Randomized Crossover Trial

A - Click here for explanation of classification scheme.

POSITIVE: See Quality Criteria Checklist below.

• To assess the feasibility of oral glutamine supplementation in patients with gastrointestinal cancers receiving 5-FU and folinic acid. 
• To determine its effect on the incidence and severity of mucositis, particularly in the oral cavity.

• Advanced metastatic GI cancer.

Not specified

Recruitment

Not specified

Design

Double-blind RCT

1. Patients were randomized into placebo or intervention groups.
2. Patients to receive assigned intervention/placebo with the first cycle of treatment and the alternative with cycle two. (crossover)
3. In this way each patient serves as their own control.

Blinding used

Patients and investigator unaware of the randomization order of the subjects.

Intervention

Procedure

• Treatment and control both were dissolved in 150 ml of water or other cold fluids immediately prior to consumption.
• Patients were to drink as a mouthwash before swallowing.
• Supplementation began 24 hours before treatment and continued for a total of 8 days.
• Supplementation ended 48 hours after the final infusion of chemotherapy. (Chemotherapy was folinic acid IV bolus followed by 5-FU IV bolus for 5 days and repeated 4 weeks from start of treatment).

Glutamine Supplement

• 16 g glutamine daily, divided into 4 equal doses taken at intervals throughout the day after meals and before bed.

Placebo

• Polycal, a glucose polymer, given in the same schedule described for glutamine

Statistical Analysis

Differences between the glutamine and placebo treatment cycles were assessed using Student’s paired t-test.

Timing of Measurements

Daily

• Patient record of number of sachets of supplement consumed each day
• Diary card was completed by the patients for 28 days that assessed oral mucositis, number of bowel movements, and stool consistency.

End of each cycle

• Observer assessment of maximal mucositis according to WHO classification.
• Number and nature of admissions to hospital noted with response to therapy.

Dependent Variables

• Oral mucositis
• Number of bowel movements
• Consistency of bowel movements

Independent Variables

16 g oral glutamine 4 times per day

Control Variables

Placebo; Polycal (Cow & Gate, Nutricia), a glucose polymer

Initial N: 28

Attrition (final N):

• 17 completed 2 cycles of treatment
• 6 patients expired before 2nd cycle

Cancer sites

•  3 male              0 female           stomach cancer
• 11 male            6 female           colon cancer
• 5 male              0 female           rectal cancer
• 0 male              1 female           pancreatic cancer
• 0 male              1 female           gall bladder cancer
• 1 male              0 female           unknown
• 20 males           8 females

 

Tolerance

• All supplements well tolerated, no apparent adverse effects
• Consumption mean (sd) = 93% (11%)

Mucositis

• 1^st cycle, 9 patients; 2^nd cycle, 8 patients = some mucositis (WHO score >2)
• 1^st cycle, 4 patients; 2^nd cycle, 5 patients = severe mucositis (WHO score = 3)
• No significant difference between groups

From Table II of article: Mean ± SD patient reported symptom scores

Symptom	Glutamine	Placebo
Mouth comfort	1.56 ± 0.66	1.52 ± 0.62	NS
Ease of eating	1.40 ± 0.57	1.36 ± 0.48	NS
Stool consistency	1.87 ± 0.76	1.90 ± 0.81	NS
No. of stools/day	1.62 ± 0.93	1.80 ± 0.98	NS

Hematology

• No significant difference in 9 patients who had full blood counts on day 15 of each cycle.

From Table III of article: Mean ± SD of hematological indices (n = 9)

	Day	Glutamine	Placebo
Hemoglobin    (g 1-1)	0	11.98 ± 1.37	11.88 ± 0.85	NS
	15	11.06 ± 1.20	11.71 ± 1.19	NS
	29	11.64 ± 1.08	11.99 ± 1.31	NS
WBC    (x 109 1-1)	0	6.70 ± 3.13	6.98 ± 3.96	NS
	15	4.85 ± 2.53	4.89 ± 2.10	NS
	29	8.00 ± 4.67	7.09 ± 4.67	NS
Platelets    (x 109 1-1)	0	268 ± 123	263 ± 107	NS
	15	203 ± 107	182 ± 110	NS
	29	249 ± 106	214 ± 119	NS

Serum Glutamine

• Time zero: no significant difference (P = 0.3).
• 10 patients where levels did increase.
• No change in levels for 4 other patients.
• Minimal changes observed in placebo.

 

No apparent effect of glutamine supplementation on oral mucositis.

• Improvements in gut structure and nitrogen balance cannot be ruled out.
• Further evaluation needed with appropriate dose, route of supplementation, and clinically relevant markers of benefit.
• More understanding of the mechanism of glutamine needed.
• Hypothesized mouthwash glutamine solution would be taken up by the cells of the oral mucosa, possibly did not happen because
  • stratified squamous cells do not prefer glutamine as a fuel.
  • Or not enough time exposure to glutamine.
• Increasing dose via oral route not easy due to solubility of glutamine. (Increased fluid = increased patient burden)

University/Hospital:	Addenbrooke's Hospital, Velindre Hospital
Not-for-profit	0 Foundation associated with industry:

Limited by the fact the study is a pilot study, small sample size.

Limited by 60% patient retention

For future study, staging of cancer would be useful to determine if supplementation is more beneficial in a particular stage of disease.

For future study, initiation of supplement several days prior to treatment to see if there is an effect.

• final sex of groups unknown
• needed to evaluate mucositis scores at the beginning
• did not evaluate other GI problems
• did not assess caloric intake