National Prostatic Cancer Project Criteria Research Articles

VACCINE THERAPY FOR PROSTATE CANCER

Vaccine therapy may provide an alternative for prostate cancer patients whose disease no longer responds to hormone therapy. Administration of dendritic cells pulsed with prostate-specific membrane antigen (PSMA) induces cellular immune responses against the tumor with virtually no adverse effects. About 30% of the evaluable patients were identified as partial responders, based on the National Prostate Cancer Project (NPCP) criteria. In addition, there was a 50% decrease of serum prostate-specific antigen or resolution of previously measurable lesions on imaging. Dendritic cell vaccine therapy may have a synergistic effect, when combined with other therapies.

Comparison of prostate specific antigen, prostate specific membrane antigen, and LNCaP‐based enzyme‐linked immunosorbent assays in prostatic cancer patients and patients with benign prostatic enlargement

Serum assays for prostate specific antigen (PSA; monoclonal), for prostate specific membrane antigen (PSM; Western blot), and a LNCaP/7E11.C5-based competitive enzyme-linked immunosorbent assay (ELISA) were evaluated in a small number of prostate cancer patients with localized or disseminated disease, and judged to be in clinical progression or remission based on National Prostate Cancer Project (NPCP) criteria. PSA values recognized the presence of clinical progression in localized disease (B1-C) and to a lesser degree disseminated disease (D1-D2). In contrast, to a limited degree the ELISA test recognized clinical progression mainly in disseminated disease and chiefly in stage D2. PSM values were elevated in both D1 and D2 but not in a linear fashion as observed with PSA. The ELISA and PSM results may be assessing a different clinical response to prostatic cancer than that recognized by PSA. This could reflect a developing clone of resistant prostatic cells as previously postulated. To further pursue this possibility a secondary generation of monoclonal antibodies to PSM is being developed. The ELISA levels for benign prostatic enlargement were not elevated above normal. In contrast both with PSA and PSM the assays reflected levels significantly above the normal range in benign prostatic hypertrophy (BPH).

Phase II trial of 5-fluorouracil and alpha-2b interferon in patients with hormone-refractory metastatic prostate cancer

Objectives Metastatic prostate cancer remains a disease with no effective therapy. We treated 13 patients with hormone-refractory metastatic prostate cancer with 5-fluorouracil (5-FU) and alpha-2b interferon. Our objectives were to determine the response rate and toxicity of recombinant alpha interferon and 5-FU in patients with hormone-refractory metastatic prostate cancer. Methods Patients with progressive hormone-refractory metastatic prostate cancer with adequate hematologic and renal function underwent baseline bone scans, computed tomographic (CT) scans of abdomen and pelvis, and measurement of prostate-specific antigen (PSA). Therapy consisted of a 5-day loading course of 5-FU at 500 mg/m 2 with alpha-2b interferon 9 million units subcutaneously 3 times weekly followed by weekly 5-FU and alpha interferon 3 times per week. Results When PSA was used as a response parameter with modified National ProstaticCancer Project (NPCP) criteria, no objective responses were seen. Using NPCP criteria alone, 5 patients had stable disease. Post-therapy PSA values increased from baseline in 8 of 11 patients (2% to 72%) and declined in 3 patients (3% to 16%). Frequent dosage modifications were required with the dose intensity of 5-FU and alpha interferon of 57% and 58%, respectively. Toxicity was significant, with 31 % of patients having grade 3 to 4 mucositis and 46% grade 3 to 4 fatigue. Conclusions 5-FU and alpha interferon, when administered at the dosage and schedule utilized in this study, have no clinically significant activity and are associated with unacceptable toxicity in patients with metastatic prostate cancer. The role of PSA as an indicator of response remains unclear.

