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.

Molecular targeted drugs have been developed and have come to play a part in the standard treatment of cancers. However, issues such as the optimum dose, selection of patients, and verification of the molecular targets remain to be discussed, because unexpected clinical problems related to the clinical efficacy, adverse events, and development of resistance have appeared. Therefore, proof of principle (POP) studies and pharmacodynamic or pharmacogenomic research to explore new bio-markers for the drugs are essential for clinical progress. On the other hand, the higher cost of development and care must also be discussed as new problems.

A 60-year-old female patient with a therapy-resistant Bence-Jones (BJ) lambda-type multiple myeloma was treated with bortezomib. She had been treated with tandem autologous stem cell transplantations and achieved complete remission before her disease relapsed. Sixteen hours after the first administration of bortezomib, an episode of fever, slight consciousness disturbance and vomiting occurred, which was accompanied by a remarkable elevation of LDH (3608 IU/l). Serum levels of creatinine, uric acid, and AST were also transiently elevated. Serum interleukin-6 level was also increased after the administration of bortezomib. The symptoms disappeared rapidly within 48 hours. Bortezomib at a 25%-reduced dose was administered again along with dexamethasone 26 days later, which caused a moderate increase in LDH levels, but no other symptoms. Further treatment caused no increase in LDH. The treatment was very effective and eradicated both urinary BJ protein and bone marrow myeloma cells after 8 sessions of bortezomib administration. These findings suggest that a bortezomib-induced rapid reduction in tumor burden led to tumor lysis syndrome, for which caution is needed when treating myeloma patients with this very effective agent.

The efficacy and safety of temozolomide were evaluated in 32 patients with anaplastic astrocytoma at first relapse. Temozolomide was administered orally once daily for the first five days of a 28-day cycle, at a dose of 150 or 200 mg/m(2)/day. The response rate determined by independent central review of MRI was 34% (95% confidence interval: 18.6%-53.2%), with 3 complete response and 8 partial response. The rate of "no change or better" was 91% (95% confidence interval: 75.0%-98.0%). Progression-free survival (PFS) at 6 months was 40.6%, and the median PFS was 4.1 months. The incidence of constipation (50%) and nausea (25%) was high,but these events were all mild or moderate in severity except in one subject with constipation,and could be managed with standard laxatives and antiemetics. The main laboratory test abnormalities (total incidence and incidence of grade 3/4 change) were lymphocytopenia (50%, 25%), neutropenia (47%, 6%), leukopenia (38%, 3%), thrombocytopenia (31%, 9%), and increased GPT (25%, 3%). Temozolomide was shown to have good efficacy and tolerability in patients with anaplastic astrocytoma at first relapse.

The clinical efficacy and safety of weekly paclitaxel therapy were studied retrospectively in 17 patients with advanced and recurrent gastric cancer who had previously been treated with TS-1 therapy. The overall response rate was 0%, but MST was 495 days. The adverse effects observed were grade 3 leukopenia in 2 patients (11.8%) and grade 1 and 2 alopecia in 13 patients (76.5%). However, weekly paclitaxel therapy was performed for all outpatients. Weekly paclitaxel therapy could be useful and safe as second-line chemotherapy.

We reported that the rate of conversion of lactone to carboxylate forms of irinotecan (CPT-11) and its metabolites plays a major role in the biliary excretion of these compounds. Sulfobromophthalein partially inhibited the secretion of SN-38-glucronide into the gastrointestinal lumen, whereas little change was seen in that of active metabolite SN-38. Co-administration of sulphobromophthalein with CPT-11 might lower the late-onset gastrointestinal toxicity observed during treatment with CPT-11 without lowering anticancer activity. In the ileum, the level of transport in the direction form the serosal layer to mucosal layer was significantly greater than that in the direction form the mucosal layer to serosal layer, whereas a significant difference was not observed in the jejunum. This secretory transport required metabolic energy was diminished by sulfobromophthalein. A specific transport system plays a major role in the secretion of SN-38 and that this secretory transport system predominantly exists in the ileum. Uptake of SN-38 was significantly reduced at 4 degrees C. Baicalin inhibited the uptake of SN-38. A specific transport system mediates the uptake of SN-38 across the apical membrane in Caco-2 cells. Inhibition of this transporter would be a useful means for reducing late-onset diarrhea.

