European Journal of Oncology Nursing 33 (2018) 14–21

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European Journal of Oncology Nursing

journal homepage: www.elsevier.com/locate/ejon

The effect of zinc sulfate on prevention, incidence, and severity of mucositis T

in leukemia patients undergoing chemotherapy
Masoume Ramboda, Nilofar Pasyara,∗, Mani Ramzib
a
Community-Based Psychiatric Care Research Center, Department of Medical Surgical Nursing, School of Nursing and Midwifery, Shiraz University of Medical Sciences,
Shiraz, Iran
b
Hematology Research Center, Department of Hematology and Medical Oncology, Shiraz University of Medical Sciences, Shiraz, Iran

A R T I C L E I N F O A B S T R A C T

Keywords: Purpose: This study aimed to evaluate the effect of zinc sulfate on the incidence and severity of mucositis in
Chemotherapy leukemia patients undergoing chemotherapy.
Leukemia Methods: This was a randomized clinical trial and placebo-controlled, triple blinded study. This study was
Mucositis conducted on leukemia patients undergoing chemotherapy. The subjects were randomly allocated into an ex-
Zinc sulfate
perimental (received 50 mg zinc sulfate capsules) and a control group (received placebo capsules). Zinc and
placebo capsules were administered three times daily for 14 days from the first day of chemotherapy. Mucositis
was measured by the oral mucositis index and World Health Organization mucositis scale on the 4th, 7th, and
14th days after chemotherapy. The data were analyzed using independent t-test, chi-square test, and Repeated
Measures Analysis of Variance (RM-ANOVA).
Results: The results showed a significant difference between the two groups in terms of the incidence of mu-
cositis, which was 2.1 times higher in the control group in comparison to the zinc sulfate group. The results of
RM-ANOVA also indicated a significant difference between the two groups regarding the mean score of objective
and subjective evaluation of mucositis during the three study periods (F = 7.83, p = .007 and F = 5.79, p = .01,
respectively).
Conclusion: The results of this study indicated that zinc sulfate reduced the incidence and severity of mucositis in
leukemia patients undergoing chemotherapy. As zinc sulfate prevented and relieved mucositis in leukemia pa-
tients under chemotherapy, using zinc sulfate is recommended in clinical setting. Yet, further studies are sug-
gested to confirm these findings.

1. Introduction Additionally, the highest frequency of mucositis has been reported on

Leukemia is a cancer of blood and blood cells involving an un-
regulated proliferation of leukocytes in the bone marrow (Hinkle and
Cheever, 2014). The incidence of leukemia was reported to be 3.7 per
100 000 person-years in a city in Iran and 11.25 per 100 000 person-
years in other countries, such as UK (Bhayat et al., 2009; Dastgiri et al.,
2011). Overall, 8% of total cancer patients suffer from leukemia (Koohi
et al., 2015).
To date, major advancements have occurred in management of
cancer patients (Rastogi et al., 2011). Evidence has also shown that
more aggressive regimens, such as chemotherapy, have improved lo-
coregional tumor control and survival of cancer patients (Rastogi et al.,
2011). However, these treatments lead to some problems, such as
mucositis. Chemotherapy-induced mucositis, as an acute condition,
usually occurs one week after chemotherapy (Sonis, 2009).
the 10th day after chemotherapy (Martinez et al., 2014). However, it
resolves during three weeks (Sonis, 2009). A previous study revealed
that 81.3% and 90% of patients with cancer (Al Ibraheemi and
Shamoun, 2016) and acute leukemia (Martinez et al., 2014) under
chemotherapy suffered from mucositis. It should be noted that use of
concomitant chemotherapy and/or targeted agents increased the risk
for mucositis (Villa and Sonis, 2015).
Mucositis consists of four phases, including “initial inflammatory/
vascular, epithelial breakdown, ulcerative/bacteriological and healing
phases” (Sonis, 1998). In ulcerative phase of mucositis, some compli-
cations, such as pain (Sonis et al., 2004), dysphagia (Mercadante et al.,
2015), and difficulties in eating, swallowing, and talking might occur
(Scully et al., 2006). Therefore, patients have to receive painkillers and
nutritional support (Jensen and Peterson, 2014). Other complications of
mucositis are treatment discontinuation (Campos et al., 2014) and

∗
Corresponding author. School of Nursing and Midwifery, Shiraz University of Medical Sciences, Zand St., Nemazee Sq., 7193613119, Shiraz. Iran.
E-mail addresses: rambodm@sums.ac.ir (M. Rambod), npasyar@sums.ac.ir (N. Pasyar), ramzim@sums.ac.ir (M. Ramzi).

