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A total of 465 patients with primary and multiple or recurrent, stages Ta and T1 superficial bladder cancer were included in this randomized multicenter trial to compare the prophylactic effect by 17 times instillation of 40 mg doxorubicin or 40 mg epirubicin with no instillation after transurethral resection of tumor(s). The primary endpoint was first recurrence after transurethral resection. Endoscopic examination as well as urinary cytology was performed in each case every three months. It became evident that the recurrence rate in the doxorubicin or epirubicin instillation arm was lower that in the no instillation arm. Toxicity was mainly restricted to bladder irritation in about 10% of patients in each instillation arm.

A prospective randomized joint study was conducted to evaluate the usefulness of UFT 1) as a postoperative adjuvant therapy in patients with invasive bladder cancer who had undergone curative combination therapy with operation and/or chemotherapy and/or radiation therapy, 2) as an endocrine chemotherapy in patients with newly diagnosed stage C/D prostate cancer, for a period of 3 years from January, 1992. For bladder cancer, of 36 patients with invasive bladder cancer, clinically cured by combination therapy, 20 patients were treated with UFT as an adjuvant chemotherapy over 12 months, and they were compared to 16 patients with no adjuvant therapy. After excluding 10 inappropriate patients, 12 patients in the UFT treatment group and 14 patients with no adjuvant treatment group were observed. For prostate cancer, of 29 patients with clinically stage C/D prostate cancer, 13 were treated with endocrine therapy in combination with UFT, and 16 patients were treated with endocrine therapy alone. After excluding 7 inappropriate patients, 10 patients with endocrine chemotherapy and 12 patients with hormonal therapy were observed. The non-recurrence rate, survival rate and side effects of UFT were evaluated. In the study of bladder cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. In the study of prostate cancer, neither a significant difference of non-recurrent rate nor of survival rate was seen between the two groups. These findings suggest UFT is less useful as an adjuvant therapy for the invasive bladder cancer and as an endocrine chemotherapy for newly diagnosed advanced prostate cancer.

This study was undertaken to determine the clinical usefulness of NMP22 (Nuclear Matrix Protein 22) as a urinary marker for the screening of urothelial cancer in patients with microscopic hematuria, especially in comparison with that of voided urine cytology. Urinary NMP22 values were determined for 183 patients with microscopic hematuria by use of a UNMP22 Test kit, which is based on an enzyme-linked immunosorbent assay. All patients were entered in this study before cystoscopy was performed, and were evaluated for NMP22 values and voided urine cytology simultaneously from the same urine samples. Of the 183 patients with microscopic hematuria, 14 cases of urothelial cancer were detected. For the other cases, 65 were of benign diseases and 104 were designated NED (No Evidence of Disease). The median NMP22 values for urothelial cancer, benign diseases, and NED were 26.5 U/ml (95% CI: 18.5-228.2; 4.9 U/ml (95% CI: 3.6-8.3), and 5.9 U/ml (95% CI: 4.8-6.5), respectively. The urinary NMP22 value for urothelial cancer was significantly higher than for benign diseases and NED. When the cut-off value of urinary NMP22 was set at 12 U/ml, the positive rate of NMP22 for urothelial cancer was 85.7%, significantly higher than the 50% positive rate by voided urine cytology. This study indicates that urinary NMP22 is a useful tool for the screening of urothelial cancer in patients with microscopic hematuria.

