Ultra slow infusion dynamic MR imaging using an infusion pump(IP-MRI) was performed in six patients with metastatic liver tumor or unresectable gastric cancer to evaluate ant-cancer drug distribution. We used un implanted port for the infusion of Gd-DTPA by infusion pump. On IP-MRI, the speed of Gd-DTPA infusion was very slow (0.01 ml/sec) , the same as drug infusion at chemotherapy. The contrast enhancement of tumors was extremely clear. Therefore, IP-MRI was considered feasible for the evaluation of drug distribution.

Twenty-four studies of intra-arterially slow-injected gadolinium-enhanced MR imaging through an implanted catheter-port system (reservoir-MR) were carried out in 15 patients with liver tumor. The flow rate of gadolinium injection was 0.1 ml/sec and a total of 3 mL was injected. Six consecutive phases, each with an acquisition time of 14 seconds, were obtained every 30 seconds. In all studies, the signal intensity of the drug delivery portion became very high. Twenty-three of 24 studies showed intrahepatic perfusion in the first phase. The hepatic vein was enhanced at the first phase in 10 and the second phase in 14. The abdominal aorta was enhanced at the second phase in all 24 studies. The portal vein was enhanced at the first phase in 4, the second phase in 13, and the third phase in 7 studies. Both intra- and extrahepatic perfusion were more clearly demonstrated by reservoir-MRI than by digital subtraction angiography through an implanted catheter-port system (reservoir-DSA); however, morphological changes in the hepatic artery were better demonstrated by reservoir-DSA than by reservoir-MRI.

Population pharmacokinetics deals with the typical profiles and the inter- and intra-individual variability in the target patient population to which the drug is applied. It also describes factors that can affect the inter-individual variability in pharmacokinetics, including physiological, pathological, genetic, and external factors. The sample population is the actual patients with a variety of backgrounds, which enables us to analyze the influences of several factors such as severity of illness, advanced age, childhood, and renal or hepatic dysfunction, and also to identify the special populations where dose adjustment is needed. Pharmacokinetic and pharmacodynamic information are useful to a rational dosage regimen. The findings obtained by the population pharmacokinetic and pharmacodynamic analysis, provide an advice about whether a dosage regimen should be individualized in all patients or in identified special populations, together with how to adjust the dose. The study design for population pharmacokinetic analysis is called "pharmacokinetic screen", where drug concentration data are collected from a large number of patients while only a few blood samples are taken from individual patients. The population pharmacokinetic approach is useful not only for establishing the rationale dosage regimen but also for international exchange of clinical data in the global drug development.

Although many kinds of chemosensitivity test are available for the selection of suitable anticancer agents, the results of in vitro tests against solid tumors have been generally influenced by mixed in fibroblasts, as have SDI tests. We demonstrated that the influence of fibroblasts can be excluded by performing the SDI test on an agar layer, thus significantly inhibiting the growth of fibroblasts in the liquid top layer. The sensitivity of the agar SDI test was determined on the 3-4th day after incubation because cell proliferation tended to be delayed, and there were also somewhat higher cell counts of about 40,000 per well. The inhibition indices with and without agar in vitro were the same, showing no significant differences. With nude mice, the transplanted tumor index value of the agar SDI test is higher than that of SDI, and approaches in value the SDI of a pure tumor cell, which means that the sensitivity of a solid tumor might be more accurately shown by an agar SDI test than by an SDI test.

The levels of OPRT, DPD, and TS were determined in colorectal cancer tissue specimens, and 5-FU sensitivity was measured by CD-DST. The correlation between enzyme activity and 5-FU sensitivity was then studied. Six patients with colorectal carcinoma who had undergone surgical resection in our institution between May and August 2000 were studied. The CD-DST method was used to measure the sensitivity to 5-FU under three sets of conditions: 0.2 microgram/ml x 5 days (A), 1.0 microgram/ml x 1 day (B), and 10.0 micrograms/ml x 3 h (C). The coefficients of correlation of tumor sensitivity to 5-FU and OPRT activity were A: 0.8246, B: 0.7670, and C: 0.7856, and to DPD activity were A: 0.2525, B: 0.3928, and C: 0.4337, while the coefficients of correlation to TS enzyme levels were A: -0.5240, B: -0.4770, and C: -0.6131. These findings demonstrate a high degree of correlation between OPRT activity at the tumor site and tumor sensitivity to 5-FU under a variety of conditions, suggesting that OPRT activity can be a useful indicator in predicting the anti-tumor effectiveness of 5-FU for a specific tumor.

We have investigated the correlation between the in vitro chemosensitivity to 5-FU, measured using the collagen gel droplet embedded culture drug sensitivity test (CD-DST), and the anti-tumor effect of UFT, a prodrug of 5-FU, in metastatic tumors from orthotopic implanted colon cancer in nude rats. Human colon cancer cells (KM12SM) were injected into the cecal wall of the nude rats. Five weeks later, the implanted cecal tumors were removed. Oral UFT (a daily dose of 30 mg/kg) was administered postoperatively for four weeks. After the UFT administration period, the lung and lymph nodes were analyzed macroscopically and microscopically. In vitro chemosensitivity to 5-FU in the lung and lymph node metastases was tested using CD-DST, and the enzymatic activities of thymidine synthetase (TS) and dihydropyrimidine dehydrogenase (DPD) in the lung and lymph node metastases were measured. A daily administration of UFT produced an inhibitory effect on lung metastasis compared with the control group. However, there was no difference in the frequency of lymph node metastasis. The inhibition rate produced by 5-FU in CD-DST was significantly higher for lung metastases than for lymph node metastases. There was no difference in the TS and DPD activities between the metastatic tumoral tissues. These results suggest that the organ specificity of the anti-tumor effects of UFT on colon metastases may be determined by CD-DST of 5-FU for individual tumors. The TS and DPD activity in the tumoral tissues may not affect the organ specificity of the anti-tumor effect of UFT on colon metastases.

From June 1997 through December 1999, we treated twenty-two metastatic breast cancer patients with Docetaxel (60 mg/m2 administered intravenously every four weeks). All patients had received prior chemotherapy including anthracycline, and also another agent such as MMC-VDS, HDMTX-5-FU or CPT-11. One CR, 5 PR, and 4 Long NC were achieved. Grade 3/4 leukocytopenia occurred in 16 patients. Using the Kaplan Meier method, the median time to progression was 179 days, and the median survival time was 369 days. No serious adverse effects were observed. In this study Docetaxel seems to have shown significant activity, even for poor candidates, with intensive prior therapy.

A 4-year-old boy with ALL received low-dose ara-C (50 mg/m2/day, bolus). After 10 fractions of ara-C, he developed an erythematous rash predominantly on the palms and soles, mimicking acral erythema except for the absence of pain. Chemotherapy was interrupted and the rash disappeared in four days. A similar rash occurred again just after the second cycle of ara-C had been started. Co-administration of dexamethasone improved the rash rapidly, thus allowing the chemotherapy to be continued, and suggesting the beneficial effect of corticosteroids. Although skin toxicity induced by low-dose ara-C is very rare and usually occurs after continuous infusion, it should also be borne in mind when considering bolus infusion.

We conducted a dose-finding study for combination therapy of paclitaxel (Taxol; TXL) and carboplatin (Paraplatin; CBDCA). TXL is a novel plant-derived anticancer agent that is a diterpene derivative possessing the taxane ring. The subjects were patients with ovarian carcinoma, who were evaluated by a modified Fibonacci method. The dosage of TXL was 150 to 180 mg/m2. CBDCA was administered by dose escalation from AUC = 4 to 7. The administration schedule was as follows. Pre-medication was administered before TXL was given. TXL was then administered by intravenous infusion over 3 hours, followed by CBDCA. The dose of CBDCA was determined using the Calvert formula: [AUCX (GFR + 25)]. GFR was calculated with the Jelliffe equation. The non-hematological toxicities observed in 15 eligible cases were mainly grade 1, with no grade 3 or above, and no increase in severity was observed with stepping up. The hematological toxicities were grade 3 leukopenia in 5 of 15 cases, neutropenia in 5 cases and thrombocytopenia in 0 cases. No grade 4 toxicity was observed. The lowest counts of leukocytes and neutrophils were reached after 10.8 and 11.7 days, respectively. The toxicities were reversible in most cases with subsequent recovery. The above findings indicate that the recommended dosages for TJ therapy for Japanese ovarian cancer patients should be TXL 180 mg/m2 and CBDCA at a target of AUC = 6.

An early phase II study (dose-finding study) of amrubicin hydrochloride for superficial bladder cancer was conducted. Amrubicin was dissolved in 30 ml of physiological saline and injected intravesically for 6 consecutive days. The drug solution was retained for 2 hours. Patients were randomly assigned to four groups, which were administered amrubicin at doses of 30, 60, 90, and 120 mg/day, respectively. Of 65 patients registered in this study, 63 were eligible and assessable for toxicities, and 55 assessable for efficacy. The response rate at each dose level was 50.0% (7PRs/14 patients) at 30 mg/day, 53.3% (8 PRs/15) at 60 mg/day, 61.5% (2 CRs + 6 PRs/13) at 90 mg/day, and 69.2% (2 CRs + 7 PRs/13) at 120 mg/day, respectively. These data suggests that the efficacy was related to the doses of amrubicin. The major toxicities were cystic irritabilities, such as micturition pain, pollakisuria and hematuria. These toxicities were related to the doses of amrubicin. Their incidence and the severity were not high compared with those reported about other anthracyclines such as doxorubicin and epirubicin. The optimal dose of amrubicin was estimated to be 90 to 120 mg/day in the intravesical treatment for superficial bladder cancer once a day for 6 consecutive days.

