Management of Chemotherapy-induced Oral Mucositis in Gastrointestinal Malignancies: Evidence From Randomized Controlled Trails

Randomized Control Trials for COM in Esophageal and Gastric Cancer

Five trials were conducted to prevent COM in esophageal and gastric cancer (Table I). First, we conducted a randomized trial to evaluate the efficacy and safety of Hangeshashinto in patients with gastric cancer who developed moderate-to-severe oral mucositis (CTCAE v4.0 grade ≥1) during any cycle of chemotherapy (10). The patients received either Hangeshashinto or placebo. Hangeshashinto is a traditional Japanese medicine that contains seven crude herbal drugs: Pinelliae tuber, Scutellariae radix, Glycyrrhizae radix, Zizyphi fructus, Ginseng radix, Zingiberis processum rhizoma, and Coptidis rhizome. The primary endpoint was the incidence of ≥grade 2 oral mucositis, and the secondary endpoint was the time to disappearance of oral mucositis and the incidence of adverse events. This trial was conducted at 15 institutions in Japan. A total of 91 patients were enrolled, of whom 45 were registered in the Hangeshashinto arm, and 46 patients were registered in the placebo arm. Both Hangeshashinto and placebo arms were administered same dose (for a total daily dose of 7.5 g). The incidence of grade ≥2 COM was 40% and 41.3% in the Hangeshashinto and placebo arms, respectively. There was no significant difference between the two groups (p=0.588). Furthermore, the duration of grade ≥2 COM was almost similar between the Hangeshashinto and placebo arms (14 days vs. 16 days). We concluded that Hangeshashinto treatment did not reduce the incidence of ≥2 COM in patients who developed mucositis during chemotherapy for gastric cancer. Tanaka et al. conducted a randomized phase II trial to evaluate the efficacy and safety of Elental plus glutamine (Gln) in patients with esophageal cancer who developed chemotherapy-induced COM (UMIN00 0008338) (11). The patients received Elental+Gln or Gln only, or no treatment. Patients in the Gln arm received 8,910 mg of Gln daily, and the patients with Elental+Gln received Elental (300 ml/day) daily and 6,930 mg of Gln daily. The primary endpoint was the incidence of mucositis, and the secondary endpoints were laboratory changes. The trial was conducted in Japan between 2010 and 2013. A total of 30 patients were enrolled; 10 patients were registered in the Elental+Gln arm, 10 patients were registered in the Gln arm, and 10 patients were registered in the control arm. The incidence of grade ≥2 COM was 10%, 70%, and 60% in the Elental+Gln, Gln, and control groups, respectively. Oral administration of Elental+Gln had a significant preventive effect on the development and severity of COM. Additionally, in the risk factor analysis for COM, Elental+Gln was an independent risk factor for COM. They concluded that Elental+Gln treatment reduced the incidence of ≥2 COM in patients who developed mucositis during chemotherapy for esophageal cancer. Third, Miyata et al. conducted a randomized trial to evaluate the efficacy and safety of Omega-3 (ω-3) fatty acid-rich enteral nutrition (EN) in patients with esophageal cancer who received chemotherapy (12). The patients received either ω-3 rich EN or ω-3 poor EN. The primary endpoint was the incidence of grade 3/4 neutropenia, and the secondary endpoints were chemotherapy-related adverse events including COM. A total of 61 patients were enrolled; 31 patients were registered to ω-3 rich EN arm and 30 patients were registered to the ω-3 poor EN arm. The ω-3 rich EN arm was administered Racol NF^® (Otsuka Pharmaceuticals, Tokyo, Japan) at 600 ml/d (600 kcal/d) orally and the ω-3 poor EN arm was administered ENSURE LIQUID^® (Abbott Japan, Tokyo) at 600 ml/d (600 kcal/d) orally. The incidence of grade 3/4 neutropenia was 77.4% in the ω-3 rich EN arm and 83.3% in the ω-3 poor EN arm. There was no significant difference between the two groups (p=0.363). In contrast, the incidence of grade 3/4 COM was 0% in the ω-3 rich EN arm and 16.7% in the ω-3 poor EN arm. There was a significant difference between the two groups (p=0.018). They concluded that ω-3 rich EN decreased the incidence of COM in patients with esophageal cancer who received chemotherapy. Fourth, Moriyama et al. conducted a randomized trial to evaluate the efficacy and safety of Kampo medicine in patients with esophageal cancer who received chemotherapy (13). Patients received Daiokanzoto, Hangeshashinto, or no treatment. Both Hangeshashinto and Daiokanzoto arms were administered at a dose of 2.5 g/three times per day (for a total daily dose of 7.5 g). The primary endpoint was mucositis incidence. A total of 25 patients were enrolled: 7 patients were registered in the Daiokanzoto arm, 7 patients were registered in the Hangeshashinto arm, and 9 patients were registered in the control arm. The incidence of grade ≥2 COM was 85%, 57%, and 88% in Daiokanzoto, Hangeshashinto, and control arms, respectively. There were no significant differences between the three arms. Fifth, Toyomasu et al. conducted a randomized trial to evaluate the efficacy and safety of Elental for patients with gastric cancer who received S-1 adjuvant chemotherapy (14). The patients received either Elental or diet controls. In the Elental arm, patients could consume Elental at any time of the day, regardless of mealtime. Patients in the control group continued their regular diet throughout the study period. The primary endpoint was the incidence and grade of COM. A total of 22 patients were enrolled; 11 patients were registered to the Elental arm, and 11 patients were registered to the control arm. The incidence of COM was 9.1% and 27.3% in the Elental and control arms, respectively. There was a significant difference between the two groups. Furthermore, the ENS arm had significantly higher S-1 continuation rates than the control arm. They concluded that Elental treatment reduced the incidence of COM in patients with gastric who received S-1 adjuvant chemotherapy.

