Yosuke Matsumura

Phase II study ofcis-diammine(glycolato)platinum, 254-S, in patients with advanced germ-cell testicular cancer, prostatic cancer, and transitional-cell carcinoma of the urinary tract

SummaryA multicenter cooperative study was conducted to evaluate the clinical efficacy and safety ofcis-diammine(glycolato)platinum (254-S), a second-generation anticancer platinum complex, in the treatment of genitourinary cancers. 254-S was given i. v. at 100 mg/m2 at 4-week intervals. As a result, 2 complete responses (CRs) and 8 partial responses (PRs) were obtained in 35 patients with transitional-cell carcinoma (TCC) of the urinary bladder or pyeloureter, 3 PRs were obtained in 16 subjects with prostatic cancer, and 6 CRs and 6 PRs were obtained in 15 patients with testicular cancer, generating objective response rates of 28.6% [95% confidence interval (CI), 14.6%–46.3%], 18.8% (95% CI, 4.0%–45.6%), and 80.0% (95% CI, 51.9%–95.7%), respectively. Bone marrow suppression was the dose-limiting toxicity, although it was reversible. Although no hydration was performed in approx. 40% of the patients, the incidence of nephrotoxic effects was low and most of those encountered were mild, the exception being one patient who showed severe renal insufficiency after the first treatment. Nausea and vomiting occurred in approx. 70% of the patients, but most gastrointestinal toxicities were controlled without antiemetic treatment. In addition, liver-function impairment was rarely observed. We conclude that 254-S is a promising cisplatin analogue for the treatment of genitourinary cancers and is worthy of further investigation in large-scale, randomized comparative studies with other platinum derivatives in both single-agent and combination regimens.

Endoscopic diagnosis and treatment of chronic unilateral hematuria of uncertain etiology

We evaluated 12 patients with unilateral unexplained gross hematuria by flexible ureteropyeloscopy and percutaneous pyeloscopy. All patients had localized bleeding except for 1 with diffuse bleeding caused by the nutcracker phenomenon, and 2 in whom no hematuria appeared upon examination and no gross lesions were observed. Among the 9 patients with localized bleeding transitional cell carcinoma was found in 1, hemangioma in 4 and minute venous rupture in 4. These 9 patients were treated endoscopically and no recurrences were observed during a follow-up of 6 to 21 months (average 10.3 months). Our results underscore the importance and efficacy of flexible ureteropyeloscopy in the evaluation and management of chronic unilateral hematuria.

Effect of recombinant granulocyte colony-stimulating factor (rG-CSF) on chemotherapy-induced neutropenia in patients with urogenital cancer.

SummaryThe effects of recombinant granulocyte colony-stimulating factor (rG-CSF) on the myelosuppression, especially neutropenia, induced by cancer chemotherapy in patients with urogenital cancer were investigated in a randomized, controlled clinical study. In this study, rG-CSF was given subcutaneously at a dose of 2 μg/kg per day for 14 consecutive days. Changes in neutrophil counts were compared between the first (no rG-CSF) and second cycles (rG-CSF treatment period) of chemotherapy. rG-CSF administration was found to be effective in reducing the duration of neutropenia, in elevating the neutrophil nadir, and in reducing recovery time. Based on comparisons between the randomized rG-CSF treatment group (with rG-CSF) and the control group, treatment with rG-CSF resulted in the moderation or prevention of neutropenia and the acceleration of recovery. These results demonstrate that in chemotherapy of patients with urogenital cancer, in which neutropenia is a dose- or schedule-limiting factor, the concomitant use of rG-CSF may enable an increase in the dose (higher single dose or increased dose per unit of time) or shorten the chemotherapy period.

Long-term results of intravesical chemoprophylaxis of superficial bladder cancer: experience of the Japanese Urological Cancer Research Group for Adriamycin.

