Zinc/Zinc Supplements

To evaluate the effects of oral zinc sulfate on prevention of mucositis, xerostomia, and pain induced by chemotherapy.

Patients were divided by block randomization into two groups of zinc sulfate and placebo. Patients were informed about oral hygiene and associated care. Patients in the intervention group took three 220 mg zinc sulfate capsules daily until the end of chemotherapy treatment. The placebo group took three placebo capsules that were similar in shape, taste, and color to the zinc sulfate capsules. Randomized divisions and zinc sulfate drug prescription of patients were carried out by patients’ oncologists. Patients' mucous and salivary health was checked by an oral medicine specialist and dental student prior to the initiation of chemotherapy, two weeks after initiation of chemotherapy, and every two weeks until the end of chemotherapy. The specialist and dental student were blinded to the randomization and treatment.

The study was comprised of 50 adult patients over the age of 18.

MALES 52%, FEMALES 48%

OTHER KEY SAMPLE CHARACTERISTICS: Inclusion criteria were chemotherapy treatment by a regimen with the same mucositis probability, including cyclophosphamide, doxorubicin, dacarbazine, gemcitabine, methotrexate, and 5-fluorouracil. Exclusion criteria included previous or simultaneous radiotherapy in the head and neck region, including the nasopharynx, oropharynx, and larynx, previous head and neck surgery due to malignancy, use of dentures, pregnancy, and infection.  

 

SITE: Single site

LOCATION: Oncology Department at Zahedan Imam Ali Hospital, Zahedan, Iran

PHASE OF CARE: Multiple phases of care

APPLICATIONS: Late effects and survivorship elderly care, end-of-life and palliative care
 

A double-blind, randomized study where subjects were divided by block randomization into two groups of zinc sulfate and placebo.

• Oral mucositis was graded from 0 to 4, using World Health Organization (WHO) criteria.  
• Xerostomia was diagnosed from 1 to 4 using the LENT SOMA scale.  
• The degree of pain was evaluated based on a visual analog scale.
• For quality of life, patients individually met with the dental student at each follow-up, and the student completed the EORTC LQ-OES18.
   

Xerostomia: Baseline of all patient’s salivary flows were within normal range, p = 0.13. At the first visit (during the second week of chemo), no significant differences in xerostomia were seen between groups p = 0.019. At the second visit (during the fourth week of chemo), the intensity of xerostomia in the drug group was less than the placebo, p < 0.005, and this trend continued in the 8th and 16th weeks of treatment. At the beginning of the study, none of the patients had symptoms of mucositis. During the frst, second, and third visits, there were no significant differences in mucositis intensity between groups. At weeks 8, 12, and 16 of chemo, there were significant differences between both groups. The intervention group had less intensity than the placebo group, p < 0.005. Regarding pain intensity from the third visit (wk 6 chemo) until the 10th visit (wk 20), there were significant differences between groups, indicating that pain intensity in the drug groups was less than in the placebo groups, p < 0.005.

Recovery: Mucosiits recovery period is the time interval between appearance of mucositis s/s and complete resolution. The recovery period was seven weeks and three days for the zinc treatment group and eight weeks for the placebo group, p = 0.13.

Xerostomia recovery period for xerostomia was from the time of appearance of the s/s and the complete resolution. Seven weeks in the placebo groups versus six weeks and five days in the zinc group, no significant difference was noted between the groups, p = 0.23.
 

The use of zinc sulfate was able to decrease the intensity of xerostomia, mucositis, and pain in patients that develop chemotherapy induced mucositis. There was no difference between the incidence of mucositis or delay in developing mucositis between the zinc sulfate and placebo group. The recovery period for xerostomia to complete resolution was not statistically significant between groups.

• Small sample <100
• It is not clear whether the 50 initial participants were all studied for the entire duration. There is no mention of dropouts. No information is available on patient adherence to doses and oral care plan.
   

The use of zinc sulfate might decrease the intensity of mucositis, which could help with patient compliance with treatment, affect weight loss from poor nutrition, and decrease the need for hydration.

Zinc sulfate (50 mg zinc) capsules TID at 8 hr intervals. Began day 1 of radiation, during RT, and for 6 weeks after.

Oral hygiene for all patients: drink water, brush with soft brush after each meal and with mouth jellies, including fluoride. Patients were instructed to avoid alcoholic drinks, not smoke cigarettes, not drink liquids that were too hot or too cold, not eat excessive spiced or sour foods, and to not eat hard foods.
 

