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Introduction: Cystine and theanine are amino acids that contribute to the production of glutathione, which is the most potent antioxidant in the body, and it has been reported that these amino acids prevent immunosuppression, has anti- inflammatory effect, and reduce invasiveness., Objective: To evaluate the effect of oral administration of amino acids cystine and theanine on stomatitis during chemotherapy., Subjects and Methods: For 17 patients with Grade 1(CTCAE v4.0)or worse stomatitis during chemotherapy for gastrointestinal cancer or breast cancer, cystine 700 mg and theanine 280 mg/ day were orally administered for 28 days, and the degree of stomatitis was evaluated objectively and subjectively., Results: As an objective evaluation, changes in Grade showed improvement in 11 cases(64.7%), 5 cases unchanged(29.4%), and 1 case was worse(5.9%). Subjective assessment, pain was in remission(30.8%)or disappeared(61.5%)in 4 of 13 cases. Food intake increased in 5 patients(29.4%). 15 of 17 patients(88.2%)felt it was effective., Conclusion: Oral administration of amino acids cystine and theanine during chemotherapy can reduce the symptoms of stomatitis.

Objective: Severe oral mucositis caused by chemo- and radio-therapy is a common adverse event in patients with cancer. In this study, we investigated the development of an indomethacin mouth wash(IM-MW)as a novel approach to treat pain due to oral mucositis., Methods: We examined the appropriate preparation methods for IM-MW with suitable stability. IM- MW was made from bulk IM, controlled release IM capsules, and IM capsules. Dissolution in water was tested at water temperatures of 70℃, 90℃, and 98℃(n=3), and with a shaking time of 30 or 60s(n=3). We determined the IM concentration in IM-MW by HPLC-UV analysis(n=5)at time points between just after preparation and day 7, to estimate the shelf- life at 4℃ and 25℃., Results: At 70℃, bulk IM did not dissolve, but at 90℃ and 98℃, bulk IM, controlled release IM capsules, and IM capsules all dissolved effectively. Shaking times of 30 and 60s were sufficient to dissolve bulk IM, controlled release IM capsules, and IM capsules. The stability of IM in IM-MW was 98.6±2.8%(bulk), 99.2±6.0%(controlled release capsule), and 98.5±6.0%(capsule)over 7 days at 4℃. However, at 25℃, IM stability in IM-MW decreased to 95.3±1.8% (bulk), 86.1±4.8%(controlled release capsule), and 83.6±1.6%(capsule)., Conclusion: In this study, we identified the most suitable method for the preparation of IM-MW(90℃, shaking time of over 30s). IM-MW was stable when stored at 4℃ for at least 7 days after preparation.

An 80-year-old woman was diagnosed with right breast cancer with clinical Stage IIIA 6 years previously. She underwent mastectomy and axillary lymph node dissection. The pathological diagnosis was invasive micropapillary carcinoma with lymph node involvement. Immunohistochemically, the tumor was positive for estrogen receptor and progesterone receptor, and negative for HER2. Postoperatively, the patient was treated with adjuvant chemotherapy consisting of cyclophosphamide, epirubicin, 5-fluorouracil, and paclitaxel, followed by endocrine therapy with letrozole. Four years after surgery, she experienced a recurrence of breast cancer in the thoracic wall, and was treated with exemestane, toremifene, and fulvestrant for 1 year and 5 months. However, she developed carcinomatous pleurisy and was treated with eribulin. This last treatment was ineffective. Subsequently, she received combination therapy with everolimus and exemestane. Although the pleural effusion reduced markedly after 5 weeks, stomatitis, diarrhea, melena, and interstitial pneumonia occurred as adverse events. The symptoms improved after drug discontinuation and steroid therapy. The combination therapy with everolimus and exemestane is a prospective therapy for hormone-resistant recurrent breast cancer, but the management of adverse events is very important.

Stomatitis is a characteristic adverse event of everolimus and other mTOR inhibitors, and occurs at a high incidence and impairs QOL owing to pain. Most cases of stomatitis are mild to moderate. However, when stomatitis becomes serious, it can interfere with the continuation of medication. Therefore, it is important to place more emphasis on the prevention as well as early detection and treatment. In addition, patient education is also important. The possible occurrence of stomatitis, its signs and symptoms, as well as the importance of oral care need to be thoroughly explained prior to starting treatment. In order to smoothly carry out these measures, it will also be essential that cancer-treating physicians coordinate and collaborate with dentists, nurses, and pharmacists. It is desirable to establish appropriate prevention and management methods on the basis of the results of the Phase III prospective study, Oral Care-BC, currently ongoing in Japan.

Advancements in cancer chemotherapy and the introduction of Japanese traditional medicine"Kampo"have been successful in improving the prognosis of malignant tumors. Many Kampo drugs have been used in the treatment of adverse effects. We investigated the safety and efficacy of Hangeshashinto in the prevention and treatment of chemotherapy-induced oral mucositis in patients with gastric and colorectal cancer. Hangeshashinto was shown to reduce the risk of development of mucositis. We also investigated the efficacy of Goshajinkigan in the prevention of chemotherapy-induced neurotoxicity. Goshajinkigan appears to have a promising effect in delaying the onset of neurotoxicity of gradeB2 without reducing the efficacy of treatment. Kampo drugs such as Rikkunshito, Jyuzentaihoto, and Hochuekkito have also been used successfully in the prevention and treatment of chemotherapy-induced adverse effects. It is very important to know the efficacy and safety of Kampo drugs for alleviating the adverse effects of anticancer drugs in patients undergoing cancer treatment with chemotherapy.

Background: According to the literature, 40%of all oral complications associated with chemotherapy are due to oral mucositis. Moreover, such complications increase the difficulties associated with oral intake, leading to deterioration of the patient's nutritional condition and increasing the risk of systemic infection. Therefore, oral mucositis prevention and proper treatment are very important., Patients and Methods: The conditions of intra-oral cavities and effects of oral care in patients with hematological malignancies were retrospectively evaluated by dental hygienists from April 2008 to March 2011., Results: Eleven of 28 patients(39.3%)who received routine professional oral care developed oral mucositis. In many such patients, intra-oral cavity deterioration, evidenced by a coated tongue and Candida infection, was observed. Although 25 of 28 patients with hematologic malignancies received specific oral mucositis care after chemotherapy initiation, those receiving continuous oral care subsequently made a full recovery., Conclusions: These results suggest that early and continuous professional oral health care may play an important role in the effective chemotherapy of patients with hematologic malignancies.

