Efficacy of postoperative adjuvant therapy for stage ilia breast cancer: Futraful vs futraful+tamoxifen for er-positive patients and futraful vs futraful + adriamycin for er-negative breast cancer

A multi-center, randomized controlled collaborative study was conducted in 310 institutions located throughout Japan for 3 years and 9 months from February 1985 until October 1988 to evaluate the efficacy of post-operative adjuvant therapy for patients who had previously undergone curative surgery for treatment of Stage IIIa breast cancer. Patients with estrogen receptor-positive [ER( + )] breast cancer were treated with two types of regimens, ie, cyclophosphamide + adriamycin + fluorouracil (CAF; 2 cycles) + Futraful (FT) or CAF (2 cycles) + FT + tamoxifen (TAM), and the clinical benefit of additional use of TAM was evaluated. Of the 509 ER( + ) patients registered for the trial, 473 patients (92.9%) were eligible for evaluation. The 5-year survival rate was 77.2% for the CAF + FT group and 74.6% for the CAF + FT+TAM group, and the 5-year disease-free survival rate was 56.7% for the CAF+FT group and 59.2% for the CAF + FT + TAM group. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. Analyses by factor revealed that the 5-year disease-free rate for lymph node-negative patients in the CAF + FT + TAM group was significantly higher than that for the corresponding patients in the CAF + FT group. No differences were noted in the incidence of adverse reactions between the two treatment groups, other than an increase in LDH (the frequency of which was higher in the CAF + FT+TAM group than in the CAF + FT group). Patients with estrogen receptor-negative [ER( -)] breast cancer were treated with two types of regimens, ie, CAF + FT or CAF + FT + adriamycin (ADR), and the clinical benefit of the combined use of intermittent doses of ADR was evaluated. Of the 514 ER(-) patients registered in the trial, 478 (93.0%) were eligible for evaluation. The 5-year survival rate was 64.9% for the CAF + FT group and 63.0% for the CAF + FT + ADR group, and the 5-year disease-free survival rate was 59.2% for both CAF + FT and CAF + FT + ADR groups. Neither the survival rate nor the disease-free survival rate differed significantly between the groups. There were no significant differences between these groups in analyses by nodal or menopausal status. The incidences of adverse reactions including anorexia, nausea/vomiting and alopecia were higher in the CAF + FT+ADR group than in the CAF + FT group.     

The role of chemoendocrine agents in postoperative adjuvant therapy for breast cancer: Meta-analysis of the first collaborative studies of postoperative adjuvant chemoendocrine therapy for breast cancer (ACETBC)

The first collaborative studies of postoperative adjuvant chemoendocrine therapy for breast cancer (ACETBC) were carried out in 6 regions of Japan from 1982 to 1985, and the results were subjected to meta-analysis. Subjects consisted of Stage II and IIIa cases who underwent radical mastectomy with Brt + Ax or more extensive resection for primary breast cancer. Regimen A consisted of tegafur (Futraful: FT) alone at 600 mg/day, and regimen B of FT at 600 mg/day with tamoxifen (TAM) at 20 mg/day. The duration of the treatment was one year in the Tohoku and Kinki regions, and 2 years in the other 4 regions. Meta-analysis by Peto’s method showed an odds reduction of 20 ± 7% (logrank test:P = 0.0069) for the 5-year overall survival rate in 4740 eligible patients, and 25 ± 6% (logrank test: P>0.0001) for the 5-year disease-free survival rate. The odds reductions were both statistically significant, indicating that the adjuvant chemoendocrine therapy was effective. Subset analysis of data on 5 - year disease-free survival showed that FT plus TAM therapy was better in ER-positive and postmenopausal patients, whether axillary lymph nodes were positive or negative.     

Randomized controlled trial comparing oral doxifluridine plus oral cyclophosphamide with doxifluridine alone in women with node-positive breast cancer after primary surgery.