In cases with advanced/recurrent gastric cancer undergoing single therapy with TS-1, we retrospectively discussed the antitumor effects and adverse events and considered the clinical utility of TS-1. The subjects consisted of 131 cases with advanced/recurrent gastric cancer who received one or more courses of therapy with TS-1 alone between July 1999 and August 2003. We carried out 4-week administration of 80-120 mg/day of TS-1 according to body surface area, followed by a 2-week discontinuation, then repeated administration which adjusting the dosage according to the incidence of side effects, and discussed the antitumor effects and adverse events. The response rate in all cases was 21% and the median survival time (MST) was 343 days, or 25.3% and 265 days if limited to unresectable and recurrent cases. The response rates were 38.2% for unresectable cases, 16.3% for recurrent cases and 14.6% for curability C cases, and the MSTs were 250 days, 276 days and 419 days, respectively. The response rates in terms of whether or not patients had received chemotherapy were 11.6% for those who had received chemotherapy and 40.0% for those who had not, and the MSTs were 239 days and 325 days, respectively. Thus, both were significantly better in patients who had not received chemotherapy. The response rates for patients who had not received chemical therapy by target organs were favorable on the order of 50% for stomach and 33% for liver metastasis, and the MSTs were on the order of 474 days for peritoneum, 39 1 days for liver metastasis and 326 days for lymph nodes. There were 10 cases of long-term survival of 600 days or longer, but not in unresectable cases, and the target organs in many of the cases were the peritoneum and lymph nodes. Adverse reactions were observed in 34.4% of all cases and those of grade 3 or more in 9.4%, all of which were improved only by discontinuation of the drug. It was again confirmed that single therapy with TS-1 for advanced/recurrent gastric cancer is an excellent therapy providing both high antitumor effects and safety.

Dihydropyrimidine dehydrogenase (DPD, EC 1.3.1.2) is the initial and rate-limiting enzyme in the catabolism of the pyrimidine bases, uracil and thymine, and is also known to be the key enzyme catalyzing the metabolic degradation of the anti-cancer drug 5-fluorouracil (5-FU). 5-FU has been commonly and widely used as a chemotherapeutic agent for the treatment of cancer of the gastrointestinal tract, breast, and head and neck. More than 85% of the administered 5-FU is catabolized by DPD. The clinical importance of DPD has been demonstrated with the identification of severe or lethal toxicity in patients administered 5-FU who are deficient in or have low levels of DPD activity in their peripheral blood mononuclear cells (PBMC). The importance of the role of DPD in 5-FU chemotherapy also has been shown by studies with competitive and irreversible DPD inhibitors. Population studies of DPD activity in PBMC were reported in healthy volunteers and cancer patients to evaluate the incidence of complete or partial DPD deficiency. In these studies, considerable variation was observed, and the frequency of low or deficient DPD activity (<30% and <10% of the mean activity of the normal population, respectively), was estimated to be 3-5% and 0.1%,respectively. We also found one healthy volunteer (0.7% of the population) with very low PBMC-DPD activity due to heterozygosity for a mutant allele of the DPYD gene in a population of 150 healthy Japanese volunteers. To date, at least 34 DPYD variants have been reported. However, genotyping of cancer patients with reduced or normal DPD activity showed that only 17% of those patients had a molecular basis for their deficient phenotype, which emphasized the complex nature of the molecular mechanisms controlling polymorphic DPD activity in vivo,suggesting that it is difficult to identify DPD deficiency by genotyping. Therefore, it is important to develop methods for identifying DPD deficiency in cancer patients by phenotyping before 5-FU treatment.

