Effects of Omega-3 Fatty Acids Against Chemotherapy-induced Mucositis: A Double-blind Randomized Clinical Trial

Objective. This double-blind randomized clinical trial evaluates the efficacy and route of administration of omega-3 fatty acids for the prevention and treatment of oral mucositis in patients undergoing chemotherapy in Iranian hospitals. Materials and Methods. Sixty patients developing World Health Organization (WHO) grade 1 oral mucositis were randomized to the omega-3 fatty acid (n=30) or placebo (n=30) group. Mucositis was assessed according to the WHO, Western Consortium for Cancer Nursing Research, and Oral Mucositis Weekly Questionnaire criteria at baseline and first, second, and third weeks of chemotherapy until mucositis resolved. Results. Differences in the severity of mucositis between the omega-3 and placebo groups in the first, second, and third weeks of treatment based on the WHO criteria were noted. This study showed that patients in the omega-3 group experienced less pain during the first, second, and third weeks of treatment. Conclusions. Omega-3 fatty acids are a safe, effective method for preventing and treating oral mucositis in patients receiving mucotoxic cancer chemotherapy. 

Every year, millions of people around the world develop cancer. Cancer is the second leading cause of mortality in developed countries, and about 20% of all deaths are attributed to this disease.¹ It is estimated that the number of cancer-related deaths in developed countries over the next 20 years will increase up to 50%.^2,3 Anticancer therapies include radiotherapy, chemotherapy, surgery, and immunotherapy.^4,5 Chemotherapy drugs are used in the treatment of malignant diseases as a main component or supplementary method; these drugs have different side effects, including mucositis (inflammation and mouth ulcers). 

Almost all patients receiving high-dose chemotherapy and 80% of patients with head and neck malignancies experience mucositis.⁶ Potential mucositis features include severe pain, increased risk of local and systemic infections, dysfunction, and bleeding from the mouth, oral cavity, and pharynx, which influence quality of life. The mucositis makes patients feel more ill and prolongs the duration of in-hospital treatment due to pain and limitations in patient nutrition; in severe cases, patients have to be fed intravenously and use opioid analgesics. Oral ulcers can send oral microflora into the blood and cause septicemia, particularly in immunocompromised conditions. These symptoms lead to increased economic costs to the patient.^7-9 Unfortunately, in most cases, the main focus in the treatment of patients with cancer is to inhibit cancer, and little attention is paid to the problems caused by cancer treatments, including mucositis.

Currently, there are no specific medications to treat or prevent mucositis; treatment reduces the severity and duration as well as prevents infection in that area until recovery. Patients often require analgesics for pain control. Sedation, hypnosis, and nerve stimulation through the skin can be used in combination with opioid analgesics. It has been suggested^10,11 that although systemic prednisone reduces the severity and duration of mucositis, it increases the risk of infection. Some^10,11 have recommended oral topical gel (Church & Dwight Co, Ewing, NJ) and Zilactin-B (Blairex Laboratories Inc, Columbus, IN) to reduce pain; a combined mouthwash can also be used. In addition, the use of antacids and vitamin E reduces the burning sensation. To prevent infection, chlorhexidine mouthwash is useful.^10,11 Currently, these patients are advised to use drugs that are not toxic and do not have any side effects.^12-14

The literature shows omega-3 fatty acids are used in the treatment of wounds.^15-17 Omega-3 fatty acids reduce inflammation and accelerate the healing of skin burns in healthy and diabetic animals.^15-17 Matushevskaia et al¹⁶ found that omega-3 fatty acids improved the healing of stomach and duodenal ulcers in 21 patients. The authors concluded that the use of this fatty acid can stimulate the wound healing process and recovery.¹⁶ Fatty acids increase the production of pro-inflammatory cytokines in the wound and thus can be used safely in skin wound healing.¹⁷ Hashemipour et al¹⁸ showed that omega-3 fatty acids have a positive effect on oral wound healing in rats; this fatty acid is a beneficial fat in the body and is recommended as an aviable alternative to the dietary intake. It seems this matter does not have any beneficial effects but it also has minimal side effects.¹⁸

Since the use of chemical agents in many patients with mucositis is restricted with respect to the nature of their illness and medications, it would be desirable that the drug used for the treatment of mucositis has minimal side effects.  To the best of the authors’ knowledge, there are no studies on the effect of omega-3 fatty acids on mucositis. The present study evaluates the efficacy of omega-3 fatty acids on chemotherapy-induced mucositis in cancer patients.

