Cooperative clinical trials of the national prostatic cancer project: Protocol 900

In May 1978, the National Prostatic Cancer Project Treatment Subgroup activated its first clinical trial evaluating adjuvant chemotherapy (Protocol 900). This protocol is a comparison of long-term adjuvant chemotherapy with cyclophosphamide, estramustine phosphate, or no additional treatment in patients with definitive surgical therapy for adenocarcinoma of the prostate. To date, 128 patients have been entered with an entry rate of approximately 2.2 patients per month. One hundred five patients form the basis of this report, with 96 patients still on active therapy. Estramustine phosphate has been administered at a dose of 600 mg/m² orally daily in three divided doses. The cyclophosphamide is administered 1 g/m² intravenously every 3 weeks. Results are still preliminary; only two evaluable patients have died. Approximately two-thirds of patients entered have had negative lymph nodes. Recurrent disease has been documented in 15 patients, including eight receiving cyclophosphamide, three receiving estramustine phosphate, and four on the no-treatment arm. The recurrence rate has been disproportionately high (50%) in patients receiving cryosurgery rather than radical prostatectomy (12%). Maximum survival has reached 241 weeks. Side effects have consisted of leukopenia in patients receiving cyclophosphamide (56%), and nausea and vomiting with cyclophosphamide (85%), and estramustine phosphate (36%). This study continues with patient entries now over one-half of the number anticipated in the original study design.     

Quality control of radiation therapy in multi-institutional randomized clinical trial for localized prostate cancer

The National Prostatic Cancer Project (NPCP) from 1978 through 1985 compared definitive radiation therapy for Stages B2, C, D1 lesions in those who received only radiation treatment to those who received two years of additional cyclophosphamide (Cytoxan) or estramustine phosphate (Emcyt) chemotherapy. Two hundred fifty-four patients were entered and 229 evaluated for compliance of the spatial localization of the prostate through review of the simulation and port films. In 78 per cent this was satisfactory, whereas in 12 per cent it was unsatisfactory, and another 10 per cent were not evaluable. The principle cause of an unsatisfactory rating was failure to adequately cover the prostatic target volume, especially the apex which was found to be variable in location. Routine use of retrograde urethrocystography is urged as part of the localization method in patients to receive definitive external beam radiation therapy for prostate cancer. The role and impact of quality assurance programs for radiotherapy in cooperative clinical study groups is reviewed and discussed.     

Phase II trial of vinorelbine and estramustine in the treatment of metastatic hormone-resistant prostate cancer

The purpose of this study was to investigate the efficacy and safety of combination chemotherapy using estramustine and vinorelbine in chemotherapy-na?ve patients with hormone-resistant prostate cancer (HRPC). The patients (n = 54) received oral estramustine 840 mg/day on Days 1 to 14 and IV vinorelbine 25 mg/m(2) on Days 1 and 8 of every 3 wk cycle. The median number of cycles per patient was 9 (range, 1 to 27). Fifty-three patients were evaluable for toxicity and survival and 52 for prostate specific antigen (PSA) response. Median age was 68 (range, 46-80). PSA sustained decrease >50% was seen in 52% of patients (95% CI: 38-66%). A complete response was seen in 3 and a partial response in 12 of 25 patients with measurable disease, for an overall objective response of 60% (95% CI: 41-79%). Improvement in performance status was observed in 30 out of 43 evaluable for clinical benefit response. The median duration of response was 7 mo and median time to progression was 6 mo. The median survival time was 15 mo. The most common adverse event was mild gastrointestinal toxicity. In general, toxicity G3-4 was low: granulocytopenia Grade 3-4 (8%), thrombocytopenia Grade 3 (6%), and anemia Grade 3 (13%). Other Grade 3 toxicities included deep vein thrombosis (4%), hepatic (2%), cardiac ischemia (2%), fatigue (6%), and sensory neuropathy (2%). There were 2 treatment-related deaths (4%). We conclude that vinorelbine and estramustine as used in this trial is an efficacious and well-tolerated therapeutic regimen in the management of HRPC.     

