s-1-(combination) and doxifluridine

In Japan, the history of postoperative chemotherapy for breast cancer started with 5-fluorouracil (5-FU), launched in the 1980s. Currently, oral fluoropyrimidine-based regimens indicated for the treatment of breast cancer in Japan include tegafur plus uracil (UFT); tegafur, gimeracil, and oteracil (TS-1); doxifluridine; and capecitabine. In particular, UFT represents an important option for long-term treatment because of minimal adverse events and the potential for long-term maintenance of effective plasma concentrations of 5-FU to inhibit micrometastasis after surgery. Therefore, various clinical studies of postoperative adjuvant chemotherapy with UFT have been conducted in patients with completely resected tumors. Recent studies have shown that UFT prolongs survival after tumor resection in patients with gastric cancer, colorectal cancer, and lung cancer. In patients with breast cancer, large clinical trials of UFT-based postoperative chemotherapy conducted in Japan have shown that UFT is useful for the treatment of intermediate-risk patients with no lymph node metastasis. This paper reviews the results of clinical studies of UFT conducted in Japan to assess the therapeutic usefulness of this oral 5-FU. The types of patients most likely to benefit from UFT are discussed on the basis of currently available evidence and a global consensus of treatment recommendations. The optimal timing of endocrine therapy and strategies for postoperative adjuvant chemotherapy with UFT in patients with breast cancer are also discussed.

Topics: Administration, Oral; Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Chemotherapy, Adjuvant; Cisplatin; Clinical Trials as Topic; Deoxycytidine; Drug Combinations; Female; Floxuridine; Fluorouracil; Humans; Japan; Methotrexate; Oxonic Acid; Tegafur; Uracil

5-FU has been a key chemotherapeutic agent in the treatment of advanced or recurrent gastric cancer. In order to enhance the effect of 5-FU, biochemical modulation or combination chemotherapy has been developed. Although several phase III studies were reported in the 1990s, a standard chemotherapeutic regimen has not been established worldwide. Recently, a newly developed anticancer agent, Paclitaxel, can be clinically used for advanced gastric cancer either as a single agent or in combination with such as 5-FU, cisplatin, and TS-1. It may well further improve the quality of life and prolong the survival of patients with gastric cancer. Further assessment for the well design phase III clinical trials will be necessary to establish the availability of such combination modalities for the treatment of advanced, recurrent gastric cancer.

Topics: Antineoplastic Combined Chemotherapy Protocols; Cisplatin; Drug Administration Schedule; Drug Combinations; Floxuridine; Fluorouracil; Humans; Oxonic Acid; Paclitaxel; Pyridines; Quality of Life; Stomach Neoplasms; Tegafur

5-FU has been very valuable as an anticancer agent since it was first developed by Heidelberger in 1957. For over 40 years it has been used either by itself or in combination therapy for the treatment of patients with all types of malignant tumors. To date, no better anticancer agent has been developed for the treatment of patients with gastrointestinal tract cancer. During administration, consideration for a combined regimen from the standpoints of dose intensity, schedule dependency, and biochemical modulation can improve the antitumor effectiveness of 5-FU. It has been found to be most effective if administered by long term (if possible, 4 weeks or more) intravenous or intraarterial continuous drip infusion. However, there are also negative aspects. The dose-limiting toxicity with drip infusions brings about gastrointestinal disorders such as stomatitis and diarrhea. Furthermore, the possibility of trouble and difficulty in managing a catheter kept in the body over long periods not only greatly reduces the patient's QOL, it is also very inconvenient for the patient and increases medical costs. Since the development of oral FT by Kimura, however, many 5-FU prodrugs and masked compounds have been developed in Japan. The aim has been to see how far the concentration of 5-FU in the blood and cancer tissues could be raised. UFT, 5'-DFUR, and HCFU have been developed as derivatives of 5-FU, and these are widely used clinically either alone or in combination therapy. With the aim of further improving antitumor effectiveness and reducing side effects, these compounds have been improved from the viewpoints of pharmacodynamics and pharmalokinetics, based on biochemical modulation, to create S-1 and Capecitabine. Although these are still currently undergoing clinical trials, sufficient results have already been obtained. Cisplatin and CPT-11 are effective for use in the gastrointestinal tract, and much work is going on now to allow these to be taken orally. Future prospects indeed look bright.

