The efficacy and safety of the oral fluoropyrimidine TS-1, which contains a dihydropyrimidine dehydrogenase (DPD) inhibitor, were examined in fifty-five patients with gastric cancer. The patients were divided into 28 with measurable cancer lesions (TUM group) and 27 without them (ADJ group). The total number of courses was 164 (mean: 5.9 courses) in the TUM group and 146 (mean; 5.4 courses) in the ADJ group. The response rate in the TUM group, excluding three patients who could not be evaluated because of incomplete administration, was 40% (CR: 4, PR: 6, NC: 6, PD: 9). Among responders, the mean number of courses to response was 2.2 and the median survival time (MST) was 21.7 months. In terms of safety, adverse reactions appeared in forty-five patients (82%) and the incidence was higher in the ADJ group. Major toxicities were leukopenia (38%), anorexia (27%), increased total bilirubin concentration (25%) and diarrhea (24%). Adverse reaction of grade 3 was found in only three patients (5.5%) and there were no drug-related deaths. In conclusion, TS-1 is safe and effective if attention is given to biweekly examinations for the development of adverse reactions.

A 68-year-old man was admitted to our hospital for treatment of a recurrent bladder tumor. Histological examination performed after transurethral resection of the bladder tumor (TUR-BT) revealed a nephrogenic adenoma without any evidence of malignancy. After TUR-BT, total cystectomy was performed to control severe irritative symptoms. Prolonged cystitis and intravesical pirarubicin therapy after TUR-BT may have played an etiological role. Our case is the 25th case of nephrogenic adenoma of the bladder reported in the Japanese literature.

Three cases of cyclophosphamide (CPM)-induced transitional cell carcinoma (TCC) of the bladder are reported. A 36-year-old female (case 1) and a 63-year-old male (case 2) received CPM at total doses of 104 g and 100 g, respectively, for the therapy of Wegener's granulomatosis. A 50-year-old female (case 3) received CPM at a dose of 57 g for the therapy of recurrent breast cancer. They visited our institute with the chief complaint of macrohematuria. In all cases, cystoscopy revealed bladder tumor with hemorrhagic cystitis. They underwent transurethral resection of bladder tumor. Histological examination revealed grade 2 TCC in cases 1 and 2 and grade 3 TCC in case 3. All patients underwent intravesical instillation of Mitomycin C with or without hyperthermia. Including our 3 cases, 17 cases of CPM-induced bladder tumor have been reported in the Japanese literature.

Gefitinib is a newly developed molecular-target drug with selective inhibitory activity for tyrosine kinase of the epidermal growth factor receptor and has an encouraging effect on non-small cell lung cancer in an advanced stage. The adverse drug reactions including diarrhea, skin eruptions and liver dysfunction have been considered mild. However, cases of severe acute lung injuries were reported after approval of the drug in Japan in July, 2002. We report a case of recurrent large cell carcinoma of the lung in a 73-year-old man who suffered from radiation recall pneumonitis induced by Gefitinib. Two months after radiation therapy to the mediastinal and right hilar lesions was completed, he started to take Gefitinib at a dose of 250 mg/day. Six weeks later, he complained acutely of a dry cough, slight fever and effort dyspnea, and his chest CT demonstrated ground-glass opacity corresponding to the previous radiation field. In administering Gefitinib, as well as other cytotoxic drugs, meticulous monitoring for acute lung injury and radiation recall reaction is required.

