s-1-(combination) and Mouth-Neoplasms

A case showing reinforcement of the action of warfarin and potassium in a patient administered S-1 is reported.The patient was a 71-year-old man with left upper gingival cancer.He had ventricular tachycardia (VT), hypertrophic cardiomyopathy, and a cerebellar infarction.He underwent a pacemaker implantation, and was administered warfarin.After the operation, in mid-March 2010, he was administered with S-1 and warfarin. However, the international normalized ratio of prothrombin time (PT-INR) increased to an extremely high level of 5.82, and S-1 and warfarin were stopped. They were re-administered at the end of April, and the PT-INR stabilized to approximately 2.

Topics: Aged; Anticoagulants; Antimetabolites, Antineoplastic; Cardiomyopathy, Hypertrophic; Cerebral Infarction; Drug Combinations; Drug Interactions; Humans; Male; Mouth Neoplasms; Neoplasms, Squamous Cell; Oxonic Acid; Tachycardia, Ventricular; Tegafur; Warfarin

We evaluated whether preoperative chemotherapy with S-1 and concurrent radiotherapy is feasible and efficacious in the treatment of advanced oral squamous cell carcinoma.. Participants comprised 39 patients with oral carcinoma (stage III, n = 15; stage IVA, n = 24). All patients received a total radiation dose of 40 Gy, in once-daily 2-Gy fractions, and received S-1 at 65 mg/m(2)/day for 5 consecutive days, over 4 consecutive weeks with concurrent radiotherapy.. Hematological toxicity was mild and reversible. The most common non-hematological toxicity was grade 3 mucositis, but this was transient and tolerable. Radical surgery was performed for 37 patients, with the remaining 2 patients declining the surgery. Postoperatively, local failure developed in 1 patient, and neck failure in 2 patients. Distant metastases were identified in 4 patients. At a median follow-up of 38.0 months (range 23-88 months), locoregional control, disease-specific survival, and overall survival rates at 3 years were 91.5, 83.8, and 83.8 %, respectively.. Concurrent administration of S-1 and radiotherapy combined with surgery offers a well-tolerated method of successfully treating advanced oral squamous cell carcinoma. The locoregional control rate remains high even at 3 years of follow-up, and no serious adverse effects have been encountered.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Chemoradiotherapy; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Survival Rate; Tegafur

To determine the feasibility and efficacy of preoperative concurrent chemoradiation therapy (CCRT) with S-1, an oral fluoropyrimidine derivative, in patients with T4 oral squamous cell carcinoma (SCC).. Only patients with histologically proven T4 oral SCC were included. Radiotherapy (total dose, 30 Gy) was delivered in 2-Gy daily fractions over a period of 3 weeks. Concurrently, S-1 (80 mg/m(2)/day) was administered orally twice daily for 14 consecutive days.. We enrolled 46 patients. All underwent radiotherapy as planned; however, oral S-1 was discontinued in 3 patients who manifested acute toxicity. Grade 3 toxicities were mucositis (20%), anorexia (9%), and neutropenia (4%). We encountered no Grade 4 adverse events or serious postoperative morbidity requiring surgical intervention. After CCRT, 32 of the 46 patients underwent radical resection; in 17 (53%) of the operated patients, the pathologic response was complete. During follow-up ranging from 7 to 58 months (median, 22 months), tumor control failed in 5 (16%) of the 32 operated patients; there were 3 local and 2 regional failures. Of the 14 non-operated patients, 8 (57%) manifested local (n = 7) or regional failure (n = 1). The 3-year overall survival rate for all 46 patients was 69%; it was significantly higher for operated than for non-operated patients (82% vs. 48%; p = 0.0288).. Preoperative CCRT with S-1 is feasible and effective in patients with T4 oral SCC. Even in inoperable cases, CCRT with S-1 provides adequate tumor control.

Topics: Administration, Oral; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Feasibility Studies; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Preoperative Care; Prospective Studies; Radiation-Sensitizing Agents; Radiotherapy Dosage; Tegafur; Treatment Failure

This study was conducted to identify a recommended dose for S-1, used in combination with 40-Gy radiation.. Thirty patients, 15 each with stage III and IVA oral carcinoma, were enrolled. All patients received a total dose of 40-Gy. For the S-1 treatment, patients were given either the standard Japanese dose, calculated according to body surface area, or a reduced dose. Groups consisting of at least three patients were given S-1 according to one of 8 regimens.. Hematologic toxicity was mild and reversible. The most common nonhematologic toxicity was mucositis. At level 8 that was the standard S-1 dose for 5 days per week for 4 weeks, dose-limiting toxicity was observed when 2 patients had grade 4 mucositis. This level was thus deemed the maximum tolerated dose for the regimen.. The recommended dose of S-1 with concurrent radiotherapy was the reduced dose of S-1 given for 5 days per week, for 4 consecutive weeks. Preoperative S-1 and concurrent radiotherapy was well tolerate and feasible and warrants a phase II study.

Topics: Administration, Oral; Adult; Aged; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Dose-Response Relationship, Radiation; Drug Combinations; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mouth Neoplasms; Neoplasm Metastasis; Oxonic Acid; Preoperative Period; Tegafur; Treatment Outcome

The super-selective intra-arterial infusion, which has high anti-tumor effect to infuse high concentration of drugs into arterial in the control of tumor, has been expected to have local control. S-1, developed by the scientific theory of both potentiating antitumor activity of 5-fluorouracil(5-FU)and reducing gastrointestinal toxicity induced by 5-FU, is an active agent for squamous cell carcinoma of the head and neck(HNSCC). Docetaxel(DOC)is the drug Taxanes which has anti-tumor effect by mechanism different from conventional anti-tumor mechanism of action. In Yamaguchi University, DOC+CDDP+5-FU in the three-drug combination therapy shows high anti-tumor effect for advanced oral cancer. In the present study, we conducted a phase I study to examine local control of S-1 in the combination with DOC using super-selective intra-arterial infusion with oral cancer. The study performed super-selective intra-arterial infusion of DOC on the first day, and was considered as the schedule which prescribes three-week S-1 for patients every day from same day. Since blood toxicity nature grade 4 discovered the result in S-1: 65 mg/m(2)day and DOC: 50 mg/ m(2), we decided that recommended dose(RD)was S-1: 65 mg/m(2) and DOC: 40 mg/m(2).

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Docetaxel; Dose-Response Relationship, Drug; Drug Combinations; Female; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Taxoids; Tegafur

The aim of this study was to investigate the efficacy and safety of an oral fluoropyrimidine anticancer agent, S-1, in patients with oral squamous cell carcinoma. Patients with pathologically confirmed squamous cell carcinoma and at least one measurable lesion were enrolled. Oral administration of S-1 (40 mg/m2 twice daily) for 28 days was followed by a 14-day rest period. A total of 41 consecutive eligible patients were enrolled in the study between October 2002 and August 2004. The sites of the primary tumor were the gingiva (n=18), the tongue (n=12), the palate (n=5), the oral floor (n=4), the buccal mucosa (n=1), and the labial mucosa (n=1). A median of two cycles of treatment (range, 1-5) was administered. A complete response was achieved in nine patients and a partial response in eight patients, for an overall response rate of 41.5% (95% confidence interval, 26.4-56.5%). The 3-year survival rate was 76.4% (95% confidence interval, 62.8-90.0%). Although grade 3 anemia and anorexia occurred in two patients each (4.9%), and grade 3 neutropenia, thrombocytopenia, nausea, vomiting, stomatitis, and diarrhea in one patient each (2.4%), no grade 4 toxicities were observed. S-1 exhibits definite antitumor activity in patients with oral squamous cell carcinoma and is well tolerated.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; Carcinoma, Squamous Cell; Dose-Response Relationship, Drug; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Survival Analysis; Tegafur