https://doi.org/10.1016/j.ejon.2018.01.007
Received 6 October 2017; Received in revised form 6 January 2018; Accepted 11 January 2018
1462-3889/ © 2018 Elsevier Ltd. All rights reserved.
M. Rambod et al. European Journal of Oncology Nursing 33 (2018) 14–21

weight loss (Elting et al., 2007). In addition, oral hygiene care, medical improved cancer patients' survival and treatment rates (Lin et al.,
and healthcare appointments, and hospitalization might increase as a 2009). Considering the limited number of studies on leukemia patients'
result of mucositis (Jensen and Peterson, 2014). In a study on malignant mucositis and the valuable effect of zinc sulfate, this study aims to
hematologic patients (acute leukemia and non-Hodgkin lymphoma), evaluate the effect of zinc sulfate on prevention, incidence, and severity
21.9% of hospitalization episodes were related to mucositis (Martinez of mucositis in leukemia patients under chemotherapy.
et al., 2014). Moreover, quality of life of cancer patients was sig-
nificantly affected by mucositis. Cancer patients with mucositis ex-
2. Methods
perienced pain, physical limitations, and psychological discomfort
(Martinez et al., 2014). Furthermore, inability to eat and drink and
2.1. Hypothesis
mouth pain limited the quality of life of leukemia patients with mu-
cositis (Martinez et al., 2014).
In this study, the three following hypotheses were examined:
Despite the high incidence and serious and debilitating complica-
tions of mucositis, no preventive and treatable interventions are cur-
1) Zinc sulfate would prevent mucositis in leukemia patients under
rently available. Although some Complementary and Alternative
chemotherapy.
Medicines (CAM), such as Chinese herbal medicine, have been used to
2) Mucositis in leukemia patients under chemotherapy would happen
prevent and treat mucositis, their therapeutic outcomes are not ap-
later in the zinc sulfate group in comparison to the control group.
proved (Meyer-Hamme et al., 2013). Moreover, it was shown in a
3) Severity of mucositis in leukemia patients under chemotherapy
systematic review that chlorhexidine was not effective in preventing the
would be milder in the experimental group in comparison to the
incidence of mucositis and decreasing its severity (Cardona et al.,
control group on 4th, 7th, and 14th days of the study.
2017). Some mucositis management strategies and other therapeutic
modalities, including drugs such as amifostine, palifermin, benzyda-
mine HCl, and pentoxifylline, low-level laser therapy, gene transfer 2.2. Design
interventions, and several organic products, have been also used in this
regard (Villa and Sonis, 2015). However, the effects of these interven- In this randomized clinical trial and placebo-controlled study, leu-
tions have not been completely confirmed. In order to gain better kemia patients under chemotherapy were randomly assigned to receive
treatment outcomes, some researchers preferred to use zinc sulfate. either zinc sulfate or placebo. Therefore, it was a parallel study.
Zinc is needed for multiple cellular activities, and the immune
system is particularly dependent on adequate availability of this crucial 2.3. Allocation
trace element (Chandra and McBean, 1994). Moreover, zinc performs as
an organelle stabilizer and a stabilizer of the structure of DNA, RNA, In this study, allocation concealment was used to prevent selection
and ribosome. It is also a significant cofactor for DNA synthesis, an bias. To achieve this goal, the patients and individuals who enrolled
important factor for wound healing, and a necessary trace component them into the study were unaware of group allocations. The allocation
for improving the immune system (Ertekin et al., 2004). However, how concealment mechanism was performed in three steps; i.e., capsules
zinc affects mucositis is not completely clear (Kwon, 2016). form and appearance, randomization, and outcome measurements, by
Researchers have reported that zinc increased the gastrointestinal three individuals with no clinical involvement in the trail as follows:
epithelial barrier function and consequently decreased cell death and First, zinc sulfate or placebo capsules were prepared in similar color,
detachment (Skrovanek et al., 2014). Zinc increased the overall survival shape, and weight by a pharmacologist who was a faculty member of
of patients with advanced nasopharyngeal cancer (Lin et al., 2009). Shiraz University of Medical Sciences (SUMS). He allocated zinc sulfate
Surprisingly, some researchers believed that zinc sulfate might decline or placebo capsules to A or B codes randomly. Then, he prepacked 42
the intensity of mucositis in cancer patients under chemotherapy capsules in similar bottles for each patient. He was the only person who
(Arbabi-kalati et al., 2012). In a study on pediatric cancer patients, knew the groups until the analysis was finished. Second, in order to
Cheng et al. (2001) indicated that severity of chemotherapy-induced achieve allocation concealment, a researcher's assistant who was blind
oral mucositis and the related pain was significantly reduced in zinc to the study groups performed the randomization. Third, the study
sulfate group (Cheng et al., 2001). Moreover, taste of the patients who outcomes were evaluated by a nurse who was blind to the study groups.
had received zinc sulfate was recovered more quickly one month after
radiotherapy (Ripamonti et al., 1998). On the other hand, some studies
2.4. Randomization
have reported that zinc sulfate was not effective in severity and in-
cidence of mucositis. Mansouri et al. indicated that zinc sulfate could
Leukemia patients under chemotherapy were assigned to an ex-
not prevent or decrease the severity and duration of mucositis in pa-
perimental and a control group by block randomization with block sizes
tients undergoing hematopoietic stem-cell transplantation (Mansouri
of two. In so doing, an online statistical randomization program was
et al., 2012). Additionally, Sangthawan et al. demonstrated no sig-
used to generate the randomization sequence. The randomization was
nificant differences between zinc and control groups concerning the
performed by a researcher's assistant who was not involved in the trail
incidence of grade 2 oral mucositis and pharyngitis at every week
and was blind to the study groups. In this step, based on the allocation
during radiation and within the first month after completion of radia-
sequence, bottles A or B were sequentially numbered in opaque sealed
tion (Sangthawan et al., 2013). However, the question remains whether
envelopes. They were kept in a place with appropriate humidity and
zinc sulfate is effective in preventing mucositis in leukemia patients.
temperature. To enter the study, the researcher's assistant gave the next
Previous studies on mucositis have shown somehow contradictory re-
numbered envelope to the patient.
sults regarding the effect of zinc sulfate (Arbabi-kalati et al., 2012;
Cheng et al., 2001; Ertekin et al., 2004; Mansouri et al., 2012; Mosalaei
et al., 2010). Indeed, review of the literature revealed that a few studies 2.5. Blinding
have been performed on the effect of zinc sulfate on prevention of
chemotherapy-induced mucositis (Arbabi-kalati et al., 2012; Mansouri In this triple blind study, the researchers and participants were blind
et al., 2012; Mehdipour et al., 2011). Moreover, a limited number of to zinc sulfate and placebo capsules. To achieve this aim, zinc sulfate
studies have been focused on leukemia patients. It should be noted that and placebo capsules were completely similar in color, shape, and
mucositis has many complications that decrease leukemia patients' weight. The researcher's assistant who collected the data and the sta-
quality of life (Martinez et al., 2014). On the other hand, zinc sulfate tistician who analyzed the data were also blind to the study groups.

