Cooperative study of postoperative long-term adjuvant therapy of breast cancer. First study of a series--comparative study between postoperative tegafur administration and no adjuvant chemotherapy

A prospective randomized study was performed in 22 institutions from July 1978, to evaluate the efficiency of long-term adjuvant chemotherapy with tegafur alone for primary breast cancer. Five hundred and eighty-seven eligible patients, classified into T1a, T2a, T3a, N0, N1a, N1b, and M0 were divided into two groups: Group A, radical mastectomy receiving no adjuvant chemotherapy; and Group B, radical mastectomy followed by 4 courses of adjuvant chemotherapy, each one consisting of daily administration of tegafur 600 mg p.o. for 8 weeks and 4 weeks rest. At the 66th month of median follow up time, there were no differences between the two groups on 5 year cumulative survival and disease free survival rate. In subgroup patients who have histologically 1-3 axillary involvements, there seemed to be a more meaningful prolongation of the disease-free interval in group B than in group A (logrank test; p = 0.11 generalized Wilcoxon test; p = 0.13).     

Paclitaxel and leucovorin-modulated infusional 5-fluorouracil combination chemotherapy for metastatic gastric cancer

As no standard chemotherapy regimen has been established for advanced gastric cancer, this study sought to evaluate the efficacy and safety of combination chemotherapy that included paclitaxel and leucovorin (LV)-modulated infusional 5-fluorouracil (5-FU) in metastatic gastric cancer. Patients received a three-hour infusion of 175 mg/m2 of paclitaxel on day 1. A bolus of 20 mg/m2 of LV was then administered, followed by a 24-h infusion of 1,000 mg/m2 of 5-FU on days 1 through 3. The treatment cycle was re-peated every 3 weeks until disease progression. Response evaluation was performed according to the RECIST criteria, with toxicity determined by NCI-CTC (version 2.0). A total of 66 patients, including 21 (31.8%) with a history of prior chemotherapy, were enrolled. Fifteen (71.4%) of the 21 patients with prior chemotherapy received prolonged infusional 5-FU. In the 56 evaluable patients (37 in the chemotherapy-na?ve group and 19 in the prior chemotherapy group), tumor responses according to prior exposure to chemotherapy were as follows: 17 (45.9%) partial response (PR), 6 (16.2%) stable disease (SD) and 14 (37.8%) progressive disease (PD) in the chemotherapy-na?ve group; 1 (7.1%) complete response, 3 (15.8%) PRs, 8 (42.1%) SDs and 7 (36.8%) PDs in the prior chemotherapy group. The overall median response duration was 20 weeks (range, 8-61 weeks), with a median progression-free survival of 20 weeks [95% confidence interval (CI), 13.4-26.6 weeks] and 12 weeks (95% CI, 5.7-18.3 weeks) in the chemotherapy-na?ve and prior chemotherapy groups, respectively. The median overall survival was 48 weeks (95% CI, 38-58 weeks) in the chemotherapy-na?ve group and 28 weeks (95% CI, 22-34 weeks) in the prior chemotherapy group. The most frequent grade III/IV toxicity was neutro-penia. Non-hematological toxicity of grade III/IV was rare. Paclitaxel in combination with 5-FU/LV is clinically beneficial for patients with advanced gastric cancer and is a feasible salvage regimen for 5-FU-refractory gastric cancer patients.     

胃癌术后OXA＋5-FU/LV联合DDP腹腔灌注辅助化疗疗效观察

目的：探讨OXA＋5-FU/LV联合DDP腹腔灌注辅助化疗对胃癌的疗效。方法：OXA85mg/m2d1＋LV0.2/m2d1-2＋5-FU0.4/m2d1-2＋5-FU1.2/m244h双周方案,共执行6个月化疗,腹腔灌注化疗：DDP60mg每周,共6周后停用。结果：2004年1月-2009年7月共收治96例胃癌术后病人,83例完成12周期化疗,4年生存率55.4%,5年生存率40.9%,13例因为年龄、不良反应和经费等原因未能完成计划,无不良反应致死,总体不良反应耐受良好。结论：OXA＋5-FU/LV联合DDP腹腔灌注辅助化疗胃癌疗效确切且不良反应低。     

