Comparison of oral ftorafur and intravenous 5-fluorouracil in patients with advanced cancer of the stomach, colon or rectum

In this prospective randomized study the effect of oral Ftorafur was compared with that of intravenous 5-fluorouracil in patients with advanced adenocarcinoma of the stomach, colon or rectum. Forty-five patients were evaluable. The overall response rates were 26.9% in the 5-fluorouracil group, 26.7% in the Ftorafur group. The median duration of response was 6 months in both groups. Survival in the 5-fluorouracil group was slightly better than in the Ftorafur group, but the difference was not statistically significant. The myelosuppressive effect of 5-fluorouracil was significantly stronger than that of Ftorafur. Gastrointestinal side effects were more pronounced in the Ftorafur group, but the difference was not statistically significant.     

A phase II trial of ftorafur: adriamycin and mitomycin-C (FAM II) in advanced gastric adenocarcinoma.

Fifteen patients with advanced gastric cancer were treated with the combination of Ftorafur, Adriamycin and mitomycin-C (FAM II). Three patients showed partial responses, in five the disease remained stable for at least 3 months and seven showed progression while on treatment. All responding patients showed survival in excess of 12 months. Hematologic toxicity was of only moderate severity. Median white count nadir was 3500 cells/mm3 and median platelet nadir was 187,000 cells/mm3. Four patients had white count nadirs from 2000--2500 cells/mm3 and three had nadirs from 500--1500 cells/mm3; also there were four with platelet nadirs less than 100,000/mm3. However, no drug-related infections occurred and no platelet transfusions were required. The major non-hematologic toxicities of the regimen were nausea, vomiting, dizziness, vertigo, and rhinorrhea. These toxicities were limiting and resulted in termination of the trial because of poor patient acceptance and the failure of the combination to exhibit a therapeutic advantage over the similar combination (FAM) that employed weekly 5-fluorouracil in place of Ftorafur.     

Phase II trial of UFT in advanced colorectal and gastric cancer

A phase II trial of continuous oral therapy with UFT, a combination of uracil and the 5-fluorouracil analogue 1-(2-tetrahydrofuryl)-5-fluorouracil (Futraful, Ftorafur), was conducted in 40 patients with advanced colorectal cancer and 18 patients with advanced gastric cancer. Six partial responses were seen in the 36 evaluable patients with colorectal cancer (response rate 16.6%; 95% confidence limits 6.4-32.8%), and one partial response was seen in the 16 evaluable patients with gastric cancer (response rate 6%; 95% confidence limits 0.27-30.2%). The overall toxicity of the treatment was low, and all patients were treated as outpatients. The results suggest that oral UFT has comparable activity to standard regimes of 5-fluorouracil, and because of the convenience of oral administration is a useful therapy in the management of patients with advanced colorectal cancer.     

对症治疗与联合化疗治疗晚期非小细胞肺癌

目的 评价联合化疗对晚期非小细胞肺癌（ＮＳＣＬＣ）患者生存期的影响。方法 ７０例晚期非小细胞肺癌患者配对分组;３５例拒绝化疗者,接受对症治疗（对症组）。３５例接受联合化疗,丝裂霉素８￣１０ｍｇ／ｍ＾２,第１天,顺铂２０ｍｇ／ｍ＾２,第１￣５天,长春酰胺３ｍｇ／ｍ＾２,第１,８天,每４周重复,２￣４周期后,口服喃呋啶２００￣３００ｍｇ,每天３次,至肿瘤复发或进展止。结果 中位生存期化疗组为９个月,对     

Ftorafur, adriamycin, cyclophosphamide and BCG in the treatment of metastatic breast cancer.