15
M. Rambod et al.
2.6. Settings
This study was conducted in two hematology-oncology wards in
Nemazee Hospital affiliated to SUMS, Shiraz, Iran.
2.7. Sample size
In order to determine the study sample size and detect differences
between the experimental and control groups, a pilot study was con-
ducted to assess the effect of zinc sulfate on mucositis in leukemia pa-
tients undergoing chemotherapy. Based on the pilot study, the differ-
ence in proportion prevention between the experimental and control
groups was 30% (first proportion = 60%, second proportion = 30%) in
leukemia patients undergoing chemotherapy. Similar to this pilot study,
the difference prevalence of mucositis in other previous studies on ra-
diation-induced mucositis were 30.5% (Moslemi et al., 2014), 36.6%
(Arbabi-kalati et al., 2012), and 76.67% (Ertekin et al., 2004). There-
fore, based on the 30% difference in prevention which required a larger
sample size, power of 80%, and α = 0.05, an 80-patient sample size
was estimated. Then, the sample size was increased to 86 patients to
allow dropping-out (43 patients in the experimental group and 43 in the
control group).
2.8. Sample
The target population consisted of all adult leukemia patients
treated with chemotherapy, such as 5-fluorouracil, Cytarabine,
Doxorubicin, Daunorubicin, Idarubicine, Bleomycin, Vincristine,
Cyclophosphamide, Cisplatin, Methotrexate, Ifosfamide, Mitoxantrone,
and Taxane.
The inclusion criteria of the study were being 18 years old or above,
undergoing chemotherapy, being alert and oriented, being able to
swallow capsules, and not showing mucositis symptoms such as ulcers,
erythema, edema, pain, and dysphasia. It should be noted that the
patients' levels of alertness and orientation were evaluated by asking
these four questions: who are you or who am I, where are you, what
time is it, and what just happened.
On the other hand, the exclusion criteria of the study were having
suffered from mouth ulcers and mucositis within the past 3 months,
being under radiotherapy, pregnancy and lactation, having allergy to
zinc, and suffering from systemic diseases such as diabetes, immune
system deficiency, and other malignancies. In order to assess mucositis
symptoms, the patients' mouths were evaluated for thrush, mucositis, or
wounds before the intervention. It should be mentioned that as the
patients might have not received treatment for the first time, the two
groups were matched regarding the previous number of chemotherapy
cycles.
2.9. Instruments
The study data were collected using a demographic characteristics
form, an oral mucositis index, and Oral Toxicity Scale of the World
Health Organization (WHO) (Organization, 1979). The demographic
characteristics form included patients' age, sex, education level, marital
status, diagnosis, and number of previous chemotherapy cycles.
Objective assessment of mucositis was performed using an oral
mucositis index (Cella et al., 2003; McGuire et al., 2002; Potting et al.,
2006). In this scale, 5 items including lesions, erythema, edema, diffi-
culty in swallowing, and pain were examined. Accordingly, ulcers were
scored as follows: lack of lesions (score = 0), 3 or fewer lesions
(score = 1), 4-6 lesions (score = 2), and wide ulcers and more than 6
lesions (score = 3). The scores of erythema, edema, and swallowing
difficulty have been presented in Table 1. Moreover, the severity of oral
pain was assessed using a Visual Analogue Scale (VAS). VAS is a 10-mm
line in which 0 and 10 represent no pain and the worst possible pain,
respectively. VAS scores were categorized into 3 categories: none
16
European Journal of Oncology Nursing 33 (2018) 14–21
(score = 0), VAS scores < 3 (score = 1), VAS scores 4-6 (score = 2),
and VAS scores > 6 (score = 3) (Table 1). Besides, the total score of
the scale could range from 0 to 15. In this study, inter-rater reliability of
the objective scales of mucositis was 0.89.
Mucositis was assessed by Oral Toxicity Scale of WHO. This in-
strument was designed based on objective (redness or erythema, and
ulcer development) and subjective signs (ability to swallow, sensitivity
of mucosa). Accordingly, mucosa was classified into four grades as
follows: grade 0, no changes detected in oral cavity; grade I, oral
soreness and erythema in mucosa, gums, tongue, or palate; grade II,
erythema and ulcers, but solid diet tolerated; grade III, oral ulcers, only
“pasty” food and liquid diet tolerated; and grade IV, ulcers, erythema,
pain, inability to swallow liquids, oral alimentation impossible, and
narcotics used for pain relief. The total score of this scale could range
from 0 to 4. Oral Toxicity Scale of WHO has shown good validity.
Additionally, correlation coefficients between this scale and mouth and
throat soreness questionnaire ranged from 0.45 to 0.55 (Stiff et al.,
2006). In our study, inter-rater reliability of the subjective scales of
mucositis was 0.91. It should be noted that all assessments were per-
formed by a single person.
2.10. Data collection
After getting permission from SUMS, the researcher (second author
of this study) got access to the subjects. She introduced herself to the
participants and explained the study objectives to them. It should be
