Objective responses to ketoconazole therapy in patients with relapsed progressive prostatic cancer

The contribution of adrenal androgens to the maintenance and progression of so-called hormone-unresponsive prostatic carcinoma was studied in 20 patients with advanced relapsed disease. The role played by testicular androgens had been negated by prior orchiectomy or concurrent LHRH analogue therapy. Ketoconazole, an antifungal agent which inhibits adrenal and testicular androgenesis, administered in a dose of 400 mg 8-hourly, resulted in optimal suppression of adrenal androgens. The mean serum androstenedione concentration fell from 8.01 +/- 0.84 nMol/l to 1.55 +/- 0.25 nMol/l, P less than 0.001, and serum testosterone from 1.25 +/- 0.14 nMol/l to 0.36 +/- 0.06 nMol/l, P less than 0.01, after 6 months treatment. There was, however, no significant difference between patients receiving 400 and those receiving 200 mg. Androgen suppression resulted in six objective and ten subjective clinical responses. Ablation of both testicular and adrenal androgens can now be achieved using ketoconazole in combination with orchiectomy or LHRH analogues, but the high incidence of side effects may preclude its use in all patients with prostatic cancer. The results of this study support the concept of "total androgen ablation" as primary therapy in advanced prostatic cancer as a possible means of improving survival in this common malignancy.     

Aminoglutethimide stimulates extra adrenal delta-4-androstenedione production

The source of androgens was investigated in dogs (mean weight 17.9 kg) during aminoglutethimide (AG) adrenal blockade because it has been found that AG treated postmenopausal patients maintain androgen concentrations in plasma while estrogens are suppressed. Treatment started 2 days following bilateral oophorectomy (sterile conditions). Group 1 (N = 5) received no drug, Group 2 (N = 5) received AG (20 mg/kg b.i.d. × 7 days, 10 mg/kg b.i.d. × 7 days), and Group 3 (N = 5) received AG plus Cortisol 0.5 mg/kg/day. At a second laparotomy (Na pentobarbital 35 mg/kg iv, 98% O₂/2% CO₂ controlled volume ventilation, anticoagulation, Na heparin), aortic and venous monitoring catheters and a left adrenal vein to femoral vein T-shaped silastic catheter for total left adrenal vein blood flow diversion were inserted. Five adrenal vein flow determinations with simultaneous aortic and adrenal vein blood samplings occurred over an hour. Radioimmunoassay (cortisol, 17-OH-progesterone and δ-4-androstenedione [D-4-A]) of pooled aortic and adrenal plasma of each dog with flow values allowed mean adrenal secretion rate calculations for each steroid determined. Treatments suppressed adrenal secretion of D-4-A (P ? 0.004) (Group 1: 24,000 pg/min ± 11,300 (1 SD); Group 2: 5300 ± 1299; Group 3: 9800 ± 5100), but aortic concentrations of D-4-A were comparable (Group 1: 116 pg/ml ± 27; Group 2: 114 ± 70; Group 3: 92 ± 73) in observed and treated groups (analysis of variance). Linear regression correlation of adrenal D-4-A secretion to aortic concentration (r = 0.89, P ? 0.04) in controls was absent in treated groups. Insignificant suppression of adrenal secretion of cortisol and 17-OH progesterone corresponds to the low AG dose required to avoid lethal obtundation in treated groups. AG treatment depressed the linear regression correlation of adrenal secretion to aortic concentrations of 17-OH progesterone. The results indicate a peripheral source of D-4-A. It can be hypothesized that AG induces hepatic enzymes of steroidogenesis for δ-4-androstenedione.     

Continuous systemic 5-fluorouracil infusion in refractory prostatic cancer

Twenty patients with metastatic prostatic cancer were treated on an ambulatory basis with continuous 5-fluorouracil (5-FU) infusion 250-300 mg/M2 per day through a chronic indwelling central venous catheter. All patients had symptomatic, progressive disease despite previous standard therapies. Partial remission was seen in 2 of 20 patients (10%), stable disease in 9 of 20 (45%), and progressive disease in 9 of 20 (45%); mean duration of benefit in responding and stable disease patients was six months. Improvement in pain and ECOG performance status were seen in most of the patients in the responding and stable disease categories. Forty percent of the patients experienced no significant drug toxicity; treatment interruption was necessary for stomatitis in 6 patients (30%), hand/foot syndrome in 3 patients (15%), and diarrhea in 1 patient (5%). No significant myelosuppression or other significant organ toxicities were encountered. Continuous systemic venous infusion of 5-FU may provide significant palliative effect for some patients with symptomatic, refractory carcinoma of the prostate.     

The inability of adrenal androgens to stimulate the adult human prostate: an autopsy evaluation of men with hypogonadotropic hypogonadism and panhypopituitarism

Although it is well recognized that testicular androgens provide the major hormonal stimulus to the prostate the role of adrenal androgens is less certain. Recently, it has been suggested that total androgen ablation (adrenal and testicular) is necessary to achieve a complete response to hormonal therapy in men with carcinoma of the prostate. In an effort to elucidate the influence of adrenal androgens on prostatic growth, we reviewed autopsy findings in patients (mean age 65 years, with a range of 57 to 80 years) from 3 distinct groups: group 1 consisted of 4 men with neither adrenal nor testicular function since before puberty (panhypopituitarism), group 2 included 4 men with normal adrenal glands but no testicular function throughout life (hypogonadotropic hypogonadism or prepubertal castration) and group 3 consisted of 8 age-matched controls with normal adrenal glands and normal testes. To assess the degree of androgenic stimulation each prostate was examined by a genitourinary pathologist and was analyzed morphometrically with respect to epithelial cell height, epithelial cell height: nuclear height ratio, acinar area and short axis diameter of randomly selected acini. All prostates in groups 1 and 2 were atrophic histologically, while all prostates in group 3 were enlarged and demonstrated varying degrees of benign prostatic hyperplasia. Morphometric analysis of the 3 groups revealed the same results. For all 4 parameters studied morphometrically there was no statistical difference between groups 1 and 2. However, a statistical difference did exist for these criteria when either group 1 (p less than 0.0001) or group 2 (p less than 0.0001) was compared to group 3.(ABSTRACT TRUNCATED AT 250 WORDS)     

Cisplatin-based chemotherapy in advanced adenoid cystic carcinoma of the head and neck.

Nineteen patients, nine men and 10 women, with advanced adenoid cystic carcinoma (ACC), were treated with cisplatin either alone or in combination with doxorubicin and bleomycin. Median age was 51 years (range: 32-73 years). Two groups of patients were distinguished: Group 1 (N = 10) received single-agent cisplatin (50-120 mg/m2 IV every 4 weeks) for locoregional recurrence (N = 4), pulmonary metastases (N = 5), or as neoadjuvant therapy (N = 1). Five patients failed previous chemotherapy. No objective responses were observed, five patients showed stabilization of their disease for a median duration of 20 months (range: 3-50 months). Group 2 (N = 9) received a combination of cisplatin (20 mg/m2 IV on days 1-5), doxorubicin (50 mg/m2 IV on day 1), and bleomycin (30 mg IV on days 1-5), every 3 weeks. A complete remission (CR) was seen in one patient, lasting for 2 years, a partial remission (PR) in two patients (duration: 6 months and 6 years) (33%), and a stable disease (SD) in five patients (median duration: 15 months; range 3-24 months). One patient showed progression from the start. The observed toxicity was acceptable: dose reduction was required in five patients for myelosuppression or impairment of renal function; vomiting grade III (WHO) was seen in 10 patients. The median progression-free survival was 36 months (range: 7-77 months). Median overall survival was 81 months (range: 14-216 months). The role of cisplatin in this disease remains questionable.     

