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Objective: We describe a model capable of predicting prostