A 63-year-old male with advanced esophageal cancer was admitted to our hospital. He received neoadjuvant chemotherapy with intravenous cisplatin and fluorouracil (5-FU), and underwent resection of the esophagus and placement of a gastric tube. Two months later, multiple metastases appeared in the right lobe of the liver. Intermittent arterial infusion chemotherapy with cisplatin and 5-FU were performed. To selectively infuse the drugs into the right hepatic artery, the left hepatic artery was embolized. Treatment had a marked effect in the right lobe, but new lesions were subsequently discovered in the left lobe. The patient died of pleuritis 27 days after the end of cisplatin infusion and 12 months after surgery. In total, 465 mg of cisplatin and 20 mg of nedaplatin were administered. At autopsy, tissue samples were collected to measure the platinum concentration. The result showed the highest value to be in the right lobe, 4.8 times as high as that in the left lobe. It is suggested that the concentration of platinum in tissue is correlated with the anticancer effect of cisplatin to the tissue, despite of the traditional view that the tissue concentration and the effect are not related.

A pilot trial was conducted to assess the tolerability and efficacy of a regimen with weekly docetaxel (TXT) in patients with metastatic breast cancer. The chemotherapy regimen consisted of a 30-minute weekly intravenous infusion of docetaxel (22-33 mg/m2/wk). Each 8-week cycle included 6 weekly treatments, followed by two weeks of rest. Thirteen patients were treated. All patients were evaluable for response: 0 CR (0%), 7 PR (53.8%), 3 NC (23.1%), 3 PD (23.1%). These results are almost the same as those with the administration of TXT (60 mg/m2) q3 wks. Toxicities observed were mild (< or = grade 2) and reversible, and included fatigue, nausea, neutropenia, and alopecia. This preliminary experience suggests a high level of clinical activity and excellent tolerability of the chemotherapy regimen at the given dose and schedule in patients with metastatic breast cancer.

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 76-year-old woman was admitted with a one-month history of low grade fever and dizziness. She had a palpable right supraclavicular lymph node. Abdominal ultrasonography showed swollen lymph nodes around the abdominal aorta. A specimen from the right supraclavicular lymph node showed malignant lymphoma (diffuse large B cell type). We started chemotherapy according to the low-dose THP-COP protocol (pirarubicin, cyclophosphamide, vincristine and prednisolone) on the 31st hospital day. Since no adverse effects were detected after two low-dose cycles, the patient received a third course with standard doses on the 87th hospital day. The total dose of pirarubicin was 72 mg/m2. Two days after the third course started, she suffered from dyspnea caused by congestive heart failure. A chest X-ray showed advanced cardiomegaly, severe congestion and bilateral pleural effusion. These conditions improved with transvenous administration of diuretics, a vasodilator and phosphodiesterase inhibitor. In this case, congestive heart failure developed even though the total dose of pirarubicin was lower than in previous reports of this complication. When the THP-COP protocol is indicated in elderly patients, cardiotoxicity should be monitored even if the total dose of pirarubicin is very low.

Drug resistance, which often occurs during chemotherapy, is still a great obstacle to the success of human malignancy treatment. Among many possible mechanisms of drug resistance (biological, biochemical, kinetic or pharmacological), both typical and atypical multidrug-resistance (MDR) have been extensively studied. We picked up MDR-1, MXR, MRP1, MRP2, TopoII alpha, MGMT, and GST-pi as drug-resistant gene, based on experimental data and previous reports. Expression of these genes were measured in 14 malignant glioma specimens by reverse transcription polymerase chain reaction assay. We chose anticancer drugs for each patient, based on results of drug resistant gene expression to acquire good response to drugs. Though our follow-up periods are not long enough to analyze the results of our chemotherapy, 78% (7/9) of our glioma patients who were treated with our chemotherapy are free from tumor progression. The assays, which measure the expression of drug resistant genes, are necessary to allow rapid detection of the drug-sensitivity to chemotherapy in malignant glioma patients.

