Illness perceptions and quality of life in Japanese and Dutch women with breast cancer.

Knowledge on cross-cultural quality of life (QOL) and illness perceptions may help women with breast cancer cope more effectively. The self regulation model (SRM) guided the current exploratory longitudinal pilot-study. Central to SRM is the perception of health threats and their effects on QOL. Illness perceptions and QOL were assessed in 22 Dutch and 21 Japanese patients with breast cancer who filled out questionnaires before, 1 week, and 8 weeks after the first chemotherapy course. The questionnaires assessed QOL and illness perceptions. Patients' scores were compared with groups of patients with other chronic somatic illnesses (asthma, diabetes). Patients in both samples reported major impact of chemotherapy on global health status, physical functioning, role functioning, emotional functioning, constipation and diarrhea. Differences between Japanese and Dutch patients were limited to social functioning and financial problems. Japanese patients expressed stronger concerns about their illness than Dutch patients. Results of the Japanese and Dutch patients with breast cancer differed from data in patients with asthma on consequences, timeline, concern and emotional response. Results of Japanese patients differed from patients with type 2 diabetes on timeline and concern, whereas Dutch patients differed on timeline and consequences. Japanese and Dutch breast cancer patients have-overall-similar illness perceptions and QOL responses and are aware of the typical characteristics of their disease. The results support the feasibility of cross-cultural psychosocial research in oncology and offer implications for clinical interventions which impact on self-efficacy to empower patients with breast cancer.

Evaluation of the safety and tolerability of oral TAS-108 in postmenopausal patients with metastatic breast cancer.

BACKGROUND: The potential of TAS-108 for the treatment of breast cancer has been shown by preclinical studies. We therefore investigated the safe dosage, tolerability, and effectiveness on hormone levels and bone metabolism markers and the pharmacokinetics of TAS-108 administered in postmenopausal Japanese women with metastatic breast cancer. PATIENTS AND METHODS: The subjects had previously undergone standard endocrine therapeutic modalities. TAS-108 was given repeatedly to five patients each, at three dose levels (40, 80, and 120 mg p.o.) once a day after the first daily meal for a scheduled 8 weeks. Plasma concentrations of TAS-108 and its metabolites were measured at the scheduled time points. RESULTS: Fifteen patients received TAS-108 treatment. Orally administered TAS-108 was well tolerated at doses up to 120 mg and did not cause notable changes either in hormone levels or bone metabolism markers. Pharmacokinetic results indicated dose-dependent increases in plasma levels of TAS-108 and its metabolites. A steady state was achieved by 2 weeks at all dose levels, suggesting no marked accumulation. Clinical benefits were confirmed in 5 of 15 patients. CONCLUSIONS: Repeated oral administration of TAS-108 at doses up to 120 mg was well tolerated, and the plasma level of this compound increased dose-dependently.

Phase III trial of doxorubicin plus cyclophosphamide (AC), docetaxel, and alternating AC and docetaxel as front-line chemotherapy for metastatic breast cancer: Japan Clinical Oncology Group trial (JCOG9802).

BACKGROUND: This randomized, multicenter, phase III trial compared doxorubicin plus cyclophosphamide (AC), single-agent docetaxel (D), and an alternating regimen of AC and docetaxel (AC-D) as first-line chemotherapy in metastatic breast cancer (MBC). PATIENTS AND METHODS: Patients with MBC resistant to endocrine therapy were entered in a randomized study to receive either six cycles of AC (doxorubicin 40 mg/m2 plus cyclophosphamide 500 mg/m2), D (60 mg/m2), or alternating treatment with AC-D (i.e. three cycles of AC and three cycles of D). Treatment was administered every 3 weeks. RESULTS: A total of 441 patients were entered in a randomized study. Response rates were 30% for AC, 41% for D, and 35% for AC-D. The median times to treatment failure (TTFs) were 6.4, 6.4, and 6.7 months (one-sided log-rank test, P = 0.13 for AC versus D, P = 0.14 for AC versus AC-D) and median overall survival (OS) was 22.6, 25.7, and 25.0 months (P = 0.09 for AC versus D, P = 0.13 for AC versus AC-D) in the AC, D, and AC-D, respectively. CONCLUSION: There was no difference in the TTF among the three arms. However, there was a trend toward a better response and better OS in the D than in the AC.

Breath alcohol concentrations in Japanese outpatients following paclitaxel and docetaxel infusion.