The study was comprised of 30 patients, 15 zinc, 12 placebo (3 excluded), age 18-71, with a median age of 54 years.

• Head and neck RT or chemo + RT
• Median rad dose 6400 cGy
• May 2001 – May 2002

Prospective, randomized placebo-controlled study

Assessed by two radiation MDs using RTOG morbidity scoring

13 of 15 zinc patients developed mucositis; however, no patientss developed grade 4 mucositis.
Gr 1 – 8 pts versus  0
Gr 2 – 5 pts versus 4
Gr 3 – 0 pts versus  8
Gr 4 – 0 pts versus 0

Greater severity p = 0.05

Mucositis developed later in the zinc group (p < 0.05) and  at a higher RT dose (p < 0.01)

At six weeks, only one patient in the zinc group had mucositis, while 10 of 12 patients in the placebo group had mucositis, p < 0.01.

Well tolerated
 

Local anesthetic solutions and analgesic agents were given to patients for pain.

Very small study

Need to ensure validity of MD evaluation and other agents used.
 

Zinc – 25 mg  versus placebo, 3x/day for 2 months

Patients started capsules on first day of RT and continued until completion of RT.

Block randomization

The study was comprised of 100 patients, 50 zinc, 50 placebo, with a mean age of 50–51 years.

RT dose 180–200 cGy daily in five weekly fractions

41-42% patients receiving RT + chemo
 

Jan 2003 – Aug 2004

Double-blind, randomized, placebo-controlled study

RTOG acute morbidity scoring

Serum zinc levels were higher in the zinc group: 20.5 versus –1.5 (p = 0.02).

Grade 2 mucositis appeared earlier in the placebo group (p = 0.017 and larger proportion of patients).

Grade 3 mucositis also earlier and larger proportion of patients, p = 0.0003.

Results not as significant for patients receiving concurrent chemo.
 

Oral analgesics prescribed for pain.
 

Recommend continuing treatment out past end of RT as patients in both groups had similar recoveries.

Need to determine optimal dose.

The purpose of this study was to determine the effect of zinc supplementation on radiation-induced mucositis in patients with nasopharyngeal carcinoma (NPC) and those with oral cancers (OC).
 

Patients were randomly assigned to experimental or control groups. The experimental group received 75 mg zine 4 times/day for three months during radiation therapy. Control group patients received soy bean capsules.  Patients were evaluated if mucositis was detected, weekly. Patients were followed at 3 and 12 months post-radiation therapy completion. Side effects were evaluated by a blinded physician observer.

The study was comprised of 83 patients, age >18 years of age.

MALES 85.5%, FEMALES 14.5%

KEY DISEASE CHARACTERISTICS: 40 were patients with nasopharyngeal cancers (NPC) and 43 were patients with oral cavity cancers (OC).

OTHER KEY SAMPLE CHARACTERISTICS: zinc supplementation
 

SITE: Single site

PHASE OF CARE: Active treatment

Randomized double blind study

Serum zinc, cell count, blood urea nitrogen (BUN), creatinine, glutamic oxalacetic transaminase (GOT), glutamic pyruvic transaminase (GPT), transferrin, and body weight were checked one week prior to radiotherapy and were repeated biweekly until radiotherapy was completed. The serum zinc level was checked using the atomic absorption method.
 

The study found that there is a discrepancy in the effects of zinc supplementation in preventing mucositis between patients with NPC and those with OC, as there were significant effects of zinc supplementation in improving mucositis in patients with OC. Grade 2-3 mucositis occurred earlier in patients receiving placebo.
 

Further studies need to be done to investigate the effect of zinc supplementation in preventing the severity of mucositis in relation to the different radiation fields between those associated with patients diagnosed with oral cancer and nasopharyngeal cancer. This study was focused on subgroup analysis of a previous report.

 Small sample <100

Zinc supplementation may be of benefit in the prevention of oral mucositis. It appears that efficacy may differ according to the specific type and location of the tumor.

Evaluate the effect of oral zinc sulfate for prevention of chemotherapy-induced oral mucositis in patients undergoing hematopoietic stem cell transplantation (HSCT).

Zinc sulfate at 440 mg/day provided orally in two doses every 12 hours, or placebo was provided beginning the day before starting the conditioning regimen. The capsules were administered by hospital staff. Patients were followed every day. All patients received the same prophylaxis regimen, which included 20 drops nystatin every three hours, chewable sucralfate 500 mg every eight hours, and mouthwashes such as chlorhexidine, amphotericin, and diluted povidone iodine every three hours.