胃癌术后OXA+5-FU/LV联合DDP腹腔灌注辅助化疗疗效观察

目的:探讨OXA+5-FU/LV联合DDP腹腔灌注辅助化疗对胃癌的疗效.方法:OXA 85mg/㎡ d1+LV 0.2/㎡ d1-2+5-Fu 0.4/㎡ d1-2+5-FU 1.2/㎡ 44h双周方案,共执行6个月化疗,腹腔灌注化疗:DDP60mg每周,共6周后停用.结果:2004年1月-2009年7月共收治96例胃癌术后病人,83例完成12周期化疗,4年生存率55.4%,5年生存率40.9%,13例因为年龄、不良反应和经费等原因未能完成计划,无不良反应致死,总体不良反应耐受良好.结论:OXA+5-FU/LV联合DDP腹腔灌注辅助化疗胃癌疗效确切且不良反应低.     

Complete response in a case of unresectable gastric cancer with a combination of tegafur, 5-fluorouracil and mitomycin C

A 75-year-old man with gastric cancer metastatic to the liver was treated by combined administration of Tegafur (800 mg/body/day), 5-fluorouracil (300 mg/body/day) and Mitomycin C (hepatic arterial infusion of 20 mg/body and intravenous infusion of 8 mg/body). The total dose of Tegafur was 5.6 g, that of 5-FU was 11.4 g, and that of MMC was 36 mg for one month and a half. After therapy, primary and metastatic sites was completely disappeared. The patient has survived for 6 years 8 months in a state of complete response.     

The problems of postoperative adjuvant chemotherapy in gastric cancer

We studied the survival rate and state of recurrence of histologically curatively resected cases in the 1st (Method II) and the 2nd studies of the Cooperative Study Group of Surgical Adjuvant Chemotherapy for Gastric Cancer. The administration of MMC combined with Futraful was most effective, but there was no difference of survival rate between the patients in the 1st study given Futraful for 3 months and those in the 2nd study given the drug for 12 months. Irrespective of the kind of drug and term of administration, cases with stage I showing recurrence within 2 years after surgery accounted for ca. 50% of all stage I cases recurring within 5 years. In spite of histological malignancy, cases with stage II showing recurrence within 2 years after surgery accounted for ca. 65% of all stage II cases recurring within 5 years. As to the recurrent hazard rate for each recurrent type of case with stage III, all types showed a high peak between 0.5 and 1.5 years after surgery. The peritoneal metastatic hazard rate was the highest. The hazard rates for Groups B (MMC + Futraful) and C (Futraful) were lower than those for Group A (MMC). The above findings suggest the importance of postoperative adjuvant chemotherapy, which is performed repeatedly and intensively for 2 years in order to prevent recurrence.     

5-fluorouracil, adriamycin, and mitomycin-C (FAM) combination chemotherapy in the treatment of advanced gastric cancer.

Thirty-six patients with advanced measurable gastric cancer were treated with a new combination chemotherapy program consisting of 5-fluorouracil, Adriamycin and mitomycin-C (FAM). Fifty percent of patients achieved an objective partial response. The median duration of remission was 9.5 months and the median survival for responding patients was 13.5 months, with 2 remaining alive at 14 and 26 months. The median survival for nonresponding patients was 3.0 months and all were dead by 6 months after initiation of therapy. The median survival of all 36 patients treated with FAM was 5.5 months. An analysis of possible prognostic variables including initial performance status, resectability of the primary gastric tumor and histologic differentiation of the neoplasm failed to account for differences in patient response and survival. The FAM regimen was well tolerated, and produced only moderate bone marrow suppression. These results demonstrate that some patients with advanced gastric cancer can be effectively palliated with FAM chemotherapy. Phase III trials are warranted to assess the effect of the FAM regimen on the survival of patients with advanced gastric cancer.     