PURPOSE: We compared the therapeutic usefulness of doxifluridine (5'-DFUR) alone and a combination of 5'-DFUR plus cyclophosphamide (CPM), both of which are considered effective against advanced and recurrent breast cancer, to determine which treatment is more beneficial as postoperative adjuvant chemotherapy. PATIENTS AND METHODS: A total of 1,131 women with node-positive primary breast cancer were randomly assigned after primary surgery to receive 5'-DFUR alone or 5'-DFUR plus CPM. All patients initially received 5'-DFUR in an oral dose of 1,200 mg/d for 4 weeks, starting 4 weeks after surgery. Chemotherapy was then not given for 2 weeks. Patients in the 5'-DFUR group subsequently received five 4-week cycles of treatment consisting of oral 5'-DFUR (1,200 mg/d) for the first 2 weeks and no chemotherapy for the next 2 weeks. Those assigned to the 5'-DFUR plus CPM group also received oral CPM 100 mg/d for the first 2 weeks and no chemotherapy for the next 2 weeks. Women 50 years or older concurrently received 20 mg/d of tamoxifen for 2 years in both groups. RESULTS: Of the 1,088 eligible women, 546 were assigned to receive 5'-DFUR alone and 542 were assigned to receive 5'-DFUR plus CPM. Overall disease-free survival was significantly better in women who received 5'-DFUR plus CPM than in those who received 5'-DFUR alone (log-rank test, P =.021). Toxic effects occurred in 20.0% of patients (109 of 546) in the 5'-DFUR group and 32.3% of patients (175 of 542) in the 5'-DFUR plus CPM group (chi(2) test, P <.001). CONCLUSION: Combination therapy with 5'-DFUR plus CPM is more effective in preventing recurrence than 5'-DFUR alone.     

Meta-analysis of five studies on tegafur plus uracil (UFT) as post-operative adjuvant chemotherapy for breast cancer

Meta-analysis of 5 studies on postoperative breast cancer cases (2 studies on surgery alone vs. tegafur plus uracil (UFT) and 3 studies on tamoxifen (TAM) alone vs. TAM + UFT) were carried out to evaluate the anticancer drug UFT in oral postoperative adjuvant chemotherapy. Of the 1973 patients enrolled, 1898 were eligible and 75 were excluded (exclusion rate 3.8%). There was no bias in major background factors in either the UFT-treated (965) or non-UFT-treated (933) groups. The reduction in the odds of death and the odds of recurrence were 17 +/- 17% (p = 0.33) and 21 +/- 11% (p = 0.060), respectively. Multivariate analysis using Cox's proportional hazards model emphasized the effectiveness of UFT treatment for suppression of recurrence compared with non-treatment with UFT (p = 0.038). Suppression of recurrence was remarkable in the group treated with UFT for 2 years. (the reduction in the odds of recurrence: 23 +/- 11%, p = 0.048) Stratified analysis was applied concerning recurrence, and improved results were obtained in premenopausal cases (the reduction in the odds of recurrence: 33 +/- 11%, p = 0.019). These results suggested that UFT treatment for 2 years was effective as postoperative adjuvant chemotherapy for stage I - IIIA breast cancer for the prolongation of the recurrence-free survival period.     

Cell kinetic analysis of human tumor xenografts using anti-bromodeoxyuridine monoclonal antibody

The cell kinetics of human tumor xenografts serially transplanted into nude mice was examined using bromodeoxyuridine (BrdU) and anti-BrdU monoclonal antibody. After various doses of BrdU were given intraperitoneally into tumor bearing nude mice, the tumors were resected and stained immunohistochemically, using the anti-BrdU monoclonal antibody. The number of stained cells was demonstrated as the labeling index (LI). The optimal condition for BrdU staining was assumed to be 300mg of BrdU per kg followed by an incubation period of one hour. Since the LI by BrdU closely correlated with that in autoradiography by³H-TdR, this method is more useful and safer than the conventional autoradiographic study for investigating clinical cell kinetic analysis, as there is no need to use potentially hazardous radioactive compounds and the period of assay is shorter.     

Effect of the upper instrumented vertebral level (upper vs. lower thoracic spine) on gait ability after corrective surgery for adult spinal deformity

Background Context

The relationship between gait pattern and the level of upper instrumented vertebra (UIV) in surgically treated patients with adult spinal deformity (ASD) has not been fully documented.