Topics: Administration, Oral; Antimetabolites, Antineoplastic; Antineoplastic Agents; Camptothecin; Drug Combinations; Floxuridine; Fluorouracil; Gastrointestinal Neoplasms; Humans; Irinotecan; Organoplatinum Compounds; Oxonic Acid; Prodrugs; Pyridines; Tegafur; Uracil

A pre-clinical study demonstrated that paclitaxel induced thymidine phosphorylase in the tumor tissues. The combination of paclitaxel and doxifluridine is expected to exert extra anti-tumor effects. We evaluated the efficacy of this combination in patients with unresectable or recurrent gastric cancer who had been previously treated with S-1.. Registration was started to enroll 35 patients with advanced/recurrent gastric cancer, who were selected among those with measurable lesions fitting to response evaluation criteria in solid tumors, and with resistant to S-1 treatment. This regimen is consisted of paclitaxel, 80 mg/m(2), iv on days 1 and 8; and doxifluridine, 600 mg/m(2), po on days 1-14. The treatment was repeated every three weeks. Primary endpoint was response rate (RR); and secondary endpoints were overall survival (OS), progression free survival (PFS) and onset rate of adverse events.. From September 2003 to March 2005, 35 patients were registered: including 28 men; 7 women; median age of 66 years (range, 49-75 years); and performance status (PS) levels were, zero with 21 and one with 14 patients. In 33 eligible patients, except two, clinical usefulness was evaluated resulting in RR of 18.2% (partial response, 6; stable disease, 15; progressive disease, 10; and not evaluable, 2 patients). Median survival time was 321 days and median PFS was 119 days. Severe adverse events were found in three patients to discontinue the present treatment.. The combination of paclitaxel and doxifluridine might be a treatment of choice as a second line chemotherapy for patient undergone S-1 treatment.

Topics: Adenocarcinoma; Aged; Anemia; Anorexia; Antineoplastic Combined Chemotherapy Protocols; Disease-Free Survival; Drug Combinations; Drug Resistance, Neoplasm; Female; Floxuridine; Humans; Liver Neoplasms; Lung Neoplasms; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Recurrence, Local; Neutropenia; Oxonic Acid; Paclitaxel; Peritoneal Neoplasms; Stomach Neoplasms; Survival Rate; Tegafur; Thrombocytopenia

This study was conducted to propose the optimal duration of fluoropyrimidine-based adjuvant chemotherapy consisting of fluoropyrimidine derivatives alone or combined with intravenous platinum for stage II or III gastric cancer (GC).. We analyzed retrospectively the data from 2219 patients with histologically confirmed adenocarcinoma in the stomach, who underwent a curative gastrectomy with lymphadenectomy from 2005 to 2012. Five-year overall survival (OS) and 3-year relapse-free survival (RFS) were analyzed according to the duration of fluoropyrimidine-based adjuvant chemotherapy.. Data from 617 patients with stage II or III GC were analyzable; 187 patients (30.3%) were treated with surgery alone, while 430 patients (69.7%) were treated with postoperative adjuvant chemotherapy. The duration of adjuvant chemotherapy was less than 6 months [group 1] in 147 patients (34.2%), 6 months to less than 12 months [group 2] in 94 patients (21.9%), 1 year to less than 2 years [group 3] in 139 patients (32.3%), and over 2 years [group 4] in 50 patients (11.6%). The 5-year OS in groups 1, 2, 3, and 4 was 75.7, 87, 90.3, and 93.4%, respectively, while 3-year RFS was 52.5, 58.8, 81.4, and 94.0%, respectively.. In this retrospective study, we did not demonstrate any significant improvement in OS and RFS by longer periods of fluoropyrimidine-based adjuvant chemotherapy in stage II or III GCs. Further prospective randomized studies are needed.