Treatment of patients with unresectable recurrent oral cancer is quite difficult. In particular,there is no scientific evidence to select anti-cancer drugs for patients who were given previous radiation therapy. To select optional chemotherapy regimens, we have employed a new chemosensitivity testing method, a collagen gel droplet embedded culture sensitivity test (CD-DST) for patients with unresectable oral cancer. Six oral cancer patients with recurrence and/or metastatic disease were treated with the optional chemotherapy based on the results of CD-DST. No result was obtained due to a problem of poor growth of tumor cells in one case. In another case, we could not find a sensitive anti-cancer drug among the agents we examined. These 2 patients were treated with selected palliative pain control therapy. Optional chemotherapy based on the results of CD-DST was given to 4 patients showing sensitivity to the anti-cancer drugs examined. Tumor recession or tumor dormancy was observed clinically during a definite period. Toxicity was mild and the median survival was 10.9 months. We therefore conclude that the examination with CD-DST may provide important scientific evidence to determine a suitable chemotherapy for patients with advanced oral cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Combinations; Drug Screening Assays, Antitumor; Humans; Lung Neoplasms; Mitomycin; Mouth Neoplasms; Neoplasm Recurrence, Local; Oxonic Acid; Pyridines; Tegafur

S-1 is a novel oral fluoropyrimidine inhibitory for dihydropyrimidine dehydrogenase (DPD). In the present study, we have examined the appropriate dose of S-1 in the combination with radiation and the safety and clinical efficacy. Radiation was given (2 Gy/day; 5 days/week) for a total of 60 Gy. S-1 was given orally every day for 2 weeks and then S-1 was stopped for 1 week. The levels were divided accordingly to the S-1 application as follows; level 0, 50 mg/m2/day; level 1, 65 mg/m2/day; level 2, 80 mg/m2/day. grade 3 toxicity of anorexia and the grade 3 toxicity increase in bilirubin level were observed in 2 cases of level 2. We decided that level 1 (65 mg/m2/day) was the recommended dose of the S-1 application as observed in compliance and efficacy. This therapy is a useful concurrent chemo-radiotherapy which may improve the response rate and quality of life (QOL) of patients with oral squamous cell carcinoma.

Topics: Adult; Aged; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Female; Humans; Male; Maximum Tolerated Dose; Middle Aged; Mouth Neoplasms; Nausea; Oxonic Acid; Quality of Life; Radiotherapy Dosage; Stomatitis; Tegafur

We investigated preoperative chemotherapy with S-1 and low-dose cisplatin for the untreated stage II-IV oral squamous cell carcinoma patients. The chemotherapy consisted of S-1 80 mg/m2/day (day 1-14) and CDDP 5 mg/m2/day (day 1-5 and day 8-12) intravenous drip (less than 1 hour). In the second phase clinical trial of 44 patients, the clinical response rate was 63.7% and the histological response rate by the Oboshi-Shimosato's evaluation was 61.4%. The main adverse events were myelosuppression and gastrointestinal disturbance such as nausea 36.4%, anorexia 27.3%, neutropenia 25% and leukopenia 25%. Grade 3 and 4 adverse events were neutropenia 11.4%, leukopenia 9.1%, thrombocytopenia 4.5% and oligochromemia 4.5%. The two-year overall survival rate was 92.6%. The advantages of this chemotherapy are high response rate, low adverse effects and not to prevent planned therapies such as surgery and radiation. These facts suggest that this chemotherapy is suitable for preoperative chemotherapy.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Humans; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Mouth Neoplasms; Nausea; Neutropenia; Oxonic Acid; Preoperative Care; Survival Rate; Tegafur

TS-1 is a novel oral 5-fluorouracil containing tegaful (prodrug of 5-FU) and two biochemical modulators. These modulators feature effect-enhancing and adverse reaction-reducing activity. We investigated the histological response and toxicities of combination chemotherapy with TS- 1 and low-dose cisplatin and evaluated its usefulness as preoperative chemotherapy Forty-four newly diagnosed patients with stage Il-IV oral squamous cell carcinoma were enrolled in this study from February 2002 to April 2004. Patients were administered TS-1 80 mg/m2/day (days 1-14) and cisplatin 5 mg/m2/day (days 1-5 and 8-12) followed by radical surgery within 2 weeks. The histopathological effect of chemotherapy, which was a surrogate endpoint of this trial, was evaluated with surgical or biopsy specimens. The rate of histological antitumor effect was as follows: complete response (CR) 36.4%, partial response (PR) 25.0%, minor response (MR) 18.1% and no change (NC) 20.5%. The rate of histological response (CR + PR) was 61.4%. The CR rate of effective cases was 59.3%. The main toxicities occurred in bone marrow and the digestive tract. The incidence of severe toxicity such as grade 3 or 4 was 4.5% in anemia, 9% in leukocytopenia, 11.4% in neutropenia, 4.5% in thrombocytopenia and 2.3% in anorexia, diarrhea and urticaria. Most patients showed no toxicity or mild toxicities. TS- 1 with low-dose cisplatin has highly effective antitumor activity and mild toxicities. In particular, the CR rate was very high. It is suggested that this regimen is suitable for neoadjuvant chemotherapy. We expect that this chemotherapy will contribute to avoidance of surgery for small tumors (stages I and II) and will enable function-preserving surgery for advanced tumors.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Disease-Free Survival; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Neoadjuvant Therapy; Neoplasm Staging; Oxonic Acid; Preoperative Care; Pyridines; Tegafur

It has been reported that 20% of early-stage oral squamous cell carcinoma (OSCC) patients treated with surgery alone (SA) may exhibit postoperative relapse within 2-3 years and have poor prognoses. We aimed to determine the safety of S-1 adjuvant chemotherapy and the potential differences in the disease-free survival (DFS) between patients with T2N0 (stage II) OSCC treated with S-1 adjuvant therapy (S-1) and those treated with SA. This single-center retrospective cohort study was conducted at Kumamoto University, between April 2004 and March 2012, and included 95 patients with stage II OSCC. The overall cohort (OC), and propensity score-matched cohort (PSMC) were analyzed. In the OC, 71 and 24 patients received SA and S-1, respectively. The time to relapse (TTR), DFS, and overall survival were better in the S-1 group, but the difference was not significant. In the PSMC, 20 patients each received SA and S-1. The TTR was significantly lower in the S-1 group than in the SA group, while the DFS was significantly improved in the former. S-1 adjuvant chemotherapy may be more effective than SA in early-stage OSCC.