Patients receiving paclitaxel or docetaxel also receive a significant amount of ethanol, as both products contain ethanol as solvent. Patients in our clinics have occasionally exhibited signs of alcohol intoxication immediately after paclitaxel infusion. In 2002, the Japanese government lowered the minimum ethanol concentration for the definition of drunk driving, with the threshold breath alcohol concentration (BRAC) of 0.15 mg/l. The aim of this study was to measure BRAC in Japanese outpatients treated with paclitaxel or docetaxel and to assess intoxication according to this standard. Fifty-two Japanese patients were enrolled from October 2003 to February 2004. Patient characteristics were as follows: male/female, 13/39: median age, 71 (range: 34-78); breast/lung/ovarian cancer 24/16/12; and paclitaxel/docetaxel treatment: 36/16, respectively. The mean total doses of paclitaxel or docetaxel were 178 mg (range: 107-300) and 53 mg (30-100), respectively. Breath samples were measured three times immediately following the infusion of paclitaxel or docetaxel via ethyl alcohol detector and the mean value was recorded. BRAC was detected in 20 patients (56%) with paclitaxel and in none of the docetaxel patients. BRAC was measured again 30 min after the initial measurement in BRAC-detected cases with the patients' permission. In four of six BRAC-remeasured patients, BRAC became undetectable after 30 min. There was no correlation between the total doses of paclitaxel and BRAC or between the infusion rates of paclitaxel and BRAC. In conclusion, clinicians should recognize the potential for alcohol intoxication with paclitaxel administration. Patients should be instructed to avoid driving on the day of paclitaxel administration.

Enzymatic oxidation and reduction of C19-delta5-3beta-hydroxysteroids by hepatic microsomes. V. Testosterone as a neonatal determinant in rats of the 7- and 16alpha-hydroxylation and reduction of 3beta-hydroxyandrost-5-en-17-one (DHA).

The oxido-reductive metabolism of [14C]dehydroepiandrosterone (DHA) by hepatic microsomes from 40- or 70-day-old rats of either sex castrated neonatally has been compared after several treatment regimens with testosterone propionate (TP). The low transformation rate of DHA to 16-oxygenated metabolites produced by neonatal orchiectomy (0.09 +/- 0.04 nmoles min-1 mg-1), was not restored in 70-day-old males by either neonatal or pubertal treatment with TP. The rates were only partially restored (0.74 +/- 0.44) toward nromal adult levels (1.30 +/- 0.16) by the combination of neontal and pubertal treatments, in increments that maintained normal body weight but produced no visible growth of the male accessory glands. The combination of neonatal and pubertal treatments with larger doses of TP enough to produce normal accessory gland growth, stimulated the enzymatic rates of 16alpha-7alpha-, or 7beta-hydroxylases to levels that exceeded those of intact adult males. In 40-day-old males, the 16-oxygenation rate was restored by the latter regimen, but only to the levels characteristic of yound males (0.56 +/- 0.24), and young females responded more (1.03 +/- 0.33) than the males. The 7-oxygenation rate of DHA responded in both age groups to smaller doses of TP than did that of the 16-oxygenation. None of these manipulations altered the reduction of DHA to androst-5-ene-3bets-17beta-diol. We conclude that testosterone activates hepatic DHA hydroxylases in pubertal male rats only if neonatal imprinting by testosterone preceeds the subsequent stimulus. In addition, the DHA 16alpha-hydroxylase of young males is less sensitive than that of young females, but this pattern is reversed by 70 days of age. The hepatic males are both sensitive to testosterone, but the response of the glands is diminished by age.

Enzymatic oxidation and reduction of C19-delta5-3beta-hydroxysteroids by hepatic microsomes. IV. Induction of DHA hydroxylases and aminopyrine N-demethylase in immature male rats by androgens.

The capacities of various C19 steroids for prematurely inducing the normal metabolic patterns of rat liver in adulthood (70 days old) have been studied with hepatic microsomes of 42-day-old males castrated on day 24, 30, 32, or 34 of life. Dehydroepiandrosterone 16alpha-hydroxylase activity was significantly reduced (P less than 0.05) by castration during this 10-day interval but the 7alpha- and 7beta-hydroxylases, the N-demethylation of aminopyrine, and cytochrome P-450 concentration were unaffected. Daily administration of testosterone stimulated the DHA 16-alpha- and 17beta-hydroxylases, aminopyrine N-demethylation, and increased the P-450 content, but suppressed the 7alpha-hydroxylase. These effects only appeared with more than 1 week of the continuous treatment. Testosterone was the most active of the androgens studied; dihydrotestosterone (DHT) increased the DHA 16alpha-hydroxylase to a lesser extent, but this steroid and etiocholanolone stimulated DHA 7alpha-hydroxylation; androsterone was totally ineffective. These data suggest that testosterone rather than DHT from pubertal testes plays a significant role in control of hepatic oxidative enzyme activities during puberty.