Aromatase is the rate-limiting enzyme playing a role at the final step of estrogen biosynthesis, which is attracting attention as the target enzyme of hormone therapy of postmenopausal breast cancer. Exemestane (Aromasin) is a novel steroidal irreversible aromatase inhibitor that was approved in Japan as a therapeutic drug for postmenopausal breast cancer. Exemestane selectively inhibits aromatase activity in vitro, in a time-dependent and irreversible manner, suggesting the mechanism of action that exemestane covalently binds to aromatase as a pseudo-substrate and inactivates the enzyme. In vivo studies show the inhibitory effect of exemestane on the ovarian aromatase activity and plasma estradiol level of PMSG-primed rats. In studies using DMBA-induced rat mammary tumor models, exemestane shows antitumor activity in both conventional (premenopausal) and ovariectomized, testosterone-treated postmenopausal models. Despite its steroidal structure, exemestane does not have hormonal or anti-hormonal activity, except for a slight androgenic activity. In the early and late phase II clinical trials conducted in Japan on postmenopausal breast cancer patients who received 25 mg/day of exemestane, the response rates were 31.4% and 24.2%, respectively. Blood estrogen levels were also markedly reduced. These results confirmed the clinical relevance of non-clinical study results, as well as the possibility of extrapolation to foreign trial data.

Imatinib mesylate is an inhibitor of Bcr/Abl tyrosine kinase, which essentially participates the pathogenesis of chronic myelogenous leukemia (CML). Imatinib is highly effective in the treatment of CML. Because imatinib also inhibits c-kit and platelet-derived growth-factor (PDGF) receptor, it may be efficacious against some tumors which possess c-kit or PDGF receptors.

A 32-year-old woman, gravida 4, para 2, visited Teikyo University Hospital with complaints of abnormal uterine bleeding and lower abdominal pain. Urine hCG level was 1,024 x 10(3) IU/l. MRI examination showed a vascular, rich solid mass 10 cm in diameter at the posterior region of the uterus. Under the clinical diagnosis of choriocarcinoma, she underwent total hysterectomy with right salpingooophorectomy. The ovarian choriocarcinoma was confirmed by pathologic examination. Additional chemotherapy was planned using the combined regimen of etoposide, methotrexate, actinomycin D, cyclophosphamide and oncovin. After 2 min of etoposide administration (100 mg/m2), the patient complained of acute dyspnea, which was caused by bronchospasms and cutaneous flushing. Etoposide infusion was immediately stopped, and anti-anaphylaxic treatment was done by administering hydroxyzine hydrochloride. Five min after the episode had occurred, the patient recovered. This episode was thought to have been induced by etoposide, but etoposide was a key agent for choriocarcinoma. Thus, we devised a modified chemotherapy using etoposide as follows. The regimen was hydrocortisone 100 mg i.v. q6 h and promethazine hydrochloride 50 mg i.m. q6 h for 24 h before infusion of etoposide. The etoposide concentration was diluted to 50%, and the drug administration rate reduced by half. With the modified regimen, the patient showed no anaphylaxic symptoms. The few reports on anaphylaxic reactions to chemotherapeutic agents induced by side effects must be taken into account when we use these drugs.

We report a patient with peritoneal metastasis from gastric cancer who responded to weekly chemotherapy with paclitaxel (TXL) as the third line treatment and could take meals for half a year. The patient was a 64-year-old man who underwent total gastrectomy for advanced gastric cancer with peritoneal metastasis. He was first treated with TS-1 as an outpatient treatment; however, tumor markers rose. He could not take meals and had to be hospitalized. CPT-11 was infused on the second line, but due to disease progress, the patient was administered weekly TXL. TXL (70 mg/m2) was infused over 1 hour after short premedication. Administration was continued for 3 weeks followed by 1 week rest. The tumor markers decreased, and he could take meals and was discharged from hospital. The toxic events were leukopenia (grade 2), alopecia (grade 2) and pneumonia (grade 3).

We followed patients who underwent hepatic arterial infusion chemotherapy (HAI) with 5-FU and Leucovorin for liver metastases. Since CR (complete response) and PR (partial response) were achieved, this therapy seems to be effective. 5-FU metabolized on its first pass through the liver, and the hepatic extraction with rapid HAI is lower than that with slow HAI. It is suggested that control of extrahepatic lesions thought rapid HAI is useful for life prolongation.