Topics: Aged; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Disease-Free Survival; Drug Combinations; Female; Follow-Up Studies; Humans; Male; Middle Aged; Mouth Mucosa; Mouth Neoplasms; Neoplasm Recurrence, Local; Neoplasm Staging; Oxonic Acid; Prognosis; Propensity Score; Retrospective Studies; Squamous Cell Carcinoma of Head and Neck; Tegafur; Time Factors

The present study aimed to retrospectively analyze the long-term efficacy and toxicity of concurrent chemoradiotherapy with nedaplatin and S-1 for head and neck squamous cell carcinoma.. The study enrolled 53 patients (23 with stage II disease, 13 with stage III disease, and 17 with stage IV disease). S-1 was administered orally twice a day for 14 days, followed by a two-week rest period. Nedaplatin was intravenously administered on day 4. Where possible, two courses of chemotherapy were performed. Radiotherapy was started with the administration of S-1. We analyzed the clinical response, survival rate, acute adverse events, and late swallowing toxicity.. The complete response rates for the primary tumor and neck lymph node metastases were 94.3% and 79.3%, respectively. The five-year overall survival rate was 79.5%, the five-year disease-specific survival rate was 84.8%, and the five-year relapse-free survival rate was 73.7%. The main acute adverse events were leukopenia, neutropenia, mucositis, and dermatitis. No patient had severe nephrotoxicity. Late swallowing toxicity was observed in 13 patients.. The low toxicity, and low nephrotoxicity of chemoradiotherapy with nedaplatin and S-1 have a positive impact on long-term survival. The combination of nedaplatin and S-1 can be used instead of cisplatin and 5-fluorouracil as a safer regimen, especially in patients with some complications and those requiring treatment in an outpatient setting.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemoradiotherapy; Drug Combinations; Female; Head and Neck Neoplasms; Humans; Laryngeal Neoplasms; Male; Middle Aged; Mouth Neoplasms; Organoplatinum Compounds; Oxonic Acid; Pharyngeal Neoplasms; Squamous Cell Carcinoma of Head and Neck; Tegafur; Treatment Outcome

In our department, patients with oral squamous cell carcinoma(OSCC)received preoperative chemotherapy containing S-1 to prevent the growth and dissemination of tumors during the waiting time before definitive surgery. We retrospectively evaluated the usefulness of this treatment.. One hundred and five patients comprising stages T1(26), T2(64), T3(7), and T4(8 cases)were enrolled in this study from July 2001 to June 2013. In principle, patients were administered S-1(80mg/m / 2/day, days 1-14)and followed by a drug holiday(days 15-21), continuing until 1 week before surgery.. The median administration period was 14 days(256 days). Ninety-eight patients underwent definitive surgery, but 7 patients who revealed clinical CR underwent only biopsy and showed histological CR. The histological responses of all patients were CR(24), PR(22), and NC(59), and the response rate was 43.8%. Almost all adverse effects were Grade 1 or 2, except 1 case of neutropenia(Grade 3)and 1 case of urticaria(Grade 3). The 5-year overall survival rates were 86.7% in all cases, 95.3% in CR/PR cases, and 79.7% in NC cases.. Preoperative S-1 administration during the waiting time was a safe and very effective method and was considered beneficial for patients with OSCC.

Topics: Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Drug Combinations; Humans; Mouth Neoplasms; Oxonic Acid; Retrospective Studies; Tegafur; Waiting Lists

S-1 is an oral anticancer agent containing tegafur, a prodrug of 5-fluorouracil (5-FU). Preoperative S-1 chemotherapy is performed to prevent tumor proliferation before surgery in oral squamous cell carcinoma (OSCC). The aim of this study was to evaluate the effects of preoperative S-1 chemotherapy on tumor budding.. We examined 248 cases of OSCC and evaluated the budding scores in biopsy and resected specimens by keratin immunohistochemistry.. In S-1-untreated patients, the budding scores in resected specimens tended to show a mild increase. S-1 treatment had the effect of lowering the budding score, although some cases with dramatically increased budding scores in resected specimens were found in the early phase of administration. Relapse-free survival showed a significant difference (P < .01) according to the presence or absence of S-1 treatment among patients with high budding scores.. The present findings indicate that S-1 administration may be more effective in patients with high budding scores than in those with lower budding scores.

Topics: Antimetabolites, Antineoplastic; Biopsy; Carcinoma, Squamous Cell; Drug Combinations; Humans; Mouth Neoplasms; Neoplasm Recurrence, Local; Oxonic Acid; Tegafur

　Anticancer drugs induce cell-cycle arrest and apoptosis not only in tumor cells, but also in immune cells. However, many preclinical and clinical findings show that some chemotherapeutic agents can improve the antitumor efficacy of immunotherapy. We immunohistochemically analyzed the degree of immune cell infiltration and the relevance of programmed cell death 1 ligand-1 (PD-L1) expression in surgically resected oral squamous cell carcinoma (OSCC) specimens from patients who had undergone pretreatment with certain chemotherapies and other patients without pretreatment. We divided the patients into the group of neoadjuvant chemotherapy (NAC) patients (n=8) and the nNAC (without NAC) patient group (n=10). We observed that NAC induced infiltrations of CD4, CD8 T cells and CD56 NK cells into the tumor microenvironment. Decreased numbers of Tregs and PD-1-positive cells were observed in the NAC group. No significant difference was observed in the degree of immune-cell infiltration between the patient groups except for CD56 NK cells in the stroma and PD-1 cells in cancer nests. Eighty percent of the nNAC specimens showed intermediate-to-strong PD-L1 protein expression, whereas 75% of the NAC specimens showed down-regulation of the PD-L1 protein, indicating the effectiveness of the chemotherapeutic treatment before surgery.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Agents; B7-H1 Antigen; Carcinoma, Squamous Cell; Case-Control Studies; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Neoadjuvant Therapy; Oxonic Acid; Retrospective Studies; Tegafur; Tumor Microenvironment

We reported previously that decorin (DCN) is significantly up-regulated in chemoresistant cancer cell lines. DCN is a small leucine-rich proteoglycan that exists and functions in stromal and epithelial cells. Accumulating evidence suggests that DCN affects the biology of several types of cancer by directly/indirectly targeting the signaling molecules involved in cell growth, survival, metastasis, and angiogenesis, however, the molecular mechanisms of DCN in chemoresistance and its clinical relevance are still unknown. Here we assumed that DCN silencing cells increase chemosusceptibility to S-1, consisted of tegafur, prodrug of 5-fluorouracil. We first established DCN knockdown transfectants derived from oral cancer cells for following experiments including chemosusceptibility assay to S-1. In addition to the in vitro data, DCN knockdown zenografting tumors in nude mice demonstrate decreasing cell proliferation and increasing apoptosis with dephosphorylation of AKT after S-1 chemotherapy. We also investigated whether DCN expression predicts the clinical responses of neoadjuvant chemotherapy (NAC) using S-1 (S-1 NAC) for oral cancer patients. Immunohistochemistry data in the preoperative biopsy samples was analyzed to determine the cut-off point for status of DCN expression by receiver operating curve analysis. Interestingly, low DCN expression was observed in five (83%) of six cases with complete responses to S-1 NAC, and in one (10%) case of 10 cases with stable/progressive disease, indicating that S-1 chemosensitivity is dramatically effective in oral cancer patients with low DCN expression compared with high DCN expression. Our findings suggest that DCN is a key regulator for chemoresistant mechanisms, and is a predictive immunomarker of the response to S-1 NAC and patient prognosis.