Sixty patients with malignant tumors undergoing chemotherapy treatment for the first time were included in this double-blind, randomized clinical trial. Patients were selected by the treating physician based on their leukemia or breast cancer diagnosis and were in the initial chemotherapy stage.  All patients underwent tumoral surgery before chemotherapy. Patients receiving chemotherapy alone for leukemia or breast cancer (82) were evaluated so that the effect of the drugs would reach 0. Chemotherapy drugs used included trastuzumab, raltitrexed, vinorelbine, and vincristine. 

The physician and pathologist confirmed the cancer diagnosis, and the patients did not receive radiation therapy before chemotherapy. All patients were aged 18 years or older and provided written-informed consent prior to the start of the study. Patients who had a minimum grade I mucositis as per World Health Organization (WHO) criteria¹⁹ and were not treated with chemical agents (such as chlorhexidine, topical and systemic steroids, hydrogen peroxide, sucralfate, pilocarpine, or herbal medicines) for mucositis were included.¹⁹

Exclusion criteria consisted of those who received radiotherapy before chemotherapy and head and neck radiotherapy; had white blood cell counts < 1500 mm³, platelet counts < 50 000 mm³, or hemoglobin < 10 mg/dL; were diagnosed with lichen planus or vesiculobullous diseases or bleeding disorders; took anticoagulants such as aspirin or warfarin; or had a sensitivity to seafood, uncontrolled diabetes, liver cancer, or liver disorders.^20,21

Study design

A total of 60 patients with malignant tumors undergoing chemotherapy treatment for the first time were included.  There were 34 patients in the control group; during the study period, 4 patients were excluded due to incorrect drug use, not receiving allocated intervention, being lost to follow-up, and discontinuing intervention. There were 33 patients in the omega-3 group; 3 patients were excluded during the study due to discontinuing intervention, not receiving allocated intervention, and being lost to follow-up. The remaining 30 patients in the placebo group and 30 patients in the omega-3 group were examined for mucositis and pain. The Figure illustrates the Consolidated Standards Of Reporting Trials diagram of patients. 

Prior to the study, the aim of exploring new treatments for caring for chemotherapy-related wounds was explained to all patients. Each patient was assigned to either the placebo or omega-3 group based on self-selected even or odd numbers (even and odd numbers received omega-3 and placebo, respectively). Patient selection was based on the method of randomization: numbers 1 to 100 were placed in a box and patients were assigned to the odd or even groups based on the self-selected number.  All drug and placebo capsules were placed in the same package with a special code. 

Before initiating chemotherapy treatment, the oral cavity of each patient was examined by a postgraduate student in the Department of Oral Medicine, Kerman Dental School (Kerman, Iran), and all patients were instructed on how to brush and floss their teeth. The examinations were carried out with disposable mirrors, gloves, gauze, and a flashlight. All patients received 200-mg acyclovir tablets daily and 20 drops of nystatin suspension 4 times per day to prevent herpes and Candida infections as a standard treatment. Patients in both groups received 2 capsules daily with meals. Omega-3 and placebo drugs were provided in the form of a yellow transparent pearl. A 1-g pearl of omega-3 contained 2000 mg of fish oil, 360 mg of ethyl-eicosapentaenoic acid, and 240 mg of docosahexaenoic acid; a placebo pearl contained the same amount of corn oil (1-g pearl of placebo contained 2000 mg of corn oil, 360 mg of ethyl-eicosapentaenoic acid, and 240 mg of docosahexaenoic acid).²⁰ The patients were advised to
use only the desired drug and refrain from using any chemical or herbal remedy during this period (except for medications prescribed by oncologists). In addition, sour and spicy foods were to be avoided. 