A comparison of the effect of diethylstilbestrol with low dose estramustine phosphate in the treatment of advanced prostatic cancer: final analysis of a phase III trial of the European Organization for Research on Treatment of Cancer

In a randomized phase III trial performed by the Urological Group of the European Organization for Research on Treatment of Cancer low dose estramustine phosphate (280 mg. twice daily for 8 weeks and 140 mg. twice daily thereafter) was compared to diethylstilbestrol (1 mg. 3 times daily) in patients with stages T3 to T4, M0 or M1 prostatic cancer. Of 248 patients entered 227 were evaluable for analysis: 115 received estramustine phosphate and 112 received diethylstilbestrol. The best response of the local tumor as assessed by palpation was seen in patients receiving diethylstilbestrol. There was no significant difference between treatments for response rate of metastases, interval to local progression, distant progression, over-all survival and death of carcinoma of the prostate. Duration of survival was correlated with the assessment of local response as determined by palpation. The response of distant lesions also was correlated closely with survival. Diethylstilbestrol (1 mg. 3 times daily) was associated with a significantly worse degree of cardiovascular toxicity than estramustine phosphate. This finding was especially obvious in patients who had no history of cardiovascular disease. Gastrointestinal toxicity occurred in 25 patients treated with estramustine phosphate, including 6 in whom cessation of treatment was necessary. Further studies are required to determine the optimum dose of diethylstilbestrol and estramustine phosphate, and to establish the best form of hormonal treatment for prostatic carcinoma.     

Prognostic and predictive factors in patients with androgen-independent prostate cancer treated with docetaxel and estramustine: a single institution experience

OBJECTIVES: To investigate potential prognostic and predictive factors in patients with androgen-independent prostate cancer (AIPC) treated with docetaxel chemotherapy. METHODS: This analysis included 94 consecutive AIPC patients who were treated between March 2001 and May 2006 with biweekly docetaxel 45 mg/m(2) (day 2) and estramustine 140 mg three dimes daily (days 1-3). RESULTS: Prostate-specific antigen (PSA) responses were observed in 45 of 84 evaluable patients (53%), whereas objective responses were observed in 16 of 40 patients with measurable disease (40%). Median survival (OS) was 16.2 mo (95% confidence interval [CI], 12.9-19.4) and median time to PSA progression (TTP) 5.0 mo (95%CI, 3.6-7.1). OS was independently associated with pain score baseline PSA and weight loss. Patients with only extraosseous disease had higher PSA response rate (87% vs. 49%, p=0.014) and superior TTP compared with patients with bone metastases with or without extraosseous disease (7.3 vs. 4.3 vs. 4 mo, p=0.002). Concurrent bone and extraosseous metastases were associated with worse prognosis compared with each site alone (median OS: 12.3 vs.19 vs.18.3 mo, p=0.007). CONCLUSIONS: Among patients with AIPC treated with biweekly docetaxel and estramustine, baseline PSA >100, existence of pain, weight loss, and simultaneous extraosseous and bone disease were associated with worse prognosis. Extraosseous metastases seem to be more sensitive than bone disease to this chemotherapy.     

Immunoscintigraphy with indium-111-capromab pendetide: evaluation before definitive therapy in patients with prostate cancer

Objectives. No standard noninvasive diagnostic test reliably differentiates patients with organ-confined prostate cancer from those with lymph node metastases. The ability of a radiolabeled monoclonal antibody, indium-111 (¹¹¹In)-capromab pendetide, to identify sites of metastatic disease in patients at moderate to high risk of nodal involvement was investigated.Methods. The study prospectively evaluated 160 patients with prostate cancer scheduled to undergo pelvic lymph node dissection (PLND) before or during definitive treatment. All were at relatively high risk of nodal involvement by virtue of significantly elevated baseline prostate-specific antigen (PSA) values, Gleason scores, and/or locally advanced clinical stages of disease. The histologic findings of the PLNDs were compared with the results of immunoscintigraphy, computed tomography, and magnetic resonance imaging.Results. Among the 152 evaluable patients studied with ¹¹¹In-capromab pendetide before PLND, the sensitivity of immunoscintigraphy for lymph node detection was 62% and the specificity was 72%; the positive predictive value was 62% and the negative predictive value was 72%. In comparison, the sensitivity of computed tomography and magnetic resonance imaging was 4% and 15%, respectively, and the specificity was 100% for both procedures on the basis of a large number of negative interpretations. Logistic regression analysis revealed that immunoscintigraphy with ¹¹¹In-capromab pendetide provided strong, independent evidence of the presence of lymph node metastases. Furthermore, the analysis indicated that certain combinations of PSA, Gleason score, and ¹¹¹In-capromab pendetide were particularly effective at predicting the risk of nodal involvement.Conclusions. Immunoscintigraphy with ¹¹¹In-capromab pendetide outperformed standard diagnostic imaging techniques in the detection of prostate cancer lymph node metastases and provided independent prognostic information that complemented PSA, Gleason score, and clinical stage.     