noted that before the study, all patients who met the inclusion criteria
were trained about oral hygiene both verbally and in written. Oral
hygiene was also emphasized at any stage of assessment. This included
fluid intake, rinsing teeth with a soft toothbrush, and refraining from
using alcohol, cigarettes, hot and cold fluids, and spicy and sour foods.
All participants were also evaluated by objective mucositis scale prior
to the study. Then, the patients with the score of zero in the objective
mucositis scale and Oral Toxicity Scale of WHO were enrolled into the
study. It should be noted that all subjects used chlorhexidine and nys-
tatin oral solution at the beginning of chemotherapy. This initial
treatment continued until neutrophil count was 1000 cells/mm3.
Therefore, both groups were homogeneous with respect to using
chlorhexidine and nystatin mouthwashes. After all, the experimental
group was treated with zinc sulfate and the control group with the
placebo.
2.11. Intervention
Zinc sulfate and placebo capsules were prepared by a pharmacist in
a similar form (codes A and B). The subjects were aware of the drugs
administration and dosages. They were asked to contact the researchers
or their assistant in case any adverse events occurred (nausea, vomiting,
diarrhea, rash, etc (Skidmore-Roth, 2015).). The dosage of zinc sulfate
was based on another study in which Zinco 220 capsules containing
50 mg zinc were used (Ertekin et al., 2004).
After gaining the participants' approval and providing them with
explanation about the benefits and side effects of zinc sulfate capsules,
42 capsules (zinc sulfate or placebo) were given to the patients. Then,
the patients in the experimental and control groups were asked to
consume the capsules three times daily (9 a.m., 1 p.m., and 5 p.m.) for
14 days from the first day of chemotherapy.
2.12. Outcomes
The outcomes of this study were objective and subjective evaluation
of mucositis, time of beginning of mucositis, and prevention of muco-
sitis. The subjects were evaluated on 4th, 7th, and 14th days after
chemotherapy by the researchers' assistant who was blind to the ex-
perimental and control groups.
Generally, the pattern of mucositis after drug consumption was the
M. Rambod et al.
Table 1
An objective scale assessment of mucositis.
0 points 1 point 2 points
Lesions Absent 1–3 4–6
Erythema No erythema Mild erythema Moderate: Patchy pseudomembranous
reaction (patches
generally ≤ 1.5 cm in
diameter and noncontiguous)
Edema Absent Mild Moderate
Pain None VAS score < 3 VAS score 4-6
Dysphasia Absent Mild dysphagia, but can have Moderate dysphagia, need soft or liquid
regular diet diet
same as that on days 3–5 after the beginning of chemotherapy
(Kooshyar et al., 2017). Then, it increased on days 7–10 or 7-14
(Chaveli-López and Bagán-Sebastián, 2016; Kostler et al., 2001). In
several studies conducted on patients undergoing chemotherapy, mu-
cositis was evaluated on days 3, 7, 10, and 14 (Cheng et al., 2001).
Therefore, days 4, 7, and 14 were considered as evaluation times in the
present study.
2.13. Ethical considerations
This study was registered in Iranian Registry of Clinical Trials
(www.irct) with ID: IRCT2014012713690N2. It was also approved by
the Ethic Committee of SUMS. Permission of the study was obtained
from SUMS, Nemazee hospital, and hematology-oncology wards.
Consent forms were also signed by the participants. The subjects were
explained about the objectives and procedures of the study. In addition,
they received information about the side effects of the study and drugs.
They were also informed that they had the right to withdraw during the
study. Moreover, a numerical code was used for patients' anonymity.
2.14. Data analysis
In this study, administration of zinc sulfate was the independent
variable, while objective and subjective scales of mucositis were the
dependent variables. The data were analyzed using the SPSS statistical
software, version 20. Data analysis was performed using descriptive and
inferential statistical methods. Kolmogorov-Smirnov test showed that
the data were normally distributed. Thus, difference between the two
study groups regarding demographic characteristics was evaluated by
independent t-test and Chi-square test. At baseline, the two groups were
compared using independent t-test. Moreover, Repeated Measures
Analysis of Variance (RM-ANOVA) was used to compare the two groups
regarding mucositis at the four time periods. P < .05 was considered to
be statistically significant.
3. Results
The data were collected from March to June 2014. The subjects
were followed for 14 days after beginning of chemotherapy. Flow chart
of the leukemia patients during the study has been illustrated in Fig. 1.
At the first step, eligibility assessment, 101 leukemia patients were
evaluated and 15 patients were excluded. At the second stage, alloca-
tion, the remaining 86 patients were randomized into experimental and
control groups. At the third step, follow-up, all 86 patients continued
the study on the 4th day. However, two leukemia patients in the zinc
sulfate and control groups were excluded due to death (n = 1) and no