The study was comprised of 60 patients, with a mean age 30.87 and 27.13 years per group.

Female 30%, Male 70%

All patients were receiving conditioning regimens for HSCT.

Single site, inpatient setting, Tehran, Iran

Randomized, double blind, placebo controlled

WHO mucositis grading scale

There were no significant differences between groups in mucositis grade, time of onset, or duration.

Zinc sulfate did not show any benefit for the prevention and management of oral mucositis.

Small sample <100

Findings suggest that oral zinc sulfate is not beneficial for oral mucositis induced by high-dose chemotherapy for patients undergoing HSCT. Efficacy of zinc sulfate in other patient populations is not clear.

 To evaluate the effectiveness of a zinc-containing mouthwash on chemotherapy-induced oral mucositis in comparison with chlorhexidine gluconate mouthwash as control.

Patients with acute myeloid leukemia under chemotherapy were allocated to an experimental and control groups of 15 patients each. The required dilution of 0.2% zinc sulphate and chlorhexidine gluconate mouthwashes. Subjects instructed to rinse with 10 ml of 0.2% zinc sulphate mouthwash twice a day for 14 days in the experimental group. The control group used 0.2% chlorhexidine mouthwash in the same manner. The mouthwashes were coded with A and B letters on the bottles, and the investigator, as well as the subjects were blinded to the type of the mouthwash, which was administered to the groups by a simple random method. All subjects were examined every other week for eight weeks.

The study was comprised of 30 patients, over 15 years of age.

MALES (%) Not specified, FEMALES (%) Not specified

KEY DISEASE CHARACTERISTICS: Acute myeloid leukemia

OTHER KEY SAMPLE CHARACTERISTICS: Subjects receiving an established treatment plan of Cytarabine in the induction phase and Novantrone in the consolidation phase were included in the study. Exclusion criteria included no subject <15 years of age. Allergy to zinc or chlorhexidine mouthwashes. Any systemic disease with other diagnosis of malignancies or chemotherapy-induced oral mucositis, any oral ulcers, or mucositis developed before starting chemotherapy.
 

SITE: Single site

LOCATION: The oncology ward of Shahid Gazi Hospital in Tabriz, Iran

PHASE OF CARE: Active treatment

APPLICATIONS: Acute myeloid leukemia

Randomized, double-blind, controlled

• Instrument: Spijkervet Scale was used to grade the severity of Mucositis    
• Observation: The efficacy of the treatment at each session was determined by recording the length (E) of the lesion, measured by a digital caliper, and its severity (K), based on local signs.
• Observation: Eight distinguishable irradiated areas of the mouth including buccal mucosa (left and right), soft and hard palate, dorsum and border of the tongue (left and right), and the floor were evaluated.
• Observation: The score of each area was defined as the product of the length and severity score from the Spijkervet Scale. The mucositis score (alpha) in each individual was defined as the mean of the scores assigned to the evaluated areas, and ranged from 0-16.
• Observation: Independent t-test used for evaluation of any probability of differences between the groups in regard to baseline.
   

There were no significant differences between the case and control groups in the first week (p = 0.124). The trends of changes in the assessed oral mucositis index during the course of the study were similar in both groups. The mean a (alpha) index in both groups increased from the first week to the third week and then decreased in the fourth week. Although the mean a (alpha) index was generally lower in the test group compared to the control  group at all four time intervals evaluated, repeated measure ANOVA revealed that the difference was statistically significant in weeks 2 and 3 (p = 0.025).

 Zinc mouthwash used in conjunction with chemotherapy may reduce the severity of oral mucositis lesions in patients with leukemia.

•  Small sample <100
•  Lack of  ability to generalize. Lack of the prophylactic agent (zinc) at different concentrations.  
   

The double-blind study is the most efficacious. Within the field of oncology, the occurrence of mucositis has always been associated as a side effect of chemo-radiation therapies. Mucositis is a result of radiotherapy and chemotherapy or a combination of the two. Thus, mucositis needs immediate and timely nursing interventions. The zinc mouthwash appears to be cost effective and easy to use. To this, clinical trials with randomized testing within the United States that support zinc mouthwash may be beneficial. Nurses who are in the oncology setting face challenges to plan and provide care that promotes the best possible health related outcomes for their patients.

