appearance of the treatment solution. Both groups began receiving the solutions 1 week before radiation and continued until 1 week after radiation. The total prescribed radiation dose ranged from 50 Gy to 76 Gy. The total number of sessions was not reported.
Radiation dermatitis (RDS) was assessed with use of a radiation severity score (a scoring system adapted by the Radiation Treatment Oncology Group/The Organization for Research and Treatment of Cancer Acute Radiation Morbidity Scoring Criteria [RTOG/EORTC scale]). The radiation oncologist and oncology nurse measured the score. The timing and frequency of these assessments were not reported.
In the subjects assigned to use 15 g glutamine daily, there was a significant reduction in radiation dermatitis at the end of radiation therapy compared to placebo (P=0.001). The average RTOG/EORTC score for the patients treated with glutamine was grade 1 (scale range 0-4). For the placebo group, the average score was grade 2. Per the RTOG/EORTC scale, grade 1 toxicity is associated with follicular, faint, or dull erythema; epilation; dry desquamation; and/or decreased sweating. Grade 2 reflects tender or bright erythema; patchy, moist desquamation; and/or moderate edema. Of the 18 patients in the treatment group, 16 (88.9%) were scored at grade 1; the remaining 2 patients at grade 2. Of the 20 in the placebo group, 16 (80%) were scored at grade 2; the remaining 4 were grade 3. This difference reached statistical significance (P<0.0001). Again, timing of assessments is unknown, and progression of radiation dermatitis for both groups was not given. All patients tolerated 15 g of oral glutamine without issue. This study suggests that glutamine at a dose of 15 g/day was well-tolerated by all patients.
Radiation dermatitis is a problem for most patients undergoing radiation therapy. In breast cancer alone, more than 50% of those diagnosed will undergo radiation, and current guidelines recommend it within 6 months post-surgery.1-2 The local side effects of radiation consist of but are not limited to erythema, pain, moist desquamation, compromised mucosal membranes (most notable in patients undergoing radiation of the head and neck), pruritis, edematous tissue, alopecia, and xerosis. Systemic effects may include fatigue, lymphocytopenia, anemia, diarrhea, nausea, emesis, and depression. Erythema alone typically presents within the first week of treatment. Other effects may occur months to years after treatment and may be most notable and more significant in those also undergoing additional forms of cytotoxic therapy (eg, chemotherapy). These may involve abnormal skin reactions and the possibility of developing a second cancer.3 Radiation remains an effective and important mainstay in the treatment of several cancers. Therefore, it behooves us as practitioners to incorporate means to prevent and manage side effects associated with radiation therapy.
The clinical practice guidelines for the prevention and treatment of acute and late radiation reactions from the Multinational Association for Supportive Care in Cancer (MASCC) Skin Toxicity Study Group were last updated in August 2013. MASCC recommends washing with water, with or without a mild soap, and applying only topical corticosteroids, pentoxifylline, and vitamin E for RDS.4 These conservative recommendations have been made due to insufficient clinical evidence for other substances, even those that are commonly employed in many radiation centers.
There is a small pool of research on the management of radiation dermatitis with natural treatments. Most of this research has been on the use of topical applications; minimal research has been done on oral therapies.
Topical treatments studied include a platelet-based gel, a silymarin-based preparation (Laviaderm™), hyaluronic acid, calendula, and Xenaderm (a preparation composed of balsam peru, castor oil and trypsin). Silymarin-based products may provide benefit (although validity of studies was lacking).5 Platelet gel, while intriguing and with possible benefit, carries some risk of tumor growth around the site of application due to presence of growth factors.6-7 Topical hyaluronic acid worsened radiation dermatitis in one study.8 Xenaderm was found to be effective per a 2010 meta-analysis for radiation induced dermatitis;9 however, as noted in the previous review, it is an oil-based ointment, which excludes its use during radiation therapy.10 And finally, calendula, although a topical mainstay for several skin conditions, showed no benefit in the treatment/management of radiation dermatitis.11-12
If glutamine is to be employed effectively to mitigate tissue breakdown and promote tissue integrity as a preferred fuel source for most, if not all cells, there is worry that it may also promote the growth of other rapidly dividing cells—most notably cancer cells.
One of the oral therapies studied, curcumin, does hold promise in managing and preventing radiation-induced dermatitis. One randomized, placebo-controlled, double-blind study found that 6 g curcumin daily offered a significant reduction in some measures of radiation dermatitis.13 This study proved that it is important to assess not only topical but also oral therapies in the mitigation of radiation dermatitis.
The current study has added to this pool of research on oral therapies for the mitigation of radiation dermatitis.