reason (n = 1) on the 7th day of the study. On the 14th day also, seven
patients in the intervention group and eight ones in the control group
were dropped from the study. At the fourth step, analysis, the data of
the participants were analyzed on 4th, 7th, and 14th days (Fig. 1).
Since zinc sulfate might have some side effects, the subjects were
assessed for any complications, harms, and unintended effects during
17
European Journal of Oncology Nursing 33 (2018) 14–21
3 points
>6
Severe: Confluent pseudomembranous reaction (contiguous
patches
generally > 1.5 cm in
diameter)
Severe
VAS score > 6
Severe dysphagia, need tube feeding, IV hydration or hyper-
alimentation
the study. The researchers had decided to stop the trial in case of oc-
currence of any negative events that might be related to the supplement
and placebo capsules. However, based on the reports of the researchers,
participants, and researchers' assistants, the study had no serious and
considerable side effects or adverse events.
3.1. Demographic and clinical characteristics
The mean age of the patients was 39.17 (SD = 17.07) years in the
experimental group and 33.80 (SD = 13.73) years in the control group.
The majority of the patients in both experimental and control groups
were male. In addition, 25 leukemia patients (73.5%) in the experi-
mental group and 28 ones (70.0%) in the control group were married.
Besides, 28 patients (77.8% in the experimental group and 73.4% in the
control group) had secondary and high school education. Moreover,
most patients in both experimental and control groups (58.3% and
59.0%, respectively) were diagnosed with acute myeloid leukemia.
Furthermore, the mean number of previous chemotherapy cycles was
5.72 (SD = 1.36) and 5.05 (SD = 2.18) in the experimental and control
groups, respectively. The majority of subjects in the experimental
(75%) and control (81.8%) groups used Cytarabine + Fludarabine and
Cytarabine + (Daunorubicin or Idarubicine or Doxorubicin). The re-
sults revealed that both groups were homogenous concerning all de-
mographic (age, gender, education level, and marital status) and clin-
ical (diagnosis, number of previous chemotherapy cycles,
chemotherapy regimens, and chemotherapy agents dosage) character-
istics (Table 2).
3.2. Prevention of mucositis
During the 14 days of the study, 27 subjects in the experimental
group (75.00%) and 17 ones in the control group (47.22%) did not have
the signs and symptoms of mucositis. The results of Chi-square test
showed a significant difference between the experimental and control
groups regarding the prevention of mucositis (χ2 = 5.84, p = .01).
Therefore, the hypothesis that zinc sulfate would partially prevent
mucositis in leukemia patients under chemotherapy was confirmed.
3.3. Incidence of mucositis
The findings of this study indicated a significant difference between
the two groups regarding the incidence of mucositis. During the 14 days
of the study, 9 patients (25.00%) in the experimental group and 19 ones
(54.28%) in the control group showed mucositis. Thus, the incidence of
mucositis was 2.1 times higher in the control group in comparison to
the zinc sulfate group.
3.4. Onset of mucositis
The results of this study showed that onset of mucositis occurred on
days 5.83 (SD = 3.37) and 4.58 (SD = 2.47) in the experimental and
control groups, respectively. Although mucositis had started earlier in
M. Rambod et al.
Fig. 1. Flow chart of the leukemia patients participated in this study.
the control group than in the experimental group, the results of in-
dependent t-test indicated no significant difference between the two
groups regarding the onset of mucositis (t = -0.95, p = .34). Therefore,
the second hypothesis that mucositis would occur later in leukemia
patients in the zinc sulfate group in comparison to those in the control
group was not confirmed.
3.5. Severity of mucositis
The results of this study revealed that the mean scores of objective
and subjective evaluation of mucositis were lower in the experimental
group in comparison to the control group on 4th, 7th, and 14th days of
the study (Table 3 and Figs. 2 and 3). Therefore, the third hypothesis
that severity of mucositis was milder in the experimental group com-
pared to the control group on 4th, 7th, and 14th days of the study was
18
European Journal of Oncology Nursing 33 (2018) 14–21
approved. Moreover, according to Table 3, the results of RM-ANOVA
indicated a significant difference between the two groups regarding the
mean score of objective evaluation of mucositis during the three study
periods (4th, 7th, and 14th days after beginning of chemotherapy)
(F = 7.83, p = .007). The results of RM-ANOVA also showed a sig-
nificant difference between the two groups concerning the mean score
of subjective evaluation of mucositis during the three study periods
(F = 5.79, p = .01).
4. Discussion
The results of this study showed that zinc sulfate partially prevented
mucositis in the leukemia patients undergoing chemotherapy.
Additionally, the number of patients who did not show the signs and
symptoms of mucositis was significantly higher in zinc sulfate group
M. Rambod et al. European Journal of Oncology Nursing 33 (2018) 14–21

