Vitamin E

To assess the effectiveness of interventions for treatment of oral mucositis or its associated pain for patients receiving chemotherapy or radiation therapy

Databases searched were MEDLINE, CancerLIT, EMBASE, CINAHL, LILACS (Latin American and Caribbean Health Sciences Literature), Cochrane Oral Health Group and PaPaS Trials Registers, Cochrane Central Register of Controlled Trials (CENTRAL), OpenSIGLE, and Current Controlled Trials. Handsearching carried out by the Cochrane Collaboration was included. Reference lists from relevant articles were searched and the authors of eligible trials were contacted to identify trials and obtain additional information.

Search keywords were (neoplasm* OR leukemia OR leukaemia OR lymphoma* OR plasmacytoma OR “histiocytosis malignant” OR reticuloendotherliosis OR “sarcoma mast cell” OR “LettererSiwe disease” OR “immunoproliferative small intestine disease” OR “Hodkin disease”  OR “bone marrow transplant*” OR cancer* OR tumor* OR malignan* OR netropeni* OR carino* or Adenocarcinoma* OR radioth* OR radiat* OR radiochemo* OR irradiat* OR chemo*) AND (stomatitis OR “Stevnes Johnson syndrome” OR “candidiasis oral” OR mucositis OR (oral AND (cand* OR mucos* OR fung*)) OR mycosis OR mycotic OR thrush. Extensive appendices are provided with specific search strategies used for each database. 

Studies were included in the review if they  

• Were randomized controlled trials using placebo, no treatment, or another active intervention.
• Involved patients with cancer receiving chemotherapy or radiotherapy and experiencing oral mucositis.
• Involved any intervention for the treatment of oral mucositis or its associated pain.
• Written in any languages. Papers not in English were translated by members of the Cochrane collaboration.

The final assessment incorporated 32 studies. Out of an initial 95 eligible studies, 64 were excluded because of study design issues, protocol violations, lack of useable data, or no relevant outcomes.

• The final set of studies involved a total of 1,505 patients; 1,023 patients were involved in trials investigating the effectiveness of agents to treat mucositis, and 718 patients were involved in trials evaluating pain relief. 
• Sample sizes ranged from 6–71 patients per treatment or control group.
• Twenty-eight trials included only adult patients, and four included only children.
• Trials included patients treated for a combination of leukemia and solid tumors (n = 14), patients with head and neck cancer (n = 8), and patients who had received bone marrow or stem call transplant (n = 11).

Treatment of mucositis

Summary of data from single trials showed the following interventions to demonstrate statistically significant benefit (p < 0.05).

• Allopurinal mouthwash resulted in improvement in mucositis, eradication of mucositis in some cases, and reduction in time to healing.
• Granulocyte macrophage-colony stimulating factor (GM-CSF) demonstrated mixed results, with two trials showing improved time to healing versus use of providone iodine and antimycotic mouthwash and one trial showing improvement in mucositis by the end of radiotherapy.
• Human placental extract demonstrated improvement in mucositis in one trial.
• Phenytoin mouthrinse was associated with better quality of life than placebo in one trial, but no benefit for pain was found and healing was not evaluated.
• Polyvariant intramuscular immunoglobulin was associated with improvement in mucositis versus placebo in one trial.
• Topical vitamin E was associated with improvement in mucositis and eradication of mucositis compared to systemic vitamin E in one trial.
• Debridement was associated with fewer days to clinical resolution and decreased severity of mucositis, when compared to no debridement.
• Laser treatment was beneficial in management of mild to moderate mucositis compared to sham treatment.

Other interventions for treatment of mucositis evaluated included chlorhexadine versus salt and soda, Gelclair verus sucralfate and mucaine,”Magic” mouthwash versus salt and soda, sucralfate versus placebo and versus salt and soda, and tetrachlorodecaoxide.

Management of pain with mucositis

The following interventions demonstrated statistically significant benefit in managing pain (p < 0.05).