Topics: Aged; Aged, 80 and over; Animals; Antineoplastic Agents; Biomarkers, Tumor; Biopsy; Cell Line, Tumor; Decorin; Drug Combinations; Female; Gene Knockdown Techniques; Humans; Immunoblotting; Immunohistochemistry; Male; Mice, Nude; Middle Aged; Mouth Neoplasms; Neoadjuvant Therapy; Neoplasms, Squamous Cell; Oxonic Acid; Tegafur; Xenograft Model Antitumor Assays

The recommended S-1 chemotherapy schedule for head and neck cancer is daily treatment for 4 weeks, followed by 2 weeks of rest. However, this can lead to adverse events and sometimes treatment withdrawal. Alternate-day treatment with a pyrimidine anticancer agent is reported to reduce adverse events without compromising anticancer activity. We examined the indication of alternate-day treatment with S-1 for oral cancer. Fifteen patients(3 men and 12 women; average age: 81.3 years)with oral squamous cell carcinoma started consecutive-day treatment with S-1. Treatment had to be interrupted after 0.5-10 courses because of grade >2 myelosuppression, hepatorenal and electrolyte disorder, and grade 1 digestive toxicity. After a recovery period of 8-168 days from adverse events, alternate-day treatment with S-1 was started. Adverse events on this regimen were grade 2 leucopenia and hyperbilirubinemia in some patients. It was possible for 10 of the patients to continue this treatment for longer than 1 year or until death, but 5 patients could not continue because of a recurrence of a renal or electrolyte disorder, pneumonia, or disease progression. It is thought that alternate-day treatment with S-1 reduces the incidence of adverse events compared to consecutive-day treatment, and can allow continuous administration. Alternateday treatment with S-1 for female patients aged over 80 years with grade 1 leucopenia and/or thrombocytopenia before administration may help to maintain their quality of life.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Risk Factors; Tegafur

Metronomic chemotherapy is based on administration of anticancer agents at low-doses at close regular intervals with no prolonged breaks, and aims to inhibit vascular endothelial cells as well as tumor cells. Recently, it was suggested that metronomic chemotherapy exerts anti-angiogenic effects by inducing thrombospondin-1 (TSP-1) and early growth response-1 (EGR-1), and antitumor effects by suppressing cancer stem cells. S-1 is a novel orally administered anticancer drug that is a combination of tegafur, 5-chloro-2, 4-dihydroxypyridine and oteracil potassium for maintaining efficacious concentrations of 5-FU and reducing the serious gastrointestinal toxicity associated with 5-FU. In the present study, we tried to determine the suitable administration method of S-1 against oral squamous cell carcinoma as a metronomic chemotherapy. We performed in vivo experiments in which tumor-bearing nude mice were used to examine the antitumor activity of S-1 (6.9 mg/kg). HSC2 tumors were treated with three different regimens, given as 4-week treatment and 2-week rest (4W-2W, 1 cycle); 2-week treatment and 1-week rest (2W-1W, 2 cycles); or alternate days treatment (1D-1D, 6 weeks). A fourth group served as control. Antitumor effects and body weight changes were compared in each group. Expression of TSP-1, EGR-1, CD31 and CD44 in HSC2 tumors was examined by immunohistochemistry. The treated groups showed higher tumor growth inhibition compared to the control group, and the relative tumor growth inhibition was not different between the treated groups. Briefly, each relative tumor growth inhibition was 32.4% (4W-2W), 39.6% (2W-1W) and 37.0% (1D-1D). During treatment periods, body weights were lower in the mice with 4W-2W or 2W-1W than 1D-1D or control. Moreover, reduction of microvessel density and CD44 expression, and induction of TSP-1 and EGR-1 expression was markedly seen in 1D-1D-treated tumors compared to 4W-2W-, 2W-1W-treated tumors or untreated control tumors by immunohistochemistry. These findings suggest that the 1D-1D regimen is more useful than the 4W-2W or 2W-1W regimen as a metronomic chemotherapy.

Topics: Administration, Metronomic; Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Carcinoma, Squamous Cell; Cell Line, Tumor; Cell Proliferation; Drug Combinations; Early Growth Response Protein 1; Humans; Mice; Mouth Neoplasms; Neovascularization, Pathologic; Oxonic Acid; Tegafur; Thrombospondin 1; Xenograft Model Antitumor Assays

We retrospectively evaluated the relationship between computed tomography (CT)- and histopathological findings of parotid and submandibular glands in six patients treated for advanced oral cancer. Eligibility criteria were a pathologic diagnosis of oral squamous cell carcinoma, preoperative chemoradiation therapy (CRT) with a total dose of 30 Gy and oral S-1 (80 mg/m²/day), the availability of morphological assessments by CT and of functional assessments with the Saxon test before- and 2 weeks after CRT, and the availability of histopathological slides of irradiated parotid and submandibular glands. In the histopathological interpretation, gland structures were divided into acinar-, duct-, and adipose cells and other tissues. The Mann-Whitney test and the Spearman rank correlation test were used to determine histopathological changes. After 30-Gy irradiation, saliva production and parotid and submandibular volumes were significantly decreased (P < 0.05 each). Histopathological analysis demonstrated that 30-Gy irradiation resulted in a loss of acinar cells although acinar cells in the submandibular gland were relatively retained; the median acinar rate in the parotid and submandibular glands was 1.1% and 19.0%, respectively. The CT values after CRT were inversely correlated with adipose ratios (r = -0.98, P < 0.01) and there was a strong correlation between CT values before and after CRT (r = 0.97, P < 0.01). Our results suggested that acinar cell loss is a main contributor to changes in the volume and function of irradiated human parotid and submandibular glands. The CT value may reflect the adipose ratio rather than salivary function.

Topics: Aged; Antineoplastic Agents; Carcinoma, Squamous Cell; Chemoradiotherapy; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Parotid Gland; Preoperative Period; Retrospective Studies; Salivation; Submandibular Gland; Tegafur; Tomography, X-Ray Computed

We herein present three oldest old patients with advanced oral cancer for whom low-dose S-1 treatment was effective and improved QOL. The first patient is a 90-year-old female with cancer of the maxilla(T4N0Mx). Because of her generally poor condition, her family did not desire radical therapy. S-1(40mg/m2)was administered for 2 weeks followed by a 1-week interval. Because of a partial response without serious side effects, we increased the dose of S-1 to 50mg/m2. The tumor currently shows a tendency toward reduction. The second patient is a 96-year-old female with cancer of the mandible(T4N0Mx). Because of her old age, her family desired palliative therapy. S-1(40mg/m2)was administered for 2 weeks followed by a 1-week interval. A complete response was obtained at the end of the second course. There has been no recurrence. The third patient is a 94-year-old female with cancer of the maxilla(T3N0M0). Her family selected palliative therapy. S-1(50mg/m2)was administered for 2 weeks followed by a 1-week interval. The tumor size decreased after administration of S-1, without serious side effects. However, the tumor increased after the end of the fifth course. Considering the patient's condition, S-1 administration was discontinued at the end of the eighth course. S-1 is considered to be an effective and safe treatment for the maintenance or improvement of the QOL of old and oldest old patients with advanced oral cancer.

Topics: Aged, 80 and over; Antimetabolites, Antineoplastic; Drug Combinations; Female; Humans; Mouth Neoplasms; Oxonic Acid; Tegafur

The purpose of this study was to evaluate the effectiveness and adverse events of combination chemotherapy with oral S-1 administration following docetaxel (DOC) treatment by superselective intra-arterial infusion as neo-adjuvant chemotherapy (NAC) for patients with oral squamous cell carcinoma. Thirteen patients were enrolled in this study (9 men and 4 women, with a mean age of 61. 0 years). All patients were given S-1 65mg/m(2) per day for 14 days, and DOC 40-50mg/m(2) by intraarterial infusion was administered. The locoregional response evaluated 3 weeks after administration was 100%, including a 69. 2% complete response. According to Oboshi and Shimosato's classification, histological evaluation of surgical specimens revealed that 3 cases were Grade II a, 4 cases Grade II b, 1 case Grade IV a, and 4 cases Grade IV c. The severe side effects were neutropenia and cerebral infarction. The present study suggests that combination chemotherapy with S-1 and DOC by superselective intra-arterial infusion would be an effective and safe regimen in NAC for oral squamous cell carcinomas.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cerebral Infarction; Docetaxel; Drug Combinations; Female; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Neutropenia; Oxonic Acid; Taxoids; Tegafur