SummaryLong-term results were analyzed in terms of tumor progression and survival in patients with superficial bladder cancer who were enrolled in the second intravesical chemoprophylactic study of the Japanese Urological Cancer Research Group for Adriamycin, which was started in July 1982. This study was a prospective, randomized, controlled trial conducted on primary tumors treated with a long-term instillation regimen that involved control versus intravesical instillations of Adriamycin or mitomycin C given once a week for the first 2 weeks, once every other week for 14 weeks, once a month for 8 months, and once every 3 months for 1 year, for a total of 21 instillations in 2 years. An analysis of the prophylactic effects of such treatment on bladder tumors after TUR has previously been performed, and the results have been published elsewhere. The present study represents a follow-up of the above trial. Of the 671 cases previously analyzed with regard to tumor prophylaxis, 158 cases (23.5%) were eligible to be followed for tumor progression and survival. A detailed comparison of the background factors between these 158 patients and the other 513 cases revealed no statistically significant difference. Thus, the 158 evaluable cases might reasonably be considered to represent all patients enrolled in the second study, and the results were thought to be reasonable enough to reflect the long-term efficacy of the long-term instillation regimen adopted in this study. The median follow-up for these 158 cases was 6.6 years. Tumor progression in terms of the disease stage and/or grade occurred in 43 of 127 patients who received prophylactic instillations and in 12 of 31 control cases. No significant difference in the incidence of tumor progression was found between the treatment and the control groups. In addition, no difference in survival was observed between the treatment group and the control group. Survival was also compared between patients who showed tumor progression and those who did not. All patients whose tumors did not progress survived, whereas the 7-year survival of those exhibiting tumor progression was <90%.

Intravesical chemotherapy with 4′-epi-Adriamycin in patients with superficial bladder tumors

SummaryWe evaluated the effects of 4′-epi-Adriamycin (EPI), a derivative of Adriamycin (ADR), in intravesical instillation chemotherapy. The patients received two courses of three daily instillations of 50–80 mg EPI dissolved in 30 ml physiological saline on 3 consecutive days, with an interval of 4 days between courses. Full evaluation was possible in 33 of 35 patients with superficial bladder tumors treated with EPI. Complete response was observed in 4 cases and partial response in 14 cases, giving a response rate of 55%. Side effects such as pollakiuria and pain on micturition occurred in 9 cases. EPI appears to be an effective agent for intravesical instillation chemotherapy in patients with superficial bladder tumors.

OVER‐EXPRESSION OF METALLOTHIONEIN AND DRUG‐RESISTANCE IN BLADDER CANCER

Metallothionein (MT) in tumor cells has been implicated as one of the factors involved in mechanisms of resistance to anti‐cancer drugs, including cis‐diaminedichroloplatinum (CDDP) and adriamycin (ADM). The relationship between the expression of MT and chemotherapy with anti‐cancer drugs was studied in CDDP‐ and ADM‐resistant human bladder cancer cell lines and tissue samples from clinical cases. In drug‐resistant cell lines (T‐24/ADM, CI‐7/CDDP) established in our laboratory, MT expression was studied by immunohistochemistry using the avidin‐biotin peroxidase complex (ABC) method and radioimmunoassay (RIA), using anti‐MT antibody. In addition, other potentfal mechanisms of drug resistance, such as P‐glycoprotein expression were examined and the levels of reduced glutathione (GSH), oxidized glutathione (GSSG) and glutathione‐S‐transferase (GST) determined in these cell lines. The results of these investigations demonstrate that the expression of MT in resistant cell lines increased 2.1‐ and 2.5‐fold when compared with parent cell lines (CI‐7, T‐24). GSH, GSSG and GST levels were unchanged and P‐glycoprotein was not over‐expressed. A total of 120 tissue samples from 35 clinical cases of bladder cancer, before and after chemotherapy, were stained for MT which was detected in 10 of the 35 cases before chemotherapy. The incidence of MT expression was significantly higher (p less than 0.05) in cases with lower pathological tumor grades. By analyzing the MT staining after chemotherapy in the cases whose MT staining was negative before chemotherapy, it was found that cases receiving continuous administration (intravesical chemotherapy or peroral chemotherapy) showed a higher incidence (9/13) of positive staining for MT, than patients receiving intermittent administration (intravenous chemotherapy) (1/8), (p less than 0.05). These results demonstrate that: 1) a correlation exists between MT expression and tumor differentiation and 2) repetitive and continuous administration of anti‐cancer drugs results in increased MT expression in bladder cancer cells. MT expression may therefore be one of the mechanisms by which urothelial tumors acquire resistance to anti‐cancer drugs.