A clinical investigation of adverse events was conducted to confirm the safety of concurrent chemotherapy using nedaplatin (cisplatin derivative) and radiotherapy in the high-risk carcinoma of the uterine cervix. Seven patients who were treated with radical radiotherapy and 5 patients who were treated with adjunctive radiotherapy after radical hysterectomy and pelvic lymphadenectomy were eligible for the study. Nedaplatin was given intravenously at 70 mg/m2 on day 1 and day 29, and a total of 24 courses of nedaplatin administration were observed. None of the planned radiotherapy was postponed or discontinued due to side effects. Major adverse effects observed were gastrointestinal effects such as anorexia (66.7%), nausea and vomiting (33.3%) and diarrhea (66.7%). Grade 3 (in the 2nd course) and Grade 4 (in the 1st course) diarrhea was observed in one patient, which was easily relieved by antidiarrheal. Hematologic side effects were also major, including leukopenia (62.5%), neutropenia (75.0%), anemia (75.0%), and thrombocytopenia (33.3%). Hematologic effects were generally moderate; no Grade 4 (severe) effects were observed. Although these hematologic effects were lasting longer compared with radiation therapy alone, there were no significant differences in the seriousness of these side effects. Concurrent chemoradiation therapy with nedaplatin 70 mg/m2 every 4 weeks was safe and adverse effects were self-limited or resolved with medical management. Dose escalation in the phase III clinical study may be considered.

5'-DFUR is a pro drug of 5-FU, which is known to be converted by thymidine phosphorylase (dThdPase). A recent pre-clinical study revealed that CPA upregulates dThdPase activity specifically in tumor cells. Furthermore, clinical trials have shown significant response rates in breast cancer patients, when using the chemotherapy combination of 5'-DFUR, CPA and MPA. The purpose of this study was to examine the efficacy of this regimen as a pain reduction therapy for breast cancer patients with bone metastasis. Ten patients who had bone metastasis with restricted ADL were included in the study. All of the patients had had previous exposure to such standard chemotherapy as CAF, CMF, taxol and oral 5-FU administration. The patients were administered daily oral doses of 5'-DFUR at 800-1,200 mg, CPA at 200 mg and MPA at 400-800 mg for two weeks as induction therapy, followed by two weeks rest (one to two cycles). Daily dose of 800 mg of 5'-DFUR, 100 mg of CPA, 400-800 mg of MPA was continuously administered thereafter. The main findings included a significant decrease in pain in eight patients, which continued for more than 6 months. In five patients, the effect lasted more than one year. As the pain decreased, the patients' QOL was improved. Hematological toxicity of more than grade 3 was observed in three patients but only during the induction therapy. One patient had pulmonary thrombosis and required hospitalization. In conclusion, oral administration of 5'-DFUR/CPA/MPA is well tolerated and useful in reducing pain.

The anti-emetic effect and safety in patients receiving ondansetron hydrochloride (OND group) and concurrent use of ondansetron and dexamethasone (DEX group) in cases of acute and delayed onset emesis induced by a single high dose of cisplatin, given as a chemotherapy to lung cancer patients, were comparatively studied. The study subjects were 78 lung cancer patients. The OND group received 4 mg of ondansetron via slow intravenous injection on Day 1, 30 minutes prior to cisplatin, and for Days 2 to 5, the subjects orally received 4 mg ondansetron tablet each day. The DEX group received the same dose regimen of ondansetron as the OND group for Days 1-5, but in addition the subjects received dexamethasone injection in doses of 8 mg twice daily on Day 1 and 4 mg (1 mg QID) daily for Days 2-5. An anti-emetic effect against acute nausea and vomiting was achieved in 83.8% of the OND group and in a higher rate of 94.6% of the DEX group. Significantly better efficacy was seen in the DEX group as to the complete suppression rate of nausea and vomiting and the improvement of food intake. The group also achieved better efficacy in delayed onset of emesis. Two cases of adverse reactions (hiccups and elevation of ALT and BUN) were observed in the DEX group; however, since the symptoms were all mild, we did not consider there was any problem in safety. We conclude from the above findings that concurrent administration of ondansetron hydrochloride and dexamethasone is a clinically useful treatment for acute and delayed onset emesis induced by a single high dose of cisplatin given to lung cancer patients.

The patient was a 59-year-old woman with recurrent ovarian cancer. A CT scan of the abdomen showed enlargement of abdominal para-aortic lymph nodes (PAN) after the primary operation and 8 cycles of the combination chemotherapy with paclitaxel (TXL) and carboplatinum (CBDCA). As a second line chemotherapy for the patient, weekly administration of TXL (60 mg/m2/week x 3 weeks) was given. The toxicity was acceptable and less pronounced than with the standard TXL + CBDCA therapy. Peak blood TXL concentration, about 90 ng/ml, was achieved 4 hours after the administration of TXL. The blood TXL concentration was below the detectable limit 48 h after the administration of TXL. An almost 50% shrinkage in the size of the PAN was obtained after 2 cycles of treatment. Good QOL is being maintained without any repeated aggravation of the tumor.