No guidelines for supportive drug therapy have been established for oral mucositis occurring during cancer chemotherapy. We retrospectively examined the progression of oral mucositis in 91 patients with breast cancer who received the 5-fluorouracil, epirubicin, and cyclophosphamide (FEC)-100 regimen between September 2007 and August 2008. Daily rebamipide was administered to patients with oral mucositis as per hospital protocol to evaluate the hypothesized preventive and mucosal protective effects of rebamipide(Mucosta®). Oral mucositis was observed in 43 patients (47%)during 4 courses of FEC. The median age of the patients was 55 years(range, 32-76 years). Of the 91 patients, 49 patients who did not receive rebamipide during the 4 FEC courses were classified as group A, 14 patients who received rebamipide before the start of FEC were classified as group B, and 28 patients who received rebamipide after developing oral mucositis were classified as group C. The incidence of oral mucositis at the start of FEC with or without rebamipide administration was observed in 5 patients in group B (36%) and 38 patients in groups A and C (49%) (p=0.3472). The mucositis grade was G1 in 4 patients and G2 in 1 patient in group B, and G1 in 20 patients and G2 plus G3 in 18 patients in groups A and C (p=0.2467). In group C, the grade decreased in 25 patients (89%) and did not occur (G0) in 17 patients (61%) during the next course, and 15 patients (54%) continued to the final course without any occurrence of mucositis. These results suggest that rebamipide is effective for the treatment of oral mucositis. Although significant differences were not observed in the groups, rebamipide has the potential to prevent development of oral mucositis and alleviate its symptoms, and seems promising as a new supportive drug therapy. We hope to verify the preventive and protective effects of rebamipide by conducting a prospective, randomized trial while treating oral mucositis with basic oral care and appropriate interventions provided by a multidisciplinary team.

Chemotherapy-induced oral mucositis is a common adverse event in breast cancer patients. Breakdown of the mucosal barrier predisposes the patient to bacterial, fungal and viral superinfection, especially candidiasis. We demonstrated the frequency of chemotherapy-induced oral mucositis and oral candidiasis, and the efficacy of antimycotic agents in breast cancer patients. We investigated 32 patients with advanced and metastatic breast cancer who underwent chemotherapy in our department from March, 2009 to August, 2010. The chemotherapy regimens were as follows: FEC (epirubicin/5-FU/cyclophosphamide) followed by taxanes: 21, FEC: 1, TC (docetaxel/cyclophosphamide): 7, DOC (docetaxel): 3, and CPT-11/S-1: 1. Patients had blood and bacteria tests of the oral cavity at the time mucositis symptoms appeared. We administered an antimycotic agent (itraconazole) and evaluated its effect on mucositis at the time mucositis symptoms appeared. 56. 3% of patients had chemotherapy-induced oral mucositis, and 38. 9% of the mucositis patients had oral candidiasis. The incidence of mucositis increased when severe neutropenia occurred. 92. 9% of mucositis patients were cured or improved by itraconazole. In conclusion, chemotherapy caused oral candidiasis in 40% of cases with oral mucositis, and in about 56% of breast cancer patients. The antimycotic agent may be useful for chemotherapy-induced oral mucositis in breast cancer patients.

Clinical outcomes of 53 patients with oropharyngeal and hypopharyngeal squamous cell carcinoma, treated from January, 2000 to December, 2008 by concurrent chemoradiotherapy of either CDDP or CDGP, plus 5-FU were investigated. Patients were treated with either CDDP (70 mg/m2) or CDGP (100 mg/m2) on day 1 of the chemotherapy regime, with 5-FU (700 mg/m2/day) as a continuous infusion for 5 days. Each regimen was administered as two courses in the first and final weeks of radiotherapy. Radiotherapy was administered at a daily dose of 2 Gy for five days a week, with patients receiving a total of 70 Gy by the end of seven weeks. The primary cancer was located in the oropharynx and hypopharynx in 21 and 32 patients, respectively. Twenty-six patients (49.1%) had stage IVA disease and 10 patients (18.9%) had overall stage I to II disease. Acute adverse events such as pharyngeal mucositis and leucopenia occurred in 49.1% and 43.4% of patients, respectively, and second round chemotherapy was not commenced in 56.6% of patients (n=30) due to significant adverse events. Mean weight loss following treatment was 4.1 kg. After a median follow-up of 30.0 months, 3-year overall survival was 53.0% for advanced carcinoma of the oropharynx and hypopharynx. Five-year overall survival was 46.4%. Patients receiving two courses of chemotherapy had an improved 5-year survival compared to patients receiving one course (67.0% vs 32.8%). Results indicate a significant benefit from two courses of chemotherapy. As such, minimizing the incidence of adverse effects and thereby reducing treatment discontinuation will likely improve overall treatment outcomes.

Background: The present study was designed to evaluate the preventive effects of elemental diet Elental (ED) on chemotherapy-induced stomatitis in patients with colorectal cancer., Materials and Methods: A total of 23 patients with colorectal cancer experiencing grade 1-3 stomatitis during treatment with chemotherapy (2- or 3-week per cycle) entered the current study. Their average age was 67 years, ranging from 44 to 84 years., Results: A total of 22 patients received the same chemotherapy regimen, but also received more than 80 g of Elental (ED) (including 1, 932 mg of L-glutamine), per day. FOLFOX, FOLFIRI or XELOX-based chemotherapy was used. A dose reduction of 5-FU, capacitabine or S-1 was performed in 5 patients who experienced grade 2 or 3 stomatitis. The maximum grade of stomatitis decreased in 18 of the 22 patients after the first treatment course, and decreased in 20 of 22 patients after the second course with ED.The preventive efficacy of ED on stomatitis was noted in a dose-dependent manner.Similarly, the maximum grade of neutropenia decreased in 10 of 11 patients after their first or second treatment course with ED., Conclusion: We conclude that ED can significantly decrease the severity of chemotherapy-induced stomatitis in colorectal cancer patients in association with the control of neutropenia.

Background: Oral mucositis is a frequent complication, but is poorly studied among patients with solid tumors. The purpose of this study is to clarify the incidence rate of oral mucositis in Japanese breast cancer patients receiving anthracycline-based chemotherapy(FEC100)., Methods: From June 2007 to July 2008, 61 breast cancer patients eligible for this study received anthracycline-based chemotherapy(FEC100: 5-FU 500mg/m / / 2, epirubicin 100 mg/m2, cyclophosphamide 500 mg/m2)at National Kyushu Cancer Center and Iwate Medical University Hospital. The incidence rate and grade of oral mucositis were evaluated in these patients., Results: The cumulative incidence of oral mucositis was about 50%. Episodes of oral mucositis were more common during courses with febrile neutropenia than during courses without it(75. 0% vs 44. 9%, p=0. 12). The reduction of oral mucositis was only 13. 6% after administering the steroidal ointment and/or mouthwash, including sodium azulene sulfonate., Conclusions: New methods are needed to prevent and treat oral mucositis in patients receiving anthracycline- based chemotherapy(FEC100).