We investigated the usefulness of TS-1 for the treatment of head and neck carcinoma in 29 patients who received treatment on an outpatient basis at our institution. Among the 29 patients, 22 patients in whom the response was evaluable were included in the efficacy analysis. To assess the safety of TS-1, the severity of adverse events was examined in the 29 patients. Each course of treatment consisted of oral administration of TS-1 at a dose of 80 to 120 mg/day, depending on the body surface area (BSA), for 28 consecutive days, followed by a 14-day rest period. None of the patients showed complete response (CR), 7 showed partial response (PR), 10 showed no change (NC), and 5 showed progressive disease (PD). The response rate was thus 31.8%. Severe adverse events (grades 3 and 4) occurred in 2 patients. One developed grade 3 leukopenia and grade 4 thrombocytopenia. The other developed Stevens-Johnson syndrome that was assessed as grade 4. The findings indicate that TS-1 might be useful for the treatment of patients with head and neck carcinoma on an outpatient basis without affecting their quality of life (QOL), although careful monitoring is essential to watch for the development of severe adverse events.

C-erbB-2 (HER2/neu) protein overexpression or amplification has been noted in some solid tumors a molecular target for tumor suppression. C-erbB-2 protein is localized on the membrane surface and is classified in the EGFR family. Trastuzumab is a humanized monoclonal antibody which binds to the extracellular domain of the c-erbB-2 protein in breast cancer cells. Good responders to trastuzumab may be ICH 2 + and FISH positive breast tumors, and ICH 3 + cancer. The response rate is approximately 15% with single administration of trastuzumab. Combination therapy with paclitaxel for the treatment of patients with metastatic cancer may bring more than 60% response and improve time to disease progression. Congestive heart failure associated with trastuzumab may be severe, and combination therapy which includes anthracyclines increases the incidence and severity of cardiac dysfunction. Other toxicities include infusion reaction.

Gastrointestinal stromal tumors (GIST) are composed of KIT-positive mesenchymal-origin spindle- or polygonal-shaped tumor cells in the gastrointestinal tract without immunoreactivity for desmin and S-100. The gain-of-function mutations in the c-kit gene (90%) or platelet-derived growth factor receptor alpha (PDGF-R alpha) gene (5%) are now considered to be causative for GIST. STI571 (Glivec), a molecule designed to selectively inhibit Bcr-Abl, KIT, and PDGF-R activity, shows high response rate and efficacy for non-resectable and/or relapsed GIST (PR 60%). Its serious adverse effects (more than Grade 3) were infrequent, thus, tolerability and safety are good. Glivec is the first successful case of molecular target therapy for solid tumors. However, new resistance against this new generation of drug is going to appear and becomes an urgent problem.

A 69-year-old man was diagnosed as having acute promyelocytic leukemia (APL) and was treated with all-trans retinoic acid (ATRA) and idarubicin plus cytarabine. He achieved cytogenetic complete remission (CCR). Relapse occurred 1 year after CCR. Treatment with Am80 gave him a second CCR. However, a second relapse occurred. Re-induction therapy with ATRA was started at 70 mg per day. On day 14, abdominal fullness rapidly increased and massive ascites appeared as a symptom of retinoic acid syndrome (RAS). We ceased the ATRA treatment and started administration of methylprednisolone. The ascites decreased, but an increase of ascites was recognized again temporarily after having re-started ATRA treatment. Thus we gradually increased ATRA administration from 40 mg/day to 70 mg/day of ATRA. RAS did not occur and the patient achieved a third CCR. This case indicates that a gradual increase in ATRA administration is beneficial for RAS occurring in APL patients.

We report two cases of an allergic reaction to HCO-60, which is used as an emulsifien for Multamin and enocitabine. A 55-year-old woman with M 4 Eo developed a high fever, urticaria and erythema after induction chemotherapy. After stopping the administration of Multamin, her fever and eruptions subsided. A 51-year-old woman with L 2 developed erythema and hypotension 30 minutes after the third administration of Multamin. When the patient was given enocitabine, she developed anaphylactic shock. During chemotherapy in patients with leukemia, it is important to distinguish the allergic reaction against Multamin-containing HCO-60 from infection and allergies to other drugs.