This study was undertaken to determine the clinical usefulness of NMP22 (Nuclear Matrix Protein 22) as a urinary marker for the surveillance of bladder cancer, especially in comparison with that of voided urine cytology. Urinary NMP22 values were determined for 144 patients with histologically diagnosed bladder cancer, 65 patients with other urological cancers, and 171 healthy volunteers by use of a UNMP22 Test kit, which is based on an enzyme-linked immunosorbent assay. All bladder cancer patients were evaluated for urinary NMP22 values and voided urine cytology simultaneously from the same urine samples. Based on the data from the bladder cancer patients and the healthy volunteers, the cut-off value was set at 12 U/ml. The median urinary NMP22 value for the bladder cancer patients was 17.8 U/ml (95% CI: 13.1-29.0). The sensitivities of urinary NMP22 and voided urine cytology were 61.1% (88/144) and 33.8% (48/144), respectively, a significant difference (p < 0.00001). Multivariate analysis revealed that tumor size affected the urinary NMP22 values. The positive rate by tumor size was 42.3%, 59.1%, and 85.0% for tumors of < 10 mm, 10-30 mm, and > 30 mm, respectively. Urinary NMP22 values decreased postoperatively in 82.9% of the patients. The median NMP22 values for prostate cancer and renal cancer were 4.4 U/ml (95% CI: 2.2-6.7) and 6.2 U/ml (95% CI: 3.6-12.5). The positive rates were 24.2% and 31.3%, respectively, both of which were significantly lower than for bladder cancer. Our multicenter study indicates that urinary NMP22 test is more sensitive than voided urine cytology test for the surveillance of bladder cancer.

A cross-over clinical trial was carried out to compare the antiemetic effect and safety between granisetron alone (40 micrograms/kg) and the combination of granisetron and methylprednisolone (MP: 10 mg/kg) in urological cancer patients treated with cisplatin. Forty-eight courses were given with granisetron alone and 47 courses with both granisetron and MP. The antiemetic effect of nausea and vomiting was evaluated in the acute emetic phase. during the 24 hours following the CDDP administration, and in the delayed emetic phase, 2 to 7 days after the administration. Combination therapy of granisetron and MP demonstrated a greater antiemetic effect during the 72 hours following the CDDP administration than by granisetron alone. But there was no significant difference in antiemetic effect between combination therapy and granisetron alone after the 3rd day. Combination therapy also demonstrated more efficacy in complete antiemetic effect, with no emesis and less than moderate nausea, than by granisetron alone. Both treatments showed no side effects and were safe.

Because treatment of testicular cancer has improved dramatically during the past 15 years, about 70% of the patients can be relieved of this disease today. Although this can be attributed to the availability of various tumor markers, better imaging diagnosis and improvement of surgical techniques, the improvement of chemotherapy, mainly based on cisplatin, has made the largest contribution. Hopefully, more powerful chemotherapy regimens will be available for patients who fail to respond to primary chemotherapy or relapse within a short period after primary chemotherapy. Supportive therapy, such as bone marrow transplantation, will serve to enhance the treatment for testicular cancer. On the other hand, milder therapy will given, if it is determined sufficient to treat the patient with an excellent response to the present therapeutic regimen. In the future, more therapeutic regimens will be prescribed to meet the exact needs of individual patients according to their prognoses.

Combination effect of UFT and leucovorin against the rat prostatic carcinoma (R-3327) was evaluated by the subrenal capsular assay (SRCA) using nude mice. Anticancer effect of UFT was augmented by co-administration of both low and high dose leucovorin. These results suggest a clinical usefulness of UFT administration with leucovorin for the patients with hormonally refractory advanced prostatic carcinoma.

Combination effect of UFT and CDDP against the rat prostatic carcinoma (R3327) was evaluated by the subrenal capsule assay in nude mice. The tumor growth of R3327 was inhibited in proportion to the UFT concentration. Anticancer effect of UFT was elevated by co-administration of CDDP. These data suggest a clinical usefulness of UFT administration with CDDP for hormonally refractory advanced prostatic carcinoma.

Superficial bladder cancer has a good prognosis compared with invasive bladder cancer. However, recurrence of the tumor is frequent and tumor stage and/or grade progress at the time of recurrence in many cases. Intravesical chemotherapy has been employed as a prophylactic method after trans-urethral resection (TUR). Although intravesical chemotherapy has been proved to be effective in delaying the first recurrence of tumor after TUR, it cannot improve the ultimate prognosis of superficial bladder cancer. Many primary, solitary, non-invasive (Ta) and grade 1 tumors do not recur or progress in stage and grade. In these cases, prophylactic intravesical chemotherapy is not essential. Bacille Calmette-Guérin (BCG) should be considered superior overall, to any chemotherapeutic agents. Comparative studies will give information about the best clinical schedule for the treatment of superficial bladder cancer.