In this study, mucositis was evaluated according to the WHO, Oral Mucositis Weekly Questionnaire (OMPQ), and Western Consortium for Cancer Nursing Research (WCCNR) criteria (eTable 1).¹⁹ Oral examinations were repeated on days 1, 7, 14, and 21;  WHO, OMPQ, and WCCNR questionnaires were filled out at each time point. The OMPQ is a 12-item questionnaire that examines mucositis and its impact on the patient’s condition. Questions 1 to 9 included 5 answers and were based on the Likert scale. The answers ranged from very poor (score 1) to very high (score 5). The first 2 questions concern general health and quality of life, the third is about a burning sensation, and questions 4 to 9 deal with the impact of mucositis on individual activities (ie, sleeping, swallowing, drinking, eating, talking, and brushing teeth). Questions 10 to 12 are about pain cores and irritation of the oral cavity and pharynx using a modified Visual Analog Scale (VAS).  A 0 value indicates no pain or burning, while 10 is the highest degree of irritation and pain.¹⁹ On days 1, 7, 14, and 21, the intensity of pain was measured as per the VAS, and if the pain was moderate or severe (VAS ≥ 4), according to the WHO’s 3-step “ladder” protocol, proper analgesics were prescribed. 

Based on a literature review, the authors found that omega-3 does not have any interference with other drugs. In addition, other materials that seemed problematic were considered an exclusion and thus did not enter in this study. At baseline, 82 patients were enrolled in the study, but only 60 patients were evaluated (Figure).  All data were coded and analyzed using SPSS 13.5 (SPSS Inc, Chicago, IL) with McNemar’s test, Cochran-Mantel-Haenszel test, and Wilcoxon Signed-Rank test.

Ethics

Patients expressed concern over the use of their personal information (ie, keeping their identity secret and using their information for statistical procedures). Patients’ names and medical information remained confidential, their medical history was used solely for the purposes of the current study, and they did not endure any additional costs for drugs and tests. The research proposal was approved by the ethics committee of Kerman University of Medical Sciences (Kerman, Iran; Code 148.92.k).

In this study, 60 patients undergoing chemotherapy were examined.  A total of 37 female (18 in the omega-3 and 19 in the placebo groups) and 23 male patients (12 in the omega-3 and 11 in the placebo groups) were enrolled. The age range in the drug group was 22 to 63 years (mean ± standard deviation [SD], 37.1 ± 3.5 years), and the age range in the placebo group was 24 to 59 years (mean ± SD, 38.4 ± 2.7 years). There were no significant differences in age, sex, smoking habits, tumor location, and type of leukemia between the drug and placebo groups (eTable 2). 

At 1 and 2 weeks after starting the study, the severity of mucositis was significantly lower in the omega-3 group compared with the control group (eTable 3).  After 2 weeks, there was no evidence of mucositis in the patients taking omega-3, and the patients reported satisfaction with their drug. Based on the present findings, patients taking omega-3 compared with the placebo exhibited a better ability to eat, and the difference between the 2 groups was significant (P = .002).  The average duration of mucositis in the omega-3 group was 5.5 days (range, 4–9 days). In the placebo groups, the minimum amount of time required for recovery of mucositis was 10 days, and in 12 cases, recovery took longer than 16 days. The mean pain intensity scores during the first 24 hours were 5.0 ± 5.4 and 8.0 ± 6.4 in the omega-3 and placebo groups, respectively. The maximum and minimum values of pain severity scores in the omega-3 group were 6 and 0, respectively. In the placebo group, the maximum pain severity score was 7 and the minimum was 0.  This study showed no significant differences in the mean pain intensity scores during the first 24 hours between the 2 groups (P = .74). 

