Plasma concentrations of toremifene citrate and N-desmethyltoremifene in postmenopausal patients with breast cancer--comparison of 120 mg of toremifene citrate administered once a day and divided into 3 separate doses (t.i.d.)

To determine whether plasma concentrations of toremifene citrate after administration of 120 mg/day of toremifene citrate given in three separate dose (t.i.d.) were similar to those when toremifene citrate was administered in a single daily doses (40 mg x 3 tablets), we examined changes in plasma concentrations of toremifene citrate (TOR) and its metabolite, N-desmethyltoremifene (TOR-1). In both the t.i.d. administration group and the single-dose administration group, plasma TOR and TOR-1 concentrations reached a constant state within 2 weeks after administration was started. Under the constant state, plasma TOR concentrations were 1,493.3 +/- 120.3 ng/ml in the t.i.d. administration group and 1,348 +/- 341.0 ng/ml in the single-dose administration group. Plasma TOR-1 concentrations were 2,378.3 +/- 186.5 ng/ml in the t.i.d. administration group and 2,144 +/- 475.3 ng/ml in the single-dose administration group. In both groups, plasma TOR-1 concentrations were 2 or more times higher than plasma TOR concentrations. These results show there were no differences in plasma concentrations between administration of 120 mg/day of toremifene citrate in divided daily doses (t.i.d.) and in a single daily dose. The two administration methods appear to produce clinically similar actions.     

A case of breast cancer with multiple bone metastases demonstrating complete remission with high-dose toremifene therapy

We report a 64-year-old woman who underwent mastectomy for stage II (T2N1M0) advanced breast cancer, in whom multiple spine metastases developed 18 months postoperatively. She received 6 cycles of CA (cyclophosphamide 500 mg/m2, ADM 50 mg/m2 3 wq) therapy and oral tamoxifen (20 mg/body) administration for adjuvant therapy. The multiple bone metastases of the spine were revealed by technetium bone scan. The level of serum tumor marker CA15-3 increased two times over the normal range 18 months after surgery. She also developed osteoporosis a few years later, so we selected high-dose toremifene administration (120 mg/body) as a second-line therapy. No adverse effects have occurred and bone metastases disappeared. Moreover, the tumor marker was also normalized 6 months after toremifene therapy started. It was shown that high-dose treatment of toremifene was useful for recurrent breast cancer with bone metastasis.     

Effective treatment with oral administration of UFT and leucovorin (Uzel) in a patient with liver metastasis and peritoneal dissemination from cecal cancer

A 70-year-old woman had been diagnosed with advanced cecal cancer with liver metastasis. She had initially undergone a right hemicolectomy for cecal cancer. Although secondary surgery for liver metastasis was performed 2 months after initial surgery, the intra-operative findings showed peritoneal dissemination of diaphragm and ligament teres and liver metastasis, making curative resection impossible. Therefore , combination oral administration of UFT and LV (Uzel) was started (UFT 300 mg/day, LV 75 mg/day, 4 weeks of therapy followed by a 1-week treatment break). Two months after 4 courses, the liver metastasis had markedly diminished and CEA was within the normal range. A good complete response of the liver metastasis was achieved. In conclusion, this treatment was convenient and effective.     

A 23-year delayed locoregional recurrence of breast carcinoma following mastectomy

A 77-year-old woman who underwent a right modified radical mastectomy 23 years ago with no further adjuvant treatment presented with a right chest wall mass (3 x 4 x 2 cm) at the scar. She had no symptoms nor metastasis. The laboratory data were normal including tumor marker. The mass was diagnosed as compatible with a local recurrence tumor from the previous breast cancer on the ultrasonography and chest CT. After obtaining her informed consent for the therapy, we performed 60 Gy/30 fr radiotherapy on the recurrent tumor on her right chest wall with concurrent oral chemo-endocrine therapy. The first regimens were tamoxifen 20 mg/day and 5'-DFUR 600 mg/day, followed by toremifene 80 mg/day and 5'-DFUR 600 mg/day, and then the tumor disappeared. But three years later, we found tumor regrowth. We changed the regimen, giving 5'-DFUR 1,200 mg/day and cyclophosphamide 100 mg/day for 2 weeks followed by a 1-week drug-free period, then added 10 Gy/5 fr radiotherapy and hyperthermia twice a week. Final regimens were anastrozole 1 mg/day and capecitabine 900 mg/day. The recurrent tumor decreased and the disease stabilized. After these therapies, she had very good quality of life. We recommend radiation and/or hyperthermia with concurrent oral chemo-endocrine therapy as useful for the delayed recurrence of elderly breast cancer after a modified radical mastectomy.     