Change of serum adrenal androgens in prostatic cancer patients after bilateral orchidectomy or LHRH agonist treatment

Bilateral orchidectomy (ORX) or administration of luteinizing hormone releasing hormone agonist (LHRH) for prostatic cancer patients causes suppression of testicular androgens. However, the suppression of adrenal androgens by these treatments is controversial. We measured serum concentrations of testosterone (T), 4-androstene-3, 17-dione (A-dione), dehydroepiandrosterone (DHEA), LH, follicle-stimulating hormone (FSH), adrenocorticotropic hormone (ACTH) and cortisol before and after 3-12 months of the first hormonal treatment in 17 prostatic cancer patients who had received ORX (8 cases) or LHRH (9 cases). ORX and LHRH decreased serum T to the castration level significantly (ORX: p < 0.001, LHRH: p < 0.0001). ORX increased serum LH and FSH significantly (LH: p < 0.001, FSH: p < 0.001), whereas LHRH decreased LH and FSH significantly (LH: p < 0.05, FSH: p < 0.05). Neither treatment caused any significant change in ACTH or cortisol. ORX and LHRH decreased the serum A-dione significantly (ORX: p < 0.01, LHRH: p < 0.001). LHRH decreased the serum DHEA significantly (p < 0.01), whereas ORX did not decrease serum DHEA. These data suggest that "medical" and "surgical" castration, especially LHRH agonist, may decrease not only testicular androgens but also adrenal androgens.     

Oat-cell carcinoma of the prostate. Diagnosis, prognosis and therapeutic implications

BACKGROUND: Any carcinoma of prostatic origin which is not an acinary adenocarcinoma of the prostate is considered to be an atypical carcinoma. One member of this group of atypical prostatic tumors is the oat-cell carcinoma, or small cell carcinoma (SCC) of the prostate. This variety of carcinoma constitutes the histologic basis of <1% of all prostatic neoplasms. METHODS: Between 1992 and 1997, four patients were diagnosed with SCC of the prostate at our hospital. In 3 of the 4 cases, the histopathological diagnosis was pure SCC, and in the 4th case there was a component of prostatic adenocarcinoma associated with the SCC. At the time of diagnosis, extracapsular extension of the tumor was present in all 4 cases, with T3 or higher stages in all of them (T(3A)N(0)M(1), T(3A)N(0)M(0), T(3B)N(0)M(1), and T(4)N(0)M(0)). Because of the presence of extracapsular extension, radiotherapy and radical surgery were ruled out for all 4 patients. They were all offered systemic chemotherapy with cyclophosphamide (1 g/m(2)), doxorubicin (50 mg/m(2)) and vincristine (1.2 mg/m(2)). This therapeutic protocol was carried out in only 2 cases. RESULTS: Survival was <1 year in the 3 patients with pure SCC, and the patient with a mixed tumor is alive with detectable disease 9 months after diagnosis. CONCLUSIONS: This poor vital prognosis in SCC stresses the need for early diagnosis a timely and appropriate therapeutic intervention in this condition.     

A phase II study of mifepristone (RU-486) in castration-resistant prostate cancer, with a correlative assessment of androgen-related hormones

OBJECTIVE

To evaluate mifepristone (RU‐486) in patients with castration‐resistant prostate cancer (CRPC), with a correlative assessment of serum androgens and androgen metabolites

PATIENTS AND METHODS

The androgen receptor (AR) is critical in the development and progression of prostate cancer, but available antiandrogens incompletely abrogate AR signalling. Mifepristone is a potent AR antagonist that functions by competing with androgen, preventing AR coactivator binding and by enhancing binding of AR corepressors. Patients with CRPC were treated with mifepristone 200 mg/day oral until disease progression. Testosterone, dihydrotestosterone (DHT), androstenedione, dihydroepiandrosterone sulphate and the testosterone metabolite 3α‐diol G, were measured at baseline and during therapy.

RESULTS

Nineteen patients were enrolled between April and August 2005; they were treated for a median (range) of 85 (31–338) days. The median prostate‐specific antigen (PSA) level at enrolment was 22.0 (3.0–937.2) ng/mL. No patient had a PSA response (>50% reduction in PSA). Six patients had stable disease for a median of 5.5 months. After 1 month, adrenal androgens were increased and testosterone and DHT increased by 91% and 80%, respectively, compared to baseline.