Long-term administration of PSK was made in 40 patients with urological cancer. Mean duration of the administration was 201, 358 and 243 days for the patients with bladder cancer, renal cancer and other urological cancers, respectively. The clinical evaluations were performed by the standard of Japan Society for Cancer Therapy and historical control study. In some cases, it seemed that the immunological therapy by PSK was a benefit to some degree. However, more accurate evaluation should be made by the matched control study.

A cooperative study of UFT was conducted in cases of far-advanced renal cell carcinoma. UFT was administered daily at a dose of 300-600 mg FT equivalent for at least 4 weeks. Forty-one patients were entered into the protocol from the 19 collaborating institutions in the group. The antitumor effects of the drug were clinically evaluable in 25 patients according to the response criteria proposed by the Koyama-Saito study group. Seven were not eligible and 9 were cases of protocol violation. Complete response (CR) and partial response (PR) were observed in 2 and 5 patients, respectively, showing a response rate of 28.0%. One patient showed minor response, 8 stable disease and 9 progressive disease. It took about 22 weeks and 16 weeks to attain CR and PR, respectively. Lung metastasis was the lesion showing most the favorable response to this treatment. Twenty-eight patients were used for evaluating the adverse effects of the drug. Gastrointestinal symptoms such as nausea, vomiting and anorexia, were observed most frequently, while bone marrow suppression was minimal. Only three patients had to be taken off the drug due to its adverse effects. In conclusion, UFT was considered to be one of the most effective drugs for the treatment of far-advanced renal cell carcinoma.

A Phase II clinical trial of a new anthracycline, (2''R)-4'-0-tetrahydropyranyladriamycin (THP), was performed in 137 patients with urological malignancies. Out of them, 111 patients were evaluated for tumor responses and 125 patients were evaluated for adverse effects. In cases of intravenous administration, overall response rate was 18.5% (22.2% for bladder cancer, 30.0% for tumors of the renal pelvis and ureter, and 6.7% for prostatic cancer). In the case of intra-arterial administration, overall response rate was 42.9% (50.0% for bladder cancer). For 50 patients with superficial bladder cancer intravesical chemotherapy with THP was performed. Sixteen patients showed complete disappearance of the tumor, 2 patients showed more than 90% tumor regression and 12 patients showed more than 50% tumor regression, respectively. Overall response rate was 60%. Cardiotoxicity was minimal. Alopecia was noted in a total of 16 patients, but this was minimal. Leukocytopenia was the major adverse effect among patients undergoing systemic THP administration. In conclusion, THP was most effective against transitional cell carcinoma of the urinary tract.

The effectiveness of a preoperative combination of chemotherapy and irradiation on advanced bladder cancer was evaluated. The combination therapy group (Arm I) included 21 patients, the preoperative chemotherapy group (Arm II) 14 patients, and a group without preoperative treatment, 35 patients. There were no distinguishing background factors among the three groups. Chemotherapy included vincristine, adriamycin, mitomycin, bleomycin/and 5-FU. A total of 3000 rads was irradiated locally, and the results were promising. The Arm I group was superior to the other two groups in terms of response rate, histological effectiveness and downstaging effects. Also, the 5-year-survival rate for Arm I was much better than in the other groups. There were no great differences in adverse effects between Arm I and II.

A phase II study of recombinant human interferon gamma (rHuIFN-gamma) administered intravenously and intramuscularly was carried out in 84 patients with advanced renal cell carcinoma with the cooperation of 18 institutions throughout Japan. The eligibility of the patients and evaluation of the responses were undertaken according to the general criteria proposed by Drs. Koyama and Saito. Out of 84 cases entered in this phase II study, 62 patients were evaluable for antitumor effects. In the case of continuous administration of 8-12 X 10(6) U/m2/day interferon for 4 weeks, 32 patients were evaluable. The response rate was 6.3%. In the case of intermittent therapy of 40 X 10(6) U/m2/day interferon for 8 weeks, six out of 30 patients (20%) were evaluable as responders. Among them, one patient showed a complete response, all patients tolerated this type of interferon well. Major adverse effects were fever (86.8%), anorexia (67.1%), fatigue (53.9%) and leukopenia (42.1%). No life-threatening toxicities were found. The results of this study showed that rHuIFN-gamma had antitumor activity against renal cell carcinoma.