We experienced a case in which severe alveolar hemorrhage occurred in the course of gefitinib therapy. A 56-year-old man with non-small cell lung cancer had been treated with CDDP + CPT-11, CDDP + GEM + VNR, CDDP + TXT. After the chemotherapy with these regimens was found to be ineffective, daily oral gefitinib was started. Four weeks later, the patient complained of cough, bloody sputum and dyspnea. Chest X-ray and CT showed bilateral infiltrations with air bronchogram. Fiberoptic bronchoscopy revealed alveolar hemorrhage with an increase of lymphocytes in the BALF. After the cessation of gefitinib therapy and the administration of steroid, he gradually recovered.

Forty-nine patients with unresectable pancreatic cancer (stage IV disease) received gemcitabine in a multi-center trial in the Fukuoka pancreatic cancer chemotherapy group, Japan. No complete remissions, 5 partial remissions (10%) and 25 no changes (51%) were obtained. Gemcitabine could maintain QOL. Main toxicities were hematologic, especially neutropenia. Neutropenia tended to appear in early administration. Non-hematologic toxicities were anorexia, nausea/vomiting, and skin rash. The mean overall survival period was 7.5 months. Carcinomatous ascites and/or pleural effusion resulted in a poor prognosis (average survival 3.1 months). Gemcitabine could be given without severe toxicities in outpatient clinics. These results suggested that gemcitabine is currently a first-line therapeutic agent for advanced pancreatic cancer.

A total of 40 patients with advanced and recurrent gastric cancer in our hospital were treated with TS-1 alone, and the efficacy of treatment, survival time, and adverse effects were examined. TS-1 was administered with the usual dosage and dose regimen. Response to treatment included a complete response (CR) in 3 cases, partial response (PR) in 8 cases, no change (NC) in 10 cases, and progressive disease (PD) in 7 cases. The response rate was 39.3%, and among the 28 patients with evaluable lesions TS-1 produced a high response rate of 56.3% in 16 patients who had undergone prior therapy. The median survival time (MST) was 478 days in the 28 patients with evaluable lesions, excluding patients with peritoneal dissemination, and 283 days in the 12 patients with peritoneal dissemination. The outcome was markedly poorer in the patients with peritoneal dissemination than in the patients with evaluable lesions. The incidence of grade 3 or higher adverse effects was 20%, including two cases in which decreased dihydropyrimidine dehydrogenase (DPD) activity was suspected, and one case in which decreased dihydropyrimidinase (DHP) was suspected. Although the effect of TS-1 alone on gastric cancer is significantly superior to that of any conventional cancer drugs, the results of this study suggest that the antitumor effect varies with the site of the target lesions and according to whether the lesion is a remnant or recurrence.

Amrubicin is a completely synthetic anthracycline derivative. In contrast, however, the anthracyclines used clinically thus far have been produced by fermentation or semisynthesis. Amrubicin is structurally distinguishable from other anthracyclines by the amino group at the 9-position and its unique sugar moiety. Amrubicinol, the C-13 hydroxy- metabolite of amrubicin, is associated with a 5 to 200 times greater cytotoxicity than amrubicin. Amrubicin exhibited superior in vivo antitumor activity to doxorubicin in the human tumor xenograft model. Using this model, the level of amrubicinol (active metabolite) was shown to be higher than that of doxorubicin in tumor tissues, but lower in normal tissues. These results suggest potent therapeutic activity for amrubicin because of the selective distribution of its highly active metabolite, amrubicinol, in tumors. These anti-tumor effects of amrubicin are considered to be induced by DNA topoisomeraseII inhibition. In clinical studies, amrubicin has demonstrated potent single agent activity as compared to a standard regimen in untreated patients with extensive small cell lung cancer. Its major toxicity was myelosuppression (especially neutropenia).