CONCLUSION

Mifepristone had limited activity in patients with CRPC, and stimulated a marked increase in adrenal androgens, testosterone and DHT. We hypothesise that inhibition of glucocorticoid receptor by mifepristone resulted in an increase in adrenocorticotropic hormone and subsequent increase in adrenal androgens, and that their conversion by tumour cells to testosterone and DHT probably limited the efficacy of mifepristone. These data emphasize the continued importance of alternative androgen sources in AR signalling in CRPC.     

Phase II evaluation of coumarin (1,2-benzopyrone) in metastatic prostatic carcinoma.

The unavailability of effective treatment of metastatic hormone refractory prostatic carcinoma warrants trials of new and promising treatments. Coumarin is an investigational new drug that has produced objective tumor regression in some patients with metastatic renal cell carcinoma and malignant melanoma. Coumarin has shown activity against prostatic carcinoma in the Dunning R-3327 rat prostatic adenocarcinoma model. Forty-eight patients with metastatic hormone naive (5 stage D1 and 10 stage D2) or hormone refractory (33 stage D3) prostatic carcinoma of average age 67.6 years (range 46-86) and ECOG performance status of 2 or better were given 3 grams coumarin daily by mouth and evaluated monthly for toxicity and response by rigid criteria in a multicenter trial. Toxicity was limited to asymptomatic SGOT elevations in 3 patients and nausea and vomiting in 4 patients that required cessation of therapy in 2. Eligibility and protocol violations removed 6 additional patients from response evaluation. There were no complete responses. Partial responses (3 of 40 patients, 8%) occurred in 2 patients with bidimentionally measurable disease and 1 patient with disease evaluable by bone scan and elevated prostate specific antigen and prostatic acid phosphatase. The remaining patients progressed after 1 to 12 (average 4.4) months. Coumarin is a relatively nontoxic drug that may warrant further trials in a subset of patients with prostatic carcinoma.     

DOES PROSTATE TRANSITIONAL CELL CARCINOMA PRECLUDE ORTHOTOPIC BLADDER RECONSTRUCTION AFTER RADICAL CYSTOPROSTATECTOMY FOR BLADDER CANCER?

Purpose

We determined if urethral preservation and orthotopic bladder replacement in patients with transitional cell carcinoma within the prostatic urethra or prostate placed these patients at risk for urethral recurrence or death.

Materials and Methods

The clinical course of all patients undergoing urethral preservation and orthotopic bladder replacement was reviewed. The urethra was sacrificed only if the distal prostatic urethral margin was positive for transitional cell carcinoma. The pathological T stage and the grade of the primary malignancy, local recurrence, site of recurrence (urethral, pelvic, distant) and death were documented.

Results

Of 81 patients, 70 were evaluated (June 1996) with a mean followup of 35 months. Of the 70 patients 48 were alive without evidence of disease for a mean of 38 months (range 8 to 107) and 5 died without evidence of disease. Eight of these 53 patients (15%) had prostatic involvement (carcinoma in situ in 6, intraductal carcinoma in 1 and stromal invasive transitional cell carcinoma in 1). Of the 70 patients 17 had disease recurrence (13 died of disease and 4 are alive, 1 of whom had urethral recurrence without initial prostatic transitional cell carcinoma). Of the 17 patients (35%) 6 had transitional cell carcinoma prostatic involvement (carcinoma in situ in 4 and stromal invasion in 2), and 5 of these 6 died, none with or of urethral recurrence but of the primary bladder pathology. Of these 5 patients 1 had stromal invasive transitional cell carcinoma of the prostate and experienced a bulbar urethra recurrence at 1 month and a pelvic recurrence at 3 months, and died at 5 months. Death was not secondary to the urethral recurrence. Thus, of the 14 patients who had prostatic transitional cell carcinoma, only 1 had urethral recurrence (7%), and this recurrence did not present as the cause of death.

Conclusions

The guidelines for urethral resection can be relaxed, increasing the opportunities for orthotopic reconstruction, without placing the patients at increased risk for death of transitional cell carcinoma.     