Dose intensity of uracil and tegafur in postoperative chemotherapy for patients with poorly differentiated gastric cancer

A retrospective analysis of postoperative chemotherapy had shown the continuous administration of UFT, an oral preparation of 1-(2-tetrahydrofuryl)-5-fluorouracil (tegafur) and uracil at a molar ratio of 1:4, to be effective for poorly differentiated gastric cancer. We therefore sought to determine prospectively the effective dose of postoperative chemotherapy with UFT for patients with poorly differentiated gastric cancer following a curative resection. We determined the effect of the combined intravenous administration of mitomycin C (MMC) and oral treatment with protein-bound polysaccharide Kreha (PSK), extracted from the basidiomycete Coriolus versicolor, and UFT at a dose of either 8 mg/kg or 12 mg/kg daily for 1 year. A total of 224 patients with poorly differentiated stage II–IV gastric cancer were entered into this study after undergoing a curative resection. No differences were observed between the two treatment groups in terms of prognostic factors, the toxicity rate or the doses of the drugs prescribed, other than UFT. The higher dose of UFT in maintenance therapy led to a decrease in the recurrence rate (P < 0.05), and increases in disease-free survival and cause-specific survival (P < 0.05). UFT at 12 mg/␣kg in postoperative chemotherapy was thus found- to improve the postoperative results with no increase in toxicity for poorly differentiated gastric cancer, and is also cost-effective for outpatients. Received: 8 February 1996 / Accepted: 27 November 1996     

Pharmacokinetics of 5-FU after S-1 oral administration for adjuvant chemotherapy in gastric cancer patients

We studied the pharmacokinetics of 5-FU after S-1 oral administration at the usual dose (80 mg/m2) for adjuvant chemotherapy in 13 advanced gastric cancer patients (Stage II, III), and at a decreased dose (60 mg/m2) for adjuvant or combined chemotherapy in 13 advanced gastric cancer patients. Pharmacokinetic parameters of 5-FU in the serum were as follows: Cmax, 159 .9 2+/-45.2 ng/mL, Tmax, 2.17+/-0.58 h;T1/2, 3.13+/-2.88 h; and AUC(0-8), 768.0+/-260.8 ng h/mL in the patients with the usual dose, and Cmax, 117.3+/-55.1 ng/mL; Tmax, 2.62+/-0.9 6 h; T1/2, 3.09+/-1.9 5 h and AUC(0-8), 565.9+/-216.8 ng h/mL in the patients with the decreased dose. No difference in AUC was observed between operative methods. Adverse events of more than grade 3 were recognized in 7 patients, and AUC of 6 patients were more than 800 ng h/mL. The plasma concentration of 5-FU was quite different between patients. The difference of Cmax and AUC was 3-4 times. It was concluded that we must pay attention to individual differences in the plasma concentration of 5-FU in postoperative gastric cancer patients when S-1 would be administered.     

Long-term administration of low-dose cisplatin plus 5-fluorouracil prolongs the postoperative survival of patients with esophageal cancer

To evaluate the efficacy of long-term postoperative adjuvant chemotherapy with low-dose cisplatin (CDDP) plus 5-fluorouracil (5-FU) (CDDP/5-FU), we retrospectively examined 167 patients with squamous cell carcinoma of the esophagus who received the treatment after curative surgery (R0 resection). We classified the patients into the following three groups according to their postoperative therapies and analyzed their outcomes: a) low-dose CDDP (10 mg body(-1) day(-1) x 5 days) plus 5-FU (250-500 mg body(-1) day(-1) x 5 days) repeated every 6 months for 3 years, with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) administered between each treatment cycle (low-dose CDDP/5-FU group, 98 patients); b) high-dose CDDP (80 mg body(-1) day(-1) x 1 day) plus 5-FU (750-1,000 mg body(-1) day(-1) x 5 days) administered once only, followed by treatment with an oral fluoropyrimidine (5-FU 150-200 mg body(-1) day(-1) or UFT 300-400 mg body(-1) day(-1)) for 3 years (high-dose CDDP/5-FU group, 17 patients); or c) surgery alone (surgery alone group, 52 patients). The 3-year survival rates were 83.7% in the low-dose CDDP/5-FU group, 61.4% in the high-dose CDDP/5-FU group, and 62.2% in the surgery alone group; the difference between the low-dose CDDP/5-FU group and surgery alone group was significant (log-rank, p<0.05). A significantly better outcome in the low-dose CDDP/5-FU group than in the surgery alone group was associated with pStage III disease (p<0.001), pN1 lymph node metastasis (p<0.001), and lymphatic invasion (p<0.01). We conclude that long-term postoperative treatment with low-dose CDDP/5-FU is therapeutically beneficial and prolongs survival in patients with esophageal cancer who have regional lymph node metastasis or lymphatic invasion.     