Ftorafur is a 5-fluorouracil analogue which is slowly metabolized to 5-FU, resulting in prolonged therapeutic levels of this latter drug. Ninety-one evaluable patients with metastatic breast cancer were treated with Ftorafur, Adriamycin, cyclophosphamide, and BCG (ACFTOR-BCG), in an attempt to increase the effectiveness of the program or decrease its myelosuppressive toxicity. The results of this trial were compared to those previously reported with the combination of 5-FU, Adriamycin, cyclophosphamide, and BCG (FAC-BCG). Overall objective response rates were 65% and 76% for ACFTOR-BCG and FAC-BCG, respectively. Durations of response were 12 months and 14 months for ACFTOR-BCG and FAC-BCG (p = 0.53). The median survival of responders was 22 and 23.9 months, respectively. Substantial toxicity was observed with Ftorafur: nausea and vomiting severe enough to cause weight loss was observed in a substantially higher fraction of the patients treated with this drug than with 5-FU. Other side-effects, which were not observed with the 5-FU combination, were somnolence, dizziness, personality changes, tremor, ataxia, and confusion. No differences in myelosuppressive toxicity were observed between the two combinations, and the incidence of infectious complications was identical. The combination of Ftorafur, Adriamycin, cyclophosphamide and BCG did not offer any advantages with respect to increased effectiveness or reduced toxicity over the FAC-BCG regimen in breast carcinoma.     

Ftorafur, Adriamycin and Mitomycin C (FAM II) for Extensive Bronchogenic Adenocarcinoma and Large Cell Carcinoma

Twenty-six patients with advanced bronchogenic adenocarcinomaor large cell carcinoma were treated by combination chemotherapyconsisting of Ftorafur, adriamycin and mitomycin C (FAM II).The patients had not received prior chemotherapy and were noteligible for radiotherapy and surgery. The overall responserate was 25% (5 of 20 patients). One patient with adenocarcinoma achieved a complete response,four achieved a partial response and three a minor response.In four patients the disease was stable. The response did notvary strictly with initial performance status as patients witha Karnofsky score of <70% also showed a median survival of7.5⁺ months. The FAM II combination was very well tolerated, particularlyregarding nausea and vomiting; the latter occurred in only onepatient. No patient required a reduction in the drug dose becauseof leukopenia or thrombocytopenia.     

Chemotherapeutic effects of 13 nitrosoureas on the LSA lymphoma ascites tumor of the C57BL mouse

The LSA lymphoma of the C57BL/ym mouse has been used to test 13 nitrosoureas for cure of advanced tumors and for induced tumor resistance (ITR) of surviving animals. Tumors were initiated by intraperitoneal inoculation of 10(6) LSA cells. Controls died in 8-9 days. Five-day old tumors were defined as advanced tumors, and treatment consisted of a single dose of a nitrosourea to groups of 10 male mice, 8-9 weeks old, for each compound. The nitrosoureas used were: BCNU (NSC-40992), CCNU (NSC-79037), MeCCNU (NSC-95441), chlorozotocin (CLZ) (NSC-178248), streptozotocin (STZN) (NSC-85998) CNU (NSC-47547), FCNU (NSC-87974), GANU (NSC-254174), ACNU (NSC-245382), PCNU (NSC-95466), cis-acid (NSC-153174), 153174), NSC-88104, and GCNU (NSC-114460). The major endpoint assessed was tumor cure and was grouped as follows: (1) high (greater than or equal to 80%), achieved with BCNU, MeCCNU, CCNU, CLZ, ACNU, FCNU, PCNU, and cis-acid; (2) medium (40- less than 80%), obtained with GANU, NSC-88104, and GCNU, and (3) low or nil (less than 40%), shown by CNU and STZN. The second endpoint was treatment-induced ITR. Cured mice, i.e., those surviving over 30 days after death of controls were challenged with 10(5) LSA live cells, and survivors from this challenge were challenged with 10(7) LSA cells 1 month later. Survivors from both inocula were considered highly immune (HI). High percentages of HI mice (greater than or equal to 80%) were obtained from mice cured with MeCCNU, CCNU, ACNU, FCNU, PCNU, and NSC-88104. STZN produced 0.0% cures; the other nitrosoureas showed 33.3-75% HI mice. Cure rates and ITR appeared to be agent- and structure-related. Cure alone did not lead to the resistant state.     

Chemoimmunotherapy with or without oophorectomy in premenopausal patients with advanced breast cancer.