Table 2 Table 3
Demographic and clinical characteristics of the leukemia patients in the experimental and The results of objective and subjective evaluations of mucositis in the experimental and
control groups. control groups on 4th, 7th, and 14th days after onset of chemotherapy.

Variables Groups Test, p-value Evaluation of Days RM-ANOVA

a
mucositis between
Experimental Control 4th 7th 14th groups

Age (years) Objective

Mean (SD) 39.65 (17.07) 33.80 (13.73) t = 1.63, p = .10 Experimental 0.31 1.07 1.61 F = 7.83,
Gender, n (%) group (SD = 1.07) (SD = 2.48) (SD = 3.17) p = .007
Female 18 (43.9) 18 (42.9) χ = 1.63, p = .92
2
Control group 1.91 3.05 3.70
Male 23 (56.1) 24(57.1) (SD = 1.90) (SD = 3.92) (SD = 4.2)
Education level, n (%) Subjective
Primary 5 (13.9) 4 (10.5) χ2 = 2.90, p = .40 Experimental 0.09 0.58 0.73 F = 5.79,
Secondary 9 (25.0) 14 (36.8) group (SD = 0.4) (SD = 0.89) (SD = 1.14) p = .01
High school 19 (52.8) 14 (36.8) Control group 0.54 1.07 1.40
Academic 3 (8.3) 6 (15.8) (SD = 0.86) (SD = 1.17) (SD = 1.73)
Marital status, n (%)
Single 8 (23.5) 11 (27.5) χ2 = 2.17, p = .52 a
RM-ANOVA, repeated measures analysis of variance.
Married 25 (73.5) 28 (70.0)
Widowed 0 (0.0) 1 (2.5)
Divorced 1 (2.9) 0 (0.0)
Diagnosis, n (%)
AML a 21 (58.3) 23 (59.0) χ2 = 0.97, p = .80
ALL a 13(36.1) 13 (33.3)
CML a 2 (5.6) 0 (0.0)
CLL a 0 (0.0) 1 (2.6)
Number of previous chemotherapy cycles
Mean (SD) 5.72 (1.36) 5.05 (2.18) t = -1.57, p = .12
Chemotherapy regimens
1 b
27(56.2) 18(40.9) χ2 = 7.57, p = .27
2b 9(18.8) 18(40.9)
3b 1(2.1) 2(4.5)
4b 2(4.2) 0(0.0)
5b 3(6.2) 2(4.5)
6b 3(6.2) 2(4.5)
b
7 3(6.2) 2(4.5)
Chemotherapy agents dosage
c
Cytarabine 1201.7 (1383) 1281.2(1474) t = -0.21, p = .83 Fig. 2. The objective evaluation of mucositis in the experimental and control groups on
Vincristine c 2.00(0.0) 2.00 (0.0) p = 1.00
4th, 7th, and 14th days after onset of chemotherapy.
Cyclophosphamide c 1350.0(700.0) 1000.0(0.0) t = 0.44, p = .68
Doxorubicin c 70.00(9.75) 65.00 (5.00) t = 0.94, p = .37
Daunorubicin c 78.57(8.64) 70.93(15.83) t = 1.60, p = .12
c
Fludarabine 48.75(13.29) 46.11(4.85) t = 0.55, p = .58
c
Cisplatin 65.00(7.07) 50.00(0.00) t = 3.55, p = .09
c
Idarubicine 16.57(3.40) 16.22(4.02) t = 0.18, p = .85