Formation of 6-hydroxylated progesterone in the human placenta and response to hCG.

The in vitro metabolism of 7alpha-3-H-pregnenolone by five term human placentas obtained from repeat cesarean section was studied. Incubations were carried out either with minced tissue for 1 h or by organ culture for 6 h and 24 h. Twenty-one experiments were performed to determine the effect of human chorionic gonadotropin (hCG), human placental lactogen (hPL), and heat-inactivated hCG on the metabolism of pregnenolone. The major radioactive product was progesterone (40-60%); unchanged pregnenolone accounted for only 5-15% of the radioactivity. 3-H-6beta-OH-progesterone was found and rigorously identified. In control experiments 6beta-OH-progesterone was 2-4% of the radioactivity. In the presence of hCG there was a significant (P smaller than 0.005) 2-3-fold increase of 3-H-6beta-OH-progesterone in the 1-h mince incubations and the 24-h organ cultures. There was no increase of 3-H-6beta-OH-progesterone over control values with hCG after 6-h organ cultures; with heat-inactivated hCG; or with hPL. These findings provide additional data that hCG affects steroid metabolism in the human placenta. In addition, 3-H-6alpha-OH-progesterone was found and rigorously identified in yields of approximately 0.5-1%. The effect of hCG on 6alpha-hydroxylation was not determined. This appears to be the first demonstration of 6alpha-hydroxylation of C21 steroids by human tissue.

Serum relaxin in patients with hydatidiform mole.

Human chorionic gonadotropin (hCG) is considered to be one of the factors that regulates relaxin secretion in humans. However, the secretory pattern of relaxin has not been evaluated in pregnancy complicated by hydatidiform mole, where circulating hCG levels are higher than in normal pregnancy. In the present study, relaxin, progesterone, and hCG levels were determined by radioimmunoassay in patients with hydatidiform mole before and after evacuation of the mole. Serum immunoreactive relaxin and progesterone levels in patients with hydatidiform mole were similar to those in normal women at corresponding weeks of pregnancy before evacuation of the mole, though hCG levels were significantly higher. The fall of relaxin levels after evacuation of the mole was slower than that of hCG or progesterone. This finding may reflect a continued stimulation of the corpus luteum by lower, but still effective, hCG levels persisting after evacuation of the mole. An extraluteal source of relaxin cannot be excluded.

Enhancement of immunohistochemical reactivity for thymidine phosphorylase in breast carcinoma cells after administration of docetaxel as a neoadjuvant chemotherapy in advanced breast cancer patients.

For the purpose of demonstrating possible effects of docetaxel on thymidine phosphorylase (TP) activity in human breast carcinoma, we examined breast carcinoma tissues pre- and post-administration of docetaxel, by an immunohistochemical method using an anti-TP monoclonal antibody. Eight patients with advanced breast carcinoma were initially treated with 3 cycles of 60 mg/m2 of docetaxel once every 3 weeks after incisional biopsy of tumors, and following 3 cycles of docetaxel, they underwent mastectomy with axillary dissection. Grades of immunohistochemical reactivity for TP of carcinoma cells in pre- and post-treatment specimens were compared. Five biopsy specimens (62.5%) were positive for TP. After administration of docetaxel, 6 of 8 cases (75.0%) revealed significant enhancement of reactivity for TP. Increased reactivity was recognized diffusely as well as focally in carcinoma tissues. From these results, we believe that administration of docetaxel to breast cancer patients evokes enhancement of immunohistochemical reactivity for TP in breast carcinoma cells in situ. Furthermore, we consider that docetaxel treatment might improve efficacy of additional doxifluridine and capecitabine therapy.

The role of interleukin-6 in inhibition of lung metastasis in subcutaneous tumor-bearing mice.

