Oral mucositis is frequent but serious adverse event associated with radiotherapy or radiochemotherapy in head and neck cancer severely impairs health-related quality of life, leading to poor prognosis due to discontinuation of the therapy. Although a number of compounds have been tested for prophylaxis of oral mucositis, few of them are satisfactory. We investigated the effect of polaprezinc (zinc L-carnosine), a gastric mucosal protective drug, on radiochemotherapy-induced oral mucositis, pain, xerostomia and taste disturbance in patients with head and neck cancer. Patients were randomly assigned to receive polaprezinc (n = 16) or azulene oral rinse as the control (n = 15). The incidence rates of mucositis, pain, xerostomia and taste disturbance were all markedly lower in polaprezinc group than in control. Moreover, the use of analgesics was significantly (p = 0.003) less frequent and the amount of food intake was significantly (p = 0.002) higher in polaprezinc group than in control. On the other hand, tumor response rate in patients with neoadjuvant radiochemotherapy was not significantly affected by polaprezinc, in which the response rate (complete plus partial response) was 88% for polaprezinc and 92% for control (p = 1.000). Therefore, it is highly assumable that polaprezinc is potentially useful for prevention of oral mucositis and improvement of quality of life without reducing the tumor response.
Radiotherapy alone or in combination with chemotherapy is commonly used for the therapy of head and neck cancer.1, 2 However, radiochemotherapy frequently causes oral mucositis characterized by painful mucosal ulceration that accompanied by xerostomia and dysgeusia.3 In severe case, oral mucositis causes dehydration, malnutrition, weight loss and poor prognosis. The primary cause of oral mucositis induced by radiochemotherapy is the direct toxic action of radiation or chemotherapeutic agents on oral mucosa, while secondary factor is oral infection due to the immunosuppressive action of the therapy.4 Although the precise mechanisms underlying the cytotoxic action of radiochemotherapy on oral mucosa remain to be clarified, oxidative stress, followed by the production of a series of inflammatory cytokines is implicated in the etiology of oral mucositis. A positive correlation is noted between the severity of mucositis in head and neck cancer patients and the levels of proinflammatory cytokines such as tumor necrosis factor (TNF)-α, interleukin (IL)-1 and IL-6.5 Sonis et al.6 reported that the mucosal injury induced by radiochemotherapy is comprised of the following 5 processes1: initiation by production of reactive oxygen species,2 nuclear factor-κB (NF-κB) activation followed by induction of inflammatory cytokines such as TNF-α, IL-1β and IL-6,3 TNF-α-mediated production of ceramide and caspase activation that leads to cell apoptosis,4 ulceration with inflammation and5 healing. On the basis of these assumptions, a number of compounds have been clinically tested for prevention of oral mucositis in the therapy of head and neck cancer, including antioxidants such as amifostine,7–10 vitamine E,11 melatonin12 and allopurinol,13 mucosal protectant such as sucralfate,14 benzydamine, a nonsteroidal antiinflammatory drug with local anesthetic action,15, 16 and prostaglandin E1 analog.17 However, none of them has been confirmed to reveal consistent protective action against radiation- or radiochemotherapy-induced oral mucositis.
Polaprezinc (PZ) is a zinc-containing molecule (zinc L-carnosine) and used for the therapy of gastric ulcer.18 It has been reported that this compound inhibits the induction of TNF-α as well as cellular signaling of TNF-α.19, 20 Interestingly, Mitsuhashi et al.21 reported in an animal model of chemotherapy-induced oral mucositis that PZ improves the recovery from 5-fluorouracil–induced oral mucositis in hamsters. Moreover, Katayama et al.22 also showed that PZ ameliorates mucosal ulceration in acetic acid-induced experimental oral mucositis in hamsters.
Therefore, in the present study, we investigated whether PZ prevents oral mucositis associated with radiochemotherapy in patients with head and neck cancer.