The patients’ quality of life in both groups showed no significant differences in week 1, but treatment weeks 2 and 3 showed patients in the omega-3 group experienced better quality of life; the differences between the 2 groups were significant (P = .01). There was a significant difference in the general health and the irritation of the oral cavity and throat between the omega-3 and placebo groups on day 1 and weeks 1, 2, and 3 (eTable 4). 

In addition, there were significant differences in the VAS pain and irritation scores of the oral cavity, throat, and pharynx in weeks 1, 2, and 3 between the omega-3 and placebo groups (eTable 5). 

The ability to eat, sleep, drink, and speak were assessed by the OMPQ. The present results showed significant differences between the effects of mucositis on drinking, sleeping, and teeth brushing habits during weeks 2 and 3 between the 2 groups.  A significant difference was found between the 2 groups in their ability to speak, eat, and swallow food at all 3 intervals; patients in the omega-3 group reported better performances (eTable 6).  Almost all patients (28) reported that omega-3 reduced the size of their wounds, with no toxic or allergic responses or other side effects of the drug. Outcomes were evaluated based on severity of mucositis. 

Mucositis is known as an oral mucosal lesion resulting from cancer treatment with chemotherapeutic agents. The lesion is manifested as erythema, edema, atrophy, or a mucosal ulcer with a prevalence rate of 40% to 80%.⁵ Mucositis reduces a patient’s ability to tolerate cancer treatment and results in poor prognosis for the patient. Oral mucositis, especially when severe, has a great impact on the patient’s quality of life and daily routines. It can disturb oral functions such as swallowing, eating, drinking, and talking. In addition to direct effects, oral mucositis may indirectly prolong hospitalization, thus increasing treatment costs. 

Conventional prophylactic methods for the prevention of mucositis include the use of chlorhexidine, saline solution, amphotericin B, and ice. There is no generally accepted method for the prevention and treatment of mucositis. However, some therapeutic strategies (ie, sucralfate, antiprostaglandin agents, steroidal agents, vitamins, antioxidants, silver nitrate, cryotherapy, laser, hematopoietic growth factors, and antimicrobial agents) have been proposed, though they can cause a lack of efficacy and toxicity and are difficult to use. There is a need for appropriate ways to overcome mucositis that are also effective, well tolerated, and easy to use.^6-8 Studies are underway on materials that can reduce mucositis in patients with minimal side effects.^6-8 

This study examined the effect of omega-3 fatty acids on mucositis. The results of this study showed that patients receiving omega-3 fatty acids experienced significantly less pain and irritation of the oral cavity and throat as compared with the placebo group. These patients also had a more improved quality of life and performance in terms of eating, sleeping, and swallowing liquids. Oral examinations of patients with mucositis in the 2 groups were significant.

Many studies^17-20 have shown omega-3 fatty acids have a more significant impact on accelerating wound healing. Wound healing is a complex biological process with at least 3 stages.²¹ The first stage is inflammation, which is an immediate response by the body to infection or injury.^17,22 Molecular and cellular processes during the inflammatory stage are controlled by protein mediators called pro-inflammatory cytokines. Synthesis and activation of these mediators are significantly affected by the concentration of omega-3 fatty acids. The acid is released from the cell membrane ephospholipid bi-layer in response to wounds, which affects the synthesis of proinflammatory cytokines (including leukotrienes and interferon-α [INF-α]), increases phagocytic activity, stimulates keratinocytes and fibroblasts to migrate in to the wound edge, enables the phenomenon of chemotaxis, and stimulates the release of growth factors.²³ Various studies^23-26 on the role of fatty acids in inflammation have shown these acids have a significant impact on the accumulation of mononuclear cells, and researchers believe these acids reduce inflammation in inflammatory and autoimmune diseases, such as rheumatoid arthritis, psoriasis, asthma, or cardiovascular disease.^23-26

