Volume 7, Issue 10, October – 2022 International Journal of Innovative Science and Research Technology

ISSN No:-2456-2165

“Role of Zinc Sulfate in Prevention of

Chemotherapy Induced Oral Mucositis”
Prof. Dr Fauzia Abdus Samad Prof Abdus Samad Syed Dr Asif Riaz Khan
HOD Medical Oncology HOD Radiation oncology Registrar Medical Oncology,
Fauji Foundation hospital CMH Rawalpindi, Fauji Foundation Hospital
Rawalpindi, Pakistan Pakistan Rawalpindi, Pakistan

Dr. Rimsha Zahid Dr. Noor-ul-Ain Azam Dr. Sharmin Arif

Ex PGT Medical oncology PGT Medical oncology Ex PGT Medical oncology
Fauji Foundation Hospital Fauji Foundation Hospital Fauji Foundation Hospital
Rawalpindi, Pakistan Rawalpindi, Pakistan Rawalpindi, Pakistan

Corresponding author
Dr Aalia Mushtaq Chaudhary
PGT Medical Oncology Fauji Foundation Hospital Rawalpindi, Pakistan

Abstract:- CONCLUSION: Zinc Sulphate is an effective adjunct

BACKGROUND: Chemotherapy has significantly used in our study, which not only showed its
improved survival of cancer patient, but it has many side effectiveness but also proved to be safe drug without any
effects. About 14-81% of patients receiving interactions with chemotherapies. Zinc Sulphate
chemotherapy experiences oral mucositis. Studies have significantly reduced the Mucositis.
shown zinc supplements may act as protective agent
against oral Mucositis. The aim of study was to explore LIMITATIONS: This study only evaluated the effect of
the preventive role of zinc sulfate in chemotherapy zinc Sulphate with single cycle of chemotherapy and did
induced mucositis. not compare the protective effect of zinc sulphate with
other preventive agents.
OBJECTIVES: The objective of the study to evaluate
the effectiveness of zinc sulfate in prevention or CONFLICT OF INTEREST: None
decreasing severity of chemotherapy induced oral
mucositis with chemotherapy regimens having high Keywords:- Oral mucositis, zinc sulphate, chemotherapy.
neutropenic potential. I. INTRODUCTION
DESIGN:Open label two arms interventional study, with
quantitative study design. Chemotherapy has significantly contributed to the
SETTING: Study was conducted at Medical Oncology survival of cancer patients, but its side effects remain an
Department, Fauji Foundation Hospital, Rawalpindi in 6 importantarea of concern.1As chemotherapies act on tumor
months duration. cells and rapidly proliferatingnormal cells especially the
immune cells, capillaries and gastrointestinal tract lining,
MATERIAL AND METHODS: The patients were henceseveral adverse effects occur due to this
enrolled by convenience non-probability sampling interaction.2The toxicitiesof a chemotherapeutic agent not
technique. They were randomized to interventional arm only depend upon its mechanism of action, dose and
receiving zinc sulfate plus chemotherapy and no interactions, but also on various patients’ related parameters
interventional arm receiving only chemotherapy by like their oral hygiene and genetic factors.2,3
systematic sampling.
Oral mucositis is an important non-hematological side
MAIN OUTCOME MEASURES: Incidence and severity effect of cytotoxic treatments.4About 14-81% of patients
of mucositis at day 7 and day 14 in interventional and receiving chemotherapy may experience oral
non interventional arm. mucositis.5With certain medicines it can even be a dose
SAMPLE SIZE: It was two arm study with 50 patients limiting adverse effect.6 It isassociated with profound pain,
in each arm with total of 100 patients. thus negatively affecting the patient’s nutritional status and
quality of life which in turn leads to poor tolerance to
RESULTS: Chi Square test was applied on the effect of therapy. This low tolerance may lead to dose reductions
Zinc Sulphate on Mucositis. Mucositis assessed at day 7 andincreased gaps in therapy. Thus, it not only affects
& day 14 showed statistically significant difference in patient’s survival but also causes significant economic
Mucositis incidence and severity in number of patients burden.7,8,9,10
receiving Zinc Sulphate between two arms with p value
< 0.00.

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Volume 7, Issue 10, October – 2022 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
Chemotherapy related mucositis usually presents after Zinc is an essential micronutrient requiredin trace
one week of chemotherapy while the highest number of amount and has no internal body storage.15Zinc has role in
cases noted are on day 10 post chemotherapy.7 Oral combating inflammation and cell cycle regulation. It acts as
mucositis presents in the form of erythema, swelling and a cofactor for DNA synthesis and is important for cell
ulceration which predisposes the patient tosystemic and survival and wound healing.Zinc maintains the immune
local infections.11,12 system and its deficiency causes impairment of B cells,T
cells,natural killer cells and causes decreased production of
Pathogenesis of oral mucositis consists of complex T-helper-1 cells.7,11,16
series of different microbiological and biological eventsin
which different set of cytokines, reactive oxygen species, There are many scoring systems for assessment of
second messengers and oral flora play an important role in mucositis,most widely used is World Health Organization
damaging the oral mucosa.3Mucositis develops in four (WHO) system which is based on clinical picture as well as
steps,in initial inflammatory/vascular phase chemotherapy oral intake of patient.4
releases cytokines such as IL-1 and TNF-α which causes
tissue damage and increases vascularity.In epithelial phase, Literature review showed trials supporting the role of
chemotherapies which are specific to cell cycle inhibit DNA zinc sulfate for prevention ofchemotherapy induced
synthesis in S phase of cell cycle and results in epithelial mucositis.7,9 Conflicting results were shown by some
atrophy,erythema and ulcers. Ulcerative phase is more studieswith no significant clinical benefit when used with
severe in neutropenic patients, as it causes greater release of high dose chemotherapy.No study was found on this topic in
inflammatory cytokines and reactive oxygen speciescausing Pakistan.
significantdamage. Eventually, the recovery phase requires
cell division, their differentiation, recovery of cell counts The aim of this studywas to explore the preventive role
and bacterial flora suppression.13 of zinc sulfate in chemotherapy induced mucositis in our
population.
Chemotherapy regimens including cytarabine, 5- A. Objective:
Flourouracil,platinum compoundsand alkylating agents are The objective of this study was:
linked to cause mucositis in literature.2 Different agents  To evaluate the effectiveness of zinc sulfate in
have beentried for prevention of mucositisincluding Chinese prevention or decreasing severity of chemotherapy
herbal medicines, antibiotics, anesthetic agents, anti- induced oral mucositis with chemotherapy regimens
inflammatory medicines, chlorhexidine, amifostine, having high neutropenic potential.
pentoxyfyline, low level laser therapy, cryotherapy, zinc
sulfate and non-essential amino acids. However, still there is B. Operational Definition:
lack of evidence based standard protocol in this a) Oral Mucositis:
regard.7,14Multinational association of supportive care in Erythematous and ulcerative lesions of oral mucosa
cancer (MASCC) and International Society of Oral observed in several conditions including
Oncology (ISOO) proposed that in oral cancer, zinc chemotherapy.17
supplements may act as a protective agent against oral
mucositis.14 b) Incidence of Oral Mucositis:
New cases of oral mucositis irrespective of grade
divided by the total number of cancer patients
completed the whole study.10
c) WHO grade of Mucositis:7

Grade Changes
0 No subjective or objective changes of mucositis
I Oral soreness and erythema in mucosa, gums tongue or palate
II Erythema and ulcers,but solid diet tolerated
III Erythema and oral ulcers, only “pasty” food and liquid tolerated
IV Erythema and ulcers and pain,inability to swallow liquids,oral alimentation
impossible, narcotics for pain relief.
Table 1: WHO grades of mucositis

II. MATERIALS AND METHODS C. Duration of study:

6 months starting from date of approval.
A. Setting:
After approval from ethical review committeeof D. Sample size:
ourhospital, the study was conducted at Medical Oncology It was two arm study with 50 patients in each arm. After
Department, Fauji Foundation Hospital, Rawalpindi. taking informed consent, a total of 100 patients were
enrolled.Sample size was calculated with WHO sample size
B. Study design: calculator 1.1.7
Open label two arms interventional study, with
quantitative study design.

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Volume 7, Issue 10, October – 2022 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
E. Sampling Techniques:  Patient aged ≥ 12 years
Two step sampling technique was used. First, the  Conscious and oriented patients
patients wereenrolled by convenience non-probability  No evidence of mucositis prior to chemotherapy
sampling technique. Then they wererandomized to  Patients receiving chemotherapeutic regimens
interventional arm receiving zinc sulfate plus chemotherapy withneutropenic potential of >20%.18
and no interventional armreceiving only chemotherapy by
systematic sampling by allotting all patients reporting on B. Exclusion Criteria:
odd numbers to interventional arm and even numbers to  Prior radiotherapy to head & neck region
non-interventional arm.  Pregnancy and lactation
 Patients allergic to zinc compounds.
III. SAMPLE SELECTION
 Patients with conditions predisposing to oral mucositis
A. Inclusion Criteria: like Sjogren’s syndrome.

