Shigeo Isaka

Long-term results of a randomized trial for the treatment of stages B2 and C prostate cancer: radical prostatectomy versus external beam radiation therapy with a common endocrine therapy in both modalities

OBJECTIVES To improve the treatment of locally advanced prostate cancer (Stages B2 and C), a prospective randomized trial was conducted to compare radical prostatectomy versus external beam radiotherapy with the combination of endocrine therapy in both modalities. METHODS One hundred patients were enrolled and 95 were evaluated. Forty-six patients underwent radical prostatectomy with pelvic lymph node dissection, and 49 were treated with radiation by linear accelerator with 40 to 50 Gy to the whole pelvis and a 20-Gy boost to the prostatic area. For all patients, endocrine therapy was initiated 8 weeks before surgery or radiation, and continued thereafter. The living patients were asked to respond to a quality-of-life questionnaire. RESULTS The follow-up period ranged from 6.0 to 94.4 months (median 58.5). The progression-free and cause-specific survival rates at 5 years were 90.5% and 96.6% in the surgery group and 81.2% and 84.6% in the radiation group, respectively. The surgery group had better progression-free and cause-specific survival rates (P = 0.044 and 0.024, respectively). More patients in the surgery group complained of urinary incontinence. The questionnaire revealed that quality of life was less disturbed in the radiation group. CONCLUSIONS Radical prostatectomy combined with endocrine therapy may contribute to the survival benefit of patients with locally advanced prostate cancer. External beam radiotherapy in combination with endocrine therapy can be used in selected patients because of its low morbidity.

Mutational State of von Hippel-Lindau and Adenomatous Polyposis Coli Genes in Renal Tumors

Genetic alterations of the von Hippel-Lindau (VHL) tumor suppressor gene and the adenomatous polyposis coli (APC) gene in renal tumors were examined by PCR-SSCP analysis and direct sequencing. Tissues from 58 primary sporadic human renal cell tumors (49 clear-cell carcinomas, 6 non-clear-cell carcinomas and 3 oncocytomas) from Japanese patients were used in this study. Somatic VHL mutations were detected in 26 (53%) of the clear-cell carcinomas, although no mutations in this gene were observed in any non-clear-cell carcinomas or oncocytomas. The frequency of mutations did not correlate with histological grade, clinical stage or any of several other clinical factors examined. No differences in the frequency of VHL mutations or in the exons where mutations occurred within the gene were evident when we compared our results with those reported for American patients. However, frameshifts were more common in our Japanese panel of tumors than in American cases, where single-point mutations appear to be more frequent. No APC gene mutation was detected in any of our samples. These results indicate that VHL gene mutations are related to the carcinogenesis of the clear-cell type of primary renal cell carcinomas, whereas alteration of the APC gene is not involved in the pathogenesis of this cancer.

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%.

Clinical Course of Bone Metastasis from Prostatic Cancer Following Endocrine Therapy: Examination with Bone X-Ray

X-ray findings of bone metastatic lesions from 81 cases of stage D2 prostatic cancer were examined before and following endocrine therapy. Untreated lesions were classified into five types; osteoblastic (15%), mixed, but mainly osteoblastic (31%), mixed, but mainly osteolytic (17%), osteolytic (10%), and undetermined with a positive bone scan (27%). Patients with two mixed types had a tendency of widely speeded areas of metastasis and elevated serum prostatic acid phosphatase. Temporal enlargement of sclerotic lesion immediately after the start of therapy did not indicate disease progression. In many cases, changes from osteolytic to osteoblastic patterns were noticed in the same lesion regardless of the effects of endocrine therapy. Remodeling to the sclerotic pattern appeared as curative changes. From these findings, it was concluded that the natural course of bone lesions showed a tendency to change from the osteolytic to osteoblastic type and relapse was often accompanied by an increase of the osteolytic type lesion. Evaluation of therapeutic effects based on remodeling, changes in number and areas of lesions, and the appearance of new lesion correlated well with prognosis.

Serum immunosuppressive acidic protein as a tumor marker for renal cell carcinoma

Since there are no reliable tumor markers in renal cell carcinoma, the present study was undertaken to evaluate immunosuppressive acidic protein (IAP) in patients with this tumor. Serum IAP levels were measured in 143 consecutive patients before and/or after nephrectomy by turbidimetric immunoassay. IAP levels had increased according to tumor diameter. Positivity rates of IAP were noticed as 45%, 75%, and 100% for patients with stage I/II, stage III, and stage IV diseases, respectively. Three-year survival rates also correlated with IAP: 96%, 81%, and 44% in preoperative levels below 500, of 501-1,000, and of more than 1,001 micrograms/ml, respectively. Serum IAP levels decreased within 3 months after the operation and increased with recurrence. These results suggest that serum IAP may serve as a tumor marker in patients with renal cell carcinoma.