Fatty acids act as important materials to synthesize and secrete leukotriene B4 and prostaglandin E2; these 2 substances play an important role in many proinflammatory processes: fever, increased vascular permeability, polymorphonuclear leukocytes and natural killer cell proliferation, and inhibition of the production of other leukotrienes and INF-α.²⁴ It has been reported^24,25 that increasing omega-3 fatty acids as a percentage of total phospholipids decreases systemic lymphocyte proliferation, interleukin (IL) 1β, INF-α, and IL-6 by 90%, 70%, and 60%, respectively. Dietary supplements containing omega-3 can affect molecular and cellular activities, such as initiating inflammatory cytokine gene during inflammation, healing, and the subsequent steps.²⁴  Thies et al^25,26 and Kang and Weylandt²⁷ evaluated the impact of omega-3 fatty acids on the regulation of inflammatory cytokines, and they found that the fatty acids have a positive inhibitory effect on the major mediators of inflammation such as prostaglandin E2, leukotriene B4, and IL-1β. They also showed omega-3 fatty acids have anti-inflammatory properties.^25-27 In addition, Kapoor and Huang,²⁸ Kinsella et al,²⁹ Lewis,³⁰ and Urquhart et al³¹ showed omega-3 fatty acids have properties that can be used as a modulator of the inflammatory system, as shown in other studies.^24,32-35 Hankenson et al³⁶ studied the effects of omega-3 fatty acids on the healing response of the damaged ligament fibroblasts and showed that it has a positive effect on the recovery of damaged ligaments; this effect is mediated by increasing the production of collagen, proteins, and the number of fibroblasts.  Furthermore,  Albina,³⁷ Calder,³⁸ Terkelsen,³⁹ Kapoor,⁴⁰ and Hashemipour et al¹⁸ reported more fibroblasts in the group using omega-3 topically or orally than the control group. In addition, studies^18,37-39 have shown omega-3 has a greater ability to increase fibroblast proliferation. Terkelsen et al³⁹ demonstrated that the topical application of fish liver oil can accelerate epithelialization and neovascularization in skin wounds in the ears of mice.

In other research,^15,41-43 it has been shown that omega-3 fatty acids react with the epidermal cells of the skin, gastrointestinal tract, and corneal endothelium and play a role in the reepithelialization of wounds created experimentally in rats, rabbits, and dogs. Various studies^17,24,44-46 have shown the effect of omega-3 on wound healing of the skin and gastrointestinal tract. To the best of the authors’ knowledge, the only study¹⁸ to date regarding sores in the oral cavity showed the effect of topical and oral use of omega-3 on oral ulcers of rats. The results of that study¹⁸ depicted that omega-3 has more favorable effects on the wound-healing process, which is consistent with the findings in the present study.

There was an insufficient number of patients included in this study; thus, it is recommended that a study is performed with more patients (at least 80). Patients also were not cooperative. Only patients with leukemia and breast cancer were included; therefore, the authors recommend a future study be repeated for other types of cancer.

According to the findings in this study, omega-3 fatty acids in oral form have a significant effect on wound healing induced by oral mucositis. These results may be useful to introduce new groups of substances or drugs, with omega-3 fatty acids being used in their synthesis asprophylaxis.

Affiliations: Kerman Dental and Oral Diseases Research Center, Kerman University of Medical Sciences, Kerman, Iran; Kerman Social Determinants on Oral Health Research Center, Kerman University of Medical Sciences; Department of Oral Medicine, Dental School, Bandar Abbas University of Medical Science, Bandar Abbas, Iran; and Department of Oral Medicine, Dental School, Kerman University of Medical Science

Correspondence:
Maryam Alsadat Hashemipour, DDS, MSc
Department of Oral Medicine
School of Dentistry 
Kerman University of Medical Sciences
Kerman, Iran
m_s_hashemipour@yahoo.com 

Disclosure: This study was supported by Kerman University of Medical Sciences (Kerman, Iran). This research received no specific grant from any funding agency, commercial, or not-for-profit sectors.