Randomized Control Trials for COM in Colorectal Cancer

Five trials were conducted to prevent COM in colorectal cancer (Table II).

First, Nottage et al. conducted a randomized double-blind, placebo-controlled trial to evaluate the efficacy and safety of sucralfate mouthwash in patients with colorectal cancer who received 5-fluorourcil based chemotherapy (15). The patients received either sucralfate treatment or placebo. The primary endpoint was the sum of 15 daily scores of severity of mucositis, and the secondary endpoints were an analgesic diary, pain score, and QOL measures. A total of 81 patients were enrolled; 41 were registered in the sucralfate treatment arm and 40 were registered in the placebo arm. Both the sucralfate treatment arm and placebo arm were instructed to “swish” 10 ml (using a metered vial) of mouthwash for 2 min and then swallow it. No oral intake was permitted within 20 minutes of each mouthwash swallow. The mouthwash was used four times daily. The median sum of the mucositis scores was eight in both the placebo and sucralfate groups, showing no significant differences between the two groups. Furthermore, the median number of days in which mucositis scores of 3 or 4 were reported was five in the sucralfate treatment arm and four in the placebo arm. The authors concluded that sucralfate treatment did not reduce 5-FU-induced mucositis in patients with colorectal cancer.

Second, Rosen et al. conducted a randomized placebo-controlled trial to evaluate the efficacy and safety of palifermin in patients with metastatic colorectal cancer who received fluorouracil-based chemotherapy (16). Patients received either palifermin or placebo. The primary endpoints were mucositis and diarrhea. A total of 65 patients were enrolled; 28 were registered in the palifermin treatment arm and 36 were registered in the placebo arm. Both palifermin (40 μg/kg) and placebo were administered intravenously on 3 consecutive study days before each of the 2 consecutive cycles of chemotherapy. The incidence of grade ≥2 COM during the first chemotherapy cycle was 29% in the palifermin arm and 61% in the placebo arm, showing a significant difference between the arms. The incidence of grade ≥2 COM during the first chemotherapy cycle was 11% in the palifermin arm and 47% in the placebo arm, again showing a significant difference between the arms. Furthermore, the proportion of patients who had no mucositis manifestations was higher in the palifermin group than in the placebo group (46% vs. 17%). They concluded that palifermin treatment reduced the incidence of ≥2 COM in patients with colorectal who received fluorouracil-based chemotherapy.

Third, Peterson et al. conducted a randomized phase II trial to evaluate the efficacy and safety of recombinant human intestinal trefoil factor (rhITF) oral spray for patients with metastatic colorectal cancer who received fluorouracil-based chemotherapy (17). The patients received a low dose of rhITF (10 mg/ml), high dose of rhITF (80 mg/ml), or placebo. rhITF is a dimer of a 59-amino acid polypeptide that corresponds to mature, native, human trefoil factor 3. The rhITF oral spray is an aqueous solution of rhITF dispensed in a daily-use 3.5-ml spray vial, available in 2 rhITF concentrations: 10 mg/ml (low dose) and 80 mg/ml (high dose). The placebo oral spray contained water. The primary endpoint was the incidence of grade ≥2 oral mucositis, and the secondary endpoints were the onset and duration of oral mucositis. The trial was conducted between 2006 and 2007. A total of 99 patients were enrolled; 33 were registered in the rhITF low-dose arm, 33 were registered in the rhITF high-dose arm, and 33 were registered in the placebo arm. The incidence of grade ≥2 COM was 9.1%, 12.1%, and 48.5% in the rhITF low-dose, high-dose, and placebo arms, respectively. The administration of rhITF showed a significant preventive effect on the development and severity of COM. In addition, the incidence of grade ≥1 COM was 39.4%, 30.3%, and 66.7% in the rhITF low-dose, high-dose, and placebo arms, respectively. The authors concluded that rhITF treatment reduced the incidence of COM in patients with metastatic colorectal cancer who received fluorouracil-based chemotherapy.