The present study was carried out in accordance with the guidelines for the care for human study adopted by the ethics committee of the Gifu Graduate School of Medicine, and notified by the Japanese government (approved No. 21-154 of the institutional review board). Patients with head and neck cancer who underwent radiotherapy or radiochemotherapy at Gifu University Hospital during January 2009 and October 2009 were informed of the present clinical study by physicians. Thirty-one patients who agreed to participate in the study by signing the written informed consent were randomly assigned to receive oral rinse of azulene (control, n = 15) or PZ (n = 16). Azulene was used as a control agent since this compound is approved in Japan for the therapy of oral mucositis, although there has been no evidence suggesting that the compound is effective for prevention or cure of oral mucositis induced by cancer chemotherapy or radiotherapy. Patients' demographics were shown in Table 1.
Table 1. Patients' demographics
Treatment of PZ or azulene oral rinse
PZ (Promac granules 15%, ZERIA Pharmaceutical Co., Tokyo, Japan) and azulene (Azunol Gargle liquid 4%, Nippon Shinyaku Co., Kyoto, Japan) were used in the present study. PZ granules (0.5g) were dissolved in 20 ml of 5% sodium alginate solution (Kaigen, Osaka, Japan), a natural thickener used as food additive, by agitating intermittently for 1 hr. Azulene oral rinse was prepared by pouring 7 drops of 4% liquid solution into 100 ml water. At the start of radiotherepy, patients were orally rinsed with azulene solution or PZ solution for 3 min 4 times in a day and continued to the end of the radiotherapy. In case of PZ solution, the solution was swallowed after oral rinse. Our study was an open trial comparing the effect of PZ oral rinse followed by oral intake with that of azulene oral rinse on radiochemotherapy-induced oral mucositis and associated symptoms in head and neck cancer patients.
Evaluation of oral mucositis and tumor response
Primary endpoint was the prevention of oral mucositis, while secondary endpoints included the prophylaxis of pain, xerostomia and taste disturbance, reduction in the use of analgesics for the relief of oral pain, lowering the number of patients who showed inability to oral intake, and the prevention from reduction in the amount of daily meals. The incidence of mucositis, pain, xerostomia and taste disturbance were evaluated and the severity was graded according to the Common Terminology Criteria for Adverse Events v3.0 (CTCAE).23 The side effects were checked every week and the worst score during the observation period was included in the data for comparison. The frequency of the use of analgesics to relieve oral pain was examined from electric medical record. Data on the number of patients who showed inability to oral intake and the amount of daily meals (percentage of the total food) were obtained from electric medical record or nursing record system.
The objective tumor response to radiochemotherapy was evaluated by Response Evaluation Criteria in Solid Tumors (RECIST) criteria.24 The response rate was evaluated at 1 month after completion of radiochemotherapy in patients with neoadjuvant therapy.
Data were analyzed by Statistics Program for Social Science for Windows (SPSS-X, version 10, SPSS, Chicago, IL) and statistically compared between control group and PZ group. Parametric data were analyzed by t-test, while nonparametric variables were analyzed by Mann-Whitney U-test or Fisher's exact probability test. Relative risk and 95% confidence intervals (CI) for oral mucositis, pain, xerostomia, taste disturbance, frequency in the use of analgesics and the incidence of disability to oral intake were determined. The p values of less than 0.05 were regarded as statistical significant.
As shown in Table 1, there were no significant differences in gender, age, cancer area, total dose of radiation, number of radiochemotherapy or clinical data between the two groups, except for serum creatinine level, in which the values were significantly lower in control than in PZ group. However, none of patients showed values beyond the upper limit of normal (male: 1.2 mg/dl, female: 0.9 mg/dl). Mean total dose and duration of radiation were 58 Gy and 45 days, respectively, in control group, while 51 Gy and 37 days, respectively, in PZ group. Chemotherapy was concomitantly carried out in 80% for control group and 56% for PZ group. Most frequent cancer was pharyngeal cancer (33 versus 44%), followed by laryngeal cancer (27 versus 25%) in both groups.