a
AML, acute myeloid leukemia; ALL, acute lymphoid leukemia; CML, chronic myeloid
leukemia; CLL, chronic lymphoid leukemia.
1 b Cytarabine + Fludarabine.
2 b Cytarabine + (Daunorubicin or Idarubicine or Doxorubicin).
3 b Vincristine + (Daunorubicin or Doxorubicin).
4 b Vincristine + Cyclophosphamide or Cytarabine) + (Daunorubicin or Fludarabine or
Cisplatin).
5 b Cytarabine + (Vincristine or Cisplatin or Fludarabine).
6 b Cytarabine + (Fludarabine or Cyclophosphamide or Cisplatin) + (Idarubicine or
Daunorubicin).
7 b Cyclophosphamide + (Vincristine or Cisplatin or Cytarabine).
c
mg/m.2. Fig. 3. The subjective evaluation of mucositis in the experimental and control groups on
4th, 7th, and 14th days after onset of chemotherapy.
(75%) in comparison to the control group (47.22%). Although some
studies have been conducted on zinc sulfate and prevention of muco- incidence of mucositis in the leukemia patients under chemotherapy.
sitis, some information regarding prevention of mucositis is missed Ertekin et al. (2004) reported that six weeks after treatment, one patient
(Arbabi-kalati et al., 2012; Mansouri et al., 2012; Moslemi et al., 2014). in the zinc sulfate group and 10 patients in the control group had
In the current study, prevention of mucositis was seen in 60% of the mucositis and the incidence rate of mucositis was 10 times higher in the
patients in the zinc sulfate group and 29.5% of those in the control control group in comparison to the zinc sulfate group (Ertekin et al.,
group. Generally, zinc plays an essential role in improving the immune 2004). Additionally, Cheng et al. (2001) indicated that oral care pro-
system, developing T cells (Fraker and King, 2004), and relieving viral tocol reduced the incidence of ulcerative mucositis by 38% in children
warts (Al-Gurairi et al., 2002). Therefore, by increasing immune system (Cheng et al., 2001). Researchers have demonstrated that zinc defi-
activities, zinc sulfate prevents mucositis as an infectious disease. ciency led to impairment of immune defense, promotion of neoplasia,
The results showed that during the 14 days of the study, 25.00% and and enchantment of susceptibility to viral infections (Haase et al.,
54.28% of the leukemia patients undergoing chemotherapy experi- 2008). Therefore, the higher incidence rate of mucositis in the control
enced mucositis in the experimental and control groups, respectively. group might be related to zinc deficiency.
Therefore, mucositis was 2.1 times more common in the control group Although the current study results revealed no significant difference
compared to the zinc sulfate group. Thus, zinc sulfate reduced the between the two groups regarding the onset of mucositis, it started