Bone Mineral Density and Lipid Changes During 5 Years of Follow-up in a Study of Prevention of Breast Cancer with Toremifene in Healthy,High-risk Pre- and Post-menopausal Women

Summary A double-blind, randomised, placebo-controlled pilot study was initiated to evaluate the feasibility of chemoprevention with toremifene 60 mg/day in healthy women at high risk for breast cancer. Enrolment in the study was terminated earlier than planned because of slow patient accrual, although 13% of patients continued for 5 years. The revised efficacy outcomes were change in bone mineral density (BMD) from baseline at four skeletal sites, plus effects on serum lipids. In premenopausal women there was a trend for sustained increase in BMD during toremifene therapy after year 1 in lumbar spine. In postmenopausal women, toremifene had little or no effect on BMD trends. Levels of total and low-density lipoprotein (LDL) cholesterol were largely unchanged from baseline in premenopausal women treated with toremifene but were often slightly lower than in the placebo group during follow-up. Total and LDL cholesterol levels declined slightly from baseline in the postmenopausal women and were, at several points during the first 3 years, significantly lower than in the corresponding placebo group (p < 0.01). We conclude that: (a) assessment of toremifene 60 mg/day in chemoprevention will require further clinical trials; (b) toremifene 60 mg/day has no substantive negative effects on BMD in pre- or postmenopausal women and may exert a minor favourable influence (in particular, the effects of toremifene 60 mg/day on BMD in premenopausal women may make the drug an attractive alternative to tamoxifen 20 mg/day for that patient subset); (c) lipid effects of toremifene 60 mg/day are, at minimum, neutral and may be modestly favourable for reducing cardiovascular risk.     

A case of remnant gastric cancer with multiple bone metastasis and peritoneal dissemination; efficacy of combination therapy of docetaxel and TS-1

A 69-year-old female underwent radical surgery for advanced gastric cancer (Stage IIIA) 7 years ago. She was diagnosed as remnant gastric cancer with multiple bone metastasis and peritoneal dissemination. Treatment with docetaxel and TS-1 was started with the following regimen: daily oral administration of 100 mg/body TS-1 for 14 days, followed by a 7 day rest and infusion of 40 mg/m2 docetaxel on day 1. Two months after the initial administration of docetaxel/TS-1, the sites of the remnant gastric cancer and bone metastasis were reduced in size, and the ALP returned to almost the normal level. The site of peritoneal dissemination had disappeared. Currently (nine months after diagnosis), she is undergoing therapy with TS-1. The combination of docetaxel and TS-1 can be a new tool for the management of gastric cancer with bone metastasis.     

A case of liver metastases from cecal cancer successfully treated with fluorouracil and folinic acid (UFT/LV)

A 76-year-old man had undergone a right hemicolectomy for cecal cancer. Oral UFT (450 mg/day) administration alone was started 2 months following the operation. From a CT scan of the abdomen performed 3 months postoperatively, he was diagnosed with liver metastasis. Because the liver metastasis had progressed, combination oral administration of UFT+LV was started (UFT 450 mg/day, LV 75 mg/day, 4 weeks of therapy followed by a 1-week treatment break). After 1 cycle, a good partial response of that lesion was achieved. The pulmonary metastasis had almost disappeared to within normal limits. In conclusion, this treatment was very safe and effective.     

Antiangiogenic and antimetastatic effects of toremifene citrate

In this study, we demonstrated that toremifene citrate (TOR) inhibited the tube formation and migration of human umbilical vein endothelial cells (HUVEC) in vitro. Moreover, TOR suppressed angiogenesis in rabbit cornea and lung metastasis of human fibrosarcoma HT-1080 cells in nude mice. The antiangiogenic activity in vitro was apparent at the concentration of 5 microM which is clinically achievable by oral administration of 120 mg/kg of TOR. These results suggest that clinical treatment with 120 mg/day of TOR might be expected to exhibit antiangiogenesis and antimetastasis effects, in addition to inhibition of estrogen-dependent tumor cell growth.     