IV. CONCEPTUAL FRAMEWORK OF THE STUDY

 Open label two arms interventional study with quantitative study design

Checked for
Patient receiving mucositis as per
Zinc sulfate plus WHO grade of
chemotherapy AECC at 7 & 14
day
Patient Patients'
enrolled by consent
Radomization
Ethical non- taken & by systematic
approval prabability detailed
sampling
convenience counselling
technique
sampling for oral
technique hygiene

Checked for
mucositis as
Patient receiving only
chemotherapy per WHO
grade of AECC
7 & 14 day

Fig. 1: Conceptual framework of study

V. DATA COLLECTION assessment of mucositis was accessed by oral toxicity scale

of World Health Organization.Mucositis was accessed on7
Patient fulfilling the inclusion criteria were enrolled and day 14 post chemotherapy for incidence as well as
in the study.Patients receiving chemotherapy with high severity.
neutropenic potential (>20%) without any baseline
mucositis were enrolled in the study by non- VI. RESULTS
probabilityconvenience sampling technique. After taking an
informed consent for participation in the study, patients In this study a total of 100 patients were enrolled in
were randomized into two arms by systematic sampling two arms; intervention arm (Zinc Sulphate supplementation
technique. Randomization of all patientswas done by giving n=50) and control arm (n=50). Overall, the mean age of
odd serial numbers to interventional arm andeven numbers patients was 48.33 ± 12.2. SPSS version 23 was used to
to non-interventional arm. Atotal of 50 patients were analyze data.Various histological diagnoses were included
enrolled in each arm. Interventional armreceived zinc sulfate and the commonest diagnosis was breast cancer (87 patients,
syrup plus chemotherapy while the other arm received 87%), followed by ALL (8 patients,8%)and lymphoma
chemotherapy alone.The zinc sulfate syrup was prescribed (NHL and Hodgkin lymphoma) as shown in table 2.
for 14days as thrice aday dosage schedule.Patients were Majority of patients were given dose dense ACPaclitaxel
counseledon oral hygiene including soft tooth regimen (87%), followed by HyperCVAD regimen and
brush,avoidance of tobacco and alcohol etc.Objective DHAP. Descriptive statistics are given as percentages and

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Volume 7, Issue 10, October – 2022 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
frequency of all these qualitative variables (histologies and
chemotherapy regimens)in table 2.
n (%)
Diagnosis
CA Breast 87 (87%)
ALL 8 (8%)
NHL 3 (3%)
Hodgkin’s lymphoma 2 (2%)
Chemotherapy
AC→PACLI 87 (87%)
HyperCVAD 8 (8%)
DHAP 5 (5%)
Zinc Sulphate intervention
Done 50 (50%)
Not done 50 (50%)
Table 2: Overall baseline characteristics of patients (n=100)

As part of analytical statistics, Chi square test was thatmucositis assessed at day 7 showed statistically
applied to identify statistical significance of any reduction in significant difference in mucositis incidence as well as
severity of mucositis in Zinc Sulphate arm. A p value of severity in patients receiving Zinc Sulphatewith a p value <
≤0.05 was considered significant. This analysis showed 0.00 and Pearson chi square value was 40.108.

Value Df Asymp. sig. (2-sided)

Pearson chi-square 40.108 3 .000
Likelihood ratio 48.315 3 .000
Linear-by-linear association 37.637 1 .000
N of valid cases 100
Table 3: Chi square test for mucositis at day 7

Only 9 patient (18%) developedgrade 1 mucositis at day 7 in intervention arm as opposed to 21(42%) patients in non-
interventionarm, while none of the patient had grade 2 or grade 3 mucositis in intervention arm. Thus,the incidence as well as the
severity of mucositis was markedly reduced with the co-administration of ZnSO4, when assessed at day 7 in patients receiving
various chemotherapies in our study, as shown in figure 2.