• Opiod use was associated with lower average pain scores when compared to antidepressant use.
• Morphine pharmacokinetically patient controlled analgesia (PKPCA) was associated with lower average pain score than morphine standard patient controlled analgesia (PCA).
• When morphine PCA was compared to continuous morphine infusion, meta-analysis showed no difference in mean pain scores; however, mean opiate intake was reduced with PCA, and PCA was associated with fewer days of pain.

Other findings

• Interventions reviewed that showed no statistical benefit for treatment of mucositis included chlorhexadine, Gelclair, “Magic” mouthwash, and sucralfate.
• Interventions reviewed for management of associated pain that demonstrated no statistical benefit included hydromorphone PCA versus morphine, Alfentanil versus morphine, Dicofenic versus placebo, PCA versus staff controlled, hypnosis, relaxation, and imagery.
• Out of 27 different interventions evaluated for treatment of mucositis, only one comparison was significant for one outcome: low level laser treatment reduced the severity of mucositis.
• No evidence was found to suggest a difference in pain control between continuous infusion and PCA; however, the PCA group required less morphine, and the pain lasted two less days.

• Some evidence exists that low level laser treatment may help reduce severity of mucositis.
• No evidence suggests that PCA is more effective than continuous infusion for controlling pain. Weak evidence is available to support that PCA is associated with less opiate used per hour and that the duration of pain may be reduced.
• No clear benefit appears to be associated with antimicrobial use and GM-CSF for prevention or management of mucositis.
• This review demonstrated weak and unreliable evidence of benefit for interventions for mucositis.

The lack of independent duplication of studies investigating the same intervention limits the strength of evidence and ability to generalize results.

Most studies reviewed had small sample sizes and may have been underpowered to demonstrate significant differences in outcomes.

Different scoring systems for mucositis were used, and, in some studies, the method of scoring was not defined.

The need for further well-designed trials to evaluate the effectiveness of interventions continues.

Adoption of standard clinical outcome measures should be considered, including patient-based measures and inclusion of the cost of interventions.

Evaluate and compare effectiveness of topical vitamin E and pycnogenol (pine bark extract) in treatment of chemotherapy-induced oral mucositis.

Children were randomly assigned to the use of vitamin E, pycnogenol, or sterile water rinses. All were also to follow a uniform oral care protocol, including brushing with a soft tooth brush and chlorhexidine mouth rinse 3 times/day. All study interventions were applied topically three times a day using a dropper. Medications were stored in a refrigerator before usage. The medication was kept in the patient’s mouth for 30 seconds and then swallowed. Patients were blinded to the treatment group. Patients were followed for seven days.

The study was comprised of 72 patients, with a mean age of 9.25 and a range of 6-15 years.

MALES 79%, FEMALES 21%

KEY DISEASE CHARACTERISTICS: All had hematological cancers, including ALL, AML, and NHL, and all were in induction or intensification phases of treatment.

SITE: Single site

SETTING TYPE: Multiple settings

LOCATION: India

PHASE OF CARE: Active antitumor treatment

APPLICATIONS: Pediatrics

 Single, blind, randomized placebo controlled

• WHO oral mucositis grading scale
• Oral Mucositis Assessment Scales (OMAS)
• Children’s International Mucositis Evaluation Scale
   

Mucositis grades in those receiving either vitamin E or pine bark extract were significantly lower than those on placebo (p </= 0.006). OMAS scores declined significantly and consistently across days 1-7, while these scores remained the same in the placebo group. There was significant improvement in pain scores in both intervention groups from day 4 onward, compared to placebo. There were no significant differences in study outcomes between those treated with vitamin E or pine bark.

Topical vitamin E and pine bark extract (pycnogenol) were of benefit in reducing severity of mucositis and pain associated with mucositis in these patients.

• Small sample (<100)
• Risk of bias (no blinding)
• Unintended interventions or applicable interventions not described that would influence results.*
• Other limitations/*explanation. Short study duration. Baseline mucositis scores not described, and it is not known if there were differences between study groups at baseline. ANOVA was used, but it is not clear what the potential time effect was, as mucositis declined in all subjects. Patients were blinded, but evaluators were not. There is no information provided regarding compliance with the oral care regimen, though it is stated that compliance was evaluated, it is not clear how. There is no information provided about use of analgesics.