Pharmacodynamics (PD), anti-tumor effects, safety and pharmacokinetics of a 3-month formulation of goserelin (Zoladex LA 10.8 mg depot: "10.8 mg depot") were investigated in a collaborative multicenter study. Study participants were 40 Japanese patients with prostate cancer comprising 20 untreated patients and 20 switch patients who had been receiving Zoladex 3.6 mg depot for 3 months or longer. Serum testosterone levels, serum LH levels, prostate-specific antigen (PSA) levels and drug concentrations were measured until 12 weeks after a single subcutaneous dose of 10.8 mg depot. Anti-tumor effects were evaluated by means of changes in the tumor lesions and the PSA levels at 12 weeks. After administration to the untreated patients, 10.8 mg depot reduced serum testosterone to the castrate range within 4 weeks and the reduction was maintained for up to 12 weeks. In the switch patients, serum testosterone suppression that had been produced by previous treatment with Zoladex 3.6 mg depot was maintained for up to 12 weeks following 10.8 mg depot administration. The anti-tumor effect at 12 weeks was 90.0% including partial response cases. The ratio of PSA normalization at 12 weeks was 75.0%. Fifty-seven adverse reactions were observed in 27 of the 40 patients (67.5%), but none were clinically significant. Although a disease flare presented as urinary retention in 1 of the untreated patients, all patients completed the study. Serum goserelin was detected up to 12 weeks after the administration of 10.8 mg depot. In conclusion a single dose of 10.8 mg depot showed a satisfactory PD-effect and brought about clinical efficacy persisting for at least 12 weeks and was well tolerated in patients with prostate cancer.

We describe in this paper a therapeutic modality which is based on a self-rescuing concept (SRC) featuring dual activity, i.e., effect-enhancing activity and adverse reaction-reducing activity. We present the theory and practice of S-1, a novel oral fluoropyrimidine anticancer agent designed to enhance anticancer activity and reduce gastrointestinal toxicity through the deliberate combination of the following components: an oral fluoropyrimidine agent, tegafur (FT); a DPD inhibitor (CDHP: 5-chloro-2, 4-dihydroxypyridine) which is about 200-fold more potent than uracil used in UFT; and an ORTC inhibitor (Oxo: potassium oxonate) which is localized in the gastrointestinal tract. We devised a novel oral anticancer agent, S-1, as a combination drug with a molar ratio of 1:0.4:1 for FT, CDHP, and Oxo, respectively. To compare S-1, FT, and UFT in terms of their anticancer activity and adverse reactions, a colon cancer implantation model in rats was used for 4-week consecutive oral administration from the time when the postimplantation tumor weight become about 2 g. The tumor disappeared on day 16 at a given dose of S-1 (as 22.5 mg/kg FT), and the tumor did not reappear for at least three months. Antitumor activity was more marked with S-1 than FT and UFT. Adverse reaction, i.e., stomatitis, depilation, and weight loss, were less frequent in the S-1 group than in the other groups. A clinical pharmacology study examined blood concentrations of 5-FU after twice-a-day administration after meals of S-1 at a dose of 40 mg/m2. Blood concentrations of 5-FU were 60 to 200 ng/ml in all twelve patients examined. Late phase II clinical trials of S-1 were conducted in patients with advanced and recurrent stomach cancers, in the same regimen as for the clinical pharmacology study. It basically consisted in four cycles, each of which comprised 4-week, twice-a-day, consecutive oral administration with a 2-week withdrawal. The overall response rate was 44.6% (45/101). Median survival time (MST) was 224 days. S-1 was given manufacturing approval by the Ministry of Health and Welfare of Japan after a priority review, with indications for advanced and recurrent stomach cancers. A late phase II clinical study of S-1 in patients with advanced/recurrent head and neck cancer was conducted in 59 eligible patients. Objective responses were 4 complete response (CR) and 13 partial response (PR), for a response rate of 28.8% (17/59). MST was 344 days. Grade 4 hemoglobin decrease was observed in one case; however, this returned to normal after the termination of drug administration and blood transfusion. Therefore, this event was confirmed to be reversible. A late phase II clinical trial of S-1 was conducted to evaluate the efficacy and toxicities in patients with metastatic colorectal carcinoma. Sixty-three patients with measurable metastatic colorectal carcinoma were enrolled in this clinical trial. The overall response rate was 35.5% (22/62), and the MST was 378 days. The main adverse reactions were myelosuppression and GI toxicities. The incidence of neutropenia (Grade 3 or 4) was 13%, while the incidence of other adverse reactions was 10% or below. None of 53 outpatients required to be hospitalization due to adverse reactions. Late phase II clinical trials of S-1 are in progress for colorectal cancer, breast cancer and non-small cell lung cancer. To establish the standard therapeutic modality for cancers, including gastrointestinal cancers, in Japan, the conduction of clinical trials combining S-1 and other anticancer drugs holds promise for the future.