Mucositis %

Fig. 2: Bar chart showing relationship between grades of mucositis in intervention & non- intervention arm at day 7

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Volume 7, Issue 10, October – 2022 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
For the Assessment for mucositison day 14, chi square arm.Neither Grade 2, nor grade 3mucositis was observed in
test was applied and Pearson chi square value was 42.949, intervention arm in comparison to non-intervention cohort
confirming positive affect of intervention on incidence at where 6 patients developed grade 2 mucositis. Thus, the
day 14 as well. At day 14 also, among intervention arm, total incidence of mucositis was72% in non-intervention
only 4 patients (8%) developed grade 1 mucositis as arm as compared to 8% in intervention arm, with ap valueof
compared to 30 patients (60%) in non-intervention less than 0.00, confirming its statistical significance as well.

Value Df Asymp. sig. (2-sided0

Pearson chi-square 42.949 2 .000
Likelihood ratio 48.806 2 .000
Linear-by-linear association 38.805 1 .000
N of valid cases 100
Table 4: Chi square test for mucositis at day 14

Mucositis %

Fig. 3: Bar chart showing relationship between grades of mucositis in intervention & non- intervention arm at day 14

VII. DISCUSSION We used Google scholar and pub med for literature
search regarding the zinc sulphate and oral mucositis. Zinc
Chemotherapy is an important modality in the sulphate has been reported in literature to have some
armamentarium against various malignancies. It has good protective effect against chemotherapy induced
cure rates but there are various hinderances in its use mucositis.7,9,19 Zinc sulphate is believed to have protective
including cost, chemotherapy phobia, side effects and post role by combating inflammation, acting as a cofactor for
chemotherapy care required at home.One of the commonest DNA synthesis and maintaining immune system.7,11,16 But
factors affecting compliance of chemotherapy is side effects there is no clear evidence as conflicting results are shown by
of the treatment that the patients experience.1These side some studies, where no significant benefit is shown with
effects are haematological as well as non-haematological high dose chemotherapies esp. the pre-transplant
affecting several organs of the body. Oral mucositis is a conditioning regimens.20Moreover, no local study is
non-hematological side effect of chemotherapy and about available to study this dimension of mucositis. Hence, it is
14-81% patients experience this side effect.4,5 Thus, an important area to explore if mucositis can be prevented or
negatively affecting patients’ nutrition and leading to poor minimized to improve outcome of patients receiving various
tolerance,dose reductions and gaps in chemotherapy which chemotherapies. With this background we studied the effect
affects survival of the patients and causes economic burden of zinc sulphate in prevention or decreasing the severity of
as well.7,8,9,10. Different agents have been tried for chemotherapy induced oral mucositis in our population.
prevention of mucositis including Chinese herbal medicines,
antibiotics, anesthetics, anti-inflammatory agents,laser Rambod et al studied effect of zinc sulphate on
therapy, cryotherapy, zinc sulphate and non-essential amino prevention and reduction in severity of mucositis in adult
acids. However, still there is lack of evidence based patients treated for leukemia.7 We included solid and
standard protocols for the prevention of chemotherapy hematological malignancies who were treated with
related mucositis.7,14 chemotherapy with high neutropenic potential > 20%. Their
Mean age in the intervention arm was 39.17 ±17.07 years

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Volume 7, Issue 10, October – 2022 International Journal of Innovative Science and Research Technology
ISSN No:-2456-2165
and 33.80±13.73 years in non-intervention arm.7 In our VIII. CONCLUSION
study, mean age in experimental group was 47.5 year ±
12.97 years and in non-experimental group it was 49.14 Zinc Sulphate is an effective adjunct used in our study,
±11.5. They showed a reduction in the incidence of which not only showed its effectiveness by reducing both
mucositis by 75% in investigational arm and it was found to the incidence as well as severity of mucositis in our patients.
be 47.7% in control arm in their study.7While,in our study, Also,it proved to be a safe drug without any interactions
82% patient didn’t experience mucositis in investigational with chemotherapies. The significant reduction of mucositis
arm as compared to 22% in non-investigational arm on day by Zinc Sulphatetranslated into improved patients’
7. This rate was 92% reduction as compared to 28% in non- compliance and better tolerance of chemotherapy, resulting
experimental arm when assessed on day 14. Regarding the in expected improved outcomes.
severity of mucositis, there was a marked difference
between the two cohorts concerning the mean score of We recommend further studies to study the
severity of mucositis with p value = 0.01.7 Our study effectiveness of zinc sulphate and imply this useful drug in
showed significant reduction as well both on day 7 and day prevention of this challenging side effect of chemotherapies.
14 in severity of mucositis with p value < 0.00.
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