Objective treatment response to endocrine therapy in metastatic prostate cancer

A ten-year review of 198 patients with Stage D2 prostate cancer identified 13 patients (6.6%) who exhibited objective responses to hormonal treatment, as indicated by regression of a positive bone scan, CT scan, or chest x-ray film. Four patients had complete responses and 9 patients achieved partial responses as judged by the National Prostatic Cancer Project criteria. Median survival for those with objective treatment response has not yet been reached (>44 months) compared with twenty-four months for the nonresponders (p = 0.00006). Although relatively uncommon, objective treatment response in Stage D2 prostate cancer is correlated with an improved prognosis.

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.

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The clinical courses of bone metastases in 81 cases of prostatic cancer were examined using conventional X-ray. All patients received endocrine therapy as the initial treatment; castration and estrogen were given to 46 cases, castration and antiandrogen to 19, LH-RH analog to 11, flutamide to 5. The response to endocrine therapy was evaluated every 6 months after the start of the treatment according to National Prostatic Cancer Project criteria. The prognosis was calculated by cause-specific survival. The types of untreated bone metastases on X-ray were classified into five: sclerotic in 12 cases (15%), mixed but mainly sclerotic in 25 (31%), mixed but mainly lytic in 14 (17%), lytic in 8 (10%) and undetermined with positive scintigraphy in 22 (27%). Two mixed types showed more spread metastases and tendency of elevated prostatic acid phosphatase when compared with other types. Temporary enlargement of sclerotic area within 6 months after start of the treatment did not correlate with deterioration of disease. Remodeling of metastatic areas occurred 6-36 months after start of the treatment showed curative course and the prognosis of these groups were favorable. Most of lytic areas tended to sclerotic finding following endocrine therapy regardless of effects by endocrine therapy. Sclerotic and two mixed types showed better and worse tendencies, respectively. On viewpoint of remodeling, change of metastatic area and newly appearance of metastases, an evaluation criteria of response to the therapy was proposed, which showed good correlation with prognosis. From these observations, it was concluded that bone metastases tended from lytic to sclerotic changes and that lytic-sclerotic cycles occurred repeatedly along with disease progression regardless of effect to therapy. Remodeling seemed to be curative signs of metastatic area.

Combined hormonal therapy with high-dose diethylstilbestrol diphosphate (DES-DP) intravenous infusion plus vindesine (VND) for the treatment of advanced prostatic carcinoma: A controlled study

Fifty-one patients with stage D prostate cancer, who had failed primary hormone treatment, were treated with diethylstilbestrol diphosphate (DES-DP) 1.5 g 24 hr intravenous infusion from day 1 to day 7 (group A). In group B, patients were treated with DES-DP as in A, plus vindesine (VND) 3 mg/m2 intravenously on days 8, 15, and 22. Cycles were repeated every 28 days for six consecutive cycles. All 51 patients were evaluable for response, toxicity, time to progression, and survival. Pretreatment clinical and laboratory characteristics were comparable. The National Prostatic Cancer Project Criteria were used for evaluation. A minimum of two cycles were required for evaluation of response. No complete response was seen. In group A, 9 "partial response" and 7 "no change" (80%), and in group B, 11 "partial response" and 12 "no change" (74%) were registered. Median survival time was 40 weeks. Toxicity ranged from mild to moderate. DES-DP + VND seemed to improve duration of objective response compared to DES-DP alone, but the difference was not significant.

Leuprorelin Acetate Depot: Results of a Multicentre Japanese Trial

The clinical efficacy and safety of 3.75 or 7.5 mg leuprorelin acetate depot given subcutaneously once every 4 weeks was evaluated in a collaborative study of 81 patients with untreated prostatic cancer. Efficacy of treatment was assessed using criteria based on a meeting of the Prostatic Cancer Study Group funded by the Japanese Ministry of Health and Welfare and using National Prostatic Cancer Project criteria. Japanese criteria enabled evaluation of individual parameters, unlike the National Prostatic Cancer Project system which classified a patient as unevaluable if one evaluation parameter was unavailable. Leuprorelin acetate depot suppressed serum luteinizing hormone, follicle stimulating hormone and testosterone concentrations. Objective response rates of the prostate, bone metastases, serum prostatic acid phosphatase and soft tissue metastases, and subjective dysuria and pain responses were comparable to those found with conventional hormone therapy. Leuprorelin acetate depot was well tolerated, with no significant differences in response to the two doses.