S-1 is a newly developed oral fluoropyrimidine derivative that is now widely used as a chemotherapeutic agent in the treatment of various carcinomas. This study was performed to assess the efficacy and safety profile of the combination of S-1 and cisplatin(S-1/CDDP)in patients with oral cancer as neo-adjuvant chemotherapy. We reviewed our experience of 12 patients diagnosed with oral carcinoma, who were treated with S-1/CDDP. S-1 was administered orally at a dose of 50mg twice a day for 21 consecutive days, followed by a 14-day rest period. CDDP(60mg/m2)in 500 mL physiological saline was administered by intravenous drip as a 120-min infusion on day 8, together with standard premedications and hydration. Seven partial responders were obtained. The median follow-up duration was 54. 8 months, and all patients were alive excluding one case. This regimen was well tolerated, with only one case of grade 3 thrombocytopenia, and no grade 4 patient. No treatment-related death was observed. Moreover, we evaluated immunohistochemical expressions of thymidylate synthase (TS), dihydropyrimidine dehydrogenase(DPD), and orotate phosphoribosyl transferase(OPRT)which are associated with chemosensitivity to 5-FU-based therapies. We investigated the relation between the immunohistochemical score and clinicopathological factors, however we could not clarify the relationship between the efficacy of chemotherapy and results of immunohistochemistry.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Biopsy; Cisplatin; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Female; Humans; Immunohistochemistry; Male; Middle Aged; Mouth Neoplasms; Neoadjuvant Therapy; Orotate Phosphoribosyltransferase; Oxonic Acid; Tegafur; Thymidylate Synthase

The purpose of this study was to investigate the effectiveness and safety of palliative chemotherapy using S-1 alone. We clinically analyzed 8 oral squamous cell carcinoma patients showing a complete response(CR)to chemotherapy with S-1 alone. These patients received chemotherapy consisting of 2 weeks' administration, including 5-days' administration and 2- days' termination, following a 1-week rest. Adverse effects were observed in 4 patients. However, all of them were grade 1 toxicities. The average length of S-1 administration before achieving CR was 9. 8 ± 3. 1 weeks(3. 3 ± 1. 0 courses). Seven patients had a recurrence. The prognosis of this group was 5 deaths by local recurrence, and 1 death by lymph node metastasis. The average length of disease progression was 447. 4 ± 479. 5 days. Two patients, one who received surgery and the other who received irradiation after chemotherapy by S-1, are alive without tumors. The 1-year and 3-year disease-free survival rates were 100% and 37. 5%, respectively.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Recurrence; Survival Rate; Tegafur

Combination therapy with S-1, superselective intra-arterial infusion of CBDCA and radiation therapy has been used to treat patients with oral cancer since 2005. In this study, the histopathological effects and toxicities following concurrent chemoradiotherapy were examined. The subjects consisted of 15 patients (10 men and 5 women) who were treated with S-1 (60-80 mg/day, 4 weeks), superselective intra-arterial infusion of CBDCA (300 mg/body) and radiation therapy (total dose 30-36 Gy) in our department from 2005 to 2009. Nine patients, showed T2 disease, 3 showed T3 disease, and another 3 showed T4 diseases. The primary cancer sites were the tongue (6 cases), buccal mucosa (4 cases), mandible gingival (3 cases), maxillary gingiva (1 case), and the floor of the mouth (1 case). The histopathological effects were evaluated according to Oboshi-Shimosato classification. Grade IV was shown in 10 cases (66. 7%), grade III in 1 case (6. 7%), II bin 3 cases (20. 0%), and II a in 1 case (6. 7%). All patients completed the treatment. The pathological response of the resected tumor was grade IIbor higher in 14 cases (93. 3%). While good histological effects were noted, there was one patient for whom viable tumor cells remained in the central part of the tumor. The present study indicates that further investigation is needed to determine the best dosing and dosing schedule.

Topics: Administration, Oral; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Antineoplastic Combined Chemotherapy Protocols; Carboplatin; Chemoradiotherapy; Drug Combinations; Female; Humans; Infusions, Intra-Arterial; Male; Middle Aged; Mouth Neoplasms; Neoplasm Staging; Oxonic Acid; Tegafur

S-1 is a newly developed oral fluoropyrimidine derivative that is now widely used as a chemotherapeutic agent in the treatment of oral squamous cell carcinoma (SCC). Thymidylate synthase (TS) is the rate-limiting enzyme in the de novo DNA biosynthetic pathway, and improves clinical response to chemotherapy with fluoropyrimidines. We have retrospectively evaluated the predictive value of thymidylate synthase activity in 75 patients with oral SCC with an enzyme-linked immunosorbent assay (ELISA). Mean (SD) activity (pmol/mg) in the specimens was 0.078 (0.080) (median 0.059). The median value was taken as the cut-off value based on which the patients were divided into high and low activity groups. Both the clinical and histopathological responses to chemotherapy and radiochemotherapy were higher in the group with low TS activity. The group with low TS activity also differed significantly in their clinical response to S-1-based chemotherapy (p<0.05). However, there was no significant difference in cause-specific survival. Measurement of TS activity may aid in predicting the clinical response to chemotherapy including S-1 for oral SCC.

Topics: Adult; Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Humans; Kaplan-Meier Estimate; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Prognosis; Retrospective Studies; Statistics, Nonparametric; Tegafur; Thymidylate Synthase

Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Lentinan, beta-(1-->3)-D-glucan, an extract from the edible mushroom, Lentinus edodes, has been reported to show direct antitumor effects and various immunomodulatory effects. S-1 is an oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence, combined treatment of cancer cells with Lentinan and S-1 might exert dramatic antitumor effects on OSCC cells. In this study, the response of human OSCC cells to Lentinan alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (6.9 mg/kg/day, 7 times/week) was administered orally and Lentinan (0.1 mg/kg/day, 2 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The gene expression level of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD) and orotate phosphoribosyl transferase (OPRT) was determined using microdissection and RT-PCR, and their protein levels were determined using ELISA. Combined therapy of Lentinan and S-1 markedly exerted antitumor effects on human OSCC xenografts and significantly induced apoptotic cells in tumors treated with Lentinan plus S-1. Microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy. These findings demonstrate that the combination of Lentinan and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Combinations; Female; Fluorouracil; Humans; Lentinan; Mice; Mice, Nude; Mouth Neoplasms; Oxonic Acid; Tegafur; Xenograft Model Antitumor Assays

Chemotherapy has shown little antitumor activity against advanced oral squamous cell carcinoma (OSCC) patients. Therefore, there is an urgent need to develop more effective therapeutic methods for patients with advanced OSCC. Cepharanthine is a biscoclaurine alkaloid extracted from Stephania cepharantha Hayata, which is widely used for the treatment of many acute and chronic diseases, and can exert antitumor effects on several human cancer cells. S-1 is a new oral antineoplastic agent that can induce apoptosis in various types of cancer cells, including OSCC. Hence combined treatment of cancer cells with cepharanthine and S-1 might exert dramatic antitumor effects on OSCC cells.. In this study, the response of human OSCC cells to cepharanthine alone and in combination with S-1 was examined using nude mouse xenograft models. S-1 (10 mg/kg/day, 5 times/week) was administered orally and cepharanthine (20 mg/kg, 5 times/week) was injected into peritumoral tissue for three weeks. Apoptotic cells were detected by a TUNEL method. The protein expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), and orotate phosphoribosyl transferase (OPRT) were assessed using immunohistochemistry; their gene expression was determined using microdissection and RT-PCR, and their protein levels using ELISA.. Combined therapy of cepharanthine and S-1 exerted antitumor effects on human OSCC xenografts markedly and significantly induced apoptotic cells in tumors treated with cepharanthine plus S-1. Immunohistochemistry showed that the expressions of TS and DPD were down-regulated, and that OPRT expression was up-regulated in tumors treated with cepharanthine plus S-1. In the same way, microdissection and RT-PCR revealed that the expression of TS and DPD mRNA was down-regulated and that expression of OPRT mRNA was up-regulated in tumors administered the combined treatment. Moreover, ELISA indicated that the protein levels of TS and DPD were down-regulated, and that OPRT was up-regulated in tumors treated with the combined therapy. During the experimental period, no loss of body weight was observed in mice treated with the combined therapy.. These findings demonstrate that the combination of cepharanthine and S-1 is effective against OSCC and has the potential of being a new therapeutic tool for future treatment of these tumors.