A case of gastric cancer with multiple bone metastasis that responded to S-1 with low-dose cis-platinum

We report a patient with multiple bone metastasis who was treated successfully using S-1 and low-dose cis-platinum (CDDP). Metastasis was diagnosed 4 years after distal gastrectomy for early gastric cancer in a woman now 68 years old. Surgery was performed on February 9, 1999. The primary tumor was located in the midportion of the gastric body, and had invaded the submucosa with metastasis to lymph nodes in the area of the lesser curvature. She was discharged from our hospital 24 days after surgery. About 4 years after surgery, she experienced a backache and her CEA and CA19-9 levels had risen to 15.30 ng/mL and 996.5 U/mL, respectively. The results of an imaging examination were suggestive of multiple bone metastasis. Treatment with S-1+CDDP was started with the following regimen: daily oral administration of 100 mg/body/day S-1 for 14 days, followed by a 7-days rest and CDDP 20 mg/body infusion on day 1 and 8. Three months after initiation of therapy, the CEA and CA19-9 levels decreased 2.80 ng/mL and 36.8 U/mL, respectively. No severe adverse effects were observed with this therapy. The combination of S-1 and CDDP can be a good tool for the management of gastric cancer with bone metastasis.     

Combination therapy of fluoropyrimidine (TS-1) administration and selective intra-arterial cisplatin infusion for tongue carcinoma--a case report

A 64-year-old male with primary squamous cell carcinoma of the tongue (T3N0M0) was treated with the novel fluoropyrimidine oral anticancer drug TS-1 and selective intra-arterial infusion of CDDP. His past history revealed pulmonary emphysema as a complication. Since his pulmonary function was reduced and it would have been difficult to perform surgery under general anesthesia, we started administration of TS-1 (100 mg/day) first and added selective arterial infusion of CDDP (5 mg/day) after one week of TS-1. On day 8 of TS-1 administration (day 2 of arterial infusion), the tumor had shrunk considerably, and on day 15 of TS-1 administration (day 9 of arterial infusion) the tumor had almost completely disappeared. Nausea and vomiting developed as adverse effects on day 20 of TS-1 administration (day 14 of arterial infusion), and administration of the anticancer drugs was stopped. Nutrition management and an antiemetic agent were started by intravenous drip infusion, and the adverse effects improved one week after administration was stopped. By the 5th week after the start of treatment, the tumor had disappeared macroscopically, and a CR had been achieved. Interstitial radiotherapy was performed as supplemental therapy, and as of this writing, September 3, 2002, 16 months after the start of treatment, the patient is being followed on an outpatient basis. His course has been favorable and recurrence-free. Although there were some slight adverse reactions, they were relatively mild, and since sufficient efficacy was observed, oral TS-1 plus selective intra-arterial CDDP therapy was concluded to be an effective method of treatment for patients with a past medical history making their general condition unfavorable.     

A case of hepatic arterial infusion chemotherapy with docetaxel for liver metastasis from breast cancer

We experienced a case of hepatic arterial infusion chemotherapy using docetaxel for liver metastasis, which showed no response to CEF therapy, from breast cancer. A 63-year-old woman had undergone modified radical mastectomy for right breast cancer (T2aN1bM0: Stage II) in October, 1995. Six-cycle CMF therapy and toremifene citrate (40 mg/day) were administered as adjuvant therapy, but multiple recurrent tumors in liver, lung, and local site were detected in February 1997. Six-cycle CEF therapy was given for recurrent disease and there was a complete response for lung and local recurrence, but no change in liver metastasis. Chemoendocrine therapies using 5'-DFUR or CMitF in addition to TAM and fadrozole hydrochloride hydrate had developed progressive disease for liver metastasis. A catheter and port kit were operatively inserted and implanted in March 1998. Hepatic arterial infusion of docetaxel (30-40 mg/body/month, one hour administration) was repeated 4 times, once in our clinic. Leukopenia, general fatigue and fever, which were mild and did not require any treatment, appeared as side effects. This treatment reduced multiple liver metastatic sites on abdominal CT finding and was thought to be a partial response. However, the patient had multiple brain metastasis and died on August 2, 1998. While docetaxel, even by systemic administration, has a 36-77% response rate for liver metastasis, arterial infusion might have a good response and mild side effect with a lower dose than by intravenous administration.     

A case of unresectable advanced gastric cancer with peritoneal dissemination responding to UET/low-dose CDDP combination chemotherapy

We report the case of a 69-year-old female with unresectable gastric cancer (T3, N2, P3, H0, Stage IVb) accompanied by peritoneal dissemination, diagnosed on laparotomy. UFT/low-dose cisplatin (CDDP) combination chemotherapy was performed after surgery. UFT 300 mg/day was administered orally every day, and CDDP 10 mg was injected intravenously every week. Chemotherapy was continued for ten months with a total dose of CDDP of 380 mg, but was stopped after oral mucositis developed as a side effect. Seven months after the chemotherapy was started, endoscopy revealed that the gastric cancer tumors had disappeared and the gastric mucosa was intact. Gastric cancer recurrence occurred 2 years and 2 months after chemotherapy was started. Low-dose CDDP/5-FU chemotherapy and TS-1 chemotherapy were performed, but no effects were observed. The patient died 3 years and 6 months after the start of initial chemotherapy, and was treated as an outpatient for 3 years while maintaining a good quality of life. UFT/low-dose CDDP combination chemotherapy offers promise as an effective tool in the clinical management of advanced gastric cancer with peritoneal dissemination.     