Side effects due to administration of anti-cancer drugs often cause the treatment to be abandoned or a decrease in the amount of anti-cancer drugs. Recently, the anti-tumor effects of "low-dose CPT-11", which can be administered at the outpatient clinic, are reported. We performed "low-dose CPT-11 + CDDP" as a neoadjuvant chemotherapy to a patient with advanced gastric cancer. CPT-11 and CDDP combination chemotherapy caused very few side effects, so we could continue the treatment and achieve anti-tumor effects. Consequently, surgery could be performed, but disseminated metastasis was found so that the surgery ended as a non-curative operation. However, it was considered that this method of "low-dose CPT-11 + CDDP" was very effective as the neoadjuvant chemotherapy in a patient with advanced gastric cancer.

Since 1997, we have used docetaxel and paclitaxel as the second-line and third-line chemotherapies against anthracycline-resistant metastatic breast cancer. However, these taxane compounds induced neutropenia and leukopenia, which may be reversed by G-CSF (Nartograstim). We thus examined the therapeutic efficacy of nartograstim for time-course changes in neutrophil and leukocyte counts in these patients. No difference was observed in neutrophil or leukocyte count whether the patient was treated with docetaxel or paclitaxel. Neutrophil and leukocyte counts reached a nadir on days 7 to 8 after administration. With a 5-6 day administration of nartograstim, neutrophil or leukocyte counts recovered by the second or third day after the nadir, indicating that the chemotherapy was given safely with nartograstim. In these same patients receiving a given treatment cycle, the number of days until reaching the nadir were almost identical for neutrophils and leukocytes; however, the duration of the nadir and the time to count recovery was significantly longer for neutrophils than for leukocytes. In the clinical setting, the parameter "leukocyte count" has been occasionally used for evaluation of the severity of myelosuppression, because the data is more readily available. However, at least during the nadir, the "neutrophil count" should be used as the parameter of choice.

HCFU (carmofur; Mifurol) is an 5-FU analog. The maximum blood concentration of HCFU in HCFU fraction (Cmax) after gastric resection was higher than before resection. Hot sensation and pollakiuria, characteristic side effects of HCFU, are dependent on concentration of HCFU fraction in blood. Therefore, it is considered that the frequency of occurrence of side effects after gastric resection is high. For that reason, we thought that if absorption of HCFU could be reduced, fewer side effects would result. We focused on the fact that drugs which include aluminium gel may decrease absorption in combined drugs, and thought it would be possible to delay absorption in HCFU by using them. We studied the HCFU concentration in the HCFU fraction and 5-FU concentration in blood, respectively, in two cases: 1) single oral administration of HCFU 100 mg and 2) coadministration with hydroxyaluminium gel (ALG) 10 ml in the whole or partial resection of gastric cancers for 8 patients. We found that the concentration of HCFU in the HCFU fraction 2 hours after its administration decreased significantly: 3.24 +/- 1.78 (single administration), 1.37 +/- 0.91 (coadministration with ALG) (p = 0.023). HCFU concentration in the HCFU fraction seemed to decrease for coadministration with ALG in the area under the time-blood concentration curve (AUG) (p = 0.071). The 5-FU concentration did not seem to decrease in either case. From these results, the coadministration of HCFU with ALG seems to be effective for the inhibition of adverse drug reaction after the resection of gastric cancers.

To evaluate the safety and efficacy of weekly docetaxel (weekly TXT) in cases of advanced or recurrent breast cancer, 31 patients were enrolled in this pilot study of weekly TXT given at 25 mg/m2/w. Each cycle consisted of 3 weeks of therapy followed by a 1-week treatment break in an outpatient setting. Patients received a median of 15 infusions with a median cumulative dose of 680 mg. The median time to treatment failure was 8 months. The overall response rate was 32.3%, and 22.6% of patients had stable disease for at least 6 months. The response rate was consistent regardless of prior chemotherapy with anthracycline. There was no grade 3 or 4 toxicity, and the regimen was generally well tolerated. Although 37.5% of patients had grade 1 or 2 nail change, myelosuppression, fatigue, nausea, vomiting and fluid retention were mild. Weekly TXT seems to be an effective and feasible treatment for advanced or recurrent breast cancer patients.