Ninety-eight premenopausal patients with stage IV breast cancer were treated with chemoimmunotherapy alone, or with combination oophorectomy-chemoimmunotherapy either simultaneously (chemoimmunotherapy within four weeks of oophorectomy) or sequentially (delayed chemoimmunotherapy until evidence of progressive disease or no response to oophorectomy). The chemoimmunotherapy consisted of a three-drug combination of Adriamycin, cyclophosphamide, and 5-fluorouracil or Ftorafur; immunotherapy consisted of either oral levamisole, BCG by scarification, or a combination of both. Forty patients underwent simultaneous oophorectomy-chemoimmunotherapy, with a response rate of 85% and a median duration of response of 25 months. Response rate of 69% and a median duration of response of 16.6 months was observed with the 29 patients who received sequential oophorectomy-chemoimmunotherapy. Another 29 patients were treated with chemoimmunotherapy alone and achieved a response rate of 87% and a median duration of response of 11.8 months. Though there were no significant differences in the response rate, patients treated with chemoimmunotherapy alone had a significantly shorter median duration of response (P less than 0.05). This would suggest that oophorectomy in combination with chemoimmunotherapy is the most favorable treatment modality for premenopausal patients with advanced metastatic breast cancer.     

Phase I study of ftorafur, an analog of 5-fluorouracil.

Ftorafur, a furanyl analog of 5-fluorouracil (5-FU), is reported to be five to six times less toxic and possibly more effective in cancer of the breast and colon than 5-FU. The drug was synthesized, formulated, and utilized in toxicologic studies, and then in 24 patients with advanced incurable malignancies. When Ftorafur is given by intravenous push, it results in immediate flushing, dizziness, nausea, retching, and in some cases transient hypotension. These immediate side effects are largely eliminated by administering the drug slowly by infusion. In patients, 60 mg/kg of Ftorafur given i.v. daily for up to 10 days resulted in mild toxicity. However, 80 mg/kg given i.v. daily for 7 days resulted in severe toxicity, with nausea, vomiting, stomatitis, leukopenia, and thrombocytopenia. These studies confirm those of the Russian investigators as to toxicity and dosage, even with a different method of administration more convenient for therapy. Phase II studies are presently being carried out to compare the effectiveness of Ftorafur and 5-FU.     

LFP方案双途径化疗治疗胃肠道肿瘤的临床观察

[目的]探讨腔内化疗配合全身化疗治疗晚期胃肠道恶性肿瘤的临床疗效。[方法]将术后腹腔转移或失去手术时机的晚期胃肠道癌随机分为治疗组和对照组。治疗组亚叶酸钙(CF)、呋喃氟尿嘧啶(FT 207)、顺铂(PDD)联用 ,行腹腔联合静脉化疗 ,对照组行CF、FT 207、PDD联用单纯静脉化疗 ,两组化疗药物总剂量相同。[结果]治疗组有效率为66.67 % ,1年生存率为60 % ;对照组有效率为40.54% ,1年生存率为35 % ,统计学差异明显(P<0.05) ,而治疗组不良反应明显轻于对照组(P<0.01)。[结论]LFP方案腹腔联合静脉化疗是治疗晚期胃肠道恶性肿瘤的有效方法 ,较单纯静脉化疗毒副作用明显减轻 ,有效率及1年生存率有所提高。     

Modelling of ftorafur and 5-fluorouracil pharmacokinetics following oral UFT administration. A population study in 30 patients with advanced breast cancer

PURPOSE: The pharmacokinetics of ftorafur, 5-fluorouracil (5FU) and uracil were investigated in order to built a population pharmacokinetic model for the anticancer drug UFT, administered with leucovorin and vinorelbine. METHODS: A total of 31 patients with metastatic breast cancer were treated with escalating oral doses of UFT (300 to 500 mg per day) plus leucovorin (90 mg per day) in combination with intravenous vinorelbine (15 to 25 mg/m(2)). Concentration-time data were obtained on days 1, 8, 15 and 21 of cycle 1. RESULTS: Of the 31 patients treated, 30 were available for the pharmacokinetic analysis. Ftorafur, 5FU and uracil appeared rapidly in plasma and showed large interpatient variations. Ftorafur concentrations were higher than those of 5FU and uracil. AUC significantly increased between day 1, and days 8, 15 and 21. Ftorafur C(max) and AUC values were proportional to UFT dose, whereas C(max) and AUC values of 5FU and uracil were not linearly related to UFT dose. The pharmacokinetics of ftorafur were ascribed to a two-compartment open model in which 5FU was produced from the central compartment. The absorption and exponential distribution rate constants were assumed equal. The effect of uracil on 5FU elimination was straightforward, since no reasonable curve-fitting could be obtained for 5FU data when this covariate was not taken into account. The uracil concentration inducing a 50% reduction in 5FU elimination was 2.67 micro mol.l(-1). This result confirms the important role played by uracil as a competitive inhibitor of 5FU catabolism. CONCLUSION: A pharmacokinetic model for ftorafur and 5FU was developed and should be useful to further study drug interactions and establish dosing guidelines.     