Chemohormonal therapy as primary treatment for metastatic prostate cancer: A randomized study of estramustine phosphate plus luteinizing hormone-releasing hormone agonist versus flutamide plus luteinizing hormone-releasing hormone agonist

BACKGROUND: The present study was undertaken mainly to investigate whether chemohormonal therapy with estramustine phosphate plus luteinizing hormone-releasing hormone (LHRH) agonist has a more beneficial effect than the hormonal therapy with flutamide plus LHRH agonist for newly diagnosed patients with metastatic prostate cancer. METHODS: A total of 57 patients with metastatic prostate cancer aged 59-80 years (median 74 years) were entered in the study and were randomized to the treatment of estramustine phosphate (560 mg/day) plus LHRH agonist (estramustine group) or flutamide (375 mg/day) plus LHRH agonist (flutamide group) with stratification for the degree of performance status, histological differentiation and bone metastasis. RESULTS: Both of the treatment regimens were well tolerated with similar incidences of adverse drug reactions. The overall response rates (complete response plus partial response) at 12 weeks after treatment in the estramustine and flutamide groups were 76 and 55%, respectively. The median time to objective progression for the estramustine group (25.4 months) was longer than that of the flutamide group (14.6 months). The serum levels of follicle stimulating hormone and testosterone were significantly lower in the estramustine group. CONCLUSIONS: Chemohormonal therapy with estramustine phosphate plus LHRH agonist showed longer clinical progression-free survival than the hormonal therapy with flutamide plus LHRH agonist (P = 0.03), although there was no significant difference in the overall survival. A larger-scaled trial with more statistical power is required to clarify that the former regimen is more beneficial than the latter for newly diagnosed patients with advanced prostate cancer.     

Current status of cytotoxic chemotherapy in hormone refractory prostate cancer

Adenocarcinoma of the prostate is the most prevalent neoplastic disease in men and continues to be a major cause of morbidity and mortality. Death from prostate cancer is associated with objective and biochemical progression following hormonal manipulations often described as hormone refractory prostate cancer (HRPCA). Therapy for HRPCA is primarily palliative and therapeutic efficacy has to be balanced against potential treatment-related side effects. Therapeutic efficacy may be assessed by evaluating the percentage of patients obtaining a PSA decline of > 50%, evaluating the response of bidimensionally measurable disease or by improvements in quality of life assessments. The most effective cytotoxic therapies at the present time seem to be combinations of estramustine phosphate with taxanes and etoposide. Regimes employing ketoconazole with estramustine, vinblastine or bisphosphonates seem to be worthy of further evaluation. Mitoxantrone has an impressive palliative effect in patients, particularly when combined with hydrocortisone. Oral chemotherapeutic regimens with a combination of estramustine phosphate, cyclophosphamide and prednisone appear to offer a less toxic alternative. For the future we need prospective randomized clinical phase-III studies, prognosticators identifying patients as being at high or low risk who might benefit from different therapeutic approaches and generally binding eligibility and response guidelines in order to be able to compare trials of different therapeutic approaches.     

Clinical Features and Therapeutic Outcomes in Men with Advanced Prostate Cancer and DNA Mismatch Repair Gene Mutations