Ketoconazole therapy in advanced prostatic cancer

To determine the effect of ketoconazole, a nonestrogenic antifungal agent, in patients with metastatic prostatic cancer 13 patients with symptomatic stage D2 prostatic cancer were administered 400 mg. ketoconazole orally every 8 hours. By 24 hours of treatment serum testosterone had decreased to the castrate level and the adrenal androgens, androstenedione and dehydroepiandrosterone, also had decreased significantly. By 1 week of treatment clinical response was evident in all patients. Pain was improved and serum prostatic acid phosphatase levels had decreased significantly, and by 1 month prostatic acid phosphatase had reached the normal range. The patients have been followed for 3 to 10 months without relapse. Side effects were few. Because of the ease of administration, rapidity of action, and decrease of adrenal and testicular androgen levels, as well as the relative lack of side effects, ketoconazole may prove to be an important new drug in the treatment of prostatic cancer.     

The combination of cyproterone acetate and low dose diethylstilbestrol in the treatment of advanced prostatic carcinoma

Cyproterone acetate is a steroidal antiandrogen with weak progestational activity that results in the partial suppression of pituitary gonadotropin. We demonstrate that the associated decrease in serum testosterone is more complete and prolonged if cyproterone acetate (200 mg. daily) is combined with a low dose of diethylstilbestrol (0.1 mg. daily). The effectiveness of the combination in the treatment of prostatic carcinoma was investigated in 51 patients with stage D2 malignancy. From an initial concentration of 360 +/- 23 ng. per dl. (mean +/- standard error), serum testosterone decreased to 56 +/- 5 ng. per dl. after 1 week and reached a plateau of approximately 30 ng. per dl. after 2 months. This was accompanied by a decrease in serum prostatic acid phosphatase from a mean starting concentration of 43 +/- 11 ng. per ml. to a low of 3 +/- 1 ng. per ml. at 12 months; the proportion of normal values increased from 10 to 80 per cent. A complete response was observed in 7 patients (13 per cent), partial response in 35 (69 per cent) and stable disease in 8 (16 per cent), yielding an over-all objective response rate of 98 per cent (1980 National Prostatic Cancer Project criteria). The actuarial median time to progression was 17 months and the median survival time was 23.5 months. In 26 patients who subsequently had signs of progressive carcinoma the relapse rate in bone (85 per cent) far exceeded that in nonskeletal sites (23 per cent). The incidence of cardiovascular toxicity was 12 per cent. These results indicate that cyproterone acetate and low dose diethylstilbestrol may be co-administered to achieve a synergistic and potent androgen withdrawal effect in the treatment of advanced prostatic carcinoma.     

Treatment recommendations for adrenal metastasis of non-small cell lung cancer

To evaluate the optimum treatment strategy for metastatic adrenal tumors derived from non-small cell lung cancer (NSCLC), we retrospectively analyzed 17 consecutive cases (8 resection cases: 4 synchronous and 4 metachronous: 9 non-resection cases: 3 synchronous and 6 metachronous) who received surgical resection for NSCLC. The patients included 12 males and 5 females with a mean age of 63.9 years. Of these, 9, 3, 2, 2, and 1 patient (s) were diagnosed as having adenocarcinoma, squamous cell carcinoma, pleomorphic carcinoma, large cell carcinoma, and adenosquamous cell carcinoma, respectively. The mean interval after lung resection and treatment of metachronous adrenal metastasis was 9.9 months. The mean time to progression from treatment of metachronous adrenal metastasis to disease progression was 8.9 months. A survival analysis showed no significant prognostic difference between the patient age, gender, pathological stage, synchronous/metachronous classification, CEA, and site of metastases. However, patients who received an adrenalectomy had a more favorable prognosis. The 2-year survival of patients following resection versus those who did not undergo a resection for adrenal metastasis was 62.5 and 22.8%, respectively. These data indicate that metastatic adrenal tumors should be resected if the patient can tolerate surgery after appropriate selection.     