Metastasis is the most important factor for prognosis in cancer patients, and its occurrence is largely associated with host immune response. We found that the presence of a growing tumor of colon 26, a mouse colon cancer cell line, completely inhibited lung colony formation in a mouse injected with colon 26 intravenously, whereas depletion of effector cells, such as natural killer and T cell subsets, did not affect antimetastasis of colon 26. Since colon 26 releases large amounts of interleukin-6 (IL-6) spontaneously, we studied the association of IL-6 with lung metastasis. Serum IL-6 level increased gradually and reached 12.6 pg/ml five days after inoculation of colon 26 in the back of mice, while at the same time, lung colony formation was inhibited. Moreover, expression of IL-6 mRNA in lung was observed to be associated with elevated serum IL-6 level. We show the first evidence that inhibition of lung metastases in tumor-bearing mice by colon 26 is closely associated with an increase in serum IL-6, but not in cellular immunity.

Relationship between existence of lymphatic invasion in peritumoral breast tissue and presence of axillary lymph node metastasis in invasive ductal carcinoma of the breast.

Specimens obtained from 92 patients with invasive ductal carcinoma of the breast by quadrantectomy and axillary lymph node dissection were examined to evaluate the relationship between existence of lymphatic invasion in peritumoral breast tissue and presence of axillary lymph node metastasis. The number of lymphatic invasions was classified into 4 groups (ly0-3) by counting the number of peritumoral lymphatic invasions. In addition, immunohistochemistry for cytokeratin was performed to locate micrometastasis in the dissected lymph nodes. Thirty-seven (40.2%) of 92 cases had foci of lymphatic invasion and 29 (31.5%) cases revealed lymph node metastasis on initial routine examination. The rate of diagnosis of lymph node metastasis assessed by the existence of lymphatic invasion had an accuracy of 84.8%, a sensitivity of 89.7% and a specificity of 82.5%. On the other hand, all 3 cases (4.8%) with micrometastasis detected by immunohistochemistry for cytokeratin, showed lymphatic invasion. The rate of diagnosis after detection of micrometastasis increased and exhibited 88.0% accuracy. In addition, the rate of prediction of lymph node metastasis in cases with tumor larger than 15 mm was also high, and its accuracy was 88.2%. These results suggest that the assessment of peritumoral lymphatic invasion is very useful for predicting the presence of axillary lymph node metastasis including micrometastasis. They also suggest that excision specimens should be examined for lymphatic invasion, and that the results of the examination might be necessary to pick up false-negative cases and those at high risk for lymph node metastasis among patients who have not undergone lymph node dissection based on the result of sentinel lymph node biopsy.

Relationship between grade of intraductal component of breast cancer within main tumor and extent of intraductal spread in surrounding tissue.

Ninety-three specimens obtained by quadrantectomy of invasive ductal carcinoma of the breast were examined to evaluate the correlation between the grade of the intraductal component within the tumor and the extent of intraductal spread in the surrounding tissue. We used immunohistochemistry of a-smooth muscle actin to visualize the contour of intraductal components. The grade of the intraductal component within the tumor was classified into 4 groups (td0 to td3) by counting number of intraductal components; the extent of intraductal spread in the surrounding tissue was also divided into 4 groups (sd0 to sd3) according distance from the tumor margin. Fifty-eight (89.2%) of 65 cases with low-grade td were low-grade sd, and 17 (60.7%) cases of high-grade td were high-grade of sd. The grade of the intraductal component correlated with the extent of intraductal spread in the surrounding tissue, significantly (p < 0.001, Spearman rank correlation test). From these results, we believe that investigation of intraductal components within the tumor is useful for estimating the extent of intraductal spread in the surrounding tissue, and excision specimens from diagnostic lumpectomy should be examined for the extent of the intraductal component, the results being important in estimating the risk of local recurrence.

Interruption of pregnancy with vaginal suppositories containing 16,16-dimethyl-trans-delta 2-prostaglandin E1 methyl ester.

A new synthesized Prostaglandin E1 analogue, 16,16-dimethyl-trans-delta 2-Prostaglandin E1 methyl ester, has been shown to be effective in termination of 1st and second trimester pregnancy following vaginal administration. Suppositories, each containing 1 mg Prostaglandin E1 derivative, were administered five times to each of fifty pregnant women of five to twenty gestational weeks at three-hourly intervals. The procedure was clinically effective in 86% of the patients resulting in 56% complete and 30% incomplete abortions. The cervix of all patients was dilated up to 7 mm in diameter at the second insertion of the suppository. Vaginal bleeding and lower abdominal pain not requiring sedation were observed in all patients. Diarrhea (42%), vomiting (6%), and fever (4%) were the most common side effects. The Karyopyknotic Index of the vaginal smear increased significantly (p less than 0.01) twelve hours after the initial insertion. The superficial cells of the cervix gradually degenerated during the termination procedure.