The purpose of the study was to evaluate the effect of zinc sulfate on the incidence and severity of mucositis in patients with leukemia undergoing chemotherapy.

This is a randomized, placebo-controlled, triple-blinded study conducted on patients with leukemia undergoing chemotherapy. The subjects were randomized into an experimental arm where they received zinc sulfate (50 mg) three times daily for 14 days from the first day of chemotherapy; the control group received placebo capsules three times per day. Mucositis was measured by the Oral Mucositis Index and World Health Organization mucositis scale on the 4th, 7th, and 14th day after chemotherapy.

• N = 69   
• MEAN AGE: 36.725 years
• MALES: 57%  
• FEMALES: 43%
• CURRENT TREATMENT: Chemotherapy
• KEY DISEASE CHARACTERISTICS: AML, ALL, CML

SITE: Multi-site   
SETTING TYPE: Not specified    
LOCATION: Nemaze Hospitals affiliated to SUMS, Shiraz, Iran

• PHASE OF CARE: Active anti-tumor treatment
• APPLICATIONS:  Palliative care

This is a randomized clinical trial and placebo-controlled study for patients undergoing chemotherapy for leukemia. Patients were randomly assigned to receive either zinc sulfate or placebo.

• IBM SPSS Statistics, version 20
• Kolmogorov-Smirnov test 
• Independent t test and chi-square test
• Repeated measures analysis of variance (RM-ANOVA)

There is significant difference in the incidence of mucositis during the 14 days of the study, 9 patients (25%) in the experimental group (zinc sulfate) and 19 (54%) in the control group (placebo) showed incidence of mucositis was 2.1 times higher in the control group. Onset of mucositis occurred on days 5.83 (SD = 3.37) (zinc sulfate) and 4.58 (SD = 2.47) (placebo), t test showed no difference between these two groups regarding the onset of mucositis (t = 0.95, p = 34). There is no confirmation of mucositis occurring later in the zinc sulfate group in comparison to the control group. The severity of mucositis was milder in the experimental group compared to the control group on 4th, 7th, and 14th day. RM-ANOVA indicated significant difference between mean score objective evaluation of mucositis the two groups (F = 7.83, p = 0.07). Results also showed significant difference between the two groups' mean score of subjective evaluation of mucositis (F = 5.79, p = 0.01)

The results of the study show that zinc sulfate is helpful in preventing mucositis in patients with leukemia undergoing chemotherapy. The current study does not support any significant difference between the two group in delaying onset of mucositis. The severity of mucositis was milder in the zinc sulfate group in comparison to the control group.

• Small sample (< 100)
• Risk of bias (sample characteristics)
• Findings not generalizable
• Other limitations/explanation: Length of the study, evaluation of mucositis for a longer time

Using zinc sulfate at the dose of 50 mg three times per day for 14 days helped to prevent and decrease the severity of mucositis in the leukemia population undergoing chemotherapy. This along with standard of care oral hygiene could be an effective treatment to prevent and decrease the severity of mucositis. Additional research is needed.

To determine the efficacy of zinc sulfate supplements in reducing oral mucositis in patients with head and neck cancer

Patients were randomized to receive zinc supplementation or placebo during radiation therapy. Patients received 50 mg zinc sulfate daily at meal times in a syrup form or an identical placebo syrup. All patients received visous Xylocaine^® and analgesics as considered necessary. The primary study end point was to evaluate the frequency of development of greater than grade 2 mucositis and pharyngitis.

• N = 139   
• MEAN AGE = 62 years
• MALES: 86.8%, FEMALES: 13.2%
• KEY DISEASE CHARACTERISTICS: 53% had stage 3–4 disease, 85% were smokers, and 76% used alcohol

• SITE: Single site  
• SETTING TYPE: Not specified   
• LOCATION: Thailand

• PHASE OF CARE: Active antitumor treatment

• Double-blind, placebo-controlled

• National Cancer Institute Common Toxicity Criteria version 2
• Visual analog scale for pain scoring

There was no difference between groups in proportion with greater than grade 2 mucositis. Seventeen percent in the placebo group and 23% in the zinc sulfate group developed grade 3 mucositis. There were no significant group differences in pain severity.

Zinc sulfate supplementation during radiation therapy for head and neck cancer did not produce any benefit in reducing or relieving symptoms of oral mucositis.

• Measurement/methods not well described
• Other limitations/explanation: Timing of pain rating and data used were not well described.

There was no benefit of zinc supplementation for the prevention and management of oral mucositis in this group of patients.

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.