Topical vitamin E and pine bark extract may have some promise for the management of oral mucositis. Further research on these interventions is warranted.

Eight hundred mg vitamin E was diluted with corn oil (volume = 2 mL). Patients swished for at least 30 seconds then spat it out. The control group received corn oil only. Subjects did not rinse mouths for 30 minutes after spitting out the solution. Forty-five cycles of the study drug were administered (one cycle: four patients, two cycles: five patients, three cycles: one patient, four cycles: four patients, six cycles: five patients; vitamin E = 22 cycles, placebo = 23 cycles).

• N = 16
• AGE: Pediatric patients aged 6–18 years
• KEY SAMPLE CHARACTERISTICS: Planned chemotherapy for two identical cycles of doxorubicin-containing chemotherapy with doxorubicin at least 60 mg/m². Patients had chemotherapy regimens with one to three treatment sets consisting of two to six doxorubicin-containing chemotherapy cycles.

• Randomized, controlled, double-blind N-of-1 Bayesian analysis study

• Oral Mucositis Assessment Scale (OMAS) days 7, 10, 14, and 17 of each cycle
• Visual analog scale (VAS) score for pain and difficulty swallowing
• World Health Organization (WHO) scale in diary by participant or parent
• Amount of opioid analgesia
• Topical oral analgesia
• IV hydration
• Total parenteral nutrition
• Episodes of febrile neutropenia
   

Compliance was 84% with no statistically significant findings. Vitamin E was not associated with reduction in pain VAS scores or swallowing difficulty. WHO mucositis scores were similar for vitamin E and placebo cycles. No differences for the additional secondary outcomes between vitamin E and placebo cycles were found. Authors noted that vitamin E should not be used in this context. N-of-1 study design was found to be a potentially effective design method.
 

• Small study
• Data collection issues
• No significant findings
• The order in which the placebo and vitamin E cycles were administered is unclear.
   

PURPOSE: Review evidence and provide guidelines for use of natural agents in the prevention and management of oral mucositis in cancer

TYPES OF PATIENTS ADDRESSED: Patients receiving chemotherapy, radiation therapy, or stem cell transplant

RESOURCE TYPE: Evidence-based guideline

PROCESS OF DEVELOPMENT: Systematic review of evidence, quality rating using Hadorn criteria, and level of evidence classified via Somerfield criteria

DATABASES USED: MEDLINE

KEYWORDS: Alternative, complementary, homeopathic, aloe vera, beta carotene, chamomile, chines herbal, folic acid, and numerous other specific natural agents

INCLUSION CRITERIA: Not specified, other than use of a natural agent

EXCLUSION CRITERIA: Not specified

PHASE OF CARE: Active antitumor treatment

APPLICATIONS: Pediatrics

Ninety-nine papers were identified, and, of these, 49 papers were included in the review.

• Glutamine (20 studies)—not recommended for prevention in patients undergoing hematopoietic cell transplantation. For other situations, no guideline was deemed possible.
• Vitamins A  or E (eight studies)—no guideline possible
• Honey (four studies)—no guideline possible. Each study used a different type of honey.
• Zinc (four studies)—no clear recommendation is given, but the committee suggested it may be of benefit for prevention in patients with oral cancer during radiation or chemoradiation therapy.
• Twelve studies of various other agents were reviewed. No guidelines were possible in any of these.

• Many studies were of low quality, and some were more than 10 years old. 
• Hadorn criteria reliability is questionable. 
• For many products, only one study was found.

Findings do not support efficacy of currently studied natural herbal agents and other agents for prevention of oral mucositis. Systemic zinc supplementation may be helpful for patients with oral cancer receiving treatment. Glutamine is not recommended in patients undergoing cell transplant. Further, well-designed research in this area continues to be needed.