Glutamine is the most abundant free amino acid in the body. It is a primary nutrient used in myriad functions: the promotion of rapid healing response, the mitigation of several symptoms associated with gastrointestinal distress/imbalance, the promotion of cytokines/chemokines that promote tissue healing, the maintenance of redox balance via the krebs cycle,14-15 the enhancement of muscle anabolism in athletes,16 and the mitigation of side effects associated with cytotoxic therapy.17 Glutamine also stimulates growth hormone and, in effect, insulin production, and decreases protein degradation.18-20 Studies have shown that oral glutamine shortens hospital stays for those previously compromised from massive tissue degradation (eg, post-surgery, post-burn).14,17 Basically, when the body is under trauma, the uptake of amino acids must overcome the total loss of protein breakdown. Glutamine is the primary amino acid employed in this process. Therefore the sole purpose of this non-essential amino acid may be in its ability to act as an integral fuel source for immune cells, enterocytes, and other rapidly proliferating cells. Here is where we find debate.
If glutamine is to be employed effectively to mitigate tissue breakdown and promote tissue integrity as a preferred fuel source for most, if not all cells, there is worry that it may also promote the growth of other rapidly dividing cells—most notably cancer cells. In fact, some studies have shown interfering with glutamine metabolism in cells may be effective in slowing tumor growth.21-22 There is also concern that when the primary fuel source of cancer cells (ie, glucose) is taken away, glutamine becomes the primary fuel driving tumorigenesis and invasion.23 And some forms of cancer (namely some pancreatic cancers) have a proclivity for glutamine over glucose as their preferred carbon (fuel) source.24
This becomes a conundrum: if we are employing glutamine to mitigate duration of physiological compromise, post cytotoxic treatments (here, in radiation) and in the promotion of well-being and longevity of these patients, are we, in so doing, also putting patients at risk for disease recurrence? Due to this concern, several practitioners have curbed the use of glutamine as primary therapy.
While this is a valid concern, there is another side to it. There is thought that glutamine will not promote proliferation and that glutamine, much like oxygen, water, and glucose, is simply a necessary exogenous material required by all cells. The need for it becomes more prominent when the body, as noted above, undergoes stressors such as long-term illness, infection, trauma, surgery and the extreme catabolic effects of cancer treatments that make glutamine necessary for physiological integrity and bodily function. Additionally, some research appears to provide evidence that glutamine may actually support the survival rates of patients undergoing cytotoxic forms of therapy.25 Further, glutamine supplementation in cancer patients may improve the overall clinical situation without increasing tumor growth.26 And like that of many other energy sources, the use of glutamine is dependent on and driven by the hormonal state of the organism and/or the microenvironment of the tumor.14,22 For example, a high insulin state is key to the development and support of unregulated glutamine (and glucose) consumption in tumor cells.27 Therefore, glutamine may be an integral piece of overall survival in catabolic states as long as the hormonal and inflammatory state of the patient is sound. In effect, it may come down to the “terrain” of the individual.
Obviously, there is no clear consensus here and therefore the ongoing debate continues regarding the use of glutamine supplementation for those patients with cancer.
While this study does seem to shine light on a potential significant and viable therapeutic avenue for patients undergoing radiation, there are some limitations to its methodology. The placebo employed was glucose. We do not know how much glucose was administered. There are multiple studies citing the effects of glucose not only on cancer progression but also on immune suppression and poor healing response. Might this have been a complication in this study? Would patients receiving only water or normal saline have had less risk and presence of grade 2 and 3 radiation dermatitis? In addition, no data were supplied regarding the timing and completion of assessments. Therefore, we cannot know if there was difference in symptom progression between treatment groups or how long dermatitis prevailed.
Overall, this study does add to our limited research pool on oral therapies in the management of radiation dermatitis. Clearly, more studies will aid in the elucidation of just how important glutamine may be. As discussed, more studies that clarify the true risk of glutamine supplementation in those who have or have had cancer are also much needed.
- Colleoni M, Bonetti M, Coates AS, et al. Early start of adjuvant chemotherapy may improve treatment outcome for premenopausal breast cancer patients with tumors not expressing estrogen receptors: the International Breast Cancer Study Group. J Clin Oncol. 2000;18:584-590
- Goldhirsch A, Glick JH, Gelber RD, Coates, AS, Senn, HJ. Meeting highlights: International Consensus Panel on the treatment of primary breast cancer. J Clin Oncol. 2001;19:3817-3827.
- Schreiber GJ, Meyers AD. General principles of radiation therapy. http://emedicine.medscape.com/article/846797-overview. Updated October 15, 2015. Accessed June 27, 2016.
- Wong RK, Bensadoun RJ, Boers-Doets CB, et al. Clinical practice guidelines for the prevention and treatment of acute and late radiation reactions from the MASCC Skin Toxicity Study Group. Support Care Cancer. 2013;21(10):2933-2948.