Mismatch repair (MMR) gene mutations are rare in prostate cancer, and their histological and clinical characteristics are largely unknown. We conducted a retrospective study to explore disease characteristics and treatment outcomes of men with metastatic prostate cancer harboring germline and/or somatic MMR mutations detected using clinical-grade genomic assays. Thirteen patients with a deleterious MMR gene mutation were identified. Median age was 64 yr, 75% had grade group 5 (Gleason sum 9 or 10), 23% had intraductal histology, 46% had metastatic disease at initial diagnosis, and 31% had visceral metastases. Most patients (46%) had MSH6 mutations, 73% demonstrated microsatellite instability, and median tumor mutational load was 18/Mb (range, 3–165 mutations/Mb). Surprisingly, responses to standard hormonal therapies were very durable (median progression-free survival [PFS] of 67 mo to initial androgen deprivation and median PFS of 26 mo to abiraterone/enzalutamide). Two of four men receiving PD-1 inhibitors achieved a ≥50% prostate-specific antigen response at 12 wk, with a median PFS duration in these four men of 9 mo. Despite aggressive clinical and pathological features, patients with MMR-mutated advanced prostate cancer appear to have particular sensitivity to hormonal therapies, as well as anecdotal responses to PD-1 inhibitors. Certain histological features (grade group 5, intraductal carcinoma) should prompt evaluation for MMR deficiency. These data are only hypothesis generating.

THE TREATMENT OF DISSEMINATED PROSTATE CANCER WITH ESTRAMUSTINE

Forty-three patients with disseminated prostate cancer, resistant to orchidectomy or hormone therapy with estramustine were treated. Of the 33 evaluable patients, three patients had stable disease and two had a partial tumour response according to National Prostatic Cancer Project criteria. Twenty-five patients (58%) showed improvement in pain and urinary symptoms. Ten patients (23%) had side effects requiring cessation of therapy. These results show that estramustine has a limited role in the treatment of advanced prostate cancer and that therapy is frequently associated with intolerable side effects.     

Progression and complications after external beam radiation therapy for carcinoma of prostate

Sixty patients with prostatic carcinoma localized to the pelvis have been treated by external beam radiation therapy: 2 patients (2%) were Stage A, 12 (20%) Stage B, 14 (23%) Stage C, and 32 (53%) Stage D1. Twenty-two patients received adjuvant therapy (11 estramustine phosphate [Estracyt] and 11 cyclophosphamide [Cytoxan]) after radiation. Progression occurred in 22 patients (37%): 6 (10%) had local recurrence while 16 (27%) failed distally. The incidence of late major complications was 12 percent.     

Neoadjuvant docetaxel/estramustine prior to radical prostatectomy or external beam radiotherapy in high risk localized prostate cancer: A phase II trial

Background

Patients with locally advanced or organ confined, high risk, prostate cancer are at significant risk of having disease recurrence despite definitive local therapy. We evaluated the 2-year progression-free survival of subjects treated with chemotherapy administered prior to definitive therapy with surgery or radiation.

Patients and methods

Patients (n = 24) with locally advanced and high risk localized prostate cancer were treated with neoadjuvant docetaxel 36 mg/m2 i.v. weekly for 3 weeks and estramustine 140 mg orally 3 times daily for 3 consecutive days every 28 days prior to definitive treatment with prostatectomy or radiation.

Results

All evaluable patients, except 1, completed the proposed cycles of neoadjuvant chemotherapy with minimal dose reductions or delays. Of the 22 evaluable patients, 12 underwent radical prostatectomy and 10 underwent external beam radiation therapy. Twenty-one of 22 patients achieved a prostate-specific antigen (PSA) reduction > 25%. There were no pathologic complete responses. With a median follow-up of 24 months, the 2-year progression-free survival was 45%.

Conclusions

Our findings support the safety, tolerability, and efficacy of neoadjuvant chemotherapy in patients with men with high risk, locally advanced prostate adenocarcinoma, although the relative contributions of androgen deprivation therapy and docetaxel cannot be determined. The effectiveness of neoadjuvant chemotherapy in preventing prostate cancer relapses should be studied in a randomized trial.     

Current indications for chemotherapy in prostate cancer patients

Recently, data from two randomized studies, TAX327 and SWOG 9916, which compared docetaxel-based chemotherapy to mitoxantrone-based therapy, have demonstrated that treatment with docetaxel can prolong life in a statistically significant way in patients with hormone refractory prostate cancer (HRPC). In the TAX237 trial the median overall survival rates for patients treated with docetaxel every 3 wk was 18.9 mo, compared with 16.4 mo for the patients in the control arm (p=0.009). Patients treated with the combination of docetaxel and estramustine in the SWOG trial had a significant improvement in median survival (18 mo vs 16 mo, p=0.01), longer progression-free survival (6 mo compared with 3 mo, p<0.0001), and a 20% reduction in the risk of death. The optimal timing of docetaxel-based chemotherapy is still unknown because there are no prospective clinical trials indicating whether earlier treatment is more effective than delayed treatment. There are now increasing options also for second-line therapies in the palliative treatment of HRPC, and ongoing studies on new drugs such as satraplatin and ixabepilone will define the role of these agents in this setting. Preliminary neoadjuvant and adjuvant chemotherapy studies in high-risk prostate cancer patients have demonstrated that these approaches are feasible and do not add morbidity to surgery or radiotherapy, but their impact on survival still needs to be proven in randomized studies.     