Sequential instillation therapy with mitomycin C and Adriamycin for superficial bladder cancer

SummaryIntravesical chemotherapy involving the sequential instillation of mitomycin C (MMC) and Adriamycin (ADM) was performed in 40 patients with superficial bladder cancer (pathological stages Ta and T1). In all, 20 mg MMC on day 1 and 30 mg ADM on day 2 were instilled into the bladder. This treatment was repeated weekly for 6 consecutive weeks and then monthly for 22 months in cases patients who did not experience serious side effects. A total of 20 patients were treated for multiple recurrences, and the efficacy was evaluated. In all, 9 subjects (45%) achieved a complete response and 6 (30%) showed a partial response, for an overall response rate of 75%. The other 20 patients, including 9 with primary multiple or high-grade tumors and 11 with recurrent tumors, received prophylactic instillation therapy after undergoing transurethral resection (TUR) of their lesions. Of the 9 primary cases, 3 recurred at 19, 8, and 3 months after TUR, respectively, whereas 6 showed no recurrence over a mean follow-up period of 14 months. Of the 11 recurrent cases, the 100-patient-month recurrence rate of 11.9 obtained prior to this treatment fell to 1.4 after the start of therapy. Chemical cystitis was observed in 20 of the 40 patients treated, but the symptoms were transient and tolerable.

Combined treatment of pelvic exenterative surgery and intra-operative pelvic hyperthermochemotherapy for locally advanced rectosigmoid cancer: Report of a case

A huge rectosigmoidal cancer which extended into the urinary bladder in a 64-year-old man is herein described. The tumor occupied the pelvic and lower abdominal cavities, while the rectosigmoid was totally obstructed. No hepatic or pulmonary metastasis was evident. The ventral and flank sides of the peritoneum in the right lower abdomen, right common iliac vessels, bilateral ureters, terminal ileum, cecum, ascending colon, and urinary bladder were all directly invaded by the tumor, but the aorta, sacrum, and lower rectum were free of cancer. Consequently, an anterior pelvic exenteration was carried out along with an ileal conduit and a right hemicolectomy. Immediately after the exenteration, intra-pelvic hyperthermochemotherapy was performed using a 46–47°C perfusate containing 40 μg/ml of mitomycin C (MMC) and 200 μg/ml of cisplatin (CDDP), for 90 min, in an attempt to prevent any further local recurrence. A right hemicolectomy and a permanent colostomy were done simultaneously with the hyperthermia treatment. After an uneventful postoperative course, the patient was prescribed adjuvant chemotherapy, i.e., two administrations of 17 mg/m2 and 21 mg/m2 of MMC, and ten doses of 710 mg/m2 of 5-fluorouracil (5-FU) followed by five doses of 535 mg/m2 of 5-FU. At the time of this writing, the patient is still alive without recurrence at 21 months after surgery.

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.

Clinical and radiological aspects of infiltrating transitional cell carcinoma of the kidney.

We reviewed the sonographic, CT and angiographic findings in 19 patients with infiltrating transitional cell carcinoma of the kidney. Sonography revealed a defect of the central echo in 18 patients, and a low or slightly low echoic tumor in 15. Enhanced CT showed a poorly marginated tumor with lower attenuation than that of normal parenchyma in all 8 patients examined. Angiography showed narrowing and stretching of interlobar and arcuate arteries arranged radially from the renal hilus in all 11 patients examined and fine neovascularity in 10. These findings, especially the angiographic findings, were useful for distinguishing this disease from the common type renal cell carcinomas, and other infiltrating diseases of the kidney, such as lymphomas and sarcomas. Since the prognoses of these patients were poor with 1- and 2-year survival rates of 11.6 and 5.8%, respectively, careful examination of the above-mentioned findings was stressed to diagnose this disease.

Prophylactic chemotherapy with intravesical instillation of Adriamycin and oral administration of 5-fluorouracil after surgery for superficial bladder cancer

The Japanese Urological Cancer Research Group for Adriamycin has conducted a series of clinical trials to investigate the efficacy and safety of prophylactic intravesical chemotherapy for superficial bladder cancer. In the third trial, reported herein, patients with recurrent bladder cancer or multiple primary cancer were selected and randomized to one of four groups using the envelope method after complete resection of the original tumors. Group A was given Adriamycin alone, group B received oral 5-fluorouracil (5-FU), group C was given Adriamycin and oral 5-FU, and group D served as the control group. Of the 544 patients registered, 331 were evaluable for the purpose of this study. The administration of 5-FU (group B) failed to prevent the recurrence of bladder tumors. Although group C (both Adriamycin and 5-FU) did not fare better than group A (Adriamycin only), Adriamycin was effective in preventing the recurrence of tumors, especially in high-risk patients with recurrent and multiple tumors. The risk of recurrence was reduced to 0.21 (95% confidence interval, 0.10–0.44) relative to the control group. There was no indication of a synergistic effect between 5-FU and Adriamycin. As side effects, cystitis syndrome was observed in 23%–30% of the patients in the Adriamycin groups and mild myelosuppression was observed in the 5-FU groups.