Aminoglutethimide for advanced prostatic cancer resistant to conventional hormonal therapy

Aminoglutethimide (AG) and hydrocortisone (HC) were given to 20 patients with advanced prostatic cancer resistant to conventional hormonal therapy. Most patients had painful bone metastases and were heavily pretreated. 12 of 16 patients required narcotic analgetics. 8 of 20 were bedridden. AG + HC produced relief of bone pain in 12 patients (75%) and only 4 required narcotics after treatment. The performance status improved in 8 of 20 patients (40%). However, the number of bone metastases seen in bone scans decreased in only 4 patients (22%). The level of serum alkaline phosphatase decreased in 11 of 18 patients and that of acid phosphatase in 8 of 16 patients. The reduction of bone pain lasted approximately 4 months (range 1-15 months). The median lifespan between the start of AG treatment and death was 8 months (range 2-22 months). There was no difference in survival between responders and nonresponders. 3 patients had skin rash, 1 lethargy and 1 thrombocytopenia.     

Diagnostic and therapeutic problems in Cushing's syndrome. Series of 7 cases

A series of 7 patients (all females) with Cushing's syndrome are presented. The syndrome was due to an adenoma of the cortex in 4 cases, to a carcinoma in 1 and to bilateral adrenal hyperplasia in another. In the 7th patient the cortical hyperplasia was due to a bronchogenic carcinoma (ectopic production of ACTH). Surgery was performed in all patients except 1. In 5 patients (adenoma, carcinoma) the diseased adrenal was removed. In 1 patient a left total and a right subtotal adrenalectomy were performed. Out of those 7 patients 4 survived and 3 died. 1 died a few hours after surgery, another 3 months after operation and the last one was never operated on.     

Combination chemotherapy with ifosfamide, 5-fluorouracil, cisplatin for stage D2 prostatic cancer

Twelve patients with stage D2 adenocarcinoma of the prostate were treated with the combination chemotherapy of ifosfamide (2 g/body, i.v., day 1-3), 5-fluorouracil (250 mg/body, i.v., day 1-5) and cisplatin (20-30 mg/body, i.v., day 1-5). The averaged age was 62 years (from 52 to 73 years) with mean performance status of 70% (from 40 to 90%). Six patients were refractory to prior hormone therapy or chemotherapy and the other six had received no prior treatment for prostatic cancer. Based on criteria of National Prostatic Cancer Project, 4 patients achieved partial response (PR) which was maintained from 11 to 23 months with the mean of 17.8 months. Two patients achieved objectively stable stage (NC). Response rate (PR + NC) was 50%. Response rate of patients without prior therapy was 80%, whereas that of hormone-resistant group was 30%. There was a trend toward unfavorable response in patients with prior therapy. Adverse effects were mild to moderate gastric problems and myelosuppression except in one case Adverse effects were mild to moderate gastric problems and myelosuppression except in one case with low performance status under 60%. IFP combination chemotherapy achieved favorable responses and toxicities were tolerable. Therefore, it appears worth while to study whether IFP combination chemotherapy could extend the life of patients with advanced prostatic cancer.     

Hormonal effects of high dose medroxyprogesterone acetate treatment in males with renal or prostatic adenocarcinoma

In 18 patients, 12 with renal and 6 with prostatic carcinoma, the gonadal, pituitary and adrenal functions were studied by measurements of steroid hormones and gonadotrophins, before and after six weeks treatment with medroxyprogesterone acetate (MPA), injected intramuscularly 500 mg per day for 5 days each week. The testosterone-oestradiol-binding globulin (TeBg) was measured and the amount of albumin and TeBg bound and unbound testosterone was calculated. Treatment with high doses of MPA caused a profound decrease in serum concentrations of testosterone, dehydroepiandrosterone sulphate (DHEAS), cortisol and TeBg. There were significant decreases in serum concentrations of luteinizing hormone (LH), follicle stimulating hormone (FSH) and oestradiol-17 beta. The serum concentration of prolactin was significantly elevated. The protein unbound testosterone fraction was lowered by MPA treatment but less than total testosterone. In conclusion, MPA therapy in high dose alters the gonadal, pituitary and adrenal functions suppressing serum concentrations of androgens, gonadotrophins, cortisol and TeBg but elevating prolactin concentration.     