We report a case of follicular lymphoma in which pulmonary cryptococcosis occurred with cladribine therapy. The case involved a 72-year-old man. He was diagnosed as having follicular lymphoma, grade 1, clinical stage IVA from a tongue tumor biopsy in January 2003. A total of 6 courses of R-CHOP therapy was performed, but no clear effect was found. A new cervical lesion appeared, so he was treated with a total of 2 courses of R-EPOCH therapy, and the effect was classed as stable disease. We started cladribine therapy (0.09 mg/kg, seven days of continuous infusion) from February 2004, and complete remission was achieved after 4 courses of cladribine therapy. In January 2005, an abnormal nodular shadow in the right S10 area was found on chest CT images which was diagnosed as pulmonary cryptococcosis by serum antigen and a trans-bronchial lung biopsy. We started fluconazole (200 mg a day, initially intravenous drip infusion, followed by oral intake), following which both the pulmonary shadow and serum antigen improved. Afterward, the fifth course of cladribine therapy and local radiation therapy were performed against a relapse of lymphoma, but cryptococcosis did not reappear. The prolonged bone marrow suppression after cladribine therapy was considered to be a severe adverse event. These findings suggest that it is very important to pay attention to any opportunistic infection such as pulmonary cryptococcosis.

Early and late phase II studies of S-1 were conducted for the treatment of metastatic pancreatic cancer. In both trials, S-1 was administered at a dose of 80 mg/m2/day. One course consisted of consecutive administration of S-1 for 28 days, followed by 14 days of rest. This regimen was repeated every 6 weeks until the occurrence of progressive disease or unacceptable toxicities. The early phase II study demonstrated a response rate of 21.1% with a median survival time of 5.6 months in 19 patients. The major drug-related adverse events were gastrointestinal toxicities like nausea, and anorexia, though most of them were tolerable and reversible. Other treatment-related adverse events, like ileus, colitis, and abdominal distension, were less frequent. The late phase II study confirmed favorable responces with a mild toxicity profile in 40 evaluable patients. S-1 is active and well tolerated in patients with metastatic pancreatic cancer. Randomized trials are warranted to determine the effectiveness of S-1 for the treatment of pancreatic cancer.

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 purpose of this study was to evaluate the efficacy and safety of a novel oral anticancer fluoropyrimidine derivative, S-1, in patients receiving initial chemotherapy for unresectable, advanced non-small-cell lung cancer (NSCLC). Between June 1996 and July 1998, 62 patients with NSCLC who received no previous chemotherapy for advanced disease were enrolled in this study. Fifty nine patients (22 in stage IIIB and 37 in stage IV) were eligible for the evaluation of efficacy and safety. S-1 was orally administered twice daily after meals. Three doses of S-1 were prescribed according to body surface area (BSA), so that they would be approximately equivalent to 80 mg/m2/day. One cycle of S-1 consisted of consecutive administration for 28 days followed by a 2-week rest, and the cycle was repeated up to 4 times. The partial response (PR) rate of the eligible patients was 22.0% (13/59) (95% confidence interval: 12.3-34.7%). Grade 4 neutropenia was observed in one of the 59 patients (1.7%). There were no irreversible, severe or unexpected toxicities. The median survival time (MST) of all of the patients was 10.2 months (95% confidence interval: 7.7-14.5 months), and the one-year survival rate was 41.1%. S-1 was considered to be an active single agent against NSCLC.

Most cases of head and neck squamous cell carcinoma (HNSCC) are in the advanced stages, resulting in a poor prognosis. To improve the poor outcome, adjuvant chemotherapy is indispensable for advanced cases with a high relapse risk after standard definitive treatments including surgery and/or radiotherapy. To define an adequate administration schedule in adjuvant chemotherapy with S-1, a controlled randomized study in multi-institutes was done. The results showed the 2-week administration followed by 1-week rest was superior to the 4-week administration followed by the 2-week rest in terms of safety and efficacy. In the present paper, some problems of adjuvant chemotherapy were discussed, and the protocol was described in terms of a multi-institutional controlled randomized comparison study of S-1 versus UFT in an adjuvant chemotherapy setting for locally advanced HNSCC.