Buserelin treatment of advanced prostatic cancer: A phase II study

From August 1986 to September 1988, 76 eligible patients with advanced prostatic carcinoma, measurable or evaluable disease, no previous hormonal treatment, were treated with Buserelin at a dosage of 500 micrograms every 8 h for 7 days, followed by 400 micrograms intranasally three times a day. No concomitant antiandrogens were administered. In the 63 evaluable patients (11 patients not yet evaluable because of short treatment time, two lost to follow-up), three complete remissions, 28 partial remissions, 30 stable disease and two progressions were obtained (National Prostatic Cancer Project criteria). Median duration of response was 55+ weeks. Side effects were modest, mostly related to the endocrinological effects of Buserelin. Transient increase in serum testosterone levels was found in 37% of the evaluable patients, but transitory 'flare-up' was present in seven patients only. With a median follow-up time of 11.5 months, median survival has not been reached. In conclusion, this study confirmed the activity of Buserelin and the feasibility of its middle-term administration.

Phase III studies to compare goserelin (zoladex) with orchiectomy and with diethylstilbestrol in treatment of prostatic carcinoma

Two multicenter, open, randomized phase III clinical trials were conducted in the United Kingdom to compare the effectiveness and safety of the depot formulation of the luteinizing hormone-releasing hormone (LHRH) agonist goserelin (Zoladex, ICI Pharma, Wilmington, Delaware), 3.6 mg sc/28 d, with orchiectomy and with diethylstilbestrol (DES), 1 mg tid, in the treatment of advanced prostatic cancer. In the Zoladex versus orchiectomy trial, there was no significant difference between the treatment groups with regard to subjective and objective responses (British Prostate Group criteria), endocrine responses, clinical effects and side effects, time to treatment failure and death, or survival after similar median follow-up periods. It was concluded that depot Zoladex had behaved as a truly medical alternative to orchiectomy. In the Zoladex versus DES trial, subjective and objective responses (British Prostate Group and National Prostatic Cancer Project criteria), response duration and survival were similar. However, there was a more rapid response to treatment in the depot Zoladex group. Side effects from Zoladex such as flare symptoms during the initial stages of treatment required no discontinuation of therapy; in contrast, 15 percent of patients receiving DES required cessation of therapy during the first three months because of side effects. It was concluded that depot Zoladex was superior to DES in its attainment of an early objective response and in its absence of side effects, and that Zoladex was comparable with DES in terms of response rates and survival.

Phase II trial of combination chemotherapy with fluorouracil (F), doxorubicin (A), and cisplatin (P) (Fap) in hormonally resistant metastatic prostatic adenocarcinoma.

From October 1985 to December 1986, 25 patients with advanced prostatic carcinoma were entered in a phase II trial and were administered fluorouracil (F) 600 mg/m2, on days 1 and 2, doxorubicin (A) 40 mg/m2, on day 1, and cisplatin (P) 90 mg/m2, on day 1, every month. The response was evaluated after three cycles of chemotherapy according to National Prostatic Cancer Project criteria. There were no complete remission, 1 partial remission, 13 stabilizations, 11 progressions. Toxicity was assessed using WHO criteria. Alopecia and vomiting were universal; there were 11 grade 1 anemias, 2 aplasias, and 1 grade 1 renal toxicity. A FAP regimen appears to exert a marginal effect in advanced prostatic carcinoma.