Early postoperative intraperitoneal chemotherapy with mitomycin C, 5-fluorouracil and cisplatin for advanced gastric cancer

OBJECTIVE: The long-term survival of patients who undergo surgery for stage IV gastric cancer is poor, due to metastatic spread of the tumor. Intraperitoneal chemotherapy (IPT) as a possible treatment for peritoneal dissemination has been investigated in a number of different tumors. The aim of this study was to investigate the toxicity and impact of early postoperative IPT on the survival of patients with advanced gastric cancer. METHODS: Between 1993 and 1997, a total of 91 patients with stage IV gastric cancer who underwent potentially curative or palliative resection received intraperitoneal mitomycin C before closure of the abdominal wound. 5-Fluorouracil and cisplatin were administered intraperitoneally on postoperative days 1-4, and this was repeated at 4-week intervals. RESULTS: All patients received a median of 3 IPT perfusions. There were 24 (26.4%) postoperative complications and 1 (1.1%) mortality. The most frequent hematologic toxicity (grade 3-4) was leukopenia. The major nonhematologic toxicities (grade 3-4) were emesis and nephrotoxicity. After a median follow-up period of 26 months, 14 patients remain alive without evidence of recurrence, whereas 75 patients died due to recurrence or progression of disease. The median survival period for all 91 patients was 15.4 months. When survival according to the residual tumor was analyzed, median survival was 36.0 months in the R0 (curative resection) group, 20.6 months in the R1 group (margins of resected specimens showing microscopic residual tumor or diameter of each residual tumor less than 3 mm) and 9.0 months in the R2 group (macroscopic residual tumor larger than 3 mm) (p < 0.001). CONCLUSIONS: IPT was found to be safe, and it appears to improve the prognosis in patients with minimal residual tumors. However, complete cytoreductive surgery is mandatory for achieving the beneficial effect of IPT.     

Expression of thymidylate synthase in gastric cancer patients treated with 5-fluorouracil and doxorubicin-based adjuvant chemotherapy after curative resection

We evaluated the expression of thymidylate synthase (TS) in locally advanced gastric cancer patients treated with adjuvant chemotherapy after curative resection and investigated the association between TS expression and clinicopathologic characteristics including prognosis of the patients. TS expression was evaluated by immunohistochemical staining using TS106 monoclonal antibody in 103 locally advanced gastric cancer patients (stage IB-IV) who underwent 5-fluorouracil (5-FU) and doxorubicin-based adjuvant chemotherapy after curative resection. 65 patients (63%) had primary tumours with high TS expression (> or = 25% of tumour cells positive), and 38 patients (37%) demonstrated low TS expression (< 25% of tumour cells positive or no staining). High TS expression was associated with male gender (P = 0.002), poorly differentiated histology (P = 0.015), and mixed type in Lauren's classification (P = 0.027). There were no statistically significant differences in 4-year disease-free survival (60.0% vs. 57.2%, P = 0.548) and overall survival (59.6% vs. 59.3%, P = 0.792) between high-TS group and low-TS group. In conclusion, although high TS expression was associated with poorly differentiated histology and mixed type in Lauren's classification, it did not predict poor disease-free and overall survival in gastric cancer patients treated with 5-FU and doxorubicin-based adjuvant chemotherapy after curative resection. Further prospective studies including the evaluation of other biological markers associated with the resistance to 5-FU and doxorubicin are necessary.     

5-fluorouracil pharmacokinetics predicts disease-free survival in patients administered adjuvant chemotherapy for colorectal cancer.