Estramustine and vinblastine for patients with progressive androgen-independent adenocarcinoma of the prostate

A phase II trial was performed to assess antitumor activity and toxicity of estramustine and vinblastine in 31 consecutive patients with androgen-independent prostate cancer. All patients presented with disease progression following castrate serum testosterone levels of less than 50 ng/dl and were treated for 6 consecutive weeks with three daily 140-mg doses of oral estramustine and vinblastine at 6 mg/m(2) weekly by intravenous bolus. Prostate specific antigen (PSA) levels decreased by greater than 50% from baseline in 13 (46%; 95% confidence intervals, 27%-66%) of 28 evaluable patients. Patients who demonstrated a greater than 50% reduction in PSA had a longer delay in time to disease progression. Nonhematologic toxicity was mild, predominantly gastrointestinal. Hematologic toxicity was apparent in 13 patients with grade III granulocytopenia and in 7 patients with grade IV granulocytopenia. No patient was admitted to the hospital for neutropenic fever. Estramustine and vinblastine is a well-tolerated combination. This combination and the clinical significance of this decline in PSA warrants further investigation.     

Evaluation of docetaxel plus estramustine in the treatment of patients with hormone-refractory prostate cancer

Objectives:   To investigate the feasibility and efficacy of docetaxel-based chemotherapy in patients with hormone-refractory prostate cancer (HRPC).
Methods:   Forty-six consecutive HRPC patients treated between January 2003 and March 2008 were included in this analysis. Docetaxel was given at a dose of 35 mg/m² twice every 3 weeks and oral estramustine concurrently for three consecutive days during weeks 1 and 2 of each cycle. During each treatment week, the dose of estramustine was 1260 mg on the first day, 980 mg on the second day and 840 mg on the third day. Patients were premedicated with 4 mg twice a day of oral dexamethasone for three consecutive days. Treatment was continued until evidence of disease progression or unacceptable toxicity. Prostate-specific antigen (PSA) levels were evaluated at least once every 4 weeks.
Results:   Patients received a median of three cycles of chemotherapy. Of the evaluable 46 patients, 25 (54%) had a ≥50% PSA decline and 12 (26%) had a ≥75% PSA decline. Median time to PSA progression and overall survival time were 10.1 and 27.0 months, respectively. Median follow-up was 15.0 months. Major severe toxicities were grade 3 or 4 leukopenia in five (11%) patients. Mild toxicities included grade 1 or 2 nausea in eight (17%) patients. Two patients could not continue the treatment because of interstitial pneumonitis and a gastric hemorrhage, respectively.
Conclusions:   Docetaxel plus estramustine chemotherapy represents an active and well tolerated treatment for Japanese HRPC patients.     

The effect of estramustine phosphate on prostatic cancer estimated by transrectal ultrasonotomography

Transrectal Ultrasonotomography was performed in 44 patients with prostatic cancer before, during, and after estramustine phosphate (Estracyt®) administration. In 75.7% of 37 previously untreated patients, the deformity of the horizontal section of the prostate with prostatic cancer was corrected considerably, while in 89.2%, prostatic weight was remarkably reduced. In 57.1% of seven previously treated patients, appreciable changes were also observed in the shape and weight of the prostate. We concluded that estramustine phosphate was effective not only for untreated prostatic cancer, but also, at least in some degree, for relapsed cases.     

