Phase I/II study of S-1 in combination with sorafenib for metastatic renal cell carcinoma.

BACKGROUND: The potential of S-1 for the treatment of metastatic renal cell carcinoma (mRCC) has been shown in two phase II studies. We aimed to assess the safety, tolerance, pharmacokinetics and clinical activity of S-1 combined with sorafenib in patients with mRCC. PATIENTS AND METHODS: In this multicenter, single-arm, open-label, phase I/II study of S-1 plus sorafenib, we recruited patients with clear-cell or papillary renal cell carcinoma who had received a maximum of one prior cytokine-based regimen. The phase I primary end points were the maximum tolerated dose (MTD) and recommended dose (RD). S-1 was administered orally at 60, 80, 100 or 120 mg/day on days 1-28 of a 42-day cycle in combination with sorafenib (400 or 800 mg/day), given daily with dose adjustment. In phase II, the primary end point was to assess the overall response rate (ORR) at the RD. RESULTS: Nine patients were enrolled into phase I and 21 (including 6 patients who received the RD in the phase I portion) were enrolled into phase II. In the phase I portion, the MTD could not be determined, and the RD was defined as S-1 80 mg/m(2)/day on days 1-28 + sorafenib 800 mg/day on days 1-42. In the phase II portion, 21 patients were fully assessable for efficacy and safety. The confirmed ORR was 52% [95% confidence interval (CI) 29.8-74.3], including one complete response (5%) and 10 partial responses (48%). The median progression-free survival was 9.9 (95% CI 6.5-17.1) months. The most frequently reported treatment-related adverse event for all grades was hand-foot skin reaction (100%). The major reasons for dose reduction were hand-foot skin reaction (38%) and rash (14%). CONCLUSION: Combination therapy with S-1 plus sorafenib is effective and tolerable for patients with mRCC. However, skin events management is important in S-1 plus sorafenib combination therapy.

Oral estramustine phosphate and oral etoposide for the treatment of hormone-refractory prostate cancer.

BACKGROUND: The purpose of the present study was to evaluate the antitumor activity and toxicity of oral estramustine phosphate (EMP) in combination with oral etoposide in patients with hormone-refractory prostate cancer. METHODS: Twenty patients with adenocarcinoma of the prostate that progressed after one or more regimens of androgen-deprivation therapy were enrolled into this trial. Oral EMP was administered twice daily, for a total daily dose of 560 mg, and oral etoposide (50 mg/bodyweight per day) was given on days 1-21 and was stopped on days 22-35. Treatment was continued until evidence of disease progression appeared or two consecutive rises in the prostate-specific antigen (PSA) value were observed. RESULTS: Ten of 20 patients showed a decrease of 50% or greater in the PSA value from initially elevated PSA levels after therapy. The median progression-free duration and 2 year cause-specific survival rate of these 10 patients were 208 days (range 71-693 days) and 67.5%, respectively. There were no significant differences in age, pretreatment PSA value, duration from initial treatment to relapse, prior therapy or survival between patients who had a decrease of 50% or greater in PSA values after this combination therapy and those who did not. The main toxicities (> or =grade 2) were anemia, leukocytopenia, thrombocytopenia, gastrointestinal and hepatic disorders, which occurred in 40, 15, 10, 15 and 5% of patients, respectively. CONCLUSIONS: The combination of oral EMP and etoposide is considered to be a well-tolerated outpatient treatment regimen for patients with hormone-refractory prostate cancer and the therapy deserves further investigation.

Radical retropubic prostatectomy: time trends, morbidity and mortality in Japan.