The 4th study of prophylactic intravesical chemotherapy with Adriamycin in the treatment of superficial bladder cancer: the experience of the Japanese urological cancer research group of Adriamycin

SummaryA multicentric randomised trial was conducted for the purpose of investigating the efficacy of intravesical chemoprophylaxis of superficial bladder cancer. A total of 443 patients (number of evaluable patients, 284) were registered from July 1987 to December 1989 and randomised into 3 groups. Group A received 21 intravesical instillations of Adriamycin (ADM) at 20 mg/40 ml physiological saline for 2 years after undergoing transurethral resection (TUR); group B was given the same dose as group A but received 6 intravesical instillations for 2 weeks before undergoing TUR; and group C served as a control and underwent TUR only. Better prophylactic effects were obtained in group A. The overall non-recurrence rates calculated for groups A and B differed significantly (P<0.05) on day 240, and those determined for groups A and C were also significantly different (P<0.01) on day 480. No benefit was obtained using intravesical instillation prior to TUR (group B). The major side effects encountered were pollakisuria and miction pain, which occurred in 32% of the patients in group A and in 52% of those in group B.

Intra-Arterial Infusion Chemotherapy in Combination with Angiotensin II for Advanced Bladder Cancer

A combination of 50 to 80 mg. per m.2 cis-platinum and 30 to 50 mg. per m.2 doxorubicin or 30 to 50 mg. per m.2 tetrahydropyranyl-doxorubicin instead of doxorubicin was infused into the bilateral internal iliac artery for the treatment of 20 patients with T3 or T4 advanced bladder cancer. Angiotensin II was administered together with these chemotherapeutic agents by means of an infusion pump at a rate of 1.5 to 2.0 micrograms. per minute for 20 minutes for both sides. Among the 20 patients complete (9) and partial (8) responses were obtained after only 1 or 2 courses of this intra-arterial treatment. Histological examination showed severe tumor destruction with no viable cells in 6 and no tumor in 4 of the 15 evaluable cases. Selective enhancement of regional blood flow in the tumor region after intra-arterial infusion of angiotensin II was observed by continuous target arterial 81mkrypton infusion. Intra-arterial chemotherapy with combined angiotensin II may be clinically useful for treatment of primary or metastatic bladder carcinoma.

Intravesical Adriamycin chemotherapy in bladder cancer

SummaryIn an experimental study undertaken to elucidate the mechanism whereby Adriamycin (ADM) instilled into the bladder produces its side-effects, the time course of ADM concentration in blood, urine, and tissues of various organs, and also histopathological changes in the bladder mucosa were investigated in normal adult dogs that had undergone bilateral ureterostomy and then received intravesically instilled ADM. Clinically, ADM was used in the treatment of superficial bladder tumors in an attempt to facilitate the transurethral operative procedure. A total of 261 patients were included in this trial. ADM was instilled into the bladder at the following dosages: 1,000 μg/ml (30 mg ADM per 30 ml physiological saline), 1,600 μg/ml (50 mg ADM per 30 ml physiological saline), and 2,000 μg/ml (60 mg ADM per 30 ml physiological saline). The rate of effectiveness was 32%, 66%, and 60%, respectively. The incidence of side-effects was 29%, 20%, and 45%, respectively. The systemic uptake of the drug was small and the side-effects were pain an micturition, pollakiuria, and urgency. From the aspects of efficacy and toxicity, 1,600 μg/ml was found to be the optimal dosage.

Intravesical instillation of adriamycin in the presence or absence of verapamil for the treatment of superficial bladder cancer : preliminary report of a collaborative study

SummaryA case-controlled collaborative study on the intravesical administration of Adriamycin in the presence or absence of verapamil, a calcium-channel blocker, as chemotherapy of superficial bladder cancer was carried out at two universities, Okayama and Kagoshima, and their affiliated hospitals. Although little is known about the expression of P-glycoprotein in superficial bladder cancer, it may be a cause of multidrug resistance (MDR). Verapamil was used as an inhibitor of P-glycoprotein. Arm A consisted of Adriamycin given at 50 mg/50 ml saline, and arm B constituted Adriamycin given at 50 mg/40 ml saline plus 5 ampules (10 ml) of injectable verapamil. The drugs were instilled into the bladder for 3 consecutive days in each of 3 consecutive weeks for a total of 9 instillations. No significant difference in antitumor effects was observed between arm A and arm B. Recurrent tumors responded better than did primary tumors to both arm-A and arm-B treatments (P=0.012). In both treatment arms, significant differences (P=0.031) in the response rate were found between tumors with, diameters of <1 cm and those measuring 1–3 cm in diameter. Although the number of evaluable patients was limited, recurrent subjects who had previously received Adriamycin instillations responded in both treatment arms.