Megestrol Acetate Plus Minidose Diethylstilbestrol in the Treatment of Carcinoma of the Prostate

A multicenter randomized trial comparing megestrol acetate 120 mg/d, plus diethylstilbestrol (DES) 0.1 to 3 mg/d in patients with stage D2 prostate cancer was undertaken to compare the efficacy and toxicity of these two regimens. Pretreatment characteristics, including pathologic grade, performance status, age, and disease-related symptoms were similar in the two groups. Of 81 patients who have been entered in the study, 77 are evaluable for response and toxicity at a mean follow-up of 13.3 months. Using National Prostate Cancer Project (NPCP) criteria, no difference in response rate is noted (73% v 76%) or in disease-free survival and overall survival. The ability to suppress serum testosterone to castration levels and to maintain this suppression is equivalent in both treatment groups. However, treatment-related toxicity, including edema, hypertension, and gynecomastia, occurred at a significantly greater frequency, severity, and after a shorter treatment period in the DES-treated group. No difference in major cardiovascular events was noted. Since megestrol acetate plus minidose DES is equivalent to DES in achieving treatment responses in patients with carcinoma of the prostate, it is a preferable treatment because of its improved side-effect profile.

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 (200mg. daily) is combined with a low dose of diethylstilbestrol (0.1mg. 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 ± 23ng. per dl. (mean ± standard error), serum testosterone decreased to 56 ± 5ng. per dl. after 1 week and reached a plateau of approximately 30ng. per dl. after 2 months. This was accompanied by a decrease in serum prostatic acid phosphatase from a mean starting concentration of 43 ± 11ng. per ml. to a low of 3 ± 1ng. 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.

Buserelin treatment of advanced prostatic carcinoma. Long-term follow-up of antitumor responses and improved quality of life.

The safety and efficacy of buserelin, a luteinizing hormone-releasing hormone (LH-RH) agonist, was tested in 33 evaluable patients with Stages C or D adenocarcinoma of the prostate. With a minimum follow-up duration of 10 months, there was one complete response and 22 partial responses (69%) by National Prostatic Cancer Project criteria, with a median duration greater than 18 months. Six patients (18%) had stable disease, median duration greater than 25 months, and only 12 patients have progressed. Performance status improved in 67%, patient-scored pain improved in 75%, and quality of life improved in 58%. Symptoms occurring during treatment consisted of hot flashes, loss of libido, and impotence. Buserelin produces a high frequency of durable objective and subjective responses in patients with advanced prostatic carcinoma.

Phase II study of megestrol acetate for metastatic carcinoma of the prostate.

Forty-three males with recurrent and metastatic cancer of the prostate were treated with megestrol acetate (160 mg/day orally) after having failed first-line hormonal treatment (orchiectomy or diethylstilboestrol). Thirty-seven patients were evaluated objectively for response, 28 of whom received the drug for more than 6 weeks. One patient had a partial response (National Prostatic Cancer Project criteria) and seven had stable disease. Toxicity was usually mild, although five patients developed a transient rise in liver enzymes and one patient had a grand mal fit. Three patients showed evidence of tumour "flare". Megestrol acetate has only limited efficacy in patients previously treated for prostatic cancer by hormonal manipulation.

High-dose ketoconazole therapy in patients with metastatic prostate cancer.

High-dose ketoconazole, 400 mg orally every 8 h, was administered in two groups of patients with metastatic prostate cancer. Group A consisted of 10 patients who had not undergone orchiectomy and Group B, eight patients who had orchiectomy prior to the study. Significant declines in testosterone, androstenedione, and dehydroepiandrosterone levels, reciprocal elevation of the gonadotropin levels (FSH and LH), and a persistent fall in serum acid phosphatase levels were observed in Group A patients. Three Group A patients achieved a partial objective remission (duration 9, 41+, and 69 weeks); four patients, stabilization of their disease for a median of 33.5 weeks (range 16-40+ weeks); and two progressed (The National Prostatic Cancer Project Criteria). Stable disease in two Group B patients (7 and 20 weeks) and progression in four patients were observed. Gastrointestinal irritation was the main toxicity and was similar in both groups. Two Group A patients developed symptomatology consistent with adrenal insufficiency. Ketoconazole can suppress androgen production and has a beneficial role in the hormonal therapy of patients with prostate cancer who have not undergone orchiectomy.

Phase II trial of 4'-deoxydoxorubicin (esorubicin) in hormone resistant prostate cancer.