Stomatitis is a side effect caused frequently by chemotherapy in patients with esophageal cancer, but a standard treatment for it has not been established. Reactive oxygen species are known to be among the causes of stomatitis induced by chemotherapy or radiotherapy, and some reports suggest that their influences might be reduced by the oral supplementation of glutamine. Elental® is one of the widely-used nutritional supplements, and its pack contains 1, 932 mg of L-glutamine (an especially high amount.). Therefore, we examined the preventive or reducing effects Elental® mey have on oral mucositis. Fifteen patients with esophageal cancer received chemotherapy, six of whom had grade one oral mucositis. All of those six patients entered the investigation, and seven courses of Elental® were administered. After seven courses, all six patients oral mucositis declined from grade 1 to grade 0. This result suggests that Elental® has preventive or reducing effects on oral mucositis.

Chemotherapy-induced mucositis is a clinically important and sometimes dose-limiting toxicity of cancer treatment, including standard-dose chemotherapy, high-dose chemotherapy and chemoradiotherapy. Consequently, dose reductions or treatment delays resulting from mucositis may impair treatment effectiveness. Symptoms are oral mucositis, dysphagia, abdominal pain and diarrhea, depending on the affected site. Although the underlying pathobiology of oral mucositis has been considerably elucidated over the past decade, there are few interventions for the prevention or treatment validated by randomized trials. The most commonly accepted intervention is basic oral care. Diarrhea is most common in patients treated with irinotecan and in some cases, life-threatening. No definitive interventions for the prevention of diarrhea exist, but there is evidence that loperamide and octreotide are effective for chemotherapy-induced diarrhea. In future, there is a need for well designed trials, preferably including a placebo or no treatment control, validating more effective interventions for managing chemotherapy- induced mucositis.

Rebamipide, a cytoprotective agent, has been suspected to attenuate oral mucositis through anti-inflammatory potentials and induction of endogenous prostaglandin synthesis. This prospective study was designed to assess the clinical efficacy of rebamipide gargle against oral mucositis, which is induced by fluoropyrimidines in patients with stomach and colorectal cancer. We first conducted a pilot study on gargle flavors, because the solution in this agent has a strong and bitter after taste. Nine kinds of flavors were prepared, and six characteristics were evaluated by ten volunteers: sourness, bitterness, sweetness, remain, after taste, and hard to drink. We determined the contents of rebamipide using HPLC, which showed stability in an acidic condition. Finally, we decided that 100% Pokka Lemon should be used as the flavor of the rebamipide solution. A clinical study was then started to compare the preventive effects rebamipide gargle and placebo have on stomatitis, quality of life (QOL), and the therapeutic effects of chemotherapy.

Purpose: We encountered serious oral mucositis in some patients undergoing colorectal chemotherapy with bevacizumab. We retrospectively investigated the role bevacizumab plays in the occurrence of oral mucositis., Subjects and Methods: Between January 2008 and December 2009, we encountered 11 patients for whom chemotherapy with bevacizumab had resulted in oral mucositis. The patients included 5 men and 6 women, with a mean age of 67. 9 years(range, 62-76 years). Among the patients, 5 had grade 1 oral mucositis, 3 had grade 2, and 3 had grade 3. We analyzed the risk factors, grades, symptoms, and treatments of oral mucositis in these patients., Results: In 6 patients, bevacizumab was administered in combination with mFOLFOX6, and in 5 patients, bevacizumab was administered in combination with FOLFIRI. Seven patients had undergone prior treatment without the occurrence of serious oral mucositis. With respect to oral health, 8 patients had periodontal disease, 7 had dental caries, 3 wore dentures, 3 exhibited poor oral self-care, and 2 had diabetes; in addition, 2 patients were smokers. Symptoms of oral mucositis included mucosal reddening in 11 patients, oral mucosal erosion or ulcer in 7, fungus infection in 6, aphtha in 7, pseudomembrane formation in 3, and poor oral intake in 2. All the patients had oral mucositis at the occlusal line of the buccal mucosa. The treatment for oral mucositis included polaprezinc., Conclusion: Because many factors influence the development of oral mucositis, determining the specific cause of oral mucositis is difficult. Bevacizumabmay possibly decrease the VEGF levels in saliva and delay wound healing in oral mucositis. Therefore, oral mucositis may be caused not only by diabetes and poor oral self-care but by bevacizumab.

We measured the effectiveness of the prophylactic administration of a polaprezinc suspension dispersed in sodium alginate solution (P-AG) by dividing it into two courses in the same patients, and measured the stomatitis induced by Docetaxel/Cisplatin/Fluorouracil (DCF) chemotherapy. We then evaluated the results. We defined the therapeutic course as the course where P-AG was given therapeutically for stomatitis induced after DCF chemotherapy. We defined the prophylactic course as when P-AG was prophylactically given before any incidences of stomatitis after the therapeutic course. We compared the incidences of stomatitis in the prophylactic courses with those of the therapeutic courses. The incidences of stomatitis that were higher than Grade 1 were 17 out of 17 patients (100%) in the therapeutic course. On the other hand, they were 15 out of 17 patients (88. 2%) in the prophylactic course. Compared with the mean of the Grade of Stomatitis by the Common Terminology Criteria for Adverse Events version 3. 0 (CTCAE v. 3. 0), the maximal Grade of stomatitis significantly decreased in the prophylactic courses compared to those of the therapeutic courses(p<0. 05). Therefore, these results suggested that we were able to decrease the severity of stomatitis by using P-AG prophylactically, as opposed to using P-AG therapeutically.