- Becker-Schiebe M, Mengs U, Schaefer M, Bulitta M, Hoffmann W. Topical use of a silymarin-based preparation to prevent radiodermatitis: results of a prospective study in breast cancer patients. Strahlenther Onkol. 2011;187(8):485-491.
- Iervolino V, Di Costanzo G, Azzaro R, et al. Platelet gel in cutaneous radiation dermatitis. Support Care Cancer. 2013;21(1):287-293.
- Chen L, Wang C, Liu H, Liu G, Ran X. Antibacterial effect of autologous platelet-rich gel derived from subjects with diabetic dermal ulcers in vitro. J Diabetes Res. 2013;2013:269527.
- Pinnix C, Perkins GH, Strom EA, et al. Topical hyaluronic acid vs. standard of care for the prevention of radiation dermatitis after adjuvant radiotherapy for breast cancer: single-blind randomized phase III clinical trial. Int J Radiat Oncol Biol Phys. 2012;83(4):1089-1094.
- Abraham LM. Xenaderm: an essential wound care therapy. Adv Skin Wound Care. 2010;23(2):73-76.
- McDougall CJ, Franklin LE, Gresle SO. Management of radiation dermatitis in a patient after mastectomy. J Wound Ostomy Continence Nurs. 2005;32(5):337-340.
- Sharp L, Finnilä K, Johansson H, Abrahamsson M, Hatschek T, Bergenmar M. No differences between Calendula cream and aqueous cream in the prevention of acute radiation skin reactions--results from a randomised blinded trial. Eur J Oncol Nurs. 2013;17(4):429-435.
- Babaee N, Moslemi D, Khalilpour M, et al. Antioxidant capacity of calendula officinalis flowers extract and prevention of radiation induced oropharyngeal mucositis in patients with head and neck cancers: a randomized controlled clinical study. Daru. 2013;21(1):18.
- Ryan JL, Heckler CE, Ling M, et al. Curcumin for radiation dermatitis: a randomized, double-blind, placebo-controlled clinical trial of thirty breast cancer patients. Radiat Res. 2013;180(1):34-43.
- Newholme P. Why is L-glutamine metabolism important to cells of the immune system in health, post injury, surgery or infection? J Nutr. 2001;131:2515-2522.
- Bruins MJ, Soeters PB, Deutz NE. Endotoxemia affects organ protein metabolism differently during prolonged feeding in pigs. J Nutr. 2000;130:3003-3013.
- Song QH, Xu RM, Zhang QH, et al. Glutamine supplementation and immune function during heavy load training. Int J Clin Pharmacol Ther. 2015;53(5):372-376.
- Soeters PB, Grecu I. Have we enough glutamine and how does it work? A clinician’s view. Ann Nutr Metab. 2012;60:17-26.
- Parry-Bilings M, Bevan SJ, Opara E, Liu CT, Dunger DB, Newsholme ES. The effects of growth hormone and insulin-like growth factors I and II on glutamine metabolism by skeletal muscle of the rat in vitro. Horm Metab Res. 1993;25:243-245.
- Buffington CA. Muscle glutamine concentration and protein synthetic rate. J Parenter Enter Nutr. 1992;16:297-298.
- Biolo G, Iscra F, Bosutti A, et al. Growth hormone decreases muscle glutamine production and stimulates protein synthesis in hypercatabolic patients. Am J Physiol Endocrinol Metab. 2000;279:E323-E332.
- Wang Q, Hardie RA, Hoy AJ, et al. Targeting ASCT2-mediated glutamine uptake blocks prostate cancer growth and tumour development. J Pathol. 2015;236(3):278-289.
- Villar VH1, Merhi F, Djavaheri-Mergny M, Durán RV. Glutaminolysis and autophagy in cancer. Autophagy. 2015;11(8):1198-1208.
- Yang L, Moss T, Mangala LS, et al. Metabolic shifts toward glutamine regulate tumor growth, invasion and bioenergetics in ovarian cancer. Mol Syst Biol. 2014;10:728.
- Lyssiotis CA, Son J, Cantley LC, Kimmelman AC. Pancreatic cancers rely on a novel glutamine metabolism pathway to maintain redox balance. Cell Cycle. 2013;12(13):1987-1988.
- Topkan E, Parlak C, Topuk S, Pehlivan B. Influence of oral glutamine supplementation on survival outcomes of patients treated with concurrent chemoradiotherapy for locally advanced non-small cell lung cancer. BMC Cancer. 2012;12:502.
- Kuhn KS, Muscaritoli M, Wischmeyer P, Stehle P. Glutamine as indispensable nutrient in oncology: experimental and clinical evidence. Eur J Nutr. 2010;49(4):197-210.
- Visagie MH, Mqoco TV, Liebenberg L, Mathews EH, Mathews GE, Joubert AM. Influence of partial and complete glutamine-and glucose deprivation of breast-and cervical tumorigenic cell lines. Cell Biosci. 2015;5:37.