Topics: Adenocarcinoma; Adult; Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Capecitabine; Chemotherapy, Adjuvant; Cisplatin; Drug Combinations; Female; Floxuridine; Follow-Up Studies; Humans; Lymphatic Metastasis; Male; Middle Aged; Neoplasm Invasiveness; Neoplasm Staging; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prognosis; Retrospective Studies; Stomach Neoplasms; Survival Rate; Tegafur; Time Factors; Uracil

There is no standard second-line treatment for patients with unresectable advanced or recurrent gastric cancer (URGC) in the event that first-line treatment fails. Moreover, the benefits of second-line chemotherapy in elderly patients remain uncertain. The aim of this study was to identify the benefits of the second-line paclitaxel (PTX) plus doxifluridine (5'-DFUR) regimen for URGC in elderly patients in comparison to nonelderly patients.. We retrospectively examined the clinical outcomes of the second-line PTX plus 5'-DFUR regimen in patients with URGC, who had previously been treated with S-1-based first-line chemotherapy.. A total of 27 patients (10 elderly, ≥70 years old; 17 nonelderly, <70 years old) were enrolled in the study. The clinical benefit rate (complete response, partial response, and stable disease) in the elderly group was 6 of 10 (60%), and that of the nonelderly group was 9 of 17 (53%). Age had no statistically significant influence on the response rate, and no grade 4 adverse events were observed in either group. In addition, the median survival time was 12.2 months in both groups.. Although it remains unclear whether second-line chemotherapy contributes to survival in patients with URGC, the combination of PTX plus 5'-DFUR might be the treatment of choice for second-line chemotherapy in both elderly and nonelderly patients who have already received an S-1-based first-line treatment.

Topics: Aged; Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Female; Floxuridine; Humans; Male; Neoplasm Recurrence, Local; Oxonic Acid; Paclitaxel; Retrospective Studies; Stomach Neoplasms; Tegafur

The goal of this study is to evaluate the effectiveness of S-1/Oxaliplatin vs. Doxifluridine/Oxaliplatin regimen and to identify miRNAs as potential prognostic biomarkers in gastric cancer patients. The expression of candidate miRNAs was quantified from fifty-five late stage gastric cancer FFPE specimens.. Gastric cancer patients with KPS>70 were recruited for the trial. The control group was treated with 400 mg/twice/day Doxifluridine plus i.v. with Oxaliplatin at 130 mg/m(2)/first day/4 week cycle. The testing group was treated with S-1 at 40 mg/twice/day/4 week cycle plus i.v. with Oxaliplatin at 130 mg/m(2)/first day/4 week cycle. Total RNAs were extracted from normal and gastric tumor specimens. The levels of miRNAs were quantified using real time qRT-PCR expression analysis.. The overall objective response rate (CR+PR) of patients treated with S-1/Oxaliplatin was 33.3% (CR+PR) vs. 17.6% (CR+PR) with Doxifluridine/Oxaliplatin for advanced stage gastric cancer patients. The average overall survival for patients treated with S-1/Oxaliplatin was 7.80 month vs. 7.30 month with patients treated with Doxifluridine/Oxaliplatin. The expression of miR-181b (P = 0.022) and miR-21 (P = 0.0029) was significantly overexpressed in gastric tumors compared to normal gastric tissues. Kaplan-Meier survival analysis revealed that low levels of miR-21 expression (Log rank test, hazard ratio: 0.17, CI = 0.06-0.45; P = 0.0004) and miR-181b (Log rank test, hazard ratio: 0.37, CI = 0.16-0.87; P = 0.018) are closely associated with better patient's overall survival for both S-1 and Doxifluridine based regimens.. Patients treated with S-1/Oxaliplatin had a better response than those treated with Doxifluridine/Oxaliplatin. miR-21 and miR-181b hold great potential as prognostic biomarkers in late stage gastric cancer.