Phase I study of NK 622 (toremifene citrate)]

A phase I study of NK 622 (toremifene citrate), a novel antiestrogen, was conducted in female patients with cancer. Patients received a single oral dosing or daily once oral dosing for five consecutive days. Any adverse effects were not experienced in the single dosing of 40 or 60 mg of NK 622. In the daily administration of 10, 20, 40, 60, 120, 240 and 480 mg/day, one of three patients who received 20 mg/day experienced grade 1 anorexia, three of four patients received 240 mg/day experienced adverse effects: Grade 1 leukopenia in one patient, Grade 1 general hot flush in one patient, and Grade 1 nausea, hot flush in the face and vertigo, Grade 2 anorexia, fatigue, dull headache and general hot flush in another one patient. These symptoms recovered to normal levels after treatment. Serum hormone levels were examined in postmenopausal patients, and a significant increase of the sex hormone binding globulin level was observed in the patients received 120 and 240 mg/day doses. Serum levels of NK 622 determined as free base (TOR) reached the peak levels in 2 to 4 hours after administration on the 1st and 5th day in daily treatment, while a metabolite N-demethyltoremifene (TOR-1) reached the peak level in 4 to 170 hours. Maximum serum levels and area under the concentration versus time curves of TOR and TOR-1 increased dose-dependently. These values also increased by repetition of the treatment. Half-lives of TOR and TOR-1 in serum ranged in 74.5 to 148.9 hours and 154.1 to 653.1 hours, respectively. From these results, it was concluded that safety and efficacy of NK 622 should be assessed by using 240 mg or less doses in clinical phase II studies where breast cancer patients received long term treatment with NK 622.     

High-dose toremifene in advanced renal-cell carcinoma

 Toremifene (Fareston) – a novel antiestro-genic drug with a triphenylethylene structure – is effective in the treatment of postmenopausal breast cancer patients. It can be safely given even at high doses of up to 300 mg/day. The purpose of the present study was to investigate the effect and tolerability of high-dose toremifene in the treatment of patients with advanced renal-cell carcinoma (RCC). A total of 36 patients started treatment with toremifene at 300 mg/day, including 26 men and 10 women. Their mean age was 56 years (range 35–75 years). In all, 19 patients were nephrectomized. One patient was not evaluable for response because of insufficient treatment time. The response rate was 17%, including one complete response (CR, 3%) lasting for 121+ weeks and five partial responses (PRs, 14%) with a mean duration of 40+ weeks. Ten cases of no change (NC, 28%) had a mean duration of 24 weeks. There was no significant difference in the response rate when patients with lung metastases alone were compared with patients showing metastases of other sites with or without lung metastases. Total pain control was achieved in 45% of the patients who had pain at the beginning of the treatment, and partial control was attained in 20%. Ten patients (28%) developed adverse reactions, which led to discontinuation of the treatment in one case. Blood samples were taken from 16 patients on days 0, 1, 3, 7, 14, and 28 for drug analyses. The concentration of toremifene and its main metabolites measured in serum were about 1.5 times that detected after a conventional dose of 60 mg/day. It can be concluded that high-dose toremifene is an effective and safe palliative treatment in advanced RCC. Received: 5 May 1996 / Accepted: 5 November 1996     

Successful endocrine chemotherapy in patients with multiple bone metastases of breast cancer--a case report]

A 54-year-old woman was admitted to our hospital with upper and lower back pain. She had previously developed multiple bone metastases of advanced breast cancer. Endocrine chemotherapy of tamoxifen citrate (TAM) 20 mg/day and carmofur (HCFU) 300 mg/day was started. Subsequently, medroxyprogesterone acetate (MPA) 600 mg/day and 5'-deoxy-5-fluorouridine (5'-DFUR) 600 mg/day were administered. In evaluating the treatment effect for symptomatic relief, partial response and performance status were judged to have improved from 4 to 2. At present, the patient is able to walk on her own to the hospital. She has lived 4 years with no newly developed lesions, and no adverse effects such as diarrhea or body weight gain have been observed. Substantial results can be achieved in patients with bone metastasis of breast cancer even with mild endocrine chemotherapy. A combination of radiotherapy, pain control, and orthopedic surgery suitable to each case is thought to be necessary.     