OBJECTIVES: To assess the time trends, morbidity and mortality of contemporary anatomical radical retropubic prostatectomy (RRP) in a multi-institutional study in Japan, where RRP has become more popular in the last decade. PATIENTS AND METHODS: Between January 1991 and August 1998, 638 patients underwent RRP at seven urological centres in Japan. Major complications (within 30 days of surgery) and the 30-day mortality were reviewed retrospectively. Of the patients, 12.9% were < 60 years old, 56.3% were 60-69 years old and 30.9% were >/= 70 years old (median age 67). Results The number of RRPs increased markedly, by more than sevenfold, from 1991-92 to 1996-97, mainly because there were more patients undergoing RRP in their sixth decade. The contribution of T1c disease increased in absolute and relative terms, from 13.9% in 1991-92 to 37.9% in 1997-98. Over time, the mean blood loss and the allogeneic transfusion rate decreased steadily. There was a trend toward more favourable outcomes for pathological variables (an increased percentage of organ-confined disease, decreased margin positivity and a decreased incidence of positive lymph node metastasis). The most common complications were wound-related (7.5%), or anastomotic leakage (4.1%). Major cardiopulmonary complications occurred in only two patients (0.31%, both pulmonary embolisms). One patient died from cerebral haemorrhage within 30 days of surgery, giving a mortality rate of 0.16%. CONCLUSION: s This study indicates a trend towards selecting patients most likely to benefit from RRP. Although the procedure is technically demanding, it can have an acceptably low rate of early complications, little mortality and need for allogeneic transfusion. The assessment of morbidity suggests a lower incidence of catastrophic thrombo-embolic and cardiac complications in Japanese patients than in Western men. The present data may be useful in decision-analysis models evaluating the role of therapy for Asian men with early-stage prostate cancer.

[Bilateral synchronous renal cell carcinoma: report of three cases].

We report here three cases of bilateral synchronous renal cell carcinoma. One of the 3 patients underwent bilateral partial nephrectomy, while the other 2 underwent combined partial nephrectomy and radical nephrectomy. All patients received adjuvant therapy of interferon-alpha and tegafur uracil. In the management of synchronous bilateral renal cell carcinoma, we discussed the selection of surgical procedure for primary lesions, i.e., based on the renal function of both sides, and the necessity of adjuvant therapy in such cases.

[Primary treatment for stage D2 prostate cancer: a randomized study of combined androgen blockade alone versus combined with UFT].

To evaluate the efficacy of chemoendocrine therapy for the initial treatment of stage D2 prostate cancer, we conducted a prospective randomized study which compared combined androgen blockade alone to that combined with UFT. Twenty-one patients received LH-RH agonist and flutamide (Group-A), and 23 patients received LH-RH agonist, flutamide and UFT (Group-B). The overall response rate and the PSA response rate of Group-A was 71.4% and 100% respectively, against 65.2% and 90%, respectively in Group-B. The median follow-up period was 24 months. The 2-year progression-free survival rate of Group-A was 7.4% and that of Group-B was 15.9%. The response rate and progression-free survival rate did not differ significantly between the 2 groups. Liver dysfunction due to flutamide was common in both groups, and a total of 4 patients did not continue the treatment because of this adverse effect. We conclude that in patients with stage D2 prostate cancer, treatment with combined androgen blockade and UFT is not superior to treatment with combined androgen blockade alone.

[Intra-arterial chemotherapy in combination with radiotherapy for invasive bladder cancer and prostate cancer].

Forty-five patients with muscle-invasive bladder cancer treated with intra-arterial doxorubicin chemotherapy plus low-dose radiotherapy between September 1979 and March 1990 were retrospectively studied. Twenty-eight (62%) patients achieved a complete response (CR) and in all of them, a functional bladder could be preserved. The 10-year cause-specific survival rate of patients with CR was 95.5%, but that of patients not achieving a CR was 39%. These results demonstrate that in patients who achieve a CR with this treatment, we may be able to preserve a functional bladder. In a prospective study, we designed a new intra-arterial chemotherapy regimen in order to achieve a higher degree of effectiveness and to preserve a functional bladder. Twenty-three patients were treated with concurrent pirarubicin/cisplatin intra-arterial chemotherapy and radiotherapy after complete transurethral resection. Twenty-one (91%) patients achieved CR. One of these patients had relapse with lung metastases and was treated surgically. Two patients who did not achieve a CR died of cancer, and 21 patients are alive with preservation of functional bladder. For treatment of prostate cancer, we now administer only adjuvant intra-arterial chemotherapy plus irradiation for patients after radical prostatectomy.

[Concurrent platinum-based chemotherapy and radiotherapy for locally advanced bladder cancer].