舒尼替尼治疗转移性肾癌的疗效和安全性分析:单中心37例总结

目的 评价舒尼替尼治疗转移性肾细胞癌的疗效和安全性.方法 2008年6月至2010年4月37例转移性肾细胞癌患者接受舒尼替尼治疗.其中男28例,女9例.年龄17～74岁,中位年龄52岁.行根治性肾切除手术33例,肾穿刺活检3例,腋窝转移淋巴结穿刺活检1例.vonHippel-Lindau综合征患者2例.肾透明细胞癌36例,其中伴颗粒细胞成分1例、伴肉瘤样分化4例,肾乳头状细胞癌1例.一线治疗30例,细胞因子或索拉非尼治疗进展后二线治疗7例.其中34例采用4/2方案,即口服舒尼替尼50.0 mg/d 4周,停用2周,6周为1个周期;3例予口服37.5 mg/d持续治疗,直至疾病进展或者出现不可耐受的不良反应.结果 中位随访时间12个月(8个周期).34例患者治疗2周期以上,可进行疗效评估.根据RECIST标准评价最佳疗效,部分缓解9例(26.5%),疾病稳定24例(70.6%),疾病进展1例(2.9%).客观反应率26.5%,疾病控制率97.1%.1年生存率95.8%(23/24),1年无进展生存率62.5%(15/24).主要不良反应包括血小板减少30例(81.1%)、甲状腺功能异常18/22例(81.8%)、手足反应27例(73.0%),白细胞减少23例(62.2%)、高血压18例(48.6%)等.大多数不良反应为1～2级,3级以上不良反应包括血小板降低8例(21.6%)、甲状腺功能异常4/22例(18.2%)、手足反应4例(10.8%)、血磷降低4例(10.8%)和腹泻2例(5.4%)等.10例(27.0%)在治疗过程中减量或停药,1例因严重乏力不能耐受终止治疗.通过对症支持,减量或停药,不良反应可控制并耐受.结论 舒尼替尼一线及二线治疗晚期转移性肾细胞癌可取得较高的疾病控制率,不良反应发生率多数轻而易耐受,严重不良反应较少且可控.

Abstract：

Objective To evaluate the efficacy and safety of sunitinib in the treatment of metastatic renal cell carcinoma (RCC). Methods A total of 37 patients with metastatic RCC were treated with between June 2008 and April 2010, including 28 males and 9 females. The median age was 52 (17-74) years. All patients received a pathologic diagnosis of RCC, which consisted of 1 papillary cell carcinoma and 36 clear cell carcinomas, 4 of which accompanied with partial sarcoma differentiation. Thirty cases were treated with first line therapy and 7 cases showed progression on first-line cytokine or sorafinib therapy. Sunitinib monotherapy was administered in repeated 6-week cycles of daily oral therapy for 4 weeks, followed by 2 weeks off in 34 patients, while another 3 patients received 37. 5 mg Qd continuously until disease progression or unacceptable toxicities occurred. Overall response rate and safety were evaluated. Results The median follow up was 12 months (8 cycles),range 1.5-19. 5 months (1-13 cycles). 26.5% (9/34) patients achieved partial responses, 70.6%(24/34) patients demonstrated stable disease over≥3 months and 1 (2. 9%) patient developed progressive disease. The objective response rate was 26.5%, and the disease control rate was 97. 1%.The 12 months' overall survival rate was 95.8% (23/24), and 12 months' progression-free survival rate was 62.5 % (15/24). The most common treatment-related adverse events were thrombocytopenia (30 cases, 81.1%), thyroid dysfunction (18/22, 81.8%) ,hand-foot syndrome (27 cases, 73.0%),neutropenia (23 cases, 62.2%) and hypertension (18 cases, 48.6%). The major grade 3 adverse events included thrombocytopenia (8 cases, 21.6%), hand-foot syndrome (4 cases, 10.8%) and diarrhea (2 cases, 5. 4%). Most adverse events were ameliorated by treatment interruption. Ten (27.0%) patients had dose decrement or drug discontinuation and 1 patient quit the treatment for intolerable fatigue. Conclusion The efficacy and manageable adverse event profile of sunitinib as a single agent in first- or second-line therapy for patients with metastatic RCC.     