The remedy,especially recent chemotherapy,against colorectal cancer is improving median survival time (MST) of patients with Stage IV advanced colorectal cancer. According to other reports,however,it seems to be difficult to improve it longer than 20 months. In May 2002, we devised a new regimen by intermittent dosage of 5-FU (-->S-1), CDDP and paclitaxel utilizing the difference of cell cycle between normal and cancer cells, and thirteen patients with advanced colorectal cancer (Stage IV) were treated with this regimen. As a result, a satisfactory efficacy rate of 53.8%, 1-year survival rate of 69 .2%, 2-year survival rate of 53.9%, 3-year survival rate of 44.9%, 5-year survival rate of 17.9%, and MST 36 months were achieved. Five patients had hematological toxicities over grade 3 (38.5%) and most of them were anemia (3 cases) and neutropenia (5 cases). Thrombocytopenia and gastroenterological toxicity were all under grade 2. Adverse effects related to this regimen were clinically manageable. These results, although for a limited number of patients, indicated that this may contribute to the extension of survival time of patients with Stage IV advanced colorectal cancer.

We report a case of advanced gastric cancer that responded well to low-dosage TS-1. A 72-year-old woman was diagnosed as having unresectable advanced gastric cancer with ascites and hydronephrosis in the right kidney. She was treated with chemotherapy using a low-dosage of TS-1 (80 mg/body/day) administered perorally for 4 weeks followed by a drug-free 2 weeks, in six-week cycles. However, she developed weight loss, appetite loss, and stomatitis. We therefore reduced the dosage of TS-1 from 80 mg/body/day to 60 mg/body/day. The ascites and hydronephrosis gradually improved during the following 3 months, whereupon she could undergo total gastrectomy. The postoperative findings showed no ascites and no peritoneal dissemination. The postoperative pathological findings showed that the cancer cells were localized to within the mucosa, and there were no cancer cells in the greater and lesser omentum. Three weeks after the operation, TS-1 was resumed at 60 mg/body/day. However, 3 months later,ascites and metastasis to the abdominal skin developed, and she died 9 months after the operation.

In two patients with advanced pancreatic cancer with cervical lymph node or liver metastasis and no indication of pancreatic resection and radiotherapy, oral treatment with S-1 (an anti-cancer agent of fluoropyrimidine derivative) exerted high anti-tumor activity on the metastatic lesions. Both cases responded well to this therapy in the late phase II study of S-1 in patients with advanced pancreatic cancer designed to evaluate efficacy and safety. In Case 1 (with cervical lymph node metastasis), the anti-tumor efficacy of this therapy was evaluated as a partial response (PR) after the first four courses of treatment. In Case 2 (with liver metastasis), the efficacy was evaluated as PR for overall response. Thus, the therapy indicated excellent efficacy in both cases. No grade 3 or severe adverse event was noted in either of the two cases. In Case 1, grade 2 anemia, stomatitis, vomiting and fatigue, and some other mild events were noted. When used as a systemic chemotherapy for metastatic pancreatic cancer, oral treatment of S-1 is highly effective, tolerable and convenient in an outpatient clinic. This drug is a promising way to improve and preserve the QOL essential to long-term home care.

In the treatment of recurrent breast cancer in patients previously treated with anthracycline drugs, taxane drugs are generally used. This time, we retrospectively studied the safety of docetaxel/cyclophosphamide combination therapy (hereinafter referred to as TC therapy). Ten patients (mean age: 52.8 years old) were included in the study. Metastatic/recurrent sites included 3 skin, 2 each of contralateral breast, lung and bone, and 1 each of liver, carcinomatous pleurisy and supraclavicular lymph node. Seven patients had a history of anthracycline treatment. The patients received TC at doses of 60 mg/m(2) and 500 mg/m(2), respectively, every 3 weeks. With regard to adverse events, non-hematotoxic events included alopecia in all the patients, generalized malaise in 5, and abnormal nail in 1. Hematotoxic events were grades 2 and 3 decreased neutrophil count in 5 patients. One patient had grade 4 pyrexia associated with oral candida. The patient was admitted and treated with fluid replacement and granulocyte colony-stimulating factor (G-CSF). There were no other patients in whom the treatment was prolonged or dosage was reduced due to adverse reactions. TC therapy is considered to be a beneficial treatment method in terms of safety since it can be instituted on an outpatient basis.

Cytotoxic agents such as anthracycline or taxanes have provided a good clinical response for breast cancer patients, although they have failed to prolong the survival rate and to improve the quality of life (QOL) of these patients. On the other hand, cytostatic agents such as 5-fluorouracil (5-FU) have to be focused to accommodate a long term progression with respect to efficacy and the patients' QOL improvement. S-1 was a newly developed and orally administered fluorinated pyrimidine containing 1 M tegafur (FT) and two classes of a modulator, 5-chloro-2,4-dihydroxypyrimidine (CDHP) and potassium oxonate (Oxo) at a molar ratio of FT : CDHP : Oxo= 1 : 0.4 : 1. Specific dose limiting factors such as neutropenia, diarrhea and stomatitis have been observed in a previous phase I study. Two phase II studies of 4 weeks treatment of S-1 (1 M tegafur-0.4 M gimestat-1 M otastat potassium) for the advanced or metastatic breast cancer patients were carried out in Japan. Among 108 evaluable patients for response, there were 10 complete response (CR) and 35 partial response (PR) with an overall response rate of 41.7% (95% confidence interval, 32.3-51.5%). The incidence of toxicity (> or = grade 3) was as followed: neutropenia 9.3%, anemia 0.9%, stomatitis 1.9% and nausea/vomiting 0.9%. The median follow-up period for patients was 802 days. S-1 will be the new promising oral agent like a capecitabine which has been widely used as a third-line chemotherapy for the heavily treated breast cancer patients.

The S-1 +biweekly docetaxel (DOC) combination therapy was evaluated for advanced or recurrent gastric cancer patients. This combination therapy was evaluated in vitro using the nude rat-gastric cancer xenograft system. S-1 alone or DOC alone showed antitumor activity, and the antitumor activity was synergistic when two drugs were combined. In clinical settings, the schedule was S-1 80 mg/m2 (day 1-14, orally) and DOC (day 1 and day 15, intravenously) followed by a 2-week rest. In phase I study, the dose of DOC was evaluated, and a recommended dose for phase II was determined as 35 mg/m2. The entry for phase II study was completed, and the preliminary results of 33 patients showed the response rate of 21.2%. The incidence of more than grade 3 adverse effects was 29%(neutropenia, leukocytopenia, anorexia and mucositis). The S-1 +biweekly DOC combination therapy can be a candidate for outpatient chemotherapy for advanced or recurrent gastric cancer.