Predictive implications of nucleoside metabolizing enzymes in premenopausal women with node-positive primary breast cancer who were randomly assigned to receive tamoxifen alone or tamoxifen plus tegafur-uracil as adjuvant therapy

Recent studies have demonstrated that tegafur-uracil (UFT) is useful for the adjuvant treatment of various types of cancers. To determine whether nucleoside metabolizing enzymes could be used to predict the response to UFT treatment in women with primary breast cancer, we retrospectively analyzed archived tumor tissue samples obtained from the 3rd Adjuvant Chemo-Endocrine Therapy for Breast Cancer (ACETBC) study, in which adjuvant treatment with tamoxifen (TAM) plus UFT for 2 years was compared with TAM alone for 2 years. Samples of tumor tissue were obtained from 192 premenopausal women with node-positive invasive breast cancer. The tissue samples were examined immunohistochemically to study the expression of thymidylate synthase (TS), thymidine phosphorylase (TP), and dihydropyrimidine dehydrogenase (DPD), as well as the expression of Her2 and p53. In patients with TS-positive tumors, the risk of relapse was significantly lower in the tamoxifen plus UFT group than in the tamoxifen alone group. After 2 years, however, there was a trend towards a decrease in the relative predictive value (RPV) of TS with time. No relationship to outcome was detected for TP or DPD. Expression of Her2 or p53 was a significant prognostic indicator in the tamoxifen alone group. TS, but not TP or DPD, may be a useful predictor of response to UFT therapy. After 2 years, the RPV of TS decreased with time, suggesting that 2 years of treatment with oral fluorouracil derivatives may be inadequate. Further studies are required to investigate this possibility.     

Phase I study of recombinant human tumor necrosis factor

Summary A phase I clinical and pharmacokinetic study of recombinant human tumor necrosis factor (rH-TNF) was conducted in a single dose schedule in 33 patients with advanced cancer. rH-TNF was given by i.v. infusion over 30 min with a starting dose of 1x10⁵ units/m². The dose was escalated up to 16x10⁵ units/m² according to the modified Fibonacci scheme. Toxic effects were similar but not identical to those reported with interferons and interleukin-2, and included fever, rigors, nausea and vomiting and anorexia in a non-dose-dependent manner, and hypotension, leukocytosis, thrombocytopenia and transient elevation of transaminases (SGOT and SGPT) in an approximately dose-dependent manner. DIC syndrome was observed in one patient who had received 16x10⁵ units/m². The dose-limiting toxicities were hypotension, thrombocytopenia and hepatotoxicity, and the maximum tolerated dose in a single i.v. infusion of rH-TNF appeared to be 12x10⁵ units/m² when thrombocytopenia and elevation of SGOT and SGPT were taken as the dose-limiting toxicities. However, if hypotension was included, the maximum safely tolerated dose appeared to be 5x10⁵ units/m².     

Individualized fluid resuscitation based on haemodynamic monitoring in the management of extensive burns

An evaluation has been made on the effectiveness and feasibility of the individualized fluid replacement programme based on intensive haemodynamic monitoring using a Swan-Ganz catheter. Twenty-one extensively burned patients with an average burn of 60·8 per cent BSA were resuscitated with lactated Ringer's and colloid solutions. The rate of fluid administration was adjusted to maintain the optimal ranges of the various haemodynamic parameters including cardiac index and left ventricular stroke work index. Two patients failed to respond to fluid resuscitation possibly due to inadequate emergency procedures given before arrival at our institute. The remaining patients survived the shock phase, with the amount of fluid given to the 18 adult patients being (3·38 ±1·02 ml/kg) × (percentage burn) for the first 24 hours. A negative correlation existed between the amounts of lacated Ringer's solution and colloid solution used for the fluid resuscitation. Dopamine was effective in 4 out of 5 patients who showed depressed myocardial function. The individualized fluid programme was shown to be effective and reliable for the management of critically burned patients.     

Presence of Modic type 1 change increases risk of postoperative pyogenic discitis following decompression surgery for lumbar canal stenosis

Study Design

Multicenter retrospective study.