PURPOSE: To evaluate 5-fluorouracil (5-FU) and 5-fluoro-5,6-dihydrouracil (5-FDHU) pharmacokinetics and disease-free survival (DFS) in colorectal cancer patients given 5-FU-based adjuvant chemotherapy within a nonrandomized, retrospective, pharmacokinetic study. EXPERIMENTAL DESIGN: One hundred fifteen patients including 72 men (median age, 63 years; range, 36-79 years) and 43 women (median age, 60 years; range, 36-73 years) received 6 cycles of l-leucovorin 100 mg/m(2)/day and 5-FU 370 mg/m(2)/day i.v. boluses (5 days every 4 weeks). Individual plasma concentrations of 5-FU and 5-FDHU were determined on day 1 of the first cycle with a validated high performance liquid chromatography method, and the main pharmacokinetic variables were determined. Follow-up of all patients was extended up to 5 years after the end of adjuvant chemotherapy, and DFS was recorded. Univariate and multivariate analyses were conducted to evaluate any correlation among 5-FU pharmacokinetics, clinical and pathologic variables, and DFS. RESULTS: The area under the time/concentration curve (AUC) of 5-FU was significantly lower in 58 subjects who recurred (7.5 +/- 2.9 h x mg/L) with respect to other patients (9.3 +/- 4.1 h x mg/L). Furthermore, AUC values lower than 8.4 h x mg/L together with lymph node involvement and the interruption of treatment or reduction of doses were identified as risk factors at univariate analysis. The completion of 6 cycles of adjuvant treatment without dosage modifications was the only independent risk factor at multivariate analysis, despite a trend toward significance for 5-FU AUC values (cutoff value, 8.4 hxmg/L) was observed (P = 0.06). CONCLUSIONS: Pharmacokinetics of 5-FU should be regarded as an important factor for predicting disease recurrence in colorectal cancers.     

Treatment of elderly advanced gastric cancer patients with 5-fluorouracil and leucovorin combination.

In September 1987 a phase II study was begun to verify if elderly symptomatic patients affected by advanced gastric cancer could benefit from a combination of 5-fluorouracil (5FU) and leucovorin (LV). We employed Machover's regimen: 5FU 370 mg/m2 i.v. infusion daily for 5 days; LV 200 mg/m2 i.v. bolus daily for 5 days; cycles were repeated every 3 weeks. 23 patients entered the study and 22 were evaluable for response and toxicity. We obtained only one partial response; 9 had stable disease and 12 progressed on therapy. The median duration of survival was 6 months. Symptoms were not affected by treatment. These data reflect the absence of significant improvement in the quality of life, which was further lessened by the presence of treatment side effects. Because of this we think that this regimen cannot be recommended for the treatment of elderly advanced gastric cancer patients.     

Long-term outcome of continuous 5-fluorouracil/cisplatin-based chemotherapy followed by chemoradiation in patients with resected gastric cancer

Despite substantial developments in gastric cancer treatment, the majority of patients relapse after definitive surgery. We have previously described well-tolerated adjuvant regimen that includes a combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin followed by chemoradiation after 3?months of chemotherapy. The aim of this study was to evaluate long-term outcomes of patients treated with this regimen and to determine whether expressions of the excision repair cross-complementing (ERCC1) and thymidylate synthase (TS) predict clinical outcome in those patients. The study population consisted of 36 advanced gastric cancer patients. Patients were treated with six cycles of continuous 5-fluorouracil (600?mg/m²) for 24?h, push 5-fluorouracil (400?mg/m²), and leucoverin (LCV) (200?mg/m²) on day 1?C2 every 2?weeks, cisplatin (60?mg/m²) on day 1 every 4?weeks followed by combined modality therapy using 45?Gy at 1.8?Gy per day concomitant with weekly bolus 5-fluorouracil (600?mg/m²) and LCV (50?mg). After median follow-up of 48.9?months, the median disease-free survival was 45?months and the overall survival was 66.4?months. Sixteen patients (44?%) were alive and disease-free. There was no significant correlation between ERCC1 expression and TS expression pattern and time to relapse (P?=?0.302 and P?=?0.707, respectively). In conclusion, long-term follow-up demonstrates that postoperative chemoradiation with combination of bolus 5-fluorouracil, continuous 5-fluorouracil, and cisplatin is a feasible approach.     

