Weekly low-dose adriamycin in hormone-resistant metastatic cancer of the prostate

Weekly intravenous doses of 20 mg Adriamycin were given to 22 patients with hormone-resistant metastatic cancer of the prostate. (Median duration treatment: 8 weeks; range 3-60 weeks.) Of 21 adequately treated patients, 6 achieved a subjective response (Median duration: 4 weeks; range 4-28 weeks). In 2 patients a more than 50% size reduction of measurable lymph node metastases was observed, while the disease progressed at other sites (mixed response). The median survival from treatment start (8.5 months) was unrelated to the achievement of subjective response. In 10 of 21 patients a reduction of serum alkaline phosphatase was observed and 7 of 21 patients showed a decrease of serum prostatic acid phosphatase. These biochemical changes were not related to response. Toxicity was generally mild, but one case with severe irreversible thrombocytopenia was observed after 3 weekly doses of 20 mg Adriamycin. Weekly low-dose Adriamycin has marginal subjective efficacy in progressing hormone resistant prostatic cancer, a condition where effective and feasible chemotherapy is lacking. The combination of weekly low-dose Adriamycin with other agents, preferably hormones, should be explored.     

High-dose medroxyprogesterone acetate versus prednisolone in hormone-resistant prostatic cancer. A pilot study

Medroxyprogesterone acetate (MPA) (1,000 mg daily per os) yielded (mainly subjective) remissions in 8 of 21 patients with hormone-resistant cancer of the prostate. In 24 comparable patients, treated with prednisolone (20 mg daily per os) 3 remissions were observed, indicating a slight superiority of high-dose MPA considering the response rate. The response duration for both drugs was relatively short (2-7 months). No survival benefit for either drug was observed. In patients with hormone-resistant cancer of the prostate, a significant improvement of the performance status should be registrated as subjective response. This is a major aim of any treatment in these patients. Normalization of serum acid phosphatase may also be considered as remission. The type of remission (greater than 50% reduction of measurable tumor lesions, reduction of serum acid phosphatase, subjective remission) should always be indicated in the individual report dealing with phase II/phase III studies in patients with hormone-resistant prostatic cancer.     

Quality of life assessment in patients with hormone-resistant prostate cancer treated with epirubicin or with epirubicin plus medroxy progesterone acetate - is it feasible?

OBJECTIVES: The optimal palliative treatment in patients with advanced hormone-resistant prostate cancer (AHRPC) is still under investigation. We studied the effect of epirubicin, alone or combined with medroxy progesterone acetate (MPA), in this particular patient group. The aim of the study was to investigate the feasibility of quality of life (QOL) measurement and to ascertain whether MPA added to epirubicin produces a better QOL than epirubicin alone. METHODS: Of 28 randomized patients with symptomatic AHRPC, 26 were eligible for the study. Fourteen of them received epirubicin (100 mg/m(2) i.v.) every 3 weeks in combination with an oral dose of 500 mg of MPA twice daily. Twelve patients received epirubicin alone. For the QOL assessment, the Rotterdam Symptom Checkliste was used. Toxic side effects of chemotherapy were assed by the WHO criteria. Subjective responses included performance status and pain score. RESULTS: Compliance in completing QOL questionnaires was high (87.5%). In none of the QOL domains studied did any of the patients, irrespective of their treatment, experience an improvement in their QOL. Moreover, after 12 and 24 weeks, patients in both treatment arms experienced a significant worsening of physical symptom distress when compared to study entry. Toxicity was moderate to severe. A biochemical response (drop in prostate-specific antigen of more than 50%) was observed in 5 out of 26 patients (19.1%) and a subjective response in 7 out of 26 patients (26.9%). The median survival for all patients was 30 weeks. There was no statistically significant difference between the two arms. Performance status and the global QOL as judged by the patients themselves were associated with the duration of survival. No relation was found between the initial observed subjective response and survival. CONCLUSIONS: The feasibility of measuring QOL in patients with symptomatic AHRPC is demonstrated in the present study. Subjective and biochemical responses were observed in both treatment arms, but these were not translatable as improved measured QOL domains.     

Phase II study of epirubicin in advanced hormone-resistant prostatic carcinoma.