Topical toremifene: a new approach for cutaneous melanoma?

The distribution of topically applied toremifene (0.5–1 mg/day for 5 days) in the ultraviolet B (UVB)-inducedMonodelphis domestica opossum melanoma model was examined. The mean concentration of toremifene measured in the skin was 1200 nmol/g, or >500 times that detected in any other tissues (blood, brain, liver, testicles, heart, uterus, eyes). In plasma, toremifene could be detected in only one animal of six (0.04 nmol/ml). Intraperitoneal administration of 0.5 mg toremifene daily for 5 days in three female animals resulted in a mean uterus concentration of 22.9 nmol/g, or 400-fold that achieved by topical administration of 0.5 mg/day in three other femaleMonodelphis (0.05 nmol/g). The cytostatic effect of toremifene was studied in three human melanoma cell lines and three experimental cell lines derived from UVB-induced melanocytic nevi inM. domestica. Toremifene had a cytostatic effect on all cell lines (50% growth-inhibitory concentrations, 5.8–9.6 M). Topical toremifene administration yields high local concentration with minimal systemic distribution. In addition, toremifene has a cytostatic effect at achievable concentrations in a variety of melanomatous cell lines.     

A case of breast cancer with multiple bone metastases improved by high-dose toremifene]

A 63-year-old woman underwent modified radical mastectomy with 3 cycles of adjuvant chemotherapy (cyclophosphamide, epirubicin, 5-fluorouracil) and MPA endocrine therapy for breast cancer. Because of nausea and general fatigue, she refused to continue this therapy and did not visit the hospital. When she came our hospital and 16 months later, she had developed multiple bone metastases. At the same time, she was suffering from lung tuberculosis. She was treated with toremifene at a dose of 120 mg/day without any side effects. After 3 months administration of toremifene, pain disappeared and her high serum CA15-3 and BCA225 dropped to within the normal range. On bone scintigrams, abnormal accumulation almost disappeared after 9 months of administration of toremifene. In this case, the patient was suffering from lung tuberculosis and did not desire intensive chemotherapy. Administration of high-dose toremifene was effective for multiple bone metastases without any side effects.     

Pharmacokinetics of toremifene and its metabolites in patients with advanced breast cancer

Summary A multicenter phase I pharmacokineticstudy of a new triphenylethylene antiestrogen, toremifene, was examined in 70 patients with advanced breast cancer. Patients were randomized to receive single daily oral doses of either 10, 20, 40, 60, 200, or 400 mg for 8 weeks. Plasma toremifene and its major metabolites,N-desmethyltoremifene and 4-hydroxytoremifene, were determined weekly during therapy and at 0, 7, 14, and 21 days after the discontinuation of therapy. The time to reach steady-state plasma concentrations was between 1 and 5 weeks, with steady-state being achieved earlier (1–2 weeks) at daily doses of 200 and 400 mg. The time to peak concentration following oral doses of toremifene ranged from 1.5 to 4.5 h. The terminal half-life of elimination was 5.0, 6.0, and 5.0 days for toremifene, desmethyltoremifene, and 4-hydroxytoremifene, respectively. Plasma concentrations of 4-hydroxytoremifene were detectable only at high doses (200 and 400 mg/day) of toremifene. The results of this phase I pharmacokinetic study show that toremifene has metabolic and kinetic patterns that are similar to those previously reported with tamoxifen.This work was supported by a grant from Adria Laboratories     

A case of advanced colon cancer with peritoneal dissemination completely responding to TS-1

A 55-year-old man was referred to us after transverse colostomy for intestinal obstruction caused by descending colon cancer with peritoneal dissemination. The colon lesion was palpated as a well-defined hard mass in the left lower abdomen and the disseminated lesion as a hard mass with an unclear border in the right lower abdomen. CEA level was 917 ng/ml at admission. Left hemicolectomy was performed for tumor reduction and TS-1 of 120 mg/day was started 6 days after surgery (4 weeks administration followed by a 2-week rest period). Administration discontinued due to nausea 4 weeks after commencement of the therapy, and restarted as a 2-week administration followed by a 2-week rest period. There has been no adverse reaction since then. Twenty-seven weeks after surgery, CEA level was reduced to 47 ng/ml and peritoneal dissemination was found to have disappeared upon physical examination and computed tomograph. TS-1 is expected to be an effective agent for the treatment of colon cancer with peritoneal dissemination.     

Evaluation of combination therapy of high-dose toremifene and oral chemotherapy

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.