19
M. Rambod et al.
earlier in the control group than in the experimental group. Another
study also indicated that mucositis developed earlier in the control
group compared to the zinc sulfate group (Ertekin et al., 2004). Simi-
larly, Mosalaei et al. showed no significant difference between head and
neck cancer patients regarding the time of onset of radiation-induced
oropharyngeal mucositis (Mosalaei et al., 2010). However, Lin et al.
revealed that head and neck cancer patients in the control group de-
veloped grade 2 mucositis and dermatitis earlier than those in the zinc
sulfate group (Lin et al., 2006). Differences in the results might be at-
tributed to differences among subjects, diseases, interventions, and
measurements.
During the present study days, severity of mucositis was milder in
the zinc sulfate group in comparison to the placebo group, which is
consistent with the findings obtained by Lin et al. (2006). Mehdipor
et al. also conducted a study on leukemia patients under chemotherapy
and showed that 10 mg zinc sulfate mouthwash (0.2%) reduced the
severity of mucositis (Mehdipour et al., 2011). Correspondingly, re-
searchers have reported a lower degree of radiation-induced orophar-
yngeal mucositis in head and neck cancer patients in the zinc sulfate
group compared to those in the control group (Ertekin et al., 2004;
Mosalaei et al., 2010; Moslemi et al., 2014). Therefore, zinc sulfate
could relieve mucositis and dermatitis to some extent (Lin et al., 2006).
Furthermore, researchers believed that delayed wound healing and skin
lesions occurred as a result of zinc deficiency. On the other hand, zinc
sulfate maintained epithelial and tissue integrity by promoting cell
growth, suppressing apoptosis, and functioning as an antioxidant pro-
tecting against free radical damage throughout inflammatory reactions
(Childers et al., 1993). Zinc also enhanced re-epitalization in the pro-
cess of wound strengthening (Thompson and Fuhrman, 2005). There-
fore, increase of zinc in serum both heals mucositis and reduces its
severity.
4.1. Limitations
The present study had some limitations the first of which being
inclusion of participants with different types and stages of leukemia
receiving various types and doses of chemotherapeutic agents.
Therefore, other studies are suggested to be performed on patients with
one type of leukemia; e.g. acute myeloid leukemia, receiving similar
chemotherapeutic agents. The second study limitation was that the two
groups were not matched regarding chemotherapeutic agents (although
randomization matched the groups in this regard). The third limitation
was the short study period. Zinc was used for 14 days and mucositis was
evaluated simultaneously. Thus, a longer period (e.g. 1–6 months) is
recommended for mucositis evaluation in future studies. The fourth
study limitation was selection of patients from two hematology-on-
cology wards in local hospitals in a megacity in Iran. Consequently, the
findings might not be genericized to all leukemia patients around the
world. The fifth study limitation was examination of the effect of zinc
sulfate on mucositis in patients receiving chemotherapy. Hence, further
studies are recommended to assess the effect of this supplement on
other mucosal and gastrointestinal disorders (nausea, vomiting, and
diarrhea). The effect of zinc sulfate is also suggested to be compared to
other medications, such as mouthwashes.
4.2. Implications for practice
Based on the sample size, this was a feasibility study and provided
evidence on the effect of zinc sulfate on mucositis in the leukemia pa-
tients under chemotherapy. Moreover, the implication of the study for
clinical practice is that zinc sulfate was safe and cost-effective in leu-
kemia patients and could be easily used at the beginning of che-
motherapy. Using zinc sulfate accompanied with standard care of mu-
cositis not only had no complications, but also prevented and decreased
the severity of mucositis in leukemia patients. Consequently, it has
several benefits if administered at a dose of 50 mg three times a day for
20
European Journal of Oncology Nursing 33 (2018) 14–21
14 days. Since mucositis is a common problem in leukemia patients
under chemotherapy and zinc sulfate can play a preventive role in this
regard, the advantages of this supplement are recommended to be il-
luminated to healthcare workers as well as leukemia patients.
5. Conclusion
This study indicated that zinc sulfate partially prevented and de-
creased the incidence of mucositis in leukemia patients under che-
motherapy. Moreover, objective and subjective scores of mucositis were
lower in the zinc sulfate group compared to the control group. Yet,
further researches are recommended for evidence-based practice.
Conflicts of interest
There were no conflicts of interest reported.
Ethical approval
This study was approved by the Ethics Committee of Shiraz
University of Medical Sciences (88-4914).
Funding
This project was financially supported by Shiraz University of
Medical Sciences (88-4914).
Acknowledgement
The authors would like to thank Shiraz University of Medical
Sciences and healthcare workers of two hematology-oncology wards in
Nemazee Hospital affiliated to SUMS. They would also like to ap-
preciate all 86 leukemia patients who participated in this study. Thanks
also go to Mahboubeh Zare and Narges Monjazebi for their contribution
to data collection. The Center for Development of Clinical Research of
Nemazee Hospital and Dr. Mehrdad Vossoughi and Dr. Saeedeh
Pourahmad are also appreciated for statistical assistance. Ms. A.
Keivanshekouh at the Research Improvement Center of Shiraz
University of Medical Sciences is appreciated for improving the use of
English in the manuscript.
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