Two pivotal phase II studies of S-1 in advanced gastric cancer showed response rates of 44% and 49%, and the overall survival time was 207 and 250 days, respectively. The response rate of S-1 exceeded the response rates of other approved drugs, and was comparable to that of combination chemotherapies such as 5-fluorouracil (5-FU) plus cisplatin (CDDP). These data suggested that S-1 could be used as a first-line drug for gastric cancer with a great advantage in quality of life (QOL), because it is an oral drug and can be used at an outpatient clinic. The overall incidences of adverse reactions in the phase II studies were 74.3%, and that of grade 3 or worse were 14.9%. The main adverse reactions were myelosuppression and GI toxicities. As hematological toxicity was more common than other oral fluoropyrimidine derivatives such as UFT, a careful hematological monitoring is necessary. To confirm the survival benefit of S-1 in advanced gastric cancer, a phase III trial of S-1 vs 5-FU vs CDDP plus irinotecan (CPT-11) has been conducted by the Japan Clinical Oncology Group (JCOG), and these results have been awaited. Furthermore, the combination of S-1 with CDDP, CPT-11 or taxane for the treatment of gastric cancer is feasible and active, and phase III studies of S-1 vs several combination therapies including S-1 are also in progress. The effect of S-1 in adjuvant setting is also promising. Currently, a phase III study of surgery alone vs S-1 in patients with a curative resection of gastric cancer has been developed. Further therapeutic benefits are also expected by combining S-1 with other chemotherapeutic agents such as molecular targeted agents.

We developed a combination chemotherapy, comprising weekly dosing of iv cisplatin (days 1 and 8) combined with a fixed dose (70 mg/m2/day) of S-1 (days 1-14) for patients with metastatic gastric cancer. The treatment was repeated every 3 weeks. Twenty patients were studied. Dose-limiting toxicities of grade 3 diarrhea and stomatitis were observed in one patient at the dose of cisplatin 20 mg/m2. Grade 2 gastrointestinal adverse reactions, such as nausea and anorexia, were seen in approximately half of patients at this dose level within the first two treatment cycles. This was the maximum acceptable level. The overall response rate in 18 patients evaluated was 61%. The median survival was 11 months, despite including 11 pre-treated patients. S-1 given with weekly cisplatin was a feasible and promising combination regimen for an outpatient setting.

Mucositis is a common complication of cytoreductive cancer chemotherapy. Stomatitis is associated with a higher risk of bacterial infection and treatment-related death. Basic oral care is recommended to reduce the incidence and severity of stomatitis. Recently, new effective prophylaxis against stomatitis has been developed such as human keratinocyte growth factor and AES-14. Gastritis can sometimes cause severe bleeding,and it may be life-threatening. It has been shown that prophylactic H2 blockers or proton pump inhibitors can reduce the incidence and severity of gastric mucosal injury. The risk for chemotherapy-induced diarrhea is significantly greater for chemotherapeutic regimens that contain irinotecan. Intestinal alkalization and Hangeshasin-to a Chinese herbal product are applied in clinical practice in Japan to prevent or reduce irinotecan-induced diarrhea,but careful monitoring,early detection and rapid cure are most important to prevent treatment-related death.

To evaluate ambulatory patient cancer chemotherapy, the clinical response, toxicities and survival time were analysed among 19 patients with non-curative or recurrent colorectal cancer who were treated by Uracil/Tegafur (UFT) plus oral Leucovorin (UZEL) for the past 2 years. The patients were administered UFT (300 mg/m2/day) and UZEL (75 mg/body/day) for 28 days with a one-week interval every 35 days as one course.A partial response (PR) was observed in 6 patients (31.6%) and stable disease (SD) in 8. The median survival time was 16 months. Although nausea/vomiting, diarrhea and leucopenia were noted, no severe side effects were observed. These results suggested that UFT plus Leucovorin therapy might be a useful cancer chemotherapy for ambulatory patients with advanced colorectal cancer.

Nedaplatin (CDGP) is designed to further improve the anti-tumor effect and to reduce adverse effects of cisplatin (CDDP), such as renal toxicity. We previously reported a combination therapy of superselective intraarterial CDGP infusion, and radiation therapy could be delivered safely with good efficacy for locoregional management of oral cancer. However, both the clinical and pathological response decreased with tumor progression. This study was performed to assess the feasibility of a new chemotherapy regimen by superselective intraarterial infusion of CDGP in patients with advanced oral carcinomas. This regimen is under way in which chemotherapy with 5-FU 500 mg/day on days 1 to 5 and superselective intra-arterial infusion of CDGP on day 6 combined with radiation therapy is being evaluated for locally advanced oral cancer. Eight patients were treated with this regimen. After evaluation of the response, patients underwent surgery as a therapeutic procedure. Both the complete and partial response rates were achieved in each 3 patients (37.5%), respectively. Histological effects classified according to Oboshi-Shimosato's criteria were grade IVa in 2 patients, grade III in 1, grade IIb in 1, grade IIa in 3, and grade I in 1. All patients were free from renal dysfunction, which is one of the adverse effects of CDDP. Moreover, most toxicity was relatively mild in all patients.

The stomatitis accompanying chemotherapy reduces a patient's QOL. Many reports have suggested that some kinds of gargling agents for oral mucositis shorten the duration and severity of symptoms. This study tested the prevention and efficacy against stomatitis of a herbal medicine (Syousaikotou) as a gargling agent for patients receiving chemotherapy. Compared to gargling with providone-iodine and amphotericin B, the Syousaikotou gargle showed a significantly decreased incidence of stomatitis, and a painkilling effect. Stomatitis occurred in about 17.4% among 23 chemotherapy cycles with the Syousaikotou gargle, against about 40.8% among 71 chemotherapy cycles without the Syousaikotou gargle. Among the patients suffering stomatitis pain after 22 chemotherapy cycles, the painkilling effect was seen to be 76.2%, and continues for about 2 hours. Critical side effects were not seen, but in 4 cases there were complaints about foul smells, such as oil and grass smells. Syousaikotou gargle was considered to be one of the useful methods against the stomatitis prevention and sharp pain mitigation from the chemotherapy.