We conducted a phase I study to determine a recommended dose (RD) of S-1 for chemo-radiotherapy consisting of S-1+ radiotherapy for T 2 N 0 larynx cancer. The method of administration used to assess the RD was irradiation with 2 Gy/day for 5 days a week until a total dose of 60 Gy, and concomitant administration of S-1 once a day for 2 weeks beginning on the day therapy was started followed by 2 weeks off the drug and 2 weeks on the drug with the dose escalating from S-1 60 mg/body/day (level 1) to 80 mg/body/day (level 2), and then to 100 mg/body/day (level 3). 18 patients were enrolled. 4 patients developed an adverse event of grade 3 radiation dermatitis which became a dose-limiting toxicity (DLT) at level 3. We then concluded that 100 mg/body/day was the maximum tolerated dose (MTD) of S-1 and decided that the RD of S-1 was 80 mg/body/day.

Chemotherapy for colorectal cancer is now improving rapidly due to new drugs like oxaliplatin and molecular targeting drugs. The key drug, however, is still 5-fluorouracil (5-FU). S-1 is an oral 5-FU anti-tumor drug that combines three pharmacological agents: tegafur, 5-chloro-2,4-dihydroxypyridine, which inhibits dihydropyrimidine dehydrogenase activity, and potassium oxonate, which reduces gastrointestinal toxicity. The results of the phase II study suggested that S-1 as a single agent was active against metastatic colorectal cancer: CR rate was 36-40% and MST was about one-year. Toxicity was all tolerable. Clinical trials of S-1 with oxaliplatin or CPT-11 combination chemotherapy are ongoing in Japan. S-1 with molecular targeting drugs will also be studied. Therefore, S-1 is expected to play an important part in chemotherapy for colorectal cancer.

The aim of this survey was to confirm the safety and efficacy of S-1 for advanced gastric cancer after market release.

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.

S-1 is an attractive oral fluorouracil antitumor drug, which is being called "a self-rescuing drug". This novel oral fluoropyrimidine is combined with three pharmacological agents: tegafur (FT) which is a prodrug of 5-fluorouracil (5-FU), 5-chloro-2,4-dihydroxypyridine (CDHP) which inhibits dihydropyrimidine dehydrogenase (DPD) activity, and potassium oxonate (Oxo) which reduces gastrointestinal toxicity. Phase I and an early phase II clinical trials were performed about ten years ago, and these results had already been introduced to the Journal "Clinical Cancer Research Vol. 5, pages 2000-2005, 1999". The data of this article in this journal was referred from the results of the figures and tables based on the above trial. Most of the authors in this article have contributed on that pharmacokinetics study and published the above manuscripts. In that study, the pharmacokinetics of 5-FU, intact FT, CDHP and Oxo after administration of the standard dose of S-1 had been performed. These studies were carried out at two hospitals, Department of Surgery (Section 1) Sapporo Medical University and Chemotherapy Cancer Center, Cancer Institute Hospital and Japanese Foundation for Cancer Research (Ohtsuka). The number of patients accepted for this trial is twelve, 5 patients with gastric cancer, 4 with colorectal cancer and 3 with breast cancer. Single administration trial was referred to all patients, but consecutive administration trial was limited to ten patients. The results of plasma concentration, Cmax, Tmax, AUC0-14, and T1/2 of 5-FU, FT, CDHP, and Oxo were ascertained in details. It was a surprise that the indicated data was very similar to that of the intravenous 5-FU continuous infusion. Therefore, the low dose administration of 5-FU (FT) as S-1 may result in good antitumor effects with minimum adverse effects to the patients.