PIP: 16,16-dimethyl-trans-delta2-prostaglandin El methyl ester, a newly synthesized prostaglandin E1 analogue (PGE), was evaluated to determine the clinical and cytological characteristics and efficacy of vaginally administered PGE for termination of 1st and 2nd trimester pregnancies. 50 16-45 year-old, 5-20 week pregnant, women were studied. Suppositories, each containing 1 mg of PGE derivative, were administered 5 times to each woman at 3-hour intervals. The procedure was clinically effective in 86% of the patients, resulting in 56% complete and 30% incomplete abortions. Cervix of all patients was dilated up to 7 mm in diameter at the 2nd insertion. Vaginal bleeding and lower abdominal pain, not requiring sedation, were observed in all patients. Vaginal smear karyopyknotic index increased significantly (P .01) 12 hours after the initial insertion. Superficial cells of the cervix gradually degenerated during the termination procedure. No significant difference in cervical dilatation was observed between parous and nonparous study participants.

Bone scanning with 99m-Tc-phosphates: a comparison and problems in the detection of tumor metastasis.

A comparative study on 99m-Tc-phosphate compounds (TcPP) in detecting tumor metastasis to bone and problems accompanying it are reported. TcPP revealed metastatic foci which are unrecognized by conventional bone survey. To recognize these foci, exclusion of following problems is necessary: Accumulation at front of neck, asymmetrical image of joint, increased bone density of the aged, Tc-photon absorption and radiotherapy effect. The mechanism of TcPP accumulation is discussed.

5'-deoxy-5-fluorouridine, medroxyprogestrone acetate and mitoxantrone hydrochloride for advanced or recurrent breast cancer.

BACKGROUND: In treating advanced or recurrent breast cancer, anthracycline-containing chemotherapy is used for palliation and to maintain quality of life. However, there are several drawbacks including therapeutic failure and cardiotoxicity. We evaluated the efficacy and toxicity of combination chemotherapy with 5'-deoxy-5-fluorouridine (5'-DFUR), medroxyprogestrone acetate (MPA) and mitoxantrone hydrochloride (MIT). METHODS: Sixteen patients with advanced or recurrent breast cancer were enrolled. Chemotherapy was given in a 28-day cycle, starting with MIT 10 mg/m2 intravenously on day 1, then oral 5'-DFUR 800 mg and MPA 800 mg daily. Two or more cycles were given. RESULTS: Fifteen patients were assessable for response and toxicity. Thirteen patients had been treated previously with an anthracycline containing regimen and 2 with CMF. There were 2 partial response patients (13.3%) and 1 complete response patient (6.7%). There were 11 patients showing no change (NC) (73.3%), one of whom was a minor responder and 7 with a long period of NC. There was only one with progressive disease patient. The overall response rate was 20.0%. Adverse events occurred in 5 patients (33.3%). Myelosuppression was the most common with 5 patients becoming leukopenic (33.3%). Nausea/vomiting was the second most common side effect, affecting 2 patients (13.3%). CONCLUSION: Given its high efficacy and preservation of QOL, the combination of MIT, 5'-DFUR and MPA can be a 2nd or 3rd line therapy for advanced or recurrent breast cancer, especially for anthracycline-resistant cases.

[Effects of antibiotics in the prevention of infections following vaginal and abdominal hysterectomy: an evaluation by febrile morbidity and fever index].

The current references written in English concerning effect of prophylactic antibiotics in vaginal and abdominal simple hysterectomy have been reviewed. Febrile morbidity was evaluated for antibiotic treated and untreated groups. In most studies, the definition of febrile morbidity was a temperature of 38 degrees C or greater on 2 separate occasions excluding the first 24 hours after the operation. Fever index in degree hours was also compared between 2 groups in some studies. Of 30 studies in vaginal hysterectomy reported between 1969 and 1981, 29 showed that antibiotic prophylaxis successfully decreased postoperative febrile morbidity. Of 15 studies in abdominal hysterectomy reported between 1972 and 1982, 12 showed the significant decrease of febrile morbidity in the treated group. However, pelvic infection in only 2 and wound infection in 5 were reduced. The length of hospital stay was found to be shorter for the treated group in vaginal and abdominal hysterectomy. The beneficial effect of prophylactic antibiotics in abdominal hysterectomy were less compelling than those for vaginal hysterectomy. Although recent studies indicated that a short perioperative use of antibiotics or even a single dose was effective as long-term prophylaxis, the most effective method and duration awaits further evaluation.