The evaluation of the effect of Estracyt on prostatic cancer

The clinical effect of Estracyt on untreated prostatic carcinoma was evaluated. The subjects consisted of 51 of 71 patients with prostatic carcinoma who were observed for 6 months or more after oral administration of 560 mg of estramustine phosphate. This drug was effective in all patients: markedly effective in 34 (66.6%), moderately effective in 13 (25.5%), and slightly effective in 4 (7.8%). During the observation period varying from 6 months to 2 years and 6 months, 7 patients had recurrence of progression. The interval between the drug administration and recurrence of progression varied from 6 months to 1 year and 10 months (mean, 15.8 months). Prostate acid phosphatase and gamma-seminoprotein remained normal between 3 and 15 months after the administration but became elevated due to recurrence of progression after 18 months or more in some patients. Blood testosterone, luteinizing hormone, and follicle stimulating hormone decreased while blood cortisol increased. Therefore, estrogen was acting effectively. Side effects were observed in 56.9% of the patients, the most frequent being mazoplasia in 33 patients (45.8%), and cardiovascular complications and apoplexy in 11 patients (15.3%). Estracyt was effective for untreated prostatic carcinoma but the problems such as recurrence of progression and side effects require further examination.     

The incidence of high-grade prostatic intraepithelial neoplasia and atypical glands suspicious for carcinoma on first-time saturation needle biopsy, and the subsequent risk of cancer

OBJECTIVE: To investigate the detection rate and extent of high-grade prostatic intraepithelial neoplasia (HGPIN) and atypical glands (AG) suspicious for prostate cancer, and the cancer risk in subsequent biopsies, diagnosed by a first 24-core saturation biopsy, as although the optimum extent of biopsy is controversial there is a trend to increase the number of cores taken, and apart from detecting prostate cancer, identifying HGPIN and AG is associated with a greater risk of finding cancer in subsequent biopsies, thus warranting a closer follow-up. PATIENTS AND METHODS: The study included 100 men with consecutive first-time saturation biopsies; the indications for biopsy were an abnormal digital rectal examination and/or a serum prostate-specific antigen (PSA) level of >2.5 ng/mL. Each biopsy specimen was reviewed retrospectively by two pathologists to confirm the histological diagnosis. The number and percentage of cores positive for HGPIN, bilateral involvement and multifocality (HGPIN involving two or more cores) were recorded in each case. The presence of AG and cancer was also recorded. An extended (10-12 cores) repeat biopsy was available in 23 patients. RESULTS: The median (range) age and PSA level of the patients was 63 (41-80) years and 4.9 (1.5-67.0) ng/mL, respectively. Of the 100 patients, 34% had normal findings (benign prostatic tissue, BPT), 39% had cancer, 26% had HGPIN and cancer, 22% had HGPIN alone, and 5% had AG. Repeat biopsies were available in nine of the 22 (41%) patients with HGPIN, four of five with AG, and 10 of the 34 (29%) with BPT. The median (range) interval between the first and second biopsy was 13 (4-36) months. Prostate cancer was detected at the second biopsy in a third of patients with isolated HGPIN on the first biopsy, and one of the four with AG. None of the patients with BPT had cancer on re-biopsy. The cancer detection rate was significantly greater in patients with multifocal than in those with unifocal HGPIN (80% vs none, P = 0.010). The median number of cores and percentage of tissue involved by HGPIN was 3.5 (2-5) and 1.0 (0.5-1.2)%, respectively, in patients with cancer detected in repeat biopsies, compared to 1.0 (1-3) and 0.2 (0.2-0.6)% in patients without cancer on repeat biopsy (P = 0.023 and 0.015, respectively). CONCLUSION: Identifying multifocal HGPIN on first saturation biopsy is associated with an overall cancer detection rate of 80% on repeat 10-12-core biopsy. Although there were few patients, the detection of multifocal HGPIN warrants additional searches for concurrent invasive carcinoma by repeated biopsy.