Zinc Chloride Mouthwash Limits Chemotherapy-Induced Oral Mucositis and Weight Loss

A placebo-controlled trial investigates a promising preventive treatment

By Michael Walker, ND, FABNO

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This article is part of our October 2021 special issue. Download the full issue here.

Reference

Oshvandi K, Vafaei SY, Kamallan SR, Khazaei S, Ranjbar H, Mohammadi F. Effectiveness of zinc chloride mouthwashes on oral mucositis and weight of patients with cancer undergoing chemotherapy. BMC Oral Health. 2021;21(1):364.

Study Objective

To assess whether zinc chloride mouth rinses during chemotherapy impact the severity of oral mucositis and change in body weight

Design

Double-blind, randomized, placebo-controlled trial at a single institution

Participants

In the study, 96 participants enrolled (male=51, female=45). They were aged 23 to 66 years. Average age was 46.21 years in the zinc group and 46.22 years in the placebo group.

The study was done on various cancer types, stage I or II: liver (n=7), stomach (6), uterus (5), breast (4), kidney (7), bladder (5), and lung (7).

Chemotherapy involved fluorouracil (n=28) and mitoxantrone (n=20).

Intervention

The intervention contained zinc chloride 0.2% mouthwash, and the placebo was a matching mouthwash without the added zinc chloride.

Procedure: Mouth rinse with 7.5 mL mouthwash for 2 minutes, every 8 hours, 2 times.

Study Parameters Assessed

Investigators graded oral mucositis severity weekly for 3 weeks, according to World Health Organization (WHO) criteria, on a scale from 0 to 4, using a combination of objective measures and subjective symptoms.

They measured weight at baseline and at 3 weeks following the intervention.

Primary Outcome Measures

Severity of oral mucositis per the WHO criteria

Key Findings

There were significant between-group differences in mucositis grade at week 1 (P=0.046), week 2 (P=0.01), and week 3 (P=0.01).

There was also a difference in severity of oral mucositis between groups at week 1 (P=0.026), week 2 (P=0.002) and week 3 (P=0.001)

While there was no change in mucositis from baseline in the zinc chloride group, there was an increase in mucositis in the placebo group (P=0.027).

Incidence of mucositis in the zinc chloride group was 3 out of 48 patients who initially enrolled, compared to 23 of 48 in the placebo group.

Paired t test showed a significant increase in weight at 3 weeks in the zinc chloride group compared to baseline (71.61 kg [SD 1.21] vs 67.89 kg [SD 1.17]), respectively. There was no significant change in weight in the placebo group.

Practice Implications

Oral mucositis (OM) is a common side effect of cancer therapies including chemotherapy, targeted systemic therapy, radiation therapy, and concurrent treatment regimens. The discomfort and pain directly impact quality of life and threaten oral nutritional intake. OM compounds the impact of multiple risks related to cancer treatment: risk of dehydration and weight loss, particularly in association with treatment-induced nausea, vomiting, and alterations to sense of taste and smell; as well as risk of infection and sepsis secondary to bacterial colonization of mucosal ulceration.1 Moreover, compromised efficacy of cancer treatment may result from dose delay and discontinuation when OM is severe.

The current study from Oshvandi et al comes at a time when we are fortunate, if not slightly overwhelmed, to see an expanding and diverse list of preventive treatments achieving positive results in clinical trials for OM. Furthermore, the zinc chloride is a new addition to the multiple other zinc forms and administration options (mouth rinse, enteral, rinse-and-swallow) that have been investigated and that, ultimately, will be compared for clinical use and further study.

Does the trial in question change how naturopathic doctors address this important toxicity?

The findings from Oshvandi et al are notable and encouraging primarily for the proportionately dramatic improvement in incidence and severity with use of the zinc chloride mouth rinse. Twenty-three of 48 initial participants in the placebo group developed mucositis (all grade 2 or 3), compared to 3 of 48 in the zinc chloride group. Twenty of these patients developed grade 3 oral mucositis, for a rate of 41.7%, which is uncommonly high in chemotherapy-only treatment of solid tumors.2-4 Interpretation is somewhat limited by heterogeneity of tumor type and lack of subgroup analysis by specific chemotherapy agent, as 5-fluorouracil (5-FU) is encountered far more often in practice for treatment of solid tumors compared to mitoxantrone. Nevertheless, zinc chloride merits further study in commonly used regimens posing high mucositis risk comparable with that seen in the trial, particularly concurrent chemoradiation and hematopoietic stem cell transplantation (HSCT) conditioning regimens.

What might limit incorporation of zinc chloride mouth rinse into regular practice?

The zinc chloride was studied in patients with solid tumors receiving chemotherapy only. As noted, a range of therapies have been investigated for OM prevention and treatment in the setting of chemotherapy, concurrent chemoradiation, and HSCT conditioning chemotherapies. Many are common to integrative-medicine supportive-care regimens, including L-glutamine, probiotics, curcumin, propolis, honey, and omega-3 fatty acids, though an exhaustive list is beyond the scope of this commentary. The MASCC/ISOO Mucositis Clinical Practice Guidelines, updated 2019/2020, do include a number of “natural and miscellaneous” agents for their analysis.5 In most cases such natural therapies are ingested and, therefore, systemic. Among these are several that we might consider multidimensional in the sense that clinical research finds therapeutic effect for 1 or multiple endpoints other than oral mucositis, and zinc itself is arguably included in that list. For clinicians selectively discussing therapeutic options for OM, the examples of omega-3 fatty acids and curcumin provide comparators in considering a place for zinc chloride.