[How to determine the prophylactic effect on postoperative infections].

With the cooperation of 13 medical institutions in the Tokyo area, the methods to determine the prophylactic effect on postoperative infections in gynecological surgery were evaluated. Two hundred and ninety-nine patients were enrolled for the study of postoperative infections, febrile morbidity and fever index following abdominal (275) and vaginal (24) hysterectomies. Prophylactic cefotiam (CTM) of 1 gram was intravenously administered twice a day postoperatively for 3 to 5 days. The rates of postoperative infections were 5.1% (14/275) in abdominal hysterectomy and 4.2% (1/24) in vaginal hysterectomy. The febrile morbidity (57.1% = 8/14) and fever index (52.3 +/- 41.1 degree hours) in the infection group were approximately about 4 times higher than those (12.3% = 32/261, and 15.6 +/- 13.7 degree hours, respectively) in the non-infection group. No significant differences were observed in age, body weight, height of patients, period of operation and blood loss between these 2 groups. These data suggested that febrile morbidity and fever index were able to indicate the prophylactic effect of antibiotics on patients undergoing abdominal and vaginal hysterectomies.

[Laboratory and clinical studies on latamoxef in the field of obstetrics and gynecology].

Latamoxef (LMOX) is a new antibiotic synthesized by Shionogi Research Laboratory. Chemically LMOX is especially unique with a sulfur atom replacing the oxygen atom in the 1 position of the conventional cephalosporin nucleus, and in addition, this antibiotic has a cephamycin-like structure. The antibacterial activity of LMOX shows high potency against Gram-negative bacteria, but tends to be weak against Gram-positive bacteria. The tissue levels of LMOX in humans after intravenous injection of 1 g were examined. The levels in uterine and adnexa uteri tissue at 1 hour after administration were 25.4 and 27.4 micrograms/g respectively. LMOX was administered to 147 cases in infections of obstetric and gynecological field. The clinical effect according to disease was 94.6% for intrauterine infections, 95.0% for adnexitis, 87.0% intrapelvic infections, and 100% for external genital organ infections, making a total of 92.5%. The rate of occurrence of side effects or abnormal laboratory findings was similar to or slightly less than that seen with other beta-lactam antibiotics.

[Therapeutic efficacy of pirarubicin cyclophosphamide and doxifluridine in advanced and metastatic breast cancer].

Twenty-four eligible patients (23 of whom were evaluated) with advanced and metastatic breast cancer were treated at the Saitama Cancer Center every 4 weeks with pirarubicin (30 mg/m2 i.v., day 1 and 8), cyclophosphamide (200 mg/m2 div, day 1 and 8) and doxifluridine (800 mg/day po, day 1-14). The 23 evaluable patients had a median age of 49.7 years (range 35.3-72.1) and underwent a median number of 3 cycles (range 2-5). Grade 4 leukopenia (10/24 patients) was the dose-limiting factor and led to infection in one patient. Four complete responses and 7 partial responses with a median duration of 12.1 months (range 2.6-61.0) were achieved, resulting in an overall response rate of 47.8%. The 50% survival duration was 22.9 months.

[Combination chemotherapy with vinorelbine and other cytotoxic agents for advanced breast cancer patients--a protocol of vinorelbine plus AC regimens used by the Japan Vinorelbin Study Group].

A new generation type of vinca alkaloid, vinorelbine (VNR), is a promising agent for the treatment of breast cancer patients. As a first line treatment for metastatic breast cancer, combination chemotherapy including anthracyclines plus VNR has demonstrated a high response rate and tolerability. In addition, other VNR containing regimens, such as 5-fluorouracil plus VNR, produced a 64% response rate. This evidence suggests VNR-containing combination chemotherapy may be a promising first-line treatment for breast cancer patients. In Japan, VNR is not registered, but a late phase II study has been completed. An approximately 30% response rate was obtained with its use as a monotherapy. In addition, a phase I/II study of combination VNR plus AC (adriamycin + cyclophosphamide) has been conducted. At the present time, the results are being analyzed.