A randomized cross-over study on the effects of methylprednisolone (MP), metoclopramide (MT) and droperidol (DP) on the control of nausea and vomiting associated with cis-platinum chemotherapy was performed. Sixty-three patients were entered into the study; 60 patients (21 treated with MP, 18 with MT and 21 with DP) were eligible for evaluation of antiemetic efficacy, whereas the side effects of these drugs were evaluated in all of the 63 patients. Out of the above 60 patients, 36 were entered into the cross-over treatment. Antiemetic efficacy was evaluated in terms of duration of nausea, duration of vomiting, frequency of vomiting, duration of inability to take food and the amount of food first taken after cis-platinum treatment. Generally, the MP-treated group of patients showed favorable effects in these points, MP being especially more effective than other drugs with a statistically significant difference for the control of nausea and disturbed intake of food during the first 24 hours after the treatment with CDDP. Anticipatory nausea and vomiting were not observed in this study. Side-effects were minimal and all of the patients except one, who showed severe diarrhea following administration of MT and could not tolerate the treatment thereafter, were safely treated.

During the period from August 1980 to April 1989, preoperative intra-arterial infusion chemotherapy was performed in 22 patients with resectable bladder cancer. An oblique incision approximately 12 cm long was made in the gluteal lesion to expose the inferior gluteal artery, into which a Teflon catheter was inserted and fixed. Via this catheter, a single dose of 10-20 mg CDDP and/or 10 mg ADM was injected 1-2/week. The majority of patients were treated with radiation and/or hyperthermia as a combined therapy. The 5-year survival rates (Kaplan-Meier method) were 81.6% in patients treated with intra-arterial infusion chemotherapy as an adjuvant to total cystectomy, compared with 37.5% in patients treated with total cystectomy only. There was a statistically significant difference between the two groups (p less than 0.01). Therefore, inferior-gluteal-artery infusion chemotherapy is effective as a preoperative adjuvant therapy with no serious side effects.

Testicular cancer is divided pathologically into two categories; seminoma and non-seminomatous germ cell tumor (NSGCT). Seminoma is a radio-sensitive tumor, so that radiation has been mainly used for stages I and II. Stage III seminoma is treated in the same way as NSGCT. Several years ago stages I and II NSGCT were treated primarily by retroperitoneal lymph node dissection. These days, chemotherapy, such as PVB, or VAB-6 therapy, is adopted as the first choice of treatment, followed by surgical intervention to elucidate the remaining bulky mass if present. Stage III NSGCT is also managed by chemotherapy. By these procedures 70-90% CR of patients with NSGCT is obtained. Prostatic cancer has been treated mainly according to its stages. As for stage A cancer palliative therapy has been shown to yield good results. However, in the case of poorly-differentiated tumors, local irradiation with anti-androgenic treatment should be employed. Stage B cancer should be treated by radical surgery. Local lymph node dissection is usually indicated. In addition local irradiation and anti-androgenic therapy should be considered. Most stage C or D patients do well for a while with antiandrogenic therapy. Within two or three years, however, drug resistance ensues, recessitating a change in the therapeutic modality. Treatments of choice include in chemotherapy, radiotherapy, and others. Treatment of penile cancer involves chemotherapy with bleomycin and irradiation, which result in considerable improvement.