Phase II trial of cisplatin and tegafur (Ftorafur) as initial therapy in squamous-cell carcinoma of the head and neck

Cisplatin and 5-fluorouracil infusion combination produces a high response rate in squamous-cell carcinoma of the head and neck. Tegafur (Ftorafur) is an analog of 5-fluorouracil, and its oral form is well absorbed. This agent has a moderate toxicity. We report a study to determine the efficacy of the cisplatin (100 mg/m2, day 1) and tegafur (1,000 mg/m2 daily for 21 days) combination. Thirty-nine patients entered the study; 36 were evaluable for response. Overall response was 94%, with a 22% complete response. Toxicity was moderate. We conclude that the cisplatin and tegafur combination is active in untreated patients with head and neck cancer.     

Oral Ftorafur Versus Intravenous 5-Fluorouracil: A comparative study in patients with colorectal cancer

The toxicities of ora] Ftorafur (1 g/m²/day 1-21) and intravenous 5-fluorouracil (5-FU) (500 mg/m²/day 1-5) were compared in a prospective randomized study in patients with colorectal cancer. The treatment courses were repeated every 6th week. Leu-copenia was more common after 5-FU. Leucocyte nadir in connection with first treatment cycle was on average seen on day 15 in patients receiving 5-FU and on day 28 in patients receiving Ftorafur. Significantly more patients on 5-FU developed stomatitis. There was no difference in the number of patients with diarrhea or nausea/vomiting. Median survival and response rates were not significantly different after the two treatment schedules.     

多西他赛联合替加氟和顺铂治疗晚期胃癌疗效观察

目的：观察多西他赛联合顺铂、替加氟（DCF1方案）治疗晚期胃癌的疗效和不良反应。方法：采用DCFt方案治疗66例晚期胃癌患者。多西他赛75m／m^2,d1;顺铂75m／m^2,d1;替加氟20mg／kg,静脉滴注d。天,3周1个周期,至少2个周期。结果166例晚期胃癌中,完全缓解（CR）0例,部分缓解（PR）36例（54．5％）,稳定（SD）16例（24．2％）,进展（PD）14例（21．2％）。中位肿瘤进展时间为6．1个月（3．5—11．5个月）,中位总生存期为11．2个月（6．0—14．5个月）。最常见的不良反应为骨髓抑制、消化道反应及可逆性体液潴留,不良反应多为Ⅰ-Ⅱ度,无Ⅳ度不良反应发生。骨髓抑制以自细胞减少为特点,血小板减少及贫血较轻。消化道反应主要表现为恶心呕吐、腹泻便秘。无治疗相关性死亡。结论：DCFt方案是治疗晚期胃癌安全有效的化疗方案。     

Experimental study on the carcinogenicity of the Cytostatic drug ftorafur (tegafur)

Long-term carcinogenicity of Ftorafur (Tegafur) was studied in rodents. Rats and mice were treated for one year per os with 40 (mice) and 60 (rat) mg/kg Ftorafur twice a week and were followed for their entire life. Analysis of the data provide no evidence for the carcinogenicity of Ftorafur in rodents. These findings are similar to other antimetabolite studies and contrasts with the carcinogenic alkylating agents.     