Topics: Animals; Antineoplastic Combined Chemotherapy Protocols; Apoptosis; Benzylisoquinolines; Blotting, Western; Carcinoma, Squamous Cell; Cell Proliferation; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Enzyme-Linked Immunosorbent Assay; Female; Humans; Immunoenzyme Techniques; In Situ Nick-End Labeling; Male; Mice; Mice, Nude; Mouth Neoplasms; Orotate Phosphoribosyltransferase; Oxonic Acid; Tegafur; Thymidylate Synthase; Tumor Cells, Cultured; Xenograft Model Antitumor Assays

S-1, an oral fluorouracil antitumor drug, is composed of three agents: tegafur (FT), 5-chloro-2,4-dihydroxypyridine (CDHP), and potassium oxonate (Oxo). Approximately 50% of oral squamous cell carcinomas (OSCC) exhibit cervical lymph node metastasis. The extent of lymph node involvement is a major determinant in both staging and prognosis of the majority of OSCC. The purpose of this study was to examine the effect of S-1 on the metastatic potential of OSCC cells. We used orthotopic green fluorescence protein (GFP) SAS-L1, in BALB/c nu/nu mice. Mice received oral doses of either 5% hydroxypropylmethylcellulose (HPMC) for control or S-1 (20 mg/kg) and were autopsied at 2 weeks. We also performed in vitro experiments using concomitant 5-fluorouracil (5-FU) and CDHP as a drug model of S-1 to determine the effect of S-1 on OSCC invasion and metastasis. Although 100% (11 of 11) of mice not treated with S-1 showed cervical lymph node metastasis, only 54.4% (6 of 11) of S-1 treated mice demonstrated metastasis. In in vitro experiments, OSCC cells treated with 5-FU and CDHP showed a marked reduction in invasiveness and in adhesion to laminin coated plates. Western blot analysis revealed that treatment with 5-FU and CDHP suppressed expression of integrins alphav, alpha3, alpha6, beta1, beta3, beta4, beta5, and beta6. These results suggest that S-1 inhibits tumor proliferation and lymph node metastasis in OSCC cells. Moreover, expression of integrin subunits and the integrin signal transduction pathway may be closely related to metastasis suppression.

Topics: Animals; Antimetabolites, Antineoplastic; Blotting, Western; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Combinations; Gene Expression; Green Fluorescent Proteins; Humans; Integrins; Lymphatic Metastasis; Mice; Mice, Nude; Mouth Neoplasms; Oxonic Acid; Signal Transduction; Tegafur; Xenograft Model Antitumor Assays

We report two cases of giant metastatic cervical lymphnode from oral squamous cell carcinoma, successfully treated with concurrent chemoradiotherapy with S-1. Case 1 was a 80-year-old male who had an ipsilateral occult neck metastasis(52x46 mm mass)at level IV after surgery of the left tongue carcinoma(T2N0M0). Radiotherapy(2.0 Gy/day; 5 days/week)was given at a total dose of 66 Gy. Two courses of oral administration of S-1(61 mg/m2/day)for 2 weeks followed by 1-week rest period as one course was repeated with the concurrent radiotherapy. After the radiotherapy, the oral administration of S-1 alone was continued for 1 year under the same regimen. Case 2 was a 51-year-old male who had left tongue carcinoma(T4bN2cM0)with ipsilateral cervical lymphnode metastasis(88x44 mm mass). The same chemoradiotherapy(1.8 Gy/day; 5 days/week; a total dose of 63 Gy; S-1 53 mg/m2/day)was carried out as in case 1. These giant metastatic lymphnodes of case 1 and 2 disappeared by 3 and 6 months after radiotherapy, respectively, and achieved a complete response. This therapy may be effective not only for primary lesion of oral cancer, but also metastatic regional lymphnodes in some cases.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Combined Modality Therapy; Drug Combinations; Humans; Lymphatic Metastasis; Male; Middle Aged; Mouth Neoplasms; Neck; Oxonic Acid; Tegafur; Tomography, X-Ray Computed

It has been reported that S-1 can exert antitumor effects on various human cancers including oral squamous cell carcinoma (OSCC). However, little is known about the detailed mechanisms of the antitumor activity of S-1. In the present study, we determined whether S-1 could suppress the angiogenesis and growth of human OSCC cells in vitro and in vivo. The S-1 component (5-FU plus CDHP) significantly suppressed the growth and migration of OSCC cells and BAEC, which inhibited tubule formation in HUVECs in vitro. Also, S-1 inhibited the nuclear factor-kappaB (NF-kappaB) activity in human OSCC cells in vitro. Moreover, S-1 inhibited the expression of survival signal, phosphorylated Akt (p-Akt), and of two major proangiogenic molecules, vascular endothelial growth factor (VEGF) and fibroblast growth factor-2 (FGF-2), in cells implanted into the subcutaneous tissue of nude mice. The decreased expression of p-Akt, VEGF and FGF-2 correlated with decreased tumorigenicity and decreased vascularization of lesions in vivo. These findings suggest that S-1 can suppress the angiogenesis and growth of OSCC cells by inhibiting the expression of p-Akt, VEGF and FGF-2 involved in the blockade of Akt/NF-kappaB pathway.

Topics: Animals; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Cell Line, Tumor; Drug Combinations; Endothelium, Vascular; Fibroblast Growth Factor 2; Gene Expression Regulation, Neoplastic; Humans; Mice; Mice, Nude; Mouth Neoplasms; Neovascularization, Pathologic; NF-kappa B; Oxonic Acid; Phosphorylation; Proto-Oncogene Proteins c-akt; Tegafur; Vascular Endothelial Growth Factor A

The present study evaluated the efficacy and safety of nedaplatin-combination therapy (NDP/5-FU [5-FU arm] or NDP/S-1 [S-1 arm] ) for the treatment of oral squamous cell carcinoma.. Previously non-treated oral squamous cell carcinoma patients were eligible. Patients received 5-FU 600 mg/m(2)iv, as a 24-hour infusion (day 1 to 5) followed by NDP 80 to 100 mg/m(2) iv (day 1), or S-1 60 to 80 mg/m(2) orally twice a day (day 1 to 14) followed by NDP 80 mg/m(2) iv (day 8) every 28 days for one or two cycles.. In total, 32 patients (18 in the 5-FU arm, 14 in the S-1 arm) were enrolled. Twenty patients were male and 12 were female. Median age was 57 years (range 20 years to 87 years). Thirty-one patients had a performance status (PS) oF 0, and 1 patient had a PS 1. Three patients were stage I, 12 stage III, and 12 were stage IV. The overall response rate was 69% (5-FU arm,72%;S-1 arm,64%). Two patients achieved a complete response, 20 patients a partial response, and 10 patients had no change. Grade 3 leucopenia, grade 3 and 4 thrombocytopenia and liver injury occurred in 6% (one in the 5-FU arm, and one in the S-1 arm), 9% (two in the 5-FU arm, and one in the S-1 arm), and 3% (one in the 5-FU arm), respectively. No other severe toxicities were observed.. Response rate and toxicities were similar in both arms. However, the psychosocial stress on patients in the S-1 arm was reduced compared to that in the 5-FU arm, which required hospitalization for a longer period. The outcome in the present study needs further investigation.