Twenty-nine patients with metastatic prostate cancer that had progressed following orchiectomy were treated with intravenous epirubicin 90 mg/m2 every 28 days. Their median age was 71 years (range 49-78) and the median Zubrod scale (WHO score) was 1. Two patients had soft tissue lesions, 20 had bone metastases and 7 had both. Tumour response was assessed according to the National Prostatic Cancer Project criteria. Of 29 patients, 11 (38%) achieved a partial remission. The median duration of response was 6 months and the median survival time of all patients was 9 months (range 2-27). It seemed that treatment with epirubicin was not associated with an increase in survival. Toxicity was moderate and consisted of alopecia and mild nausea/vomiting. There was no significant haematological toxicity and no clinical cardiotoxicity. It was concluded that epirubicin was active in hormone-resistant metastatic prostate cancer in approximately 33% of the patients.     

Effects of bicalutamide and leuprolide on prostate-specific antigen (PSA), acid phosphatase (ACP) and prostatic acid phosphatase (PAP) in men with benign prostatic hyperplasia (BPH)

The effects of the nonsteroidal antiandrogen bicalutamide (Casodex(TM)) and the luteinizing hormone releasing hormone agonist leuprolide depot (Procren Depot(TM), Lupron Depot(TM)) on serum prostate-specific antigen (PSA), acid phosphatase (ACP), and prostatic acid phosphatase (PAP) in patients with benign prostatic hyperplasia (BPH) were determined. Thirty patients with BPH were randomised to receive bicalutamide 50 mg orally once daily or a placebo for 24 weeks, followed by 24 weeks of follow-up (bicalutamide study). In another study 55 men were randomised between 3.75 mg leuprolide depot intramuscularly at every 28 days for 24 weeks or placebo injections (leuprolide study). In both studies blood sampling was performed at baseline, at week 12 at week 24 and 24 weeks after the end of therapy. Androgen suppression with bicalutamide 50 mg daily for 24 weeks resulted in a median of 56% reduction of PSA (P<0.001 when compared to placebo). Acid phosphatase and PAP did not change. Leuprolide resulted in a median of 87% reduction of serum PSA (P<0.001) and a 39% reduction of PAP (P=0.023), whereas ACP was unchanged. Both bicalutamide and leuprolide induced a pronounced decline in serum PSA in BPH patients. The studies suggest a stronger androgen suppressive effect of leuprolide than of bicalutamide, but this difference might largely be due to too low a dosage of bicalutamide. ACP and PAP were relatively insensitive to androgen suppression. Our study suggests a different degree of androgen suppression on PSA originating from benign tissue versus cancer tissue, and that the direction of this discrepancy might be different for various androgen suppressive regimens.Prostate Cancer and Prostatic Diseases (2001) 4, 173-177.     

A comparative clinical trial of adriamycin and 5-fluorouracil in advanced prostatic cancer: prognostic factors and response

In patients with metastatic hormone-relapsed adenocarcinoma of the prostate, adriamycin was compared to 5-fluorouracil in a randomized trial in 99 patients and adriamycin alone was studied in an open trial in 48 patients. Response to adriamycin was superior as judged by response of measurable disease (25 vs 8%; P less than 0.05) and survival (median 29 vs 24 weeks; Cox analysis, P less than 0.03), but comparable as judged by acid phosphatase response. Ambulatory status and site of metastases influenced rate of response to chemotherapy. Activity level, site of metastases, weight loss, and the symptom of protein aversion were prognostic factors for survival. Hematologic and gastrointestinal toxicity were frequent but were tolerated satisfactorily. Adriamycin therapy may be beneficial in patients with prostatic cancer after hormone therapy.     

Flutamide in hormone-resistant prostatic cancer.

Flutamide (250 mg. orally 3 times daily) yielded a subjective response in 5 of 25 fully evaluable patients with hormone-resistant prostatic cancer. Four additional patients had early progression. A 40% or greater decrease in the pre-treatment prostate specific antigen level was observed in 7 of 24 patients and this finding was correlated with improved survival. Toxicity was mainly gastrointestinal and resulted in permanent discontinuation of flutamide in 5 patients. Flutamide or similar antiandrogens may have a role in the management of hormone-resistant prostatic cancer when relief of subjective symptoms should be an important treatment goal together with improvement of survival. However, before the drug should be used routinely in the management of hormone-resistant prostatic cancer phase 3 studies must confirm its effectiveness, especially in comparison to less expensive drugs.     