Oral mucositis, pain and xerostomia occurred in all patients of control group, in which grade ≥ 2 events appeared in 86.7, 86.7 and 73.3%, respectively (Table 2). Taste disturbance was also observed in 87% of patients in control group, although the extent was less marked than other symptoms and grade ≥ 2 event appeared in 53.3%. Oral rinse with PZ significantly reduced the incidence of these symptoms, in which the incidence rates of grade ≥ 2 events were 40% for oral mucositis, 33.3% (p = 0.003) for pain, 13.3% (p = 0.001) for xerostomia and 19% (p = 0.0002) for taste disturbance. As a result, the frequency of the use of analgesics was reduced from 100 to 50% (p = 0.0025) (Table 3). In addition, the amount of meals was significantly larger in PZ group than in control group due to the prevention from difficulty in oral intake (78.8 ± 31.2% of total meal, mean ± SD, versus 30.7 ± 37.9%, p = 0.002). Therefore, PZ markedly reduced the risk of oral mucositis and related symptoms associated with radiochemotherapy in head and neck cancer patient. Figure 1 showed the relative risk and 95% confidence intervals for oral disturbances. Treatment with PZ reduced the risk of oral mucositis by 56.7% (grade ≥ 2) and 90.6% (grade ≥ 3), pain by 73.9% (grade ≥ 2) and 81.2% (grade ≥ 3), xerostomia (grade ≥ 2) by 83%, taste disturbance (grade ≥ 2) by 88.3%, analgesics use by 50% and disability to oral intake by 68.7%.
Table 2. Effect of polaprezinc on the incidence of oral mucositis, pain, xerostomia and taste loss in patients with head and neck cancer who received radiation/chemotherapy
Table 3. Effect of polaprezinc on the prevalence of the use of analgesics and disability to oral intake, and the amount of meals ingested in patients with head and neck cancer who received radiation/chemotherapy
On the other hand, we checked whether the tumor response to radiochemotherapy is affected by PZ. As shown in Table 4, the response rate was not significantly different between control and PZ groups, in which the response rate (complete response + partial response) was 88% for polaprezinc and 92% for control (p = 1.000).
Table 4. Effect of polaprezinc on the response rate in patients with head and neck cancer who received radiation/chemotherapy for neoadjuvant therapy
Although radiochemotherapy is highly effective for head and neck cancer, painful oral mucositis and taste disturbance occurs frequently, which results in a disability to oral intake and thus leads to a requirement of enteral nutrition or intravenous hyperalimentation. Trotti et al.25 reviewed the incidence of radiation-induced oral mucositis in head and neck cancer patients and showed that the rate is over 80%. In the present study, mild to moderate mucositis appeared in all patients in control group. In addition, all patients used analgesics for the relief of oral pain, and 6 of 15 patients (40%) revealed inability to oral intake.
A number of compounds have been clinically studied for prevention of radiation- or radiochemotherapy-induced oral mucositis; however, most of them have failed to show a definite and consistent protective action. Among a variety of agents, palifermin, a recombinant keratinocyte growth factor-1, is the only agent that is approved by the US Food and Drug Administration for amelioration of oral mucositis in patients with hematological carcinoma who receive high-dose chemotherapy for hematopoietic stem cell transplantation. The Clinical Practice Guidelines for the Prevention and Treatment of Mucositis reported by the Mucositis Study Section of the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology has recommended to use benzydamine for prevention of radiation-induced mucositis in patients with head and neck cancer receiving moderate-dose radiation therapy,26 although none of drug has been approved for prevention of radiation-induced oral mucositis. A randomized placebo controlled trial in patients with head and neck cancer has shown that oral rinse with benzydamine reduces radiation-induced erythema and ulceration by 30% but that the preventive effect of benzydamin is no longer observed in patients receiving accelerated doses of radiation.15 More recent clinical trial comparing the effect of benzydamin oral rinse against radiation-induced mucositis with that of placebo in patients with head and neck cancer indicated that the frequency of severe mucositis (grade 3–4) is significantly lower in benzydamin group (43.6%) than in placebo group (78.6%).16
We reported here that oral rinse followed by intake of PZ (zinc L-carnosine) was highly effective for prevention of oral mucositis associated with radiochemotherapy in patients with head and neck cancer. Among 16 patients in PZ group, only 1 patient (6.3%) showed grade 3 oral mucositis, while the incidence of grade 3 event was 66.7% (10 of 15 patients) in control group, indicating that PZ reduced the risk of oral mucositis by 90.6% (relative risk: 0.094, 95% CI: 0.014–0.647, p = 0.0006). Moreover, the incidence of grade 3 pain was 12.5% (2 of 16 patients) in PZ group and 66.7% in control group, thereby indicating the risk reduction of 81.2% (relative risk: 0.188, 95% CI: 0.049–0.720, p = 0.003). As a consequence, the use of analgesics for the relief of oral pain was less frequent in PZ group (50 versus 100%, p = 0.0025) and the incidence of disturbance of oral intake was lower in PZ group than in control group (12.5 versus 50%, p = 0.113). Thus, the amount of food intake was significantly larger in PZ group than in control group (78.8 versus 30.7%, p = 0.002). Taken together, it is suggested that the use of PZ prevents an impairment of quality of life induced by radiochemotherapy.