应用COAP方案及CCNU和FT—207治疗晚期非小细胞肺癌疗效观察

41例晚期非小细胞肺癌患者用环磷酰胺(600mg/m~2),长春新硷(2mg),阿霉素(50mg/m~2)和顺铂(15—20mg/M~2,第1—5天)联合化疗。能评价疗效者38例,其中完全缓解3例(7.9％),部分缓解18例(47.4％),总有效率55.3％。稳定者7例(18.4％),进展者10例(26.3％)。缓解和稳定者在上述联合化疗结束后接受环已亚硝脲(80mg/M~2),每6周1次,共4次及呋氟脲嘧啶(200—300mg),每日3次,维持治疗连续6个月,或至肿瘤复发进展止。全组病例中数生存15个月,一年生存28例(73.3％),二年生存11例(28.9％),三年生存5例(13.2％)。     

Induction chemotherapy with carboplatin and ftorafur in advanced head and neck cancer. A randomized study.

From 1987 to 1989, 42 patients with locally advanced squamous cell carcinoma of the head and neck (Stages III-IV, Mo) were randomized to receive radiotherapy (Group A) or three courses of induction chemotherapy followed by radiotherapy (Group B). There were 36 evaluable patients, 17 in Group A and 19 in Group B. The radiotherapy regimen was the same for both groups, 66-74 Gy total tumor doses with standard fractionation scheme of 2 Gy/day. The chemotherapy regimen was a combination of carboplatin 400 mg/m2 by intravenous bolus injection on day 1, and Ftorafur 1,000 mg/m2 orally once a day for 14 days. Cycles were given every 4 weeks. The complete response rate in Group A was 65%; in group B it was 31.5% after induction chemotherapy and 84% after radiotherapy. The 42-month actuarial overall survival rates were 34% for Group A and 47% for Group B (P = NS). Patients from both groups with a complete response had a significantly longer survival time than those with a partial response (P less than 0.001). No significant differences in disease-free survival were found between the two treated groups. The chemotherapy regimen was well tolerated, with moderate hematologic and gastrointestinal toxicity. Increased in radiation toxicity by chemotherapy was not observed.     

Prednimustine (NSC-134087, Leo 1031) treatment of lymphocytic and lymphocytic-histiocytic lymphomas.

Nineteen patients with advanced lymphocytic or lymphocytic-histiocytic lymphomas were treated with Prednimustine (NSC-134087, Leo 1031). The median induction dose was 25 mg/m2 a day by mouth (range 11-42). Ten patients had previously received radiation or chemotherapy, or both. Four patients had a complete remission and eleven a partial remission. The median duration of remission was 12.5+ months for complete responders and 5 months for partial responders. Thirteen patients had a moderate myelosuppression. One patient had urticaria and pruritus and refused further treatment.     

Fludarabine phosphate. Phase II evaluation in advanced soft-tissue sarcomas

Fludarabine phosphate (NSC-312878) was administered to 23 patients with advanced soft-tissue sarcomas. Patients entered on the study had a median performance status of 80 and had prior chemotherapy restricted to one previous regimen. Dose schedule was 100 mg/m2 in poor-risk patients (creatinine clearance less than 70 cc/min) and 125 mg/m2 in good-risk patients every 3 weeks. No complete or partial responses were noted in the 20 evaluable patients. Median survival was 12 weeks. Leukopenia was the most common toxicity. Fludarabine phosphate in the above schedule failed to demonstrate therapeutic efficacy in this patient population.     

Nephrotoxic potential of cis-diamminedichloroplatinum and four analogs in male Fischer 344 rats

Cis-diamminedichloroplatinum [cis-DDP; NSC-119875] and four analogs (NSC-241240, NSC-271674, NSC-263158, and NSC-268252) were evaluated for their acute nephrotoxic potential in male F344 rats following iv administration. Indices of nephrotoxicity included blood urea nitrogen, serum creatinine, kidney weights, and microscopic examination. Results indicated that renal function, organ weights, and histology are important criteria for assessing the nephrotoxic potential of cis-DDP analogs, although alterations in these parameters may have been influenced by severe body weight loss. cis-DDP appeared to be the most nephrotoxic compound studied, and NSC-241240 demonstrated minimal renal damage. Ranking of compounds in order of their nephrotoxic potential (most to least) was cis-DDP, NSC-263158, NSC-268252, NSC-271674, and NSC-241240.