We evaluated the reliability of CTC v 2.0 based on source documents and also studied the degree of inconsistency in toxicity grading. Five clinical research coordinators from the National Cancer Center Hospital independently reviewed source documents from 17 patients and graded toxicities in the following common adverse events: diarrhea, nausea, stomatitis/pharyngitis, vomiting, febrile neutropenia, infection, infection unknown source, and sensory neuropathy. If grading was already documented on the medical chart, it was masked so that the coordinator could perform the evaluation without information bias. After the completion of toxicity grading, the participating coordinators discussed each case, and a consensus was reached for final toxicity grading. The proportion of agreement for each toxicity criteria are as follows: diarrhea; 0.59 (95%CI 0.35-0.82), nausea; 0.47 (0.23-0.71), stomatitis/pharyngitis; 0.59 (0.35-0.82), vomiting; 0.71 (0.49-0.92), febrile neutropenia; 0.88 (0.73-1.04), infection; 0.82 (0.64-1.01), infection by unknown source; 0.82 (0.64-1.01), sensory neuropathy; 0.65 0.42-0.87). The cause of variability largely depended on the differences in individual clinical assessment, and misunderstanding of toxicity criteria by coordinators has been observed. Even in a single institution environment, variability exists in the toxicity assessment and grading. Good training and education on toxicity assessment using common criteria and development of translated manual, including the interpretation of criteria assessment, may help reduce variability.

We report a case of right maxillary carcinoma with metastases to the cervical lymph nodes (T4N2cM0, Stage IV). A 76-year-old woman was administered preoperative chemoradiotherapy, followed by curative surgery. TS-1 (80 mg/day), CDDP (5 mg/m2/day) and concurrent radiation (total 40 Gy) induced a complete response. Grade 2 neutropenia, thrombocytopenia and stomatitis were observed. In the primary tumor and cervical metastatic lymph nodes, no viable carcinoma cells were detected and cancer nests were replaced with marked fibrous tissue.

We compared the effectiveness of 5-FU + l-LV with CDDP + 5-FU as a systemic chemotherapy for unresectable recurrence of colorectal cancer. The protocol we carried out in one group was as follows: (Group 1) 5-FU 2,000 mg mixed with l-LV 100-200 mg in the disposable balloon pump was administered continuously for 1 week. In the other group, (Group 2) we administered CDDP 5 mg/day every 5 days for a week and continuous 5-FU 500 mg/day for 3 weeks in the hospital, and in the outpatient clinic CDDP 5 mg/day every 2 days for a week with UFT-E 300-600 mg/day, orally, everyday. The response rate of Group 1 was 18.8% and that of Group 2 was 19.3%; the median survival time (MST) was 10.8 months for Group 1 and 8.4 months for Group 2. There were no significant differences between the 2 groups regarding these parameters. Hand foot syndrome (HFS) was observed in 43.8% of the patients, and stomatitis in 37.5% of all cases as adverse effect of systemic chemotherapy using 5-FU + l-LV. But the grade of the adverse effect was low and patients could continue with this systemic chemotherapy.

We compared the effectiveness of 5-FU + l-LV with CDDP + 5-FU as a systemic chemotherapy for unresectable recurrence of colorectal cancer. The protocol we carried out in one group was as follows: (Group 1) 5-FU 2,000 mg mixed with l-LV 100-200 mg in the disposable balloon pump was administered continuously for 1 week. In the other group, (Group 2) we administered CDDP 5 mg/day every 5 days for a week and continuous 5-FU 500 mg/day for 3 weeks in the hospital, and in the outpatient clinic CDDP 5 mg/day every 2 days for a week with UFT-E 300-600 mg/day, orally, everyday. The response rate of Group 1 was 18.8% and that of Group 2 was 19.3%; the median survival time (MST) was 10.8 months for Group 1 and 8.4 months for Group 2. There were no significant differences between the 2 groups regarding these parameters. Hand foot syndrome (HFS) was observed in 43.8% of the patients, and stomatitis in 37.5% of all cases as adverse effect of systemic chemotherapy using 5-FU + l-LV. But the grade of the adverse effect was low and patients could continue with this systemic chemotherapy.

Docetaxel is classified among the microtubule-inhibiting compounds called taxanes, which are currently used as agents to treat head and neck cancers. To investigate the efficacy and safety of a neoadjuvant radiation therapy combined with docetaxel/cisplatin, we used this combination to treat 6 patients with oral squamous cell carcinoma. The patients received a low-dose fraction of docetaxel (20 mg/m2/week; total dose: 123.0 +/- 35.0 mg) and cisplatin (5 mg/m2/day, 5 days a week; total dose: 160.0 +/- 42.1 mg) combined with simultaneous irradiation of 40 Gy. Of the 6 patients, 5 (83.3%) showed a partial response (PR) and 1 showed no response (NC). Pathological efficacy was revealed in 4 patients (66.7%). All patients experienced stomatitis over grade 2, and 4 experienced neutropenia.

Hand-foot syndrome (HFS) is a rare adverse reaction to oral fluoropyrimidine TS-1, which contains the dihydropyrimidine dehydrogenase (DPD) inhibitor. We treated a recurrent gastric cancer patient with chronic renal failure who developed grade 2 HFS, grade 2 conjunctivitis and grade 3 stomatitis soon after TS-1 administration. Those symptoms improved with the administration of vitamin B6, topical emollient therapy, and so on. We thought that the continuous elevation of serum 5-FU concentration, due to the accumulation of DPD inhibitor from the renal dysfunction, led to the development of HFS, although the participation of 5-FU metabolites such as F-beta-alanine cannot be ruled out.

The present study was conducted to evaluate the effect of allopurinol spray on stomatitis induced by chemotherapy for esophageal cancer. The chemotherapeutics used consisted of 5-FU + CDDP (FC) given to 40 patients and 5-FU + ND (FN) given to 9 patients. Allopurinol solution for spray was prepared using a gelatin agent as base. The allopurinol spray was used 3-5 times daily before and after chemotherapy. The Japan Society for Cancer Therapy's criteria for stomatitis were used. With FN-therapy, no stomatitis was observed. With FC-therapy, 9 of 40 patients developed stomatitis of grade 1 (8 patients) or grade 2 (1). The incidence of stomatitis was 18.4% with all therapies and 22.5% with FC-therapy. The average graded toxicity was 0.20 for all therapies and 0.25 for FC-therapy. These results suggest that allopurinol spray is markedly effective for the prevention of stomatitis induced by chemotherapy. In addition, allopurinol spray is portable and convenient, and resulted in less nausea or vomiting than mouthwash.

Management of the side effects of chemotherapy in cancer patients is important because side effects can affect the tolerability and continuation of therapy, in addition to lowering the quality of life of patients. A significant efficacy of serotonin receptor antagonists against nausea and vomiting due to cancer chemotherapy, and granulocyte colony-stimulating factor against neutropenia secondary to chemotherapy, has been recently demonstrated. New chemoprotective drugs have been developed, such as amifostine for cisplatin-induced nephrotoxicity and neurotoxicity, and dexrazoxane for cardiac toxicity due to anthracyclines. Antiviral agents including lamivudine and interferons suppress virus replication, preventing the development of fulminant hepatitis during chemotherapy in cancer patients who have chronic hepatitis B infection. Various supportive therapies have resulted in the advance of cancer chemotherapy.