It was notable that the tumor response to radiochemotherapy was not significantly influenced by PZ. Therefore, it is likely that PZ inhibits the oral mucosal damage induced by radiochemotherapy without reducing the antitumor effect of the therapy.
PZ contains zinc in its molecule, and this metal ion may contribute to the protective action on oral mucosa against radiochemotherapy, since zinc sulfate is reported to be beneficial in decreasing the severity of radiation-induced mucositis and oral discomfort in patients with head and neck cancer.27 Alternatively, the protective effect may result from PZ moiety itself. It has been demonstrated that PZ reveals a variety of cytoprotective mechanisms, including suppression of aspirin-induced lipid peroxidation and TNF-α induction induced by aspirin in rat gastric mucosa,19 reduction of TNF-α–induced NFκB activation and interleukin-8 secretion from gastric epithelial cells,20 inhibition of superoxide generation induced in primary monolayer cultures of rat gastric fundic mucosa by ethanol,28 induction of an antioxidant heme oxygenase-129 or a cytoprotective protein 72-kDa heat shock protein30 in rat mucosal cells. In particular, it is highly assumable that the protective effect of PZ against radiotherapy-induced oral mucositis observed in the present study is attributable to the anti-TNF-α action of the compound, since the activation of NF-κB by irradiation followed by the induction of several cytokines including TNF-α and subsequent activation of caspases is considered to be implicated in the etiology of radiation-induced oral mucositis.3, 5, 6, 31
On the other hand, it has been demonstrated by a double-blinded control clinical trial that PZ improves the disease conditions of idiopathic taste disorders.32 It has also been shown that zinc sulfate prevents taste alterations associated with radiation in patients with head and neck cancer,33 although inconsistent result showing no preventive effect of zinc sulfate against radiation-induced taste alteration was also reported.34 Zinc deficiency causes taste disturbance and xerostomia, both of which are reversed by supplementation of zinc in humans.35 In the present study, 13 of 15 patients (86.7%) complained of grade 1 (33.3%) or grade 2 (53.3%) hypogeusia and all patients showed xerostomia in control group (grade 1: 26.7%, grade 2: 46.7%, grade 3: 26.7%). PZ greatly prevented taste disturbance (grade 1: 12.5%, grade 2: 6.3%) as well as xerostomia (grade 1: 43.8%, grade 2: 12.5%, grade 3: 0%).
We are now planning to carry out a large-scale multi-institutional randomized control study to further confirm the prophylactic effect of PZ against oral mucositis in patients with head and neck cancer who receive radiochemotherapy and in those with hematological carcinoma who undergo high-dose chemotherapy for hematopoietic stem cell transplantation.
In conclusion, we carried out a clinical trial comparing the effects of PZ and azulene (control) on the incidence of oral mucositis and its accompanied symptoms induced by radiochemotherapy in patients with head and neck cancer. PZ was found to be highly effective in reducing the incidence of oral mucositis, pain, xerostomia and taste disturbance without reducing the tumor response to radiochemotherapy. In addition, PZ prevented the disturbance of oral intake and reduction in the amount of food, indicating an improvement of quality of life. PZ is a low-cost medicine with no serious side effect. Therefore, it is highly assumable that the compound is potentially useful for supportive care in patients with head and neck cancer who receive radiotherapy with or without chemotherapy.