A randomized study on hormone-resistant prostatic cancer: estramustine phosphate versus low dose epirubicin with or without medroxyprogesterone acetate. A Norwegian multicenter study

A prospective randomized study has been carried out in order to compare three different treatment modalities for symptomatic metastatic hormone-resistant prostatic cancer. A total of 79 patients were included. One group was treated with estramustine phosphate, another with Epirubicin plus Medroxyprogesterone acetate (MPA), while the third arm consisted of Epirubicin plus placebo. Best palliation was obtained by the combination of Epirubicin and MPA. This combination also seemed to be associated with the longest response duration.     

Megestrol acetate in relapsed carcinoma of prostate

A series of 22 patients with advanced carcinoma of the prostate who had failed first-line hormonal therapy (orchiectomy, stilboestrol, luteinising hormone-releasing hormone agonist) were treated with 160 mg megestrol acetate daily. Treatment was well tolerated, side effects were minimal and 21 patients were evaluable. There were no complete or partial responses, although 8 patients had a good subjective response. In 6 patients the disease was stabilised for 6 to 12 months and there was a 40 to 50% reduction in their prostatic acid phosphatase (PAP) levels. It was concluded that megestrol acetate has a role as second-line hormonal therapy in the management of prostatic carcinoma.     

A multicenter randomized trial comparing the luteinizing hormone-releasing hormone analogue goserelin acetate alone and with flutamide in the treatment of advanced prostate cancer. The International Prostate Cancer Study Group.

A prospective randomized trial was conducted to compare the effects of the nonsteroidal antiandrogen flutamide (250 mg. 3 times daily) plus the luteinizing hormone-releasing hormone analogue goserelin acetate (Zoladex) (3.6 mg. subcutaneous depot injection every 28 days) with goserelin acetate alone in advanced prostatic carcinoma. A total of 571 eligible patients, of whom 57% had distant metastases, showed no difference in subjective or objective response rates, interval to progression, treatment failure or survival after a median followup of 2 years. In the combination group more patients had an early decrease in elevated levels of tumor markers and the small number of patients with an increase in signs and symptoms within the first 4 weeks showed a significant decrease. However, increased gastrointestinal and hepatic toxicity in the combination group resulted in 44 patients being withdrawn from the trial. These results indicate that the combination of goserelin acetate with flutamide provides no long-term clinical benefit in patients with advanced prostatic carcinoma compared to goserelin acetate alone.     

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.     

Long-term survival of a patient with primarily chemo-resistant metastatic breast cancer treated with medroxyprogesterone acetate

The prognosis of breast cancer patients with liver metastases is extremely poor. Here we present the case of a 66-year-old female breast cancer patient with multiple liver metastases diagnosed 2 years after a radical modified mastectomy followed by adjuvant tamoxifen. At progression, anthracycline-based chemotherapy was administered, but a CT scan following two cycles of FEC (5-fluorouracil, epirubicin, cyclophosphamide) showed progression of the liver metastases. Chemotherapy was therefore switched to medroxyprogesterone acetate (MPA). After 3 months the patient's general status improved, and disease stabilization was observed at the next CT scan. A further 4 months of MPA treatment resulted in complete response of all liver lesions. Treatment with oral MPA was continued for 4 years. At present, 11 years after the diagnosis of metastatic liver involvement, the patient is alive, free of cancer, and fully ambulatory. Despite bulky visceral disease and chemoresistance, hormonal treatment with MPA resulted in a spectacular and long-lasting response.     

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.     

Estracyt in hormone-resistant prostatic carcinoma

Hormonal treatment of prostatic carcinoma may give rise to secondary hormone resistance that poses serious problems. Estramustine phosphate (Estracty, ® AB Leo, Helsingborg, Sweden) has been studied in 50 patiens with prostatic carcinoma that had developed secondary hormone resistance. The results of the clinical study were evaluated at the end of a fllow-up period ranging from 6 months to 2 years. A positive response has been noted in a large proportin of the patients: viz. shrinkage of the primary tumour, decrease in residual urine in nearly 50%, and subjective relief and improvement of the general condition in a still larger proportion. On the other hand, with the exception of one patient, the skeletal metastases remained unaffected. Secondary effects, if any, were rare. Estracyt recommends itself for hormone-resistant patients are still in a good general condition: on the other hand, it offers little benefit in the far-advanced state of the disease, i.e. with extreme cachexia.     