A phase I study of a recombinant gamma interferon (S-6810) was conducted in a cooperative study involving 11 institutions. S-6810 was administered at doses of 2, 4, 8, 12, 32 and 64 X 10(6) U/m2 by one-hour infusion for 5 consecutive days. A total of 40 courses were administered to 31 patients. High fever exceeding 38 degrees C with chills occurred in about 80% of patients. The incidences of other toxicities were fatigue in 50%, gastrointestinal toxicities in 30-40%, and changes in hepatic enzymes and hematologic toxicities in 20-30%. Dose-limiting factors were judged to be hypotension, leukopenia and central nervous toxicity. Maximum tolerated dose was 64 X 10(6) U/m2 and an optimal dose for phase II study was considered to be 6 X 10(6) U/m2 by daily chronic schedule. Blood concentration was highest at the end of infusion, and then decreased rapidly with a biphasic curve. The peak concentrations were elevated by escalation of doses. A partial response was observed in a patient with mycosis fungoides.

Treatment of urogenital cancer has made great progress due to early detection by various imaging techniques. Renal cancer is a good example of cancer that has been diagnosed in the earlier stages by the routine imaging methods. BRM therapy of interferons and interleukin II has been proved useful for renal cancer. It has been difficult to diagnose the wall invasion of the bladder cancer. However, ultrasonic imaging has made it possible to detect precisely the invasion into the vesical muscles and adventitia. Also, prostatic acid phosphatase and prostatic specific antigen have become more specific markers for prostatic cancer. Various treatments for this malignancy, including operative surgery, have made progress. The results of chemotherapy for testicular cancer have become fruitful by the use of cisplatin.

This study compared the histological changes induced by human bladder tumor xenografts following their implantation in the subrenal capsular space of immunocompetent mice (CDF1, 6-10 weeks age). Ten human bladder tumors were studied by light microscopic and electron microscopic methods. All materials were obtained from cold-cup biopsy using endoscopic procedure. Single fragments (1 mm X 1 mm X 1 mm) were implanted on Day 0 under the renal capsule of each mouse. Animals were serially sacrificed from day 2 to day 6 and in some cases as late as day 10. All kidneys were sectioned up to 3 levels at the xenograft and stained with appropriate histological reagents. The results of this study were; 1) infiltration of the tumor with mononuclear cells and neutrophils began on day 4, 2) pretreatment with 200 mg/kg cyclophosphamide before implantation reduced cell infiltration into the xenograft, 3) complete rejection of the tumor on day 8, 4) electron microscopic study showed minimum changes of intracellular organs on day 2, 5) but microscopic architecture was preserved in the tumor explants removed on day 4. This morphological study suggested that histological evaluation on day 4 might be a suitable method of subrenal capsule assay using immunocompetent mice. We therefore tested genitourinary carcinomas to determine their sensitivities to commonly use chemotherapeutic agents using histological criteria. Groups of tumor-bearing mice were treated daily for 3 days. Sensitivities for assays were assessed on day 4 by comparison of histological score. Of the 15 cases evaluated, 20% demonstrated significant oncolytic activity. These data also suggested that a clinically relevant chemosensitivity assay might enhance the selection of appropriate therapy.

Chemotherapy of advanced bladder cancer aims to destroy all the cancer cells in the host. For this purpose the most suitable and effective anticancer agents should be chosen. There have been many methods to select the anti-cancer drugs: sensitivity test. However, no reliable tests are available. We developed new anti-cancer sensitivity test, using the radio-active nucleic acids precursors; C14-Formate and C14-Adenine. This test revealed that Cisplatin, Adriamycin, and Mitomycin C were the most potent for the transitional cell carcinoma of the urinary bladder. Chemotherapy with a single agent was disappointing. Combined use of these agents was rather promising. Among them combination of cis-platin with Adriamycin and/or cyclophosphamide was the most effective. However, the overall response rate was reported around 50%. Multi-disciplinary treatment including surgery, irradiation, chemotherapy, and immunotherapy was disclosed to be useful for the treatment of bladder cancer. Since 1977 25 cases were treated with this mode of therapy in our clinic. Anti-tumor effect was remarkable. The categories, disappeared, and over 50% decrease of the mass, were found in 96% of the patients. Also, down-staging was demonstrated in 20% of the cases. Histologically no cancer cells were found in the surgical specimens of 3 cases and no viable cancer cells in 3 cases respectively. From these results it is now assumed that multi-disciplinary treatment is promising for the treatment of bladder cancer.