In developing new anticancer agents, the most important thing is the balancing of antitumor activity and toxicity. To achieve high activity and low toxicity, S-1 was designed, in which tegafur, prodrug of 5-FU, was combined with two classes of modulators. CDHP, inhibitor of 5-FU degradation in liver and Oxo, inhibitor of 5-FU phosphoribosylation in digestive tract, respectively. This cooperative study with 15 nation-wide institutes was conducted to evaluate the antitumor activity and toxicity of S-1 in patients with advanced head and neck cancer from Jan. 1994 to March 1996 in Japan. Out of 26 patients, CR was achieved in 1 and PR in 11 with a response rate of 46.2%, while adverse events of grade 3 were as follows: hemoglobinemia (7.7%), leukocytopenia, neutropenia, stomatitis and anorexia (3.8%), each. Neither grade 4 adverse event nor treatment-related deaths were observed. Based on these findings, it was concluded that S-1 is a useful anticancer agent with the low grade toxicities for treatment of the patients with advanced head and neck cancer, and the effects of CDHP and Oxo found in preclinical studies might be also reflected in these results.

Fourteen patients with unresectable primary or metastatic liver cancer were divided into two groups: group A, continuous hepatic arterial infusion of 5-FU in 10 cases; group V, continuous intravenous infusion of 5-FU in 4 cases. In group A, 5-FU (360 mg/m2/day x 5 days/week x 4 weeks) was continuously infused into the hepatic artery via femoral or gastroduodenal artery through Infuse A Port. In group V, 5-FU (360 mg/m2/day x 2 weeks) was continuously infused into the subclavian vein through IVH route. On day 1, the concentration of 5-FU in peripheral blood in group A (12.1 +/- 12.8 ng/ml) was significantly lower than in group V (43.8 +/- 19.8 ng/ml, p = 0.004). On day 5, it was also decreased in group A (24.6 +/- 24.1 ng/ml) compared with that in group V (61.8 +/- 34.4 ng/ml, p = 0.039). Side effects of 5-FU like nausea, abdominal discomfort and stomatitis were recognized in 4 out of 10 patients in group A (40%) and 3 out of 4 patients in group V (75%). In group A, a complete response was obtained in one patient with synchronous multiple liver metastases of sigmoid colon cancer. These results suggest that systemic toxicity of 5-FU is alleviated by continuous hepatic arterial infusion in the patients with unresectable liver cancer because of its low concentration in peripheral blood.

The chronomodulation of anticancer drugs arouses our interest as a method for cancer chemotherapy. The author reviewed recent clinical studies regarding circadian rhythms in 1) target tissues: healthy and cancer tissues; 2) chronopharmacology of anticancer drugs; and 3) chronotoxicity of anticancer drugs. A brief review is made of the main results of clinical phase II trials.

Stomatitis caused by a combined chemotherapy with 5-fluorouracil (5-FU) and cisplatin (CDDP) is a serious problem in the course of treatment for patients with oral carcinoma. In the present study, we proposed a form of cryotherapy using an ice-bar containing fibrinolysin and deoxyribonuclease (Elase) to inhibit the stomatitis. The therapeutic effect of the ice-bar cryotherapy was evaluated in 20 patients with oral squamous cell carcinoma who were undergoing 5-FU-CDDP chemotherapy. Nine of the 20 patients were given the ice-bar cryotherapy while the remaining patients were not. As a result, although there was no significant difference between the incidence of stomatitis in the groups with and without the ice-bar cryotherapy, the incidence of severe stomatitis with ulcers and/or eating disturbance in the 11 cases without the ice-bar cryotherapy (90%) was significantly higher than that in the 9 cases with the cryotherapy (44%) (p < 0.05). However, no significant difference in the clinical response rate of the 5-FU-CDDP chemotherapy was observed between the two groups.

We estimated the utility of daily oral administration of etoposide (ETOP) in 25 cases of refractory hematological malignancies who had been admitted to our hospital between February, 1988 and October, 1995. Patients were 9 cases of malignant lymphoma, 7 cases of adult T cell leukemia (ATL), 7 cases of acute leukemia, 1 case of primary macroglobulinemia, and 1 case of chronic lymphocytic leukemia (CLL). Eight cases were elderly patients over 65 years old, 7 cases were refractory to previous chemotherapies, and 13 cases were relapsed cases. ETOP was administered at 25 or 50 mg per day for at least more than 3 consecutive weeks, if the peripheral white blood cell count exceeded 1,000/microliter. Complete and partial responses were obtained in 64% of all cases, especially in 81% of malignant lymphoma and ATL. Probability of survival for 3 years of malignant lymphoma and ATL was 36.7%. As mild toxicities, 2 cases (8%) had nausea and vomiting, 2 cases (8%) had diarrhea, and 3 cases (12%) had stomatitis. Grade 3 leukocytopenia was observed in 16% of cases. Twelve out of 16 evaluable patients recovered in performance status (PS) after this therapy. Daily oral administration of ETOP might be an effective therapy for refractory hematological malignancies, especially for malignant lymphoma.

Radiotherapy combined with daily administration of low-dose cisplatin (CDDP) was applied to 12 cases with head and neck cancer. They consisted of 12 carcinomas, occurring in the epipharynx (3 cases), mesopharynx (3), oral cavity (1), larynx (3) and parasinuses (2). The total response rate (CR + PR) was 83.3%. There was a remarkable effect in reducing tumor size, particularly on patients with laryngeal or epipharyngeal carcinoma. Severe mucositis with ulcers as a side effect was seen in eight cases after the irradiation of 20 to 30 Gy. Six of them tolerated a full dose of irradiation, but CDDP administration was stopped except in one case. To continue the CDDP administration in cases having irradiation of over 40 Gy, it is necessary to reduce the frequency of CDDP administration and/or to give post-irradiative hydration with 500 ml saline. When this combination therapy is used as a preoperative treatment, daily administration should be continued. Incidence of nausea or vomiting was not so frequent and they could be easily controlled by a serotonin-antagonist. Leukopenia was not severe.

