Double-blind, placebo-controlled, randomized phase II study of TJ-14 (hangeshashinto) for gastric cancer chemotherapy-induced oral mucositis

Gastric cancer is the second most frequent cancer-related cause of death after lung cancer [1]. Chemotherapy is one of the most important modalities for treating advanced gastric cancer as well as curatively resected cancers in the adjuvant setting. Numerous chemotherapy regimens have been used in cases of operable or inoperable gastric cancer [2‐5]. Although several studies have shown that chemotherapy improves and prolongs survival, it often causes severe toxicity, seriously compromising the patient’s quality of life and precluding the continuation of the treatment.

Oral mucositis is a common toxicity associated with cytotoxic chemotherapy used in the gastric cancer treatment. In pivotal phase III trials of chemotherapy for gastric cancer, the incidence of all grades of chemotherapy-induced oral mucositis (COM) was observed to be 6.3–32 % [4‐8]. COM results in severe discomfort, impairing the patient’s ability to eat, swallow, and talk, and has an indirect effect on tumor outcomes, as its presence often necessitates the unfavorable modification of anticancer therapy, such as breaks in the administration of chemotherapy or dose reduction in the chemotherapy regimen [9‐11]. One factor associated with COM exacerbation is the activation of the cyclooxygenase pathway, which mediates ulcer formation and pain via the upregulation of pro-inflammatory prostaglandins. Indeed, Richard et al. demonstrated, after having enlisted 20 patients treated with chemotherapy drugs and performing a biopsy of the oral mucosa in each case, a statistically significant increase in the number of endothelial cells in the oral mucosa with nuclear factor-kappa B (NF-κB) and cyclooxygenase 2 (COX-2) expressions in the postchemotherapy treatment period compared to that observed in the pretreatment period. The expression of COX-2 in these cells represents the initial sign of the inflammatory cascade that determines the production of prostaglandins and further tissue damage. COX-2 is also upregulated by NF-κB, which plays an important role in the inflammatory process [12]. COM invariably requires treatment with systemic analgesics, adjunctive medications, physical therapy, and psychological therapy in addition to oral care [13]. Treatment guidelines developed by the Multinational Association of Supportive Care in Cancer and the International Society for Oral Oncology have been published; however, they also highlighted the need for a higher level of evidence [14]. Although a range of interventions have been developed to prevent and treat COM, a more rational approach is warranted [11].

Hangeshashinto (TJ-14) is a traditional Japanese medicine containing 7 herbal crude drugs. Seven herbal crude drugs are as follows; Pinelliae tuber, Scutellariae Radix, Glycyrrhizae Radix, Zizyphi Fructus, Ginseng Radix, Zingiberis Processum rhizoma, and Coptidis rhizome [15‐17]. TJ-14 is prescribed in Japan to treat inflammatory diarrhea, gastritis, and stomatitis. Recently, Kono et al. [18] found that TJ-14 was effective as a gargle therapy for the treatment of COM in a pilot clinical study and a randomized, placebo-controlled clinical trial. TJ-14 has been demonstrated to directly inhibit PGE2 production in human gingival fibroblasts and reduce the PGE2 content in the colon in several animal models of diarrhea using anticancer drugs, cholera toxin, or castor oil, resulting in the amelioration of inflammatory damage [19‐22]. It has also been reported that some ingredients of TJ-14 inhibit PGE2 production and/or the COX-2 expression [23‐32]. Phenylpropanoids, such as [6]-shogaol and [6]-gingerol, flavonoids, such as wogonin, baicalein, and baicalin, and isoquinoline alkaloids, such as berberine, are well established to possess an anti-PGE2 activity via various particular mechanisms.

Considering these clinical and biochemical study findings, in the present study, the efficacy of TJ-14 in the prevention and/or treatment of COM was investigated in a randomized, double-blind, placebo-controlled clinical trial of patients receiving chemotherapy for gastric cancer.

To date, this randomized trial is the first evaluation of the use of TJ-14 to treat COM in patients with gastric cancer in a prospective placebo-controlled randomized phase II study. The primary purpose of this study was to prove the effects of TJ-14 in reducing the incidence of ≧grade 2 oral mucositis. The incidence of oral mucositis of ≧grade 2 was 40.0 % in the TJ-14 group and 41.3 % in the placebo group in the overall study population. Therefore, treatment with TJ-14 did not exhibit any effect with regard to reducing the frequency of grade 2 events or the duration of grade 2 chemotherapy-induced oral mucositis in gastric cancer patients receiving fluorinated pyrimidine-based chemotherapy. Why did this trial not meet its primary objective? The most likely reason is that the dose reduction of chemotherapy performed before the administration of TJ-14 treatment may have affected the incidence and duration of COM. Generally, among patients who developed ≧grade 2 COM before being entered into this study, the physicians may have been inclined to stop or postpone the original chemotherapy and reduce the dose at the time of the next chemotherapy cycle, which was exactly the time of study treatment and observation [33]. The incidence of oral mucositis of ≧grade 2 was 36.4 % in the patients who received chemotherapy dose reduction and 42.0 % in the patients who did not receive dose reduction. With regard to the incidence of toxicity in this study, 36 patients developed CTCAE v4.0 ≧grade 2 oral mucositis during the screening cycle. Among these patients, seven received dose reduction before the protocol cycle. The median duration of ≧grade 2 oral mucositis was 10.0 days in the patients treated with prophylactic dose reduction and 16.0 days in the patients treated without prophylactic dose reduction. There was a significant difference between the two groups (p = 0.034). It has been reported that the COM was depending on the dose and type of chemotherapy [34, 35]. Coleman et al. [36] evaluated 116 women with measurable metastatic breast cancer participated in a randomized phase II study of single-agent liposomal pegylated doxorubicin given either as a 60 mg/m² every 6 weeks (ARM A) or 50 mg/m² every 4 weeks (ARM B) schedule. They found that the adverse event profiles of the two schedules were distinctly different, and mucositis was more common with ARM A (35 % CTC grade 3/4 in ARM A, 14 % in ARM B). More, Elting et al. [37] retrospectively analyzed 599 patients who developed chemotherapy-induced oral mucositis. They found that a reduction in the dose of the next cycle of chemotherapy was twice as common after cycles with mucositis as it was after cycles without mucositis (23 vs. 11 %; p ≤ 0.0001). Taking these findings into consideration, dose reduction in the chemotherapy regimen may have been a key issue improving the incidence and/or the duration of COM. We assume that the effects of TJ-14 in oral mucositis may be less prominent due to the use of chemotherapy dose reduction just before the experimental cycles. Taking these findings into consideration, dose reduction in the chemotherapy regimen may have been a key issue improving the incidence and duration of COM. We assume that the effects of TJ-14 in oral mucositis may be less prominent due to the use of chemotherapy dose reduction just before the experimental cycles.

A borderline significant difference, however, was observed in the patients who developed ≧grade 1 COM at the time of screening. The median duration of any grade of oral mucositis was 9.0 days in the TJ-14 group and 17.0 days in the protocol treatment cycle group. Treatment with TJ-14 reduced the duration of any grade of oral mucositis compared with the placebo. In patients with grade 1 COM before the experimental cycle, it is presumed that the physicians may not have reduced the chemotherapy dose. Therefore, most of the patients who developed COM of grade 1 were not influenced by dose reduction of chemotherapy. These results suggest that the effects of TJ-14 would have been more prominent if chemotherapy dose reduction had not been performed before the experimental cycles. As mentioned above, it has been previously reported that TJ-14 exerts an anti-inflammatory effect by suppressing the levels of lipopolysaccharide-induced IL-6 and IL-8, and cyclooxygenase (COX)-1 and COX-2 [38, 39], in a dose-dependent manner [40]. Further studies are needed to clarify the exact mechanisms underlying these observations.

In conclusion, this trial did not show a beneficial effect of TJ-14 in reducing the incidence of chemotherapy-induced oral mucositis as the primary end point, likely due to the use of dose reduction before the experimental cycles, which was not prohibited by the study protocol. In the patients with >grade 1 COM at the screening cycle, an obvious reduction in the risk of COM (HR 0.60) was demonstrated. In this regard, the addition of TJ-14 to chemotherapy regimens may have shortened the duration of oral mucositis when no dose reduction was performed before the administration of the experimental agents. A further analysis may lead to a better interpretation of the study results by examining subgroups that will benefit from TJ-14 treatment. A more definitive design in a future trial of TJ-14 for chemotherapy-induced oral mucositis is needed to eliminate the influence of arbitrary dose reduction based on the discretion of the individual physician.