Topics: Administration, Oral; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Chemotherapy, Adjuvant; Drug Administration Schedule; Drug Combinations; Fluorouracil; Humans; Infusions, Intravenous; Leukopenia; Male; Middle Aged; Mouth Neoplasms; Nausea; Organoplatinum Compounds; Oxonic Acid; Tegafur; Thrombocytopenia; Vomiting, Anticipatory

The purpose of this study was to investigate the effectiveness and safety of palliative chemotherapy using S-1. We treated 19 advanced oral SCC patients including 8 men and 11 women with S-1. Of the 19 patients studied, two patients were classified as UICC Stage II, two patients as Stage III, 14 patients as Stage IV A, and one patient was classified as StageIV C. The ages varied from 54 to 9 1 years (mean ages; 78.3 years-old). The patients received this chemotherapy (80-120 mg/day) consisting of 2 weeks' administration including 5-days' administration and 2-days' termination (named 'Weekday-on/Weekend-off administration schedule' ) following 1 week rest. After this treatment, 7 CR and 4 PR were achieved, but the toxicities were only anorexia, leukopenia, thrombocytopenia, and uritication of NCI-CTC grade 1. The prognosis of 19 cases was 7 terminal by primary disease, 3 terminal by other disease, 7 lives with tumor bearing, and 2 lives without tumor bearing. We concluded that our novel S-1 administration method was extremely effective for oral SCC, including lymph node metastasis, providing high potential without any severe adverse effects for palliative therapy.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Oxonic Acid; Palliative Care; Tegafur

A 68-year-old patient with advanced oral squamous cell carcinoma (T3N2bM0, Stage IVA) was treated by concurrent radiotherapy with S-1.S-1 (120 mg/body/day) was orally administered for 4 weeks followed by a 2-week rest period as one course, and radiation was given (1.8 Gy/day; 5 days/week) for a total of 61.2 Gy. After 61.2 Gy radiation and two courses of S-1, the primary region showed a complete response (CR), and that the tumor cell was not identified as a result of biopsy. In addition, the metastatic lymph nodes in the neck were no longer seen on head and neck computed tomography (CT). Although the patient is still taking UFT, he is well with no signs of recurrence 27 months from the initial treatment.

Topics: Aged; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Administration Schedule; Drug Combinations; Humans; Lymph Nodes; Lymphatic Metastasis; Male; Mouth Neoplasms; Oxonic Acid; Radiotherapy Dosage; Remission Induction; Tegafur

A 76-year-old patient with oral squamous cell carcinoma was treated by chemotherapy with S-1. S-1 (100 mg/body/day) was orally administered for 4 weeks followed by a 2-week rest period as one course. The primary lesion markedly decreased at 7 days after the beginning of S-1 treatment, and disappeared after one course of S-1. After two courses, the primary lesion was assessed to show a complete response (CR),and no tumor cells were identified as a result of biopsy. In addition, the value of tumor marker SCC decreased from 2.13 ng/mL before treatment to 0.68 ng/mL after two courses of S-1. Although the patient is still taking UFT, she is well with no signs of recurrence 50 months from the initial treatment.

Topics: Administration, Oral; Aged; Antigens, Neoplasm; Antimetabolites, Antineoplastic; Biomarkers, Tumor; Carcinoma, Squamous Cell; Drug Combinations; Female; Humans; Mouth Neoplasms; Oxonic Acid; Serpins; Tegafur; Treatment Outcome

In the present study, we examined the appropriate schedule of S-1 medication in the combination with radiation by investigating the safety, the clinical efficacy, and antitumor effects on tumors in nude mice. In the patients with oral squamous cell carcinoma (OSCC), S-1 was given orally according to a 4-week application followed by 2-week rest regimen (4-week regimen), or a 2-week application followed by a 1-week rest regimen (2-week regimen). Radiation was given (2 Gy/day; 5 days/week) for a total of 60 Gy. In nude mouse models, human oral cancer cell lines were used as subcutaneous xenografts in nude mice. The mice were treated by S-1 (10 mg/kg) and radiation (1 Gy) with a 4-week regimen or a 2-week regimen. Apoptotic cells were detected by TUNEL method. In the patients with OSCC, the response rate with the 4-week regimen was 100% and the response rate with the 2-week regimen was 92.3%. However, a high frequency of adverse effect was found in the 4-week regimen when compared to the 2-week regimen. Grade 3 toxicity of leukopenia, neutropenia and stomatitis were seen in 3 cases, grade 3 toxicity of anorexia and nausea were seen in 2 cases, and grade 3 toxicity of decrease of hemoglobin level, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 4-week regimen. On the other hand, grade 3 toxicity of stomatitis, anorexia, nausea, heartburn/dyspepsia and increase of bilirubin level were seen in a case of the 2-week regimen. In nude mouse models, the 2-week regimen was more effective than the 4-week regimen. In addition, significant increase in the percentage of apoptotic cells was observed in the tumors treated with the 4-week regimen when compared with the tumors treated with the 2-week regimen. No loss of body weight was observed in mice treated with the 2-week regimen during the experimental period. These results suggested that the 2-week regimen might reduce adverse effects, and enhance therapeutic effects compared to the 4-week regimen. Briefly, this 2-week regimen may be a useful concurrent chemo-radiotherapy improving the quality of life (QOL) of patients with OSCC.

Topics: Aged; Animals; Antimetabolites, Antineoplastic; Apoptosis; Carcinoma, Squamous Cell; Combined Modality Therapy; Drug Combinations; Female; Humans; In Situ Nick-End Labeling; Male; Maximum Tolerated Dose; Mice; Mice, Nude; Middle Aged; Mouth Neoplasms; Oxonic Acid; Radiotherapy Dosage; Tegafur; Tumor Cells, Cultured

The purpose of this study was to evaluate the effectiveness and adverse events of combination chemotherapy with S-1 and docetaxel (DOC) as neo-adjuvant chemotherapy (NAC) for patients with oral squamous cell carcinomas. Fifteen patients were enrolled in this study (11 men and 4 women, with a mean age of 65.9 years). All patients given S-1 80 mg/body per day for 14 days and following were administered a dose of DOC 60 mg/m(2) by drip infusion for 120 minutes. The locoregional response was evaluated 3 weeks after the administration. As a result, the locoregional response rate was 60.0%, including 46.7% complete response. According to Oboshi and Shimosato's classification, histological evaluation of surgical specimens revealed that 3 cases were Grade I , 3 cases Grade IIa, 4 cases Grade IIb, 1 case Grade III, 3 cases Grade IVb, and 1 case Grade IVc. The severe side effect was neutropenia. The present study suggests that combination chemotherapy with S-1 and DOC is an effective and safe regimen in NAC for oral squamous cell carcinomas.

