Double-blind, placebo-controlled, randomized phase II study of TJ-14 (Hangeshashinto) for infusional fluorinated-pyrimidine-based colorectal cancer chemotherapy-induced oral mucositis

Oral mucositis is a common complication of systemic high-dose chemotherapy as well as radiotherapy for cancer [1, 2]. Oral mucositis is associated with higher risk of infection, pain, chemotherapy dose reduction, and infection-related death. Severe mucositis impairs oral and esophageal functions and seriously affects nutrition and quality of life of the patients. Consequently, oral mucositis can result in therapeutic noncompliance or become a dose-limiting toxicity that requires treatment modifications or interruption and eventually affect the outcome of cancer therapy. Several reviews and clinical practice guidelines have confirmed the need for increased emphasis on the management of mucositis [3‐5].

Despite the attempts to reduce cancer chemotherapy-related mucositis, there has been no standard efficacious prophylactic therapy. Treatment is mostly supportive, consisting of good oral hygiene, mouthwashes, and analgesia [2].

Evidence from randomized trials suggests that the use of oral ice tips before chemotherapy improves oral mucositis by decreasing blood flow and decreases drug absorption [6‐8]. Other clinical trials attempting to evaluate various strategies to prevent or reduce chemotherapy-induced mucositis, enrolled only small numbers of patients in their studies, and were thus inconclusive [9‐13]. Only in two studies of large randomized double-blind, placebo-controlled trials were treatments reported to be effective against mucositis. One trial involved 326 women with breast cancer receiving an anthracycline regimen, and a new agent AES-14 was reported to significantly reduce the incidence of mucositis, although this result has not yet been reproduced or reconfirmed [14]. The other study investigating the effect of human epidermal growth factor for mucositis in head and neck cancer patients, proved significant reduction in severe oral mucositis receiving radiotherapy and chemotherapy [15]. Despite those results, it is still unclear whether there is any definite evidence for the prevention and treatment of cancer chemotherapy-induced oral mucositis to date.

The mechanism of chemotherapy-induced mucositis has been investigated and a report speculated that the cyclooxygenase pathway mediates tissue injury and pain through upregulation of pain-evoking prostaglandin E2 and proinflammatory cytokines [16, 17]. TJ-14 (Hangeshashinto), a traditional Japanese herbal (Kampo) medicine, was shown to significantly decrease production of prostaglandin E2 in human oral keratinocytes in hamsters. The gene expressions of cyclooxygenase 2, cytosolic phospholipase A2, and prostaglandin E synthase were also down-regulated by exposure to TJ-14 [18]. A clinical study demonstrated that topical administration of TJ-14 significantly reduced grade 3/4 mucositis in 13 out of 14 patients with oral mucositis, and TJ-14 was considered to have therapeutic effect on chemotherapy-induced oral mucositis via down regulation of proinflammatory prostaglandins in the cyclooxygenase pathway [19].

Given those biochemical and in vivo study findings, in the present study, the efficacy of TJ-14 for the prevention and/or treatment of chemotherapy-induced oral mucositis was investigated in a randomized double-blind, placebo-controlled exploratory clinical trial in colorectal cancer patients.

Kampo medicine or Japanese/Chinese traditional herbal medicine has been used for the treatment of various diseases for over 2000 years, mainly in many Asian countries. Although the beneficial effect of those Kampo medicines has long been taken for granted, and was widely utilized among Asian populations, two substantial factors have precluded their approval in the modern western world. One reason is that Kampo medicines are the mixture of several ingredients, and it was believed that combination of those ingredients could exert a synergistic effect. Since analysis of the efficacy of each ingredient is imperative in modern science, attempts to elucidate their mechanisms have not been fully successful to date. Another reason is that the reports on the clinical effectiveness of those Kampo medicines used to be mostly anecdotal, and reliable well-conducted clinical trials to elucidate the evidence of the efficacy have not been satisfactory. In recent years, Asian investigators have attempted to clarify the mechanism and clinical efficacy of the Kampo medicine. The anti-inflammatory effect of Inchinkoto (ICKT) in Wistar rats was proved to improve mortality by ischemic reperfusion of the liver, caused by extensive hepatectomy [20]; Daikenchuto (DKT) showed its effects in revitalizing bowel movement after laparotomy operations in 30 patients [21]. Also, the efficacy of Goshajinkigan (GJG) to alleviate neuropathy after oxaliplatin treatment for colon cancers was investigated in a placebo-controlled randomized phase II trial, and promising results have recently been reported [22].

TJ-14, also one of the Kampo formulas in Japanese traditional herbal medicine, is the mixture of seven herbs including pinellia tuber, scutellaria root, glycyrrhiza, jujube, ginseng, processed ginger, and Coptis rhizome, which are registered in the Japanese Pharmacopoeia XV [23]. In clinical practice, TJ-14 has been used for acute or chronic diarrhea, acute gastroenteritis, and for chronic hypoperfusion of the gastrointestinal system [24, 25]. It is reported that TJ-14 is effective against diarrhea which is the side effect of chemotherapeutic agents for gastrointestinal cancers [26]. Since TJ-14 contains baicalin, an inhibitor of β-glucuronidase, a randomized trial for advanced small cell lung cancer demonstrated the effect of TJ-14 in significantly controlling grade ≧3 diarrhea caused by cisplatin/irinotecan treatment with a p value of 0.018 [27, 28]. Moreover, recently, TJ-14 has attracted attention not only for its effect on intestinal mucosa but also concerning its efficacy on oral mucositis. Promising results were published both in vivo [18] and in clinical studies with a topical application of TJ-14 at the ulcerated site of the oral cavity [19].

The present study was conducted to clarify the effect of TJ-14 in patients who developed grade ≧1 mucositis after the first course of chemotherapy for colorectal cancer. With the advent of prospectively randomized placebo–controlled clinical trial, results showing a significant effect of TJ-14 over placebo in terms of the duration of oral mucositis could be a robust evidence for the efficacy of TJ-14. Historically, management of oral mucositis in cancer patients has been limited to supportive care, including pain control, nutritional support, hydration, and wound care. Simple nonspecific interventions such as cryotherapy and compound mouthwashes that include a topical and local anesthetic agent were also shown to have some benefit. Although these interventions may be beneficial, they are not directed to the fundamental mechanism changes associated with the pathophysiology of oral mucositis. The current paradigm for mucosal injury in cancer patients, who underwent 5-FU-based chemotherapy, is based on a complex cascade of mucosal tissue changes that appear to be initiated within hours of exposure to cytotoxic agents [29, 30].

Previously, there was some evidence to recommend the use of benzydamine mouthwash　or misoprostol mouthwash for the prevention of oral mucositis in head and neck cancer patients receiving radiation therapy [31, 32]. Benzydamine hydrochloride is a nonsteroidal anti-inflammatory drug (NSAID), which has been shown to inhibit inflammatory cytokine production, such as TNF-α and IL-1β. Misoprostol is a synthetic analog of prostaglandin E1 (PGE1), which has anti-inflammatory properties [33, 34]. Misoprostol also protects the mucosa and has been approved for reducing the risk of gastric ulcers induced by NSAID use [32, 35]. Although positive results were reported for some other anti-inflammatory agents in the patients who received radiation therapy, no guidelines were able to be developed for any other agents due to insufficient and/or conflicting evidence for COM.

In conclusion, the present study results did not meet the primary endpoint. However, TJ-14 demonstrated a significant effect in the treatment of grade ≧2 mucositis in patients with colorectal cancer compared to the placebo. Another extensive randomized placebo-controlled phase III study to reconfirm the effect of TJ-14 is warranted.