The oestrogenic effects of ethinyl oestradiol/polyoestradiol phosphate and estramustine phosphate in patients with prostatic carcinoma. A comparative study of oestrogen sensitive liver proteins, gonadotrophins and prolactin

Thirty previously untreated patients with carcinoma of the prostate were prospectively randomised to one of the following treatments: ethinyl oestradiol (Etivex) combined with polyoestradiol phosphate (Estradurin); estramustine phosphate (Estracyt); bilateral orchiectomy. Oestrogenic effects were measured by blood levels of pregnancy zone protein, sex hormone binding globulin, LH, FSH and prolactin. During a follow-up period of 6 months, estramustine phosphate and ethinyl oestradiol/polyoestradiol phosphate induced comparable changes in these proteins, suggesting comparable oestrogenic effects of these two forms of treatment in patients with prostatic carcinoma.     

The natural history of noncastrate metastatic prostate cancer after radical prostatectomy

OBJECTIVES: To characterise the natural history of metastatic prostate cancer after radical prostatectomy (RP) in patients followed expectantly for rising prostate-specific antigen (PSA) (noncastrate metastases). METHODS: Cox proportional hazards analyses were used to assess predictors of survival among 95 patients who developed clinically detectable noncastrate metastases after RP. The initial metastatic phenotype was characterised as minimal (nodal or axial skeletal involvement) or extensive (appendicular skeletal involvement or visceral metastases). Estimates of survival after diagnosis of metastases were generated with the Kaplan-Meier method. RESULTS: Median disease-specific survival from diagnosis of noncastrate metastases was 6.6 yr (95% confidence interval [CI], 5.2, 7.9). The initial site of metastatic disease was bone, lymph node, and viscera in 63%, 36%, and 6% of patients, respectively. Thirteen patients (14%) had extensive disease at their first metastatic manifestation. Longer PSA doubling time in the rising PSA state (hazard ratio [HR] 0.8 for each month increase in doubling time; 95%CI, 0.67-0.94) and the initial metastatic phenotype (HR 0.3 for minimal vs. extensive disease; 95%CI, 0.1-0.6) were associated with improved survival. The prostatectomy Gleason score, lymph node status at RP, PSA level at diagnosis of metastases, and interval from surgery to diagnosis of metastases did not correlate with outcome. CONCLUSION: Men who develop noncastrate metastases after RP may have a durable survival. Favourable prognostic indicators include longer PSA doubling time preceding diagnosis of metastases and initial involvement of axial skeleton or lymph nodes.     

Adjuvant chemotherapy of bladder cancer: a preliminary report

Adjuvant combination chemotherapy with cyclophosphamide, doxorubicin and cisplatin was administered to 36 patients after cystectomy for bladder cancer. Therapy was tolerated well except for 1 patient who suffered a fatal chemotherapy complication. Indications for adjuvant chemotherapy included vascular invasion of the primary tumor, perivesicular tumor involvement, invasion of adjacent pelvic viscera (vagina and prostate) and nodal metastases. There were 53 concurrently treated patients who did not receive adjuvant chemotherapy despite similar unfavorable pathological indications (high risk control group). Survival rates (61 and 73 per cent, respectively) were not significantly different for those patients treated with adjuvant chemotherapy and an additional group of 158 patients who underwent cystectomy during the study period but who had no adverse pathological findings (low risk control group). Survival rates differed significantly between the low risk (73 per cent) and high risk (38 per cent) control groups (p less than 0.001). Patients with unfavorable histological findings who received adjuvant chemotherapy had a significant survival advantage over the high risk control groups (61 versus 38 per cent, p equals 0.03). These data confirm the predictive value of post-cystectomy pathological findings and suggest that adjuvant chemotherapy with cyclophosphamide, doxorubicin and cisplatin not only prolongs the survival free of disease for patients at high risk for recurrence but it also may ultimately increase the cure fraction of such patients.     

Comparison between continuous and intermittent administration of Estracyt in the treatment of carcinoma of the prostate

Summary Ninety-five patients with prostatic carcinoma, stages A-D and of all histological grades were randomized between a continuous and an intermittent treatment regimen of Estracyt^R (estramustine phosphate). 77 patients were evaluated (46 with continuous and 31 with intermittent therapy). Remissions were seen in 13 (28%) and (13%), respectively. Stable disease was recorded in 30 (65%) and 24 (77%), respectively. Progression experienced 3 (6%) and 3 (10%) respectively. 19% were unable to continue therapy due to intolerable gastrointestinal side effects (7 patients receiving continuous and 8 patients receiving intermittent therapy).