Fifteen patients with hormone resistant advanced prostate cancer were treated with anthracycline analog 4'-deoxydoxorubicin (Esorubicin). No patient had objective evidence of tumor regression. Six patients (40%) were classified using the National Prostatic Cancer Project criteria as having stable disease after two courses of therapy. Treatment was associated with significant hematologic toxicity with 50% of patients experiencing grade III or IV neutropenia. Clinical cardiac toxicity was not observed. Further trials of 4'-deoxydoxorubicin do not appear to be warranted in advanced prostate cancer.

A randomized study of doxorubicin versus doxorubicin plus cisplatin in endocrine-unresponsive metastatic prostatic carcinoma

Thirty-seven patients with hormonally refractory prostatic carcinoma entered a randomized trial comparing doxorubicin and doxorubicin plus cisplatin. All patients had failed prior hormonal treatment. Mean Karnofsky performance status (76% doxorubicin versus 75% combination), percent of patients with prior palliative irradiation (40% doxorubicin versus 35% combination), and hemoglobin levels of less than or equal to 12 g/dl (30% doxorubicin versus 24% combination) were roughly equivalent in the two treatment groups. More patients treated with doxorubicin than the combination treatment had an elevated acid phosphatase level at study entry (90% versus 65%). Measurable bidimensional tumors were present in 13 patients in 16 sites in the doxorubicin arm and in 10 patients in 11 sites in the combination arm. Partial responses were seen in 1 of 13 patients in the doxorubicin arm and 2 (20%) of 10 patients in the combination arm. Improvement in Karnofsky performance status of 20% or greater was rarely observed with either treatment (7% doxorubicin versus 8% combination). Acid phosphatase levels normalized or improved by 50% in 39% of patients who received doxorubicin and 27% of patients who received the combination. The overall response rate by National Prostatic Cancer Project Criteria was 53% for doxorubicin and 59% for doxorubicin plus cisplatin. Myelotoxicity and gastrointestinal toxicity were severe, particularly in the combination arm, and required discontinuation of treatment in some patients who responded to treatment. Moderate renal dysfunction (creatinine value 2.0-3.0 mg/dl) occurred only in the combination arm at an incidence of 23%. Time to progression and survival were similar for the two treatment groups. In this small group of 37 patients, the combination of cisplatin and doxorubicin showed no improvement over doxorubicin alone in response, response duration, or survival, and was difficult to administer in this patient population.

Buserelin as primary therapy in advanced prostatic carcinoma

The effectiveness of buserelin, a luteinizing hormone-releasing hormone agonist, was tested in 28 patients with Stages C or D adenocarcinoma of the prostate. Of 24 evaluable patients, there were 13 partial responses (54%) by National Prostatic Cancer Project criteria, median duration greater than 6 months. Nine patients had stable disease (38%), median duration greater than 5 months, and only two patients progressed. Performance status improved in 38%, patient-scored pain improved in 46%, and quality of life improved in 57%. Symptoms occurring during treatment consisted of hot flashes, loss of libido, and impotence. A flare of symptoms was observed in only one patient, despite a transient 25% increase in testosterone in 36% of patients. Buserelin is an effective treatment for inducing frequent and meaningful remissions in advanced prostatic cancer.

Buserelin as primary therapy in advanced prostatic carcinoma.

The effectiveness of buserelin, a luteinizing hormone-releasing hormone agonist, was tested in 28 patients with Stages C or D adenocarcinoma of the prostate. Of 24 evaluable patients, there were 13 partial responses (54%) by National Prostatic Cancer Project criteria, median duration greater than 6 months. Nine patients had stable disease (38%), median duration greater than 5 months, and only two patients progressed. Performance status improved in 38%, patient-scored pain improved in 46%, and quality of life improved in 57%. Symptoms occurring during treatment consisted of hot flashes, loss of libido, and impotence. A flare of symptoms was observed in only one patient, despite a transient 25% increase in testosterone in 36% of patients. Buserelin is an effective treatment for inducing frequent and meaningful remissions in advanced prostatic cancer.