Eight patients with locally advanced bladder cancer who were not candidates for radical cystectomy or concurrent intra-arterial chemotherapy and radiotherapy were treated with combined platinum-based chemotherapy and radiation therapy. Six of the eight patients (75%) achieved a clinical complete response (CR). The effect of therapy in four patients whose histopathological responses were evaluated was effect grade 3. One of the eight patients died of treatment-related myelosuppression. The other two patients died of intercurrent disease, while the remaining five patients are alive with preservation of a functional bladder. The 2-year overall survival rate was 87.5%. Adverse events due to chemotherapy were mainly bone marrow suppression. Those caused by radiation therapy were rectal irritability. We considered concurrent platinum-based chemotherapy and radiotherapy useful for the treatment of locally advanced bladder cancer.

[Small cell carcinoma of the prostate: a case report].

A 57-year-old man was admitted with the chief complaint of macrohematuria. Digital rectal examination showed a slightly enlarged, irregular prostate with stony consistency. Serum levels of prostate specific antigen (PSA), neuron-specific enolase (NSE) and progastrin-releasing peptide (ProGRP) were elevated. Transurethral resection (TUR)-biopsy of the prostate revealed small cell carcinoma with poorly differentiated adenocarcinoma. Various radiological examinations revealed metastases to pelvic lymph nodes and liver. He was treated with chemoendocrine therapy consisting of cisplatin, etoposide, flutamide and luleinizing hormone-releasing hormone (LH-RH) agonist. The primary tumor and metastatic lesion decreased and serum PSA, NSE and ProGRP levels were decreased to normal ranges after 5 cycles of chemotherapy. After the 5-cycle chemotherapy, TUR-biopsy proved viable tumor cells. During the additional chemotherapy, tumor markers increased and 4 months later liver metastasis progressed. He died 13 months after diagnosis of small cell carcinoma of the prostate.

Preliminary results of bladder preservation by concurrent intraarterial chemotherapy and radiotherapy for muscle-invasive bladder cancer.

BACKGROUND: We previously reported favorable results of intraarterial doxorubicin chemotherapy in combination with low-dose radiotherapy for locally-advanced bladder cancer. We have now designed a new intraarterial chemotherapy regimen to achieve a higher tumor response rate while preserving a functional bladder. METHODS: Twenty-one patients with muscle-invasive bladder cancer (T2,10; T3,7; T4,4) were treated with concurrent intraarterial chemotherapy and radiotherapy after an initial complete transurethral resection. Induction therapy consisted of concomitant pirarubicin (THP; 15 mg/m2/day on days 1 to 3), cisplatin (CDDP; 25 mg/m2/day on days 8 to 10) and irradiation (2 Gy/session on days 1 to 3 and 8 to 10). Maintenance treatment consisted of THP administered at 20 or 30 mg with or without 50 mg CDDP every month for 2 years. RESULTS: Nineteen of the 21 patients (90.5%) achieved a complete response (CR). One of these 19 relapsed with lung metastases 24 months after treatment and was treated surgically. The 2 patients who did not achieve a CR died of cancer, while the remaining 19 patients are alive with preservation of a functional bladder. CONCLUSION: These findings suggest that a higher tumor response rate with bladder preservation for patients with muscle-invasive bladder cancer is achieved by intraarterial THP/CDDP chemotherapy plus radiotherapy.

[Usefulness of recombinant human erythropoietin on predeposit autologous blood transfusion in patients undergoing radical prostatectomy].

The usefulness of recombinant human erythropoietin (rHuEPO) on autologous blood transfusion was investigated in 18 patients undergoing radical prostatectomy (mean age 67.4 years). A total of 800 ml blood was deposited by two donations of 400 ml each, concomitant with subcutaneous administration of 24,000 U rHuEPO at each donation. All patients completed two successive donations with no adverse effects. The mean hemoglobin concentration was 13.7 g/dl before the donation and 13.0 g/dl on the day of operation. The decrease in hemoglobin was effectively prevented in 12 patients (66.7%) with rHuEPO, when compared with the predicted decrease in the absence of recovery from anemia. During radical prostatectomy, no homologous blood transfusion was required in 16 of 18 patients (88.9%). In conclusion, predeposit autologous blood transfusion with rHuEPO is useful for diminishing the risks associated with homologous blood transfusions.

[Glutathione chemoprotection therapy against CDDP-induced neurotoxicity in patients with invasive bladder cancer].