Topics: Aged; Antimetabolites, Antineoplastic; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Docetaxel; Drug Combinations; Female; Humans; Infusions, Intravenous; Male; Middle Aged; Mouth Neoplasms; Neoadjuvant Therapy; Oxonic Acid; Taxoids; Tegafur

The purpose of this research was to evaluate the predictive value of expression of thymidylate synthase (TS), dihydropyrimidine dehydrogenase (DPD), thymidine phosphorylase (TP), or orotate phosphoribosyltransferase (OPRT) genes for response to S-1. Twenty-five patients with oral squamous cell carcinoma (OSCC) received S-1 80 mg/m2/day. Pretreatment tumor biopsies were analyzed for TS, DPD, TP or OPRT mRNA expression by real-time reverse transcription-PCR. TS protein expression was evaluated by immunohistochemistry using a polyclonal TS antibody. Twenty-five patients were evaluable for response and gene expression. Six of the 25 (24%) achieved complete remission and 4 of the 25 (16%) had a partial response. Median TS/beta-actin was 2.51 (range 0.98-7.07). Median TS/beta-actin was 1.26 in responding patients and 3.43 in non-responders (P=0.0001). Ten of 11 patients with TS/beta-actin <1.80 and 0 of 15 with higher values responded (P<0.0001). Overall survival was 29.7 months in patients with TS/beta-actin <1.80 and 41.7 months in patients with higher values (P=0.0013). No correlations were seen between expression of DPD, TP or OPRT mRNA and response or survival. Weak TS staining was seen in 6 of 25 tumors evaluable for immunohistochemistry, including 5 responders. All 4 of the patients with both weak staining and TS/beta-actin <1.80 responded. High TS mRNA expression predicts non-response to S-1. On the other hand, high levels of DPD or TP mRNA and low levels of OPRT mRNA are not associated with S-1 resistance. TS mRNA expression is considered to be a useful prognostic factor in OSCC patients with S-1 single-agent therapy.

Topics: Adult; Aged; Aged, 80 and over; Carcinoma, Squamous Cell; Dihydrouracil Dehydrogenase (NADP); Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Multienzyme Complexes; Orotate Phosphoribosyltransferase; Orotidine-5'-Phosphate Decarboxylase; Oxonic Acid; RNA, Messenger; Tegafur; Thymidine Phosphorylase; Thymidylate Synthase

We investigated the histological response and toxicities of combination chemotherapy with TS-1 and low-dose CDDP, and evaluated the usefulness of this regimen as a preoperative chemotherapy. Fourteen patients were enrolled in this study (two men and 12 women, with a mean age of 54.5 years). Patients were administered TS-1 80 mg/m2/day (days 1-14) and CDDP 5 mg/m2/day (days 1-5, 8-12) and followed by radical surgery or biopsy within 2 weeks. Ten patients completed 1 cycle of chemotherapy, two received 0.5 cycle and two others 1.5 cycle. The histological antitumor effects were evaluated with Ohboshi & Shimosato's classification using surgical or biopsy specimens of primary tumors. The response rate was 64.3% in clinical evaluation and 50.0% in histological evaluation. The number of patients who showed CR were 7/14 (50.0%) and 5/14 (35.7%) by histological and clinical evaluation, respectively. Two patients showed grade 3 neutropenia. Almost all patients revealed no or mild toxicities. TS-1 with low-dose CDDP represents a highly effective antitumor activity and mild toxicities. Especially, the CR rate was very high. These data suggested that this regimen was useful to avoid surgery or to realize minimal surgery for oral squamous cell carcinoma patients.

Topics: Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoma, Squamous Cell; Cisplatin; Drug Administration Schedule; Drug Combinations; Female; Humans; Male; Middle Aged; Mouth Neoplasms; Neutropenia; Oxonic Acid; Pyridines; Tegafur

To examine the effect of an oral fluoropyrimidine anti-cancer agent (S-1) on the radiosensitivity of a human oral cancer cell line with focusing on inhibition of survival signal, Akt/PKB. A human oral cell cancer cell line B88 was used. Activation of Akt/PKB in vivo was examined by immunohistochemistry, and apoptotic cells were detected by TUNEL method. Activation of Akt/PKB in vitro was investigated by Western blot and ELISA, and apoptotic cells were detected by Hoechst 33258 staining. S-1 (10 mg/kg/day or 50 microg/ml) greatly enhanced radiosensitivity in B88 cells by suppressing the activation of Akt/PKB. Significant increase in the percentage of apoptotic cells was observed in S-1 treated B88 cells. Survival signals Akt/PKB may be involved in determining radiosensitivity. S-1, an oral fluoropyrimidine anti-cancer agent can exert the enhancing effect on radiation by suppressing the activation of Akt/PKB.

Topics: Animals; Antineoplastic Agents; Apoptosis; Blotting, Western; Drug Combinations; Enzyme Activation; Enzyme-Linked Immunosorbent Assay; Humans; Immunohistochemistry; In Situ Nick-End Labeling; In Vitro Techniques; Male; Mice; Mice, Nude; Mouth Neoplasms; Oxonic Acid; Protein Serine-Threonine Kinases; Proto-Oncogene Proteins; Proto-Oncogene Proteins c-akt; Pyridines; Radiation-Sensitizing Agents; Tegafur

We report a case of advanced squamous cell carcinoma in the left buccal mucosa, upper gingiva, and maxillary sinus (T4N0M0) showing a complete response to oral chemotherapy with TS-1. The patient was an 89-year-old female with severe dementia. We carried out chemotherapy with TS-1 50 mg/day, without surgical treatment. The tumor disappeared clinically at 4 months after 3 courses of the TS-1 administration. Adverse drug reactions, including vomiting, leukopenia and thrombopenia, forced a stop of the administration of TS-1. Although she finally died of in senescence 2 months from the cease of administration, there was no recurrence of the cancer at the time.

Topics: Aged; Aged, 80 and over; Antimetabolites, Antineoplastic; Carcinoma, Squamous Cell; Drug Administration Schedule; Drug Combinations; Female; Gingival Neoplasms; Humans; Leukopenia; Maxillary Sinus Neoplasms; Mouth Mucosa; Mouth Neoplasms; Neoplasm Invasiveness; Oxonic Acid; Pyridines; Remission Induction; Tegafur; Thrombocytopenia; Vomiting, Anticipatory

We evaluated the orally administered S-1, in combination with ionizing radiation both in vivo and in vitro against human oral cancer cell lines. Human oral cancer cell lines were used as subcutaneous xenografts in nude mice. S-1 (10 mg/kg) was administered orally 1 h before radiation treatments (1.5 Gy), or 1 h after radiation for five consecutive days. Apoptotic cells were detected by TUNEL method. For in vitro analysis, attached cells were treated with S-1 (50 microg/ml) for 1 h and then irradiated (3, 6, 9, 12, 15 Gy), or they were treated with S-1 for 1 h after radiation. Cell survival was determined by clonogenic assay. The combination of S-1 and radiation was more effective than either agent alone. In addition, S-1 administration before radiation was more effective than S-1 administration after radiation. Moreover, the combination of S-1 and radiation could induce apoptosis significantly than either agent alone (P < 0.01). In vitro clonogenic survival experiments demonstrated the dose enhancement ratio of 1.22 (radiation + S-1), 1.45 (S-1 + radiation) in B88 cells, and 1.16 (radiation + S-1), 1.28 (S-1 + radiation) in HSG cells. These data demonstrate that the combination of S-1 and fractionated radiotherapy is more effective against human oral cancer xenografts than either agent alone, and that S-1 administration before radiation is more effective than after radiation, suggesting a potential clinical applicability of combination treatment of S-1 and radiation in oral cancer therapies.

Topics: Animals; Antimetabolites, Antineoplastic; Apoptosis; Carcinoma, Squamous Cell; Cell Survival; Combined Modality Therapy; Drug Combinations; Humans; In Situ Nick-End Labeling; Male; Mice; Mice, Inbred BALB C; Mice, Nude; Mouth Neoplasms; Neoplasm Transplantation; Oxonic Acid; Pyridines; Tegafur; Transplantation, Heterologous; Tumor Cells, Cultured; Tumor Stem Cell Assay