Incidence of mucositis in the zinc chloride group was 3 out of 48 patients who initially enrolled, compared to 23 of 48 in the placebo group.

With regard to omega-3 fatty acid interventions, in a randomized, controlled trial of “ω-3-rich” compared to “ω-3-poor” enteral nutrition, patients on chemotherapy with docetaxel, cisplatin, and 5-FU for esophageal cancer receiving the “ω-3-rich” supplementation had lower frequency of stomatitis as well as hepatic enzyme elevations.6 Additional clinical trials with omega-3 suggest improved management of several chemotherapy-induced toxicities, including peripheral neuropathy;7,8 xerostomia in patients on the frequently encountered neoadjuvant breast cancer regimen of doxorubicin/cyclophosphamide, followed by paclitaxel (+/- trastuzumab);9 maintained or increased weight during chemotherapy, specifically from muscle mass.10,11

Investigations of curcumin in various applications have demonstrated a reduction in chemoradiation-induced mucositis, including with a mouth rinse12 and nanomicelle preparations.13,14 While the anticipated selective radiosensitizing effects of curcumin have not translated clearly to clinical impact, the 2019 open-label phase IIa from Howells et al suggests there is a chemosensitization effect of curcumin in the 5-FU-containing regimen, FOLFOX.15

Does zinc chloride mouth rinse provide a unique or added benefit in the chemotherapy-treated population?

The large magnitude of effect, if confirmed, might vault zinc chloride into wider use. In further research, an active control would be preferred, and even expected, in a study group at high risk of developing severe OM. Anticipating this need, a 2019 study from Hussain et al found that in patients undergoing “7+3” induction chemotherapy with cytarabine and doxorubicin for acute myeloid leukemia, those randomized to use Nigella sativa mouth rinse had reduction in OM severity and pain when compared to a “magic mouthwash” containing nystatin, tetracycline, lidocaine, and dexamethasone.16 An additional possible advantage of zinc chloride to which the authors allude may be cost-effectiveness. This consideration was not explored in depth but may offer an avenue to demonstrate value separating this from other therapies.

In the settings of chemoradiation and HSCT conditioning chemotherapy, a nontoxic mouth rinse with exceptional preventive effect for OM and weight loss would be a welcome therapy. In the case of concurrent chemoradiation, MASCC/ISOO guidelines currently suggest (level of evidence, II) oral glutamine for prevention during chemoradiation of patients with head and neck cancer,17 and suggest honey for prevention during either radiation or chemoradiation. Supporting this is a 2021 meta-analysis of randomized, controlled trials, including 998 participants, finding that L-glutamine reduced severity of OM and incidence of severe OM.18 Moreover, a reduction in hospital stay and cost can be achieved in select clinical settings.19 The zinc chloride mouth rinse may find a niche for use in patients who decline or discontinue L-glutamine. Several other forms of zinc have been investigated for activity over the past 2 decades, including zinc sulfate, zinc L-carnosine, and zinc magnesium aspartate, and the majority of clinical studies assessing OM have been positive. However the updated MASCC/ISOO guidelines notably removed the suggestion for zinc supplementation in the 2014 iteration,20,21 citing the conflicting data seen specifically in the zinc sulfate research.22 To naturopathic doctors accustomed to splitting hairs over the form of nutrients, this bundling of zinc-based therapies may seem a minimization of potentially substantial differences. Conversely, the impulse to compare zinc-based therapies to one another is understandable and reasonable.

Any rigorous comparison is limited by the absence of head-to-head trials, in which several questions may be addressed in the future. First, is there a difference in efficacy between mouth rinse applications such as zinc chloride, encapsulated zinc (sulfate, magnesium aspartate), and forms such as lozenge or rinse-and-swallow, the latter being functionally both topical and systemic (zinc L-carnosine and possibly other forms)? For patients undergoing chemotherapy prior to HSCT, zinc carnosine is the most documented of the zinc-based therapies, and though individual studies are limited by size, variations in compounding, and lack of randomization, effectiveness in reducing OM severity is consistently found, in both adult and pediatric populations.23-25 Second, do baseline and serial measures of zinc such as serum or red blood cell zinc correlate with any protective effect of treatment? Do ingested forms of zinc confer additional protective effect during cancer treatment? Given some literature finding zinc deficiency to be not uncommon at least in head and neck cancer,26,27 laboratory informed approaches may have a future role in practice. For now, though zinc chloride may be temporarily overshadowed in terms of research volume for OM, and in clinical use by more common formulations, its potential as a widely available and even cost-effective therapy for OM prevention may have been previewed in this trial.

About the Author

Michael Walker, ND, FABNO, practices naturopathic oncology in metro Detroit, at Emcura Integrative, and through the Beaumont Health Integrative Medicine Department. Walker completed undergraduate studies at Yale University, naturopathic medical school at the Southwest College of Naturopathic Medicine, and a naturopathic oncology residency at Cancer Treatment Centers of America in Illinois. He is a fellow of the American Board of Naturopathic Oncology (FABNO) and a past board member of the Oncology Association of Naturopathic Physicians.

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