Topics: Antineoplastic Agents; Antineoplastic Combined Chemotherapy Protocols; Drug Combinations; Female; Floxuridine; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Humans; Kaplan-Meier Estimate; Male; MicroRNAs; Middle Aged; Organoplatinum Compounds; Oxaliplatin; Oxonic Acid; Prognosis; Stomach Neoplasms; Tegafur; Treatment Outcome

A 82-year-old man with advanced gastric cancer underwent distal gastrectomy in January 2006. The histological diagnosis was poorly-differentiated adenocarcinoma, T2(MP), pN2, sH0, sP0, CY0; fStage III A. Three months after the operation, two metastatic nodules were noticed on the liver. The patient was treated with S-1 in April 2006. After the 8 courses of S-1 treatment, a complete response was achieved. However, a lymph node metastasis was newly found adjacent to the remnant stomach 2 months after the complete response to S-1. 5'-DFUR+paclitaxel combination therapy was then performed. After the 2 courses, the metastatic lymph node completely disappeared. We continued a total of 18 courses of the 5'-DFUR+paclitaxel therapy approximately for 1 year without critical drug toxicity. The patient has been alive without any recurrent site. Thus 5'-DFUR+paclitaxel as a second-line therapy following S-1 should be recommended for a gastric cancer patient with a recurrent tumor.

Topics: Aged, 80 and over; Antineoplastic Combined Chemotherapy Protocols; Carcinoembryonic Antigen; Drug Combinations; Floxuridine; Humans; Liver Neoplasms; Lymphatic Metastasis; Male; Oxonic Acid; Paclitaxel; Remission Induction; Stomach Neoplasms; Tegafur; Tomography, X-Ray Computed

A 77-year-old male patient who had been receiving doxifluridine (5'-DFUR) for about a year after surgery for rectal cancer, was newly prescribed TS-1, because tumor markers were elevated and abdominal ultrasonography documented liver metastasis. However, the patient took TS-1 concomitantly with 5'-DFUR, which is contraindicated to TS-1, and experienced a severe drug interaction. This inadvertent drug interaction was caused by a combination of the newly prescribed drug and the unused drug remaining at the patient's home. This type of medication error has not been reported previously. Health professionals should be aware of such drug interactions which may be caused by newly prescribed drugs plus unused drugs remaining in the patient's home. Furthermore, health professionals should instruct patients on the nature of drug interactions as well as explaining their diagnosis and treatment. Although the severity of such drug interaction may vary, health professionals must be alerted to such incidents, which could happen frequently.

Topics: Aged; Contraindications; Drug Combinations; Floxuridine; Humans; Male; Medication Errors; Oxonic Acid; Rectal Neoplasms; Self Medication; Tegafur

High-dose toremifene therapy (120 mg/day) is useful for the recurrence of receptor-positive breast cancer. However, some reports show that combination therapy of high-dose toremifene and chemotherapy exhibits additive effects. Twelve patients were given oral chemotherapy (capecitabine, 5'-DFUR+CPA, S-1) with high-dose toremifene. The overall response rate was 41.7%, in addition to 58.3% with no change beyond three months. Adverse events were restricted to headache, stomatitis and nausea. Average time to progressive (TTP) was 5.8 months. It was shown that high-dose toremifene and oral chemotherapy were useful for breast cancer recurrence without severe side effects.

Topics: Administration, Oral; Antineoplastic Combined Chemotherapy Protocols; Breast Neoplasms; Capecitabine; Cyclophosphamide; Deoxycytidine; Dose-Response Relationship, Drug; Drug Administration Schedule; Drug Combinations; Female; Floxuridine; Fluorouracil; Humans; Liver Neoplasms; Lung Neoplasms; Lymph Nodes; Lymphatic Metastasis; Middle Aged; Neoplasm Recurrence, Local; Oxonic Acid; Quality of Life; Skin Neoplasms; Tegafur; Toremifene

A 74-year-old man was revealed to have type 3 gastric cancer with synchronous multiple liver metastases. Despite treatment with TS-1 (120 mg/body), an increase in tumor size was demonstrated by computer tomography and endoscopy. We tried a course of a combination chemotherapy consisting of paclitaxel (PTX) plus doxifluridine (5'-DFUR ) to reduce the tumor. 5'-DFUR (600 mg/m(2)) was administered day 1 to 14 followed by 7 days'rest as one course. PTX (80 mg/m(2)) was infused on days 1 and 8. After 5 courses, the tumor markers decreased markedly, and computer tomography and endoscopy revealed remarkable tumor reduction which was thought to show a partial response. After 13 courses we discontinued this chemotherapy, so increase of the tumor marker was remarkable. This case suggests that PTX/5'-DFUR protocol is effective for clinical management of gastric cancer resistant to TS-1.