An evaluation of intermediate-dose ketoconazole in hormone refractory prostate cancer

OBJECTIVES: The management of hormone refractory prostate cancer remains controversial. Among the options, second-line hormonal therapy is commonly used. We investigated the efficacy of ketoconazole, an inhibitor of testicular and adrenal androgen biosynthesis, for treating patients with advanced hormone refractory prostate cancer. METHODS: The study comprised 38 patients with progressive disease despite combined androgen blockade. Treatment consisted of intermediate-dose ketoconazole (300mg three times daily) and replacement hydrocortisone. Patients were monitored clinically and with serial psa measurements every 3 months. the principal endpoint was psa response. RESULTS: Of the 38 patients, 21 (55.3%) showed a decrease in PSA >50% (95% confidence interval 38.3%-71.4%) with a median duration of 6 months (range 3-48 months). A PSA reduction >50% was seen in 21 of 34 patients (61.8%) with established metastases. Thirteen patients (34.2%), all of whom had metastases, exhibited a PSA decrease >80% (95% confidence interval 19.6%-51.4%) with a median duration of 9 months (range 3-48 months). Age, PSA at diagnosis, Gleason score and bone scan result were not significantly associated with response to ketoconazole treatment in univariate or multivariate analyses. For the entire study group, the median time to progression was 5 months (range 0-27 months) and the median survival was 12 months (range 3-48 months). Overall, 12 patients (31.6%) reported toxicity related to intermediate-dose ketoconazole but only 6 patients (15.8%) discontinued therapy due to intolerable side effects. CONCLUSION: It is apparent from this study that a reasonable percentage of patients failing standard hormonal therapy respond favourably to intermediate-dose ketoconazole and that toxicity is mild. In the absence of studies demonstrating better survival with chemotherapy, we believe that a trial of ketoconazole should be considered when progression occurs on hormone therapy.     

Treatment of advanced prostatic cancer with anti-androgens alone and a combination of anti-androgen with anti-prolactine — A pilot study

Summary In this pilot study the treatment of advanced prostatic cancer with cyproteronacetate (Androcur^R) is compared with the treatment of a lower dose cyproteronacetate plus lisuride (Dopergin^R), an anti-prolactin derivative. Treatment was continued until progression and/or the appearance of serious side effects necssitated termination. The duration of the treatment with cyproteronacetate plus lisuride ranged from 2 to 38 months. Most cases showed a partial response, evaluated on the basis of lower levels of prostatic acid phosphatase, relief of bone pain and reduction of bone metastases. Serious side-effects other than impotence did not occur.Abbreviations CPA cyproteronacetate - T testosteron - DHT dihydrotestosteron - LH luteinizing hrmone - FSH follicle stimulating hormone - PSAP prostate specific acid phosphatase Presented at the Fourth Congress of the European Society of Urological Oncology and Endocrinology, Amsterdam, 25th–27th April 1985     

Phase II study of repeated single 24-hour infusion of low-dose 5-fluorouracil for palliation in symptomatic hormone-refractory prostate cancer

BACKGROUND: To assess the efficacy and toxicity of repeated single 24-hour infusion of low-dose 5-fluorouracil for symptomatic hormone-refractory prostate cancer using relevant endpoints of palliation and biological response. PATIENTS AND METHODS: 25 patients with histologically confirmed prostatic adenocarcinoma and symptomatic progressive disease despite one or several hormonal treatments and chemotherapy were included in the study. Treatment consisted of a single 24-hour infusion of 500 mg/m(2) 5-fluorouracil (5-FU) to be repeated on day 21. This regimen was continued until either progression or serious toxicity occurred. Response was assessed by serial measurements of serum prostate-specific antigen (PSA) as well as by health-related quality-of-life instruments (EORTC QLQ-C30 and McGill-Melzack Present Pain Intensity Scale) every 3 weeks. In 10 patients with bidimensionally measurable metastases, objective responses were assessed every 3 months. RESULTS: A mean number of four courses of repeated single 24-hour infusion of 5-FU was administered (range 2-6). Toxicity was absent or mild, and no patient had to be withdrawn from therapy. All patients required analgesics prior to treatment and only 3 patients experienced a significant reduction in pain for 9 weeks, the remaining patients experienced no deterioration for a mean duration of 12 weeks (6-18 weeks). Five patients (20%) demonstrated a biological response of a 50% or greater decrease in PSA from baseline, including 2 (12%) with a 75% or greater decline for 10 weeks (range 6-16 weeks). One partial remission was observed among 10 patients with measurable lesions lasting 12 weeks; 4 patients had stable disease with a mean duration of 12 weeks. Mean survival time from the onset of treatment with 5-FU was 7 months (2-12 months). CONCLUSIONS: Though less toxic than other 5-FU regimens, repeated single low-dose 24-hour infusion is of no significant benefit in patients with symptomatic hormone-refractory prostate cancer.     