A randomized early phase II study using l-leucovorin (l-LV) and 5-fluorouracil (5-FU) in gastric cancer was conducted. The administration schedules: Arm A was 250 mg/m2 of l-LV and 600 mg/m2 of 5-FU weekly, arm B was 100 mg/m2 of l-LV and 370 mg/m2 of 5-FU for 5 consecutive days, and arm C was 10 mg/m2 of l-LV and 370 mg/m2 of 5-FU for 5 consecutive days. PR was obtained in 10/28 (35.7%) of arm A, 7/28 (25.0%) of arm B and 0/17 (0%) of arm C, in complete cases. In eligible cases, 30.3%, 21.9% and 0%, respectively. Because there was no responder in arm C, the entry to arm C was stopped by controller at the point where 17 patients were treated with arm C. Median survival time was 9.6 months in arm A, 8.0 months in arm B and 5.9 months in arm C. Major toxicities were stomatitis, diarrhea and neutropenia. Stomatitis was seen more in arm B and C than in arm A. These data suggest that the high dose of l-LV and 5-FU seems to be a very promising combination, but there was no responder using low-dose l-LV schedule against gastric cancer. We thus selected arm A for the next late phase II study against gastric cancer.

The clinical phase I study of TNP-351, an antifolate drug having a novel structure, was performed through a multicenter cooperative program in 40 patients with solid tumors. The test drug was used on dosage schedules of single and daily doses for 5 or 3 days (by intravenous drip over 30 minutes, respectively). From the daily administration for 5 days, severe adverse reactions such as myelosuppression, became manifest at 5 mg/m2 (1n). This schedule was then switched to daily administration for 3 days. Administration of the test drug was initiated at a dose of 5 mg/m2. On a single-dose schedule, the dose was increased up to 100 mg/m2 (20 n), and on the 3-day daily administration schedule, up to 10.8 mg/m2 (2.2 n). Consequently, 26 of the study patients received single doses; three of them the 5-day daily administration, and 11 the 3-day daily administration. The dose-limiting factors were leukopenia and thrombopenia on both the single-dose and 3-day daily administration schedules. MTD was 100 mg/m2, and MAD, 75 mg/m2 for the single-dose schedule; and 10.8 mg/m2 and 9 mg/m2 for the 3-day daily administration schedule. WBC and platelet counts fell to nadirs at 1-2 weeks on either the single-dose or 3-day daily administration schedule, and it took the respective parameters about 1 week to recover. Subjective and objective adverse reactions to the test drug consisted of digestive tract disorders manifested as stomatitis, anorexia, nausea and vomiting; and laboratory abnormalities such as elevations of GOT and GPT in addition to the myelosuppression. Many of these adverse reactions subsided within 3 weeks after initiation of TNP-351 treatment. On the single-dose schedule, the test drug occurred chiefly in unchanged form in the blood, and in this form it disappeared from the blood biphasically with an alpha phase of 0.29-0.95 hours, and a beta phase of 7.8-14.4 hours. This disappearance pattern did not vary with an increase in dose. The 24-hour urinary excretion rate of the unchanged form amounted to 42-62% of the administered doses. On the 3-day daily administration schedule, the test drug was not accumulated in vivo. In the present study, two patients with malignant fibrous histiocytoma responded to the test drug with tumor regression. The results suggested that the recommended dosage regimen for the clinical early phase II study of the test drug should comprise a course of 9 mg/m2/day (by intravenous drip infusion over 30 minutes) every day for 3 days, which should be repeated every 3 weeks.

Combination chemotherapy with 5-FU and CDDP was given to two patients with far advanced gastric cancer. One patient was associated with metastases of lung, liver, pancreas and Virchow and periaortic lymph nodes, and the other was associated with metastases of periaortic lymph nodes and malignant ascitis. The regimen consisted of 5-FU 1,000 mg/m2 (day 1-5, continuous infusion) and CDDP 100 mg/m2 (day 3, 1 hr drip infusion). The interval was from the 6th to the 21st day. The response to chemotherapy showed shrinking of primary gastric lesions and metastases of liver, pancreas and periaortic lymph nodes, and disappearance of Virchow lymph nodes and malignant ascitis. Adverse reactions were thrombocytopenia (Grade 4), leukocytopenia (Grade 3), stomatitis (Grade 1, 3), vomiting (Grade 1, 2) and peripheral neuropathy (Grade 3). This therapy is thought to be effective against far advanced gastric cancer.

We carried out a phase II study on single oral administration of UFT in 17 patients with ovarian carcinoma. Two PR cases were observed out of 13 evaluable cases for a response rate was 15.4%. Side-effects, appearing in 10 of the cases (58.8%) were mainly anorexia (17.6%), stomatitis (17.8%), nausea/vomiting (11.8%), leukopenia (11.8%) and thrombocytopenia (11.8%), but they were not serious. UFT proved useful in the treatment of patients with ovarian carcinoma.

Thirty-nine patients with non-Hodgkin's lymphoma were treated with weekly alternating non-cross-resistant chemotherapy (CAMBO-VIP). We obtained a high response rate, and prolonged disease-free survival with side effects and complications of various severity were observed. Three patients were withdrawn from the study due to aggravation of liver cirrhosis, cerebral infarction, and poor tolerance. Thirty-six patients completed this 12-week intensive chemotherapy. The median treatment delay in all patients was 3 days (-4 to 29 days), and a delay of over 15 days was seen in 5 patients. The nadir of the neutrophil count was 0 to 2,100/microliters (median 140/microliters), and 15 patients were below 100/microliters. Two patients had pneumonia and 4 had herpes zoster infection. The platelet count nadir was 20,000 to 240,000/microliters (median 90,000/microliters). Ten patients were below 50,000/microliters, but none required platelet transfusion. Red cell transfusion was given in 6 patients. Elevation of transaminases was seen in 25 patients, but it was not serious except for a patient with liver cirrhosis. The elevation of serum LDH level and decrease of serum haptoglobin level seen shortly after completion of treatment seemed due to the increased blood cell destruction. Stomatitis was observed in 32 patients, 17 of whom showed more than grade 3 toxicity. Blister formation on palms and/or soles was noted in 6 patients. There was no treatment-related death observed.

A late phase II study with MST-16 for malignant lymphoma was performed with the collaboration of 11 institutions belonging to the Hanshin Hematological Disease Treatment Research Group. Out of a total 40 patients entered into the study, 37 cases (33 of NHL and 4 HD) were evaluated for efficacy and 27 cases for side effects. The response rate was 29.7% (2 cases of CR and 9 PR). The factors affecting response rate were histological classification, phenotype of tumor cell surface and stage of disease. Bone marrow suppression and G-I disorders were the main toxicities observed, but they disappeared by the cessation of MST-16 treatment.