Topics: Adenocarcinoma; Aged; Antineoplastic Combined Chemotherapy Protocols; Camptothecin; Drug Administration Schedule; Drug Combinations; Drug Resistance, Neoplasm; Floxuridine; Humans; Irinotecan; Liver Neoplasms; Male; Oxonic Acid; Paclitaxel; Pyridines; Stomach Neoplasms; Tegafur

In advanced gastric cancer, the frequency of relapses such as metastasis to the peritoneum is high. For this reason, prognostic and treatment methods were studied. In 457 cases in which diagnostic cytology was utilized, 36 (61%) of the 59 cases in which dissemination had been macroscopically observed (P 1) were positive. Moreover, 13 cases of P 0 were also positive. The prognosis of the positive cases was worse, but there was not a significant statistical difference between the positive and negative cases. Chemotherapy has become the most common treatment because of the appearance of new anticancer drugs. TS-1 and paclitaxel were repeatedly administered in 10 cases, and the median survival time was 17 months. These drugs were effective even in carcinoma of the peritoneum, and an improvement in the prognosis can be expected. Surgery was performed in 23 cases due to stenosis of the digestive tract, and in 21 cases the patients were able to eat after surgery. The median postoperative survival time was 7 months, and surgery improved the prognosis. The improved sensitivity of diagnostic cytology and the standardization of chemotherapy and surgery warrant further study.

Topics: Aged; Antineoplastic Combined Chemotherapy Protocols; Drug Administration Schedule; Drug Combinations; Female; Floxuridine; Humans; Ileus; Lymphatic Metastasis; Male; Middle Aged; Oxonic Acid; Paclitaxel; Peritoneal Cavity; Peritoneal Lavage; Peritoneal Neoplasms; Predictive Value of Tests; Prognosis; Pyridines; Stomach Neoplasms; Survival Rate; Tegafur

S-1 is an oral fluoropyrimidine reported to be most active for gastric cancer. However, few studies have documented a complete response (CR) of lung metastasis to S-1 treatment. We describe a 66-year-old woman in whom S-1 induced complete regression of lung metastasis from gastric cancer, that had been refractory to another oral fluoropyrimidine, 5'-deoxy-5-fluorouridine (5'-DFUR). After preoperative chemotherapy with a combination of etoposide, adriamycin and cisplatin and with methotrexate plus 5-fluorouracil, the patient underwent a total gastrectomy with lower esophagectomy for advanced diffuse-type gastric cancer with invasion of the esophagus in May 1993. She received postoperative adjuvant chemotherapy with 5'-DFUR (600 mg/day) for 3 years. However, a solitary metastasis to the left lung was detected in November 1996 and she underwent partial resection of the left lung. Chemotherapy with 5'-DFUR was reinitiated after operation, but re-metastasis to the left lung with elevation of the serum carcinoembryonic antigen (CEA) level was diagnosed in June 1999. Treatment with S-1 was started in August. S-1 was given orally in a dose of 100 mg/day for 28 consecutive days, followed by a 14-day recovery; treatment was repeated every 6 weeks. The metastatic lesion in the left lung completely regressed after two courses of S-1 and the serum CEA level returned to the normal range. The patient received a total of 10 courses of S-1. The dose of S-1 was reduced to 80 mg/day from the sixth course because of grade 2 skin rash. Pharmacokinetic studies after administration of S-1 revealed high and prolonged plasma 5-FU levels. Nearly 4 years have passed since complete regression of the lung metastasis. This may be the first report to document a prolonged complete response of lung metastasis from gastric cancer induced by single-agent chemotherapy with S-1.

Topics: Adenocarcinoma, Mucinous; Administration, Oral; Antimetabolites, Antineoplastic; Chemotherapy, Adjuvant; Drug Administration Schedule; Drug Combinations; Esophagectomy; Female; Floxuridine; Fluorouracil; Gastrectomy; Humans; Lung Neoplasms; Middle Aged; Oxonic Acid; Pyridines; Radiography, Thoracic; Remission Induction; Stomach Neoplasms; Tegafur; Tomography, X-Ray Computed