Fourth, Chu conducted a randomized trial to evaluate the efficacy and safety of Hangeshashinto in patients with colorectal cancer who developed moderate-to-severe oral mucositis during any cycle of chemotherapy (18). The patients received either Hangeshashinto or placebo. The primary endpoint was the incidence of grade ≥2 oral mucositis, and the secondary endpoint was the time to disappearance of oral mucositis and the incidence of adverse events. The trial was conducted at 19 institutions in Japan. A total of 93 patients were enrolled; 46 were registered to the Hangeshashinto arm and 47 were registered to the placebo arm. The placebo formulation matched the texture, flavor, and other characteristics of the active drug. Both Hangeshashinto and the placebo were administered at a dose of 2.5 g/three times per day (for a total daily dose of 7.5 g). The incidence of grade ≥2 COM was 48.8% and 57.4% in the Hangeshashinto and placebo arms, respectively, showing no significant difference between the groups (p=0.41). In contrast, the duration of grade ≥2 COM was significantly shorter in the Hangeshashinto arm than in the placebo arm (5.5 days vs. 10.5 days, p=0.018). The authors concluded that Hangeshashinto treatment did not reduce the incidence of ≥2 COM in patients who developed mucositis during chemotherapy for colorectal cancer. However, Hangeshashinto demonstrated a significant effect in the treatment of grade ≥2 mucositis in patients with colorectal cancer compared to placebo.

Fifth, Karacan et al. conducted a randomized placebo-controlled trial to evaluate the efficacy and safety of palifermin for patients with colorectal cancer who received chemotherapy (19). Patients received either an Ankaferd hemostat or sodium bicarbonate. A total of 65 patients were enrolled; 28 were registered in the palifermin treatment arm and 36 were registered in the placebo arm. The Ankaferd hemostat patients brushed their teeth at least twice a day for 2 min and gargled with an Ankaferd hemostat twice for 2 min for two weeks. The sodium bicarbonate group patients brushed their teeth for at least 2 min/day and gargled with sodium bicarbonate four times for 2 min for two weeks. The incidence of grade ≥2 COM was 0% (0/33) in the Ankaferd hemostat arm and 51.5% (17/33) in the sodium bicarbonate arm, showing a significant difference between the two arms. The authors concluded that Ankaferd hemostat treatment reduced the incidence of COM in patients with colorectal cancer who received chemotherapy.

Future Suggestions

Although some promising treatments for COM have been reported from randomized trials in gastrointestinal malignancies, there is no definitive evidence or standard treatment for COM in gastrointestinal cancers. Conversely, reductions in the duration and/or severity of COM and their utility as prevention strategies have been reported for anti-inflammatory medication, anti-microbial medication, laser-and-light therapy, herbal, mucoprotective, growth factors, cytokines, and supplements. Evidence was mainly reported in patients with head and neck cancer treated with chemotherapy and/or radiation therapy (20). However, it is difficult to introduce these treatments to patients with gastrointestinal malignancies who develop COM.

There are some background differences between patients with gastrointestinal malignancies and head and neck malignancies. First, the incidence of COM differs between these two populations. Previously, the incidence of COM was reported to be 40% in gastrointestinal malignancies but 90%-100% in head and neck malignancies. Second, the severity of COM was different. Previously, the severity of COM was much greater in patients with head and neck malignancies than in those with gastrointestinal malignancies. These differences may have affected the treatment methods. Patients with gastrointestinal malignancies only received systemic chemotherapy, whereas patients with head and neck malignancies received both chemotherapy and radiation therapy. In addition, patients with head and neck malignancies directly receive radiation therapy in the oral cavity; however, this treatment method is rare in patients with gastrointestinal malignancies. Therefore, the treatment modalities developed for COM in head and neck malignancies may represent overtreatment in gastrointestinal malignancies. Further studies are needed to establish the optimal treatment and prevention methods for COM in gastrointestinal malignancies.