Effect of medroxyprogesterone acetate, alone or in combination with epirubicin hydrochloride, on the growth of the Dunning R3327H prostatic adenocarcinoma

Rats bearing the Dunning R3327H prostatic adenocarcinoma were castrated and supplemented with testosterone propionate. Some of the testosterone-supplemented rats were treated with medroxyprogesterone acetate (MPA) alone or in combination with epirubicin hydrochloride. During the treatment period of 4 weeks, the growth rate of the prostatic tumors was measured. The testosterone-supplemented rats showed a tumor growth rate similar to that found in intact control rats. It was found that MPA has an inhibitory effect on the tumor growth rate in castrated testosterone-supplemented animals. This effect was more pronounced if the MPA treatment was combined with epirubicin hydrochloride, where the tumor growth rate was slower than that found in rats castrated as the only treatment.     

Combination chemotherapy with cisplatin and methotrexate in advanced transitional cell cancer of the bladder

We studied 53 patients with bidimensionally measurable metastases of transitional cell cancer of the bladder who were treated with a planned regimen of 70 mg. per m. cisplatin intravenously on day 1, and 40 mg. per m. methotrexate intravenously on days 8 and 15 every 3 weeks. The toxicity of this regimen, with agranulocytosis and mucositis as the most important side effects, was so severe that only 17 per cent of the patients actually received the protocol regimen without modification. Six patients were ineligible and 47 were evaluable for toxicity, including 43 who were evaluable for response. The response to treatment was assessed after each second treatment cycle. A complete response was achieved in 10 patients (23 per cent) and a partial response was achieved in 10 (23 per cent). The median duration of response was 64 weeks for patients with a complete response and 23 weeks for those with a partial response, while the median duration of survival was 81 and 37 weeks, respectively. The aforementioned regimen with allowance of routine leucovorin rescue is tested as preoperative chemotherapy in patients with stages T3 to T4 nonmetastatic bladder cancer.     

Bi-weekly epirubicin, etoposide and low-dose dexamethasone for hormone-refractory prostate cancer

BACKGROUND: Recent studies have demonstrated the efficacy and favorable toxicity profile of chemotherapy regimens given at lower doses and frequent intervals. The aim of our study was to evaluate the efficacy and toxicity of a bi-weekly chemohormonal regimen consisting of epirubicin, etoposide, and low-dose dexamethasone (EED) in patients with hormone-refractory prostate cancer (HRPC). METHODS: We treated a total of 32 patients who had failed hormonal therapy and antiandrogen withdrawal. Chemotherapy was given every 2 weeks and consisted of epirubicin (30 mg/m2 intravenously, day 1) and etoposide (50 mg/m2 orally, days 1-7). Dexamethasone (1.5 mg orally, every other day) was given continuously until disease progression. Twenty patients (63%) had received prior treatment with estramustine phosphate. Each patient's pain response was evaluated according to analgesic use. Toxicity was graded using the Common Toxicity Criteria (version 2.0). RESULTS: Prostate-specific antigen (PSA) levels showed a decline of 50% or greater in 16 of 32 patients (50%, 95% confidence interval [CI], 32-68%) with a median time to biochemical progression of 5 months (range, 4-9 months). The median survival for all patients was 10.5 months (range, 3-35 months). Four of 10 patients (40%) with measurable soft tissue lesions achieved partial response according to standard criteria. Eleven of 23 symptomatic patients (48%, 95% CI, 27-69%) experienced an improvement in pain with a median duration of 6 months. The regimen was tolerated well by the patients, with only four patients (12%) having grade 3 leukopenia. CONCLUSION: Chemohormonal EED regimen proved to be active and well-tolerated in patients with HRPC.