November 2016 E-Journal Club

Greetings,

We do not host a traineeship program in November, but we made time for journal club before everyone took some time for individual research on turkey, stuffing and pumpkin pie ingestion.  Our journal club article for November was a study investigating the effect of glutamine administration on the severity of mucositis during treatment of head and neck cancer.

November Citation:

Tsujimoto T, Yamamoto Y, Wasa M, et al. L-glutamine decreases the severity of mucositis induced by chemoradiotherapy in patients with locally advanced head and neck cancer: a double-blind, randomized, placebo-controlled trial. Oncol Rep. 2015;33(1):33-39.

Summary:

This was a double-blind, randomized, placebo controlled study of glutamine administration in 40 adult patients with head and neck cancer who were scheduled to undergo chemoradiotherapy (CRT: 66 or 70 Gy of total radiation at 2 Gy/fraction daily and 5 fractions per week with intravenous cisplatin and docetaxel once/week X 6 weeks).  The assignment of patients was stratified by gender, age (<65 or ≥65 years) and tumor location. Study participants received either 10 g of glutamine or placebo 3 times a day throughout the CRT course.  Evaluations were conducted each week by a nutrition support team. When severe mucositis prevented adequate oral intake, nutrition was provided through a feeding tube, and glutamine or placebo were dissolved in water and administered via the feeding tube 30 min before tube feedings were started.

The primary outcome was the severity of mucositis (National Cancer Institute Common Terminology Criteria for Adverse Events version 3.0). The secondary endpoints were duration and time to mucositis onset, patient-reported pain score according to a numerical rating scale (NRS), incidence and duration of opioid use, total opioid dose, incidence and duration of nutritional supplementation, and clinical data. The safety end points were the adverse effect incidence, abnormal laboratory findings and amino acid imbalance. Two ENT physicians assessed mucositis 1 X/week with the naked eye and laryngoscope until patient discharge. When grades of mucositis varied from site to site, the highest grade was chosen for the analysis. Patients assessed the strongest pain experienced during a day on a 0-10 scale. The primary treatment outcome was evaluated 10 weeks after the completion of treatment using computed tomography (CT), positron emission tomography/CT (PET-CT) and biopsy.

Inclusion and Exclusion Criteria:

Inclusion criteria:

Adult patients with pathologically diagnosed, primary squamous cell carcinoma of the nasopharynx, oropharynx, hypopharynx or larynx who were scheduled to undergo CRT.

Exclusion criteria:

Patients with active mouth or throat soreness before treatment, uncontrolled diabetes mellitus, or severe renal or hepatic insufficiency.

Major Results:

Fifty patients were initially enrolled, with data from 20 patients in each group ultimately analyzed due to 10 patients excluded due to not receiving the intended study product (1), refusal to participate (4), changes in treatment regimen (4) or “other” (1).  Baseline characteristics were similar between groups.

Some degree of mucositis developed in all patients in both groups. The mean time to mucositis onset, mean mucositis duration, time to severe mucositis, and the mean severe mucositis duration was not significantly different between the glutamine and placebo groups.

The most severe mucositis grade (Grade 4) occurred in 5 patients (25%) in the placebo group and none in the glutamine group.  Most patients in the study had grade 3 mucositis (n= 33), except 2 patients in the glutamine group had only grade 2 mucositis. The mean maximal grade of mucositis was significantly less in the glutamine group, compared to the placebo group (glutamine, 2.9±0.3; placebo, 3.3±0.4; p=0.005).  During weeks 5 and 6, the mean mucositis grade was significantly lower in the glutamine group compared to the placebo group (Data in table form only: week 5 p=0.027, week 6 p=0.002).

During weeks 4, 5 and 6, the median pain scores were significantly lower in the glutamine group compared to the placebo group (NRS scores not provided, only approximations from table 3B). The mean duration of opioid use was significantly shorter in the glutamine group compared to the placebo group (glutamine: 19±11 days; placebo: 28±14 days; p=0.029).  The mean total opioid dose was not significantly different between groups.

The need for supplemental enteral or parenteral nutrition support was not significantly different between groups, but the glutamine group received supplemental nutrition support for a significantly shorter period of time compared to the placebo group (glutamine 18±13 days; placebo, 27±11 days; p=0.046).  Treatment response and biochemical indices were similar between groups.

Author’s Conclusions:

“…the present study demonstrated that glutamine significantly decreases the severity of CRT-induced mucositis in HNC cancer patients.”

Evaluation:

Our group felt that this was a well conducted study, but the strength of the study conclusions is somewhat reduced by the short duration of the study and the limited number of patients in each treatment group.  There were only 20 patients in each group, so if several patients in one group had more severe mucositis by chance, it could easily have affected the results.

Small studies are more likely to suggest a significant difference between groups and the nutrition community has certainly been misled by small studies of glutamine in the past. The lessons learned from glutamine administration in critically ill patients was that small studies suggested beneficial effects, but adequately sized studies have revealed no benefits of supplemental glutamine in critically ill adults (and potential harm in patients with multi-organ failure).^1-2

In terms of the safety of glutamine administration to patients undergoing therapy for cancer, a 6 week study is far too short.  In a six week timespan with the variables investigated in this study, there would be no apparent harm from smoking cigarettes or chewing tobacco – and we know that neither of these are safe.

Another factor that we discussed was that the composition of the placebo was not mentioned.  It would have been desirable for the subjects to receive protein or a different amino acid as the placebo so that the nitrogen/protein delivery between the groups was similar.  The glutamine group received 30 gms/day (120 kcals/day) and the authors do not even state if the placebo was isocaloric with the glutamine supplement.  Although the calorie provision for glutamine was modest, 30 gm of glutamine/day would be a substantial contribution to the total daily nitrogen ingestion.

Our Take Home Message(s)

1. Glutamine may be beneficial to help reduce the severity of mucositis in head and neck cancer patients receiving chemo-radiation therapy.
2. There is a need for larger studies that investigate outcomes over a longer time period before is routinely used in clinical practice.
3. Studies of specific nutrients should provide an isocaloric/isonitrogenous placebo to distinguish pharmaconutrient effects compared to nutritional effects.

References:

1. Ziegler TR, May AK, Hebbar G, et al. Efficacy and Safety of Glutamine-supplemented Parenteral Nutrition in Surgical ICU Patients: An American Multicenter Randomized Controlled Trial. Ann Surg. 2016; 263(4):646-655.

2. Heyland D, Muscedere J, Wischmeyer PE, et al. A randomized trial of glutamine and antioxidants in critically ill patients. N Engl J Med. 2013;368(16):1489-1497.

Other News on the UVAHS GI Nutrition Website: (www.ginutrition.virginia.edu):

Weekend Warrior Mini-Traineeship:  March 11-12, 2017

Spring 2017 Week-Long Traineeship sessions now open for registration.

Upcoming Webinars 2017:   Stay Tuned!

Latest Practical Gastroenterology article:  Achalasia and Nutrition:  Is it Simple Physics or Biology?

 

Joe Krenitsky MS, RDN

 

PS – Please feel free to forward on to friends and colleagues.