多西他赛联合顺铂和氟尿嘧啶治疗晚期胃癌疗效观察

目的观察多西他赛联合顺铂、氟尿嘧啶(DCF方案)治疗晚期胃癌的疗效和不良反应。方法采用DCF方案治疗33例晚期胃癌患者。多西他赛75 mg/m2,d1;顺铂75 mg/m2,d1;氟尿嘧啶750 mg/m2,持续静脉滴注,d1~5,3周1个周期,至少2个周期。结果33例晚期胃癌中,完全缓解(CR)0例,部分缓解(PR)18例(54.5%),稳定(SD)8例(24.2%),进展(PD)7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。骨髓抑制以白细胞减少为特点,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Ⅳ度腹泻发生。无治疗相关性死亡。结论DCF方案是治疗晚期胃癌安全有效的化疗方案。     

A case of postoperative gastric cancer responding to adjuvant chemotherapy with TS-1--a novel oral formation of 5-fluorouracil]

TS-1 is a novel oral formation of 5-fluorouracil, developed using tegafur and two biochemical modulations. We report the case of a patient with multiple lymph node metastases from gastric cancer that markedly responded to TS-1. A 70-year-old man suffering from hematemesis was admitted to our hospital. Computed tomography showed advanced gastric cancer with huge lymph node metastases. After non-curative operation, he received adjuvant chemotherapy with TS-1 for 12 weeks. CT revealed that almost complete reduction of the metastatic nodes was obtained. No serious adverse reactions were observed.     

Comparison of intramural 5-fluorouracil and more conventional routes of drug administration on concentrations in gastric regional lymph nodes: a potential for trans-endoscopic adjuvant chemotherapy.

Intramural injection of 20 muCi (2-14C) 5-fluorouacil (5-FU) into the gastric submucosa of dogs and baboons was employed to evaluate the kinetics of 5-FU distribution following this route of administration and to compare these results with those following intraluminal, intravenous, and local intraarterial injections. Measurements of radioactivity taken over a six-hour period after injections demonstrated that the greatest concentration of isotope in samples of gastric wall and perigastric lymph nodes was found after administration of the drug directly into the stomach wall. Clinical application of intramural injections of 5-FU into the stomach wall under direct gastroscopic visual control, may be worthy of trial in patients with gastric cancer.     

紫杉醇联合5-氟尿嘧啶、亚叶酸钙方案治疗晚期胃癌近期疗效评价

 目的 评价含紫杉醇（TAX）联合5-氟尿嘧啶（5-Fu）、亚叶酸钙（LV）组成的TF方案治疗晚期胃癌的临床疗效及安全性。方法 55例病理证实的晚期胃癌患者接受TF方案治疗，21 d为1周期，连用2 ~ 3个周期后评价疗效。结果 55例患者均可评价疗效及毒副作用，有效率为45.45 %。临床受益反应（CBR）35例可评价，疼痛缓解率为86.6 %，Karnofsky评分增加≥20分者占56.4 %。白细胞数减少发生率为56.4 %，Ⅲ度以上占10.9 %。胃肠道反应发生率为43.6 %。结论 TF方案治疗晚期胃癌疗效确切，CBR高，不良反应可以耐受，对多次使用含5-Fu及衍生物方案治疗过的患者仍有一定疗效。     

Long-term results of an operation alone and postoperative adjuvant chemotherapy in advanced gastric cancer--report of 265 patients

During the period from June 1973 to December 1978, 338 patients with advanced gastric cancer were treated in our hospital. By retrospective grouping, 142 out of 265 patients with tumor resected received postoperative adjuvant chemotherapy (MMC + 5FU + Ara-C), 123 operated alone were taken for comparison. These two groups were similar in: age, sex, location of tumor, mode of resection, histological type, clinical stage and follow-up rate. The results indicated that the 1, 3 and 5 year survival rates of the combined group were much higher than those of the operation only group. Further analysis showed that the supplementary chemotherapy was particularly valid in stages III and IV. In stage III patients, the 5 year survival rate was increased by 27.8%. In stage IV patients, the 3 and 5 year survival rates of the combined group were 16.3% and 9.8% but none survived over 3 years in the operation only group. The authors believe that postoperative adjuvant chemotherapy plays an important role in controlling the micrometastatic and residual cancer foci.