A phase I study of intravesical chemotherapy with amrubicin hydrochloride for superficial bladder cancer was conducted. Amrubicin was dissolved in 30 ml of physiological saline and injected intravesically on 6 consecutive days. The drug solution was retained for 2 hours. The starting dose was 60 mg/day, and the dose was escalated to 150 mg/day in 30 mg/day increments. Fifteen patients were entered into this study, of whom 14 were eligible and assessable for toxicity, and 13 were assessable for efficacy. The incidence and severity of cystic irritabilities such as micturition pain, pollakisuria and hematuria were related to the doses of amrubicin. At 150 mg/day, one of three patients experienced grade 3 micturition pain and pollakisuria. The dose-limiting toxicities, therefore, were micturition pain and pollakisuria, and the maximal tolerated dose was estimated to be 150 mg/day, considering that none of the three patients could retain the drug solution for 2 hours. One complete response and four partial responses were obtained in 13 assessable patients, and the overall response rate was 38.5%. A breakdown according to the doses was as follows. One PR of 3 patients were achieved at 60 and 90 mg/day, respectively 2 PRs of 5 patients at 120 mg/day, and one CR of 2 patients at 150 mg/day.

Importance pharmacological analysis has been widely recognized in conducting early clinical trials of antineoplastic agents, especially phase I trials, in recent years. Pharmacokinetic-pharmacodynamic analysis during dose escalation process is one of the extremely important research endpoints in phase I trials. In addition, measurement of protein unbound drug concentration is more informative for understanding pharmacological difference between patients and animals. Achievable plasma drug concentration which would be compared with preclinical results might be useful surrogate marker to decide optimum administration dose for further clinical investigation in conducting phase I trials of non-cytotoxic or molecular targeting drugs.

A 50-year-old female underwent mastectomy for left breast cancer in June, 1991. She received tamoxifen for 36 months and tegafur for 30 months as adjuvant therapy. In November 1997, liver, lung and para-aortic lymph node recurrences were found, and we treated her six times with docetaxel 60 mg. After the chemotherapy, a complete response (CR) of all metastatic lesions was achieved and her serum CA15-3 level was decreased. Adverse reactions were grade 4 neutropenia, grade 2 alopecia, fever, and grade 1 edema. She received medroxyprogesterone acetate after the chemotherapy and has been well without re-growth of any metastases for over eight months.

We encountered a patient whose renal scintigram showed renal tubular damage four days after administration of contrast material for CT. As no secretion of radioisotope to the urinary tract was observed on the scintigram and the renogram did not show a secretionary phase, renal tubular damage was suspected. As the renal damage disappeared six days after administration of the contrast material, the damage seemed to be transient, disappearing within five days. Caution is needed with the use of renotoxic drugs such as anti-tumor drugs, especially within five days after administration of contrast materials.

Preoperative chemotherapy should be effective against cancers and have few side effects that would prevent surgery. We investigated the histological effects and side effects of low- and high-dose CDDP chemotherapy against oral squamous cell carcinoma (SCC), and discuss the therapeutic benefits of each regimen. Thirty-six patients were divided into two groups as follows, in a non-randomized manner: A) low-dose CDDP (17 patients): CDDP 5 mg/m2/day + UFT 400 mg/day (day 1-5) (1 or 2 courses), B) high-dose CDDP (19 patients): CDDP 70-100 mg/m2/day (day 1) + peplomycin 5 mg/day (day 2-6) (1 or 2 courses). Curative surgery was conducted 1 week after protocol A or 2-3 weeks after protocol B. The histological antitumor effects were evaluated with Ohboshi & Shimosato's classification using surgical materials of primary tumors. In this classification, grade IIB, III and IV were as effective. Maximum histological effect was seen with grade IIB for regimen A and grade IV for regimen B. Four of 17 patients (23.5%) responded to regimen A and 13 of 19 patients (68.4%) to regimen B. Side effects, such as nausea, vomiting and myelosuppression, appeared with regimen B, but were seen little with regimen A. The 2-year survival rate was 93.3% with regimen A and 78.9% with regimen B. With regimen A, the 2-year survival rate of effective cases was 100% and that of ineffective cases was 91.7%. With regimen B, the rate was 92.3% and 50.0%, respectively. Effective cases showed good prognosis in both groups. The low-dose CDDP regimen was not so effective against primary tumors histologically, but the prognosis was good. The low-dose CDDP regimen appears to be useful for preoperative chemotherapy of oral SCC.

Two cases of advanced and metastatic breast cancers were treated by docetaxel (TXT) in combination with intra-arterial infusion of adriamycin (ADM). Patients received 60 mg/body TXT i.v. and 30 mg/body ADM ia (AT therapy) bi-weekly. Clinical responses were observed in these two patients and the durations of responses were over 20 weeks. Critical toxicities of grade 2 leukopenia and alopecia were observed but grade 4 severe toxicities were not. Thus AT therapy can be easily and safely performed with outpatients. This therapy can improve the response rate and time to progression; therefore phase I or phase I/II clinical trials of AT therapy in Japan are recommended.