We studied the efficacy of glutathione in the prevention of CDDP-induced neurotoxicity. Nine patients with muscle-invasive bladder cancer were treated with intra-arterial THP and CDDP chemotherapy plus radiotherapy. Glutathione was given at a dose of 1,500 mg/m2 before CDDP administration and at a dose of 600 mg/body on days 2 to 4. The CR rate of 9 patients was 89%, and 2 of the 9 patients developed grade 1 neurotoxicity. These patients were then compared with 15 patients treated with the same regiment but without glutathione. The two groups did not differ in CR rate (89% vs 87%), but the incidence of neurotoxicity of patients with glutathione was significantly lower than that of patients without glutathione (22% vs 73%).

[A morphological study of renal adenoma and latent renal cell carcinoma in autopsy cases].

PURPOSE: We investigated histopathological features of renal adenoma and latent renal cell carcinoma in order to find relationship between these two entities. MATERIALS AND METHODS: Renal adenomas or latent renal cell carcinomas found macro- and microscopically in 2,201 autopsy materials were used. Histological examination was focused on the size, and the presence or absence of hemorrhage, necrosis and capsulation of tumors. Additionally, we analyzed morphologically the mean nuclear area (MNA), N/C ratio, mean nuclear volume (MNV) and nuclear roundness factor (NRF) using image analyzer system (CIA-10; Olympus). RESULTS: A total of 71 foci of renal cortical tumor was found and classified into renal adenoma (59 foci), latent renal cell carcinoma (8 foci), and intermediate type (4 foci). Intermediate type contained of small element of clear cell and were difficult to distinguish from renal cell carcinoma or ordinary adenoma. The mean diameter of renal adenomas was 1.9 mm. The capsulation was found in only 3 foci (5.1%) of them, and bleeding and necrosis were found in none of them. On the other hand, the mean diameter of latent renal cell carcinoma and intermediate type were 15.7 mm and 6.6 mm, respectively, and larger than that of renal adenomas (p < 0.005). In latent renal cell carcinoma, capsulation were found in all foci, bleeding in 6 (75.0%) and necrosis in 3 (37.5%), and their incidence were significantly higher than those of adenoma (p < 0.005). In intermediate type, capsule and bleeding were found in each two foci. Morphologically, there were significant difference in MNV and NRF but no difference in MNA and N/C ratio between renal adenomas and latent renal cell carcinomas. Intermediate type was larger in NRF compared to adenoma. CONCLUSION: Morphological characteristics of intermediate type resemble that of latent renal cell carcinoma in terms of tumor size, the presence of bleeding and capsule and NRF when compared to adenomas. These results suggest that, in some renal cell carcinoma, adenoma might be able to change to carcinoma.

[Intermittent intra-arterial chemotherapy for the treatment of patients with bladder cancer or prostate cancer using implantable injection pump].

BACKGROUND: The objective of this study is to evaluate the usefulness of intra-arterial chemotherapy using an implantable injection system for the treatment of bladder or prostate cancer. METHODS: Twenty-four patients with bladder cancer and 13 with prostate cancer were treated with intermittent intra-arterial chemotherapy using a totally implantable injection pump. A heparinized catheter was percutaneously fixed through the femoral artery with the tip 2 or 3 cm above the bifurcation of the common iliac artery, and the pump was placed in a subcutaneous pocket. RESULTS: The total number of infusion sessions for bladder cancer ranged from 4 to 38 times (mean 20.8), and 15 of the 24 patients were injected from 2 to 19 sessions (mean 8.5) as outpatients. The tumor response for 15 patients with newly diagnosis muscle-invasive bladder cancer were 12 patients in CR, 1 in PR, and 2 in NC, and 9 patients with recurrent bladder cancer were 6 patients in CR, 1 in PR, and 2 in NC. The total number of infusions for prostate cancer ranged from 6 to 35 times (mean 20.2), and 10 of the 13 patients were injected from 1 to 11 times (mean 6.3) as outpatients. All 13 patients with prostate cancer were treated with hormone therapy and irradiation, and achieved PR. Complications of this drug delivery system were obstruction of the catheter or pump observed in 7 patients, dislocation of the catheter in 2, and obstruction of right external iliac artery in 1. CONCLUSION: These findings suggest that favorable therapeutic efficacies and an improved quality of life for patients can be obtained by intra-arterial chemotherapy using an implantable injection pump.

[Prophylactic intra-arterial chemotherapy for CR patients with invasive bladder cancer after induction therapy].

Thirteen patients with invasive bladder cancer treated by induction intra-arterial chemotherapy in combination with radiotherapy achieved a complete response (CR). All of them were treated by prophylactic intra-arterial chemotherapy using pirarubicin (10), epirubicin (2) and carboplatin (1). The treatment was given once a month for 2 years. In the followup period from 14 to 43 months (median; 22.5 months), only one of the 13 patients had an invasive recurrence of bladder cancer and died of it. Ten of the 13 patients are now disease-free and alive with functional bladder. The complications of this therapy were mild and tolerable. The results suggest that prophylactic intra-arterial chemotherapy is a useful regimen for CR patients with invasive bladder cancer after induction therapy.

[Prognostic factors for muscle-invasive bladder cancer treated with a combination of intra-arterial chemotherapy and low-dose radiotherapy].

Clinical and pathological factors that affect short-term responses and long-term prognosis of muscle-invasive bladder cancer were studied in 73 patients who underwent a combination of intra-arterial chemotherapy and low-dose radiotherapy. Complete Response (CR) was observed in 41 (56%) of the 73 patients. The frequency of CR was significantly different according to the sex (males 64%, females 29%; p = 0.0239), clinical stage (T2 74%, T3 64%, T4 20%; p = 0.0005), tumor size (< 3 cm 81%. > or = 3 cm 31%; p < 0.0001), and tumor grade (G3 72%, G2 41%, p = 0.0127). By multivariate analysis, a significant difference was observed only in the tumor grade. The 5-year survival rate after bladder-preserving operations (median duration of follow-up 69 months) was significantly different according to the sex (males 75.2%, females 57.1%; p = 0.0427), clinical stage (T2 86.3%, T3 82.3%, T4 33.8%; T2 vs T4, p = 0.0005; T3 vs T4, p = 0.0107), tumor size (< 3 cm 89.6%, > or = 3 cm 47.2%; p = 0.0012), and tumor response (CR 95.0%, non-CR 38.6%; p < 0.0001). By multivariate analysis, a significant difference was observed only in the tumor response. The combination therapy of intra-arterial infusion and irradiation produced excellent short-term effects and prolonged the survival of the patients. Preservation of the bladder is considered to be possible in patients who obtained CR.

Primary diffuse large cell lymphoma of the penis.

A 66-year-old man presented with malignant lymphoma of the penis. This was of considerable interest because the penis is an extremely uncommon site for primary lymphoma. This patient had no evidence of nodal disease at presentation and so was treated with radiotherapy. He is now cured and both the structure and function of his penis have been preserved.

[Clinical and pathological efficacies of intra-arterial infusion chemotherapy and radiotherapy combined with hormone therapy in prostate cancer].

Eleven patients with prostate cancer were treated by intra-arterial infusion chemotherapy and radiotherapy combined with hormone therapy. CDDP was given one patient, THP and CDDP to eight patients, and THP and CBDCA to two others. All patients were treated by whole pelvis with prostate boost radiation. Seven patients underwent castration and four were administered LH-RH agonist in hormone therapy. Clinically, CR was observed in two patients and PR in nine. Histologically, G3 was observed in six patients, G2 in four patients and G1 in one. The main side effects were myelosuppression and rectal disturbances, but treatment could be completed in all patients. These results suggest that this treatment is a useful regimen for prostate cancer.

Scleroderma renal crisis in progressive systemic sclerosis: a case report.

We report a case of progressive systemic sclerosis with scleroderma renal crisis 10 years after onset. The patient (female) had progressive renal dysfunction, hypertension which was difficult to control, and massive gastrointestinal bleeding. An angiotensin converting enzyme inhibitor (enalapril) could not control her hypertension. Only intravenous nicardipine had a slight effect on her hypertension. Hemodialysis and plasma exchange, did not reverse the renal crisis, and the patient died. Microscopic examination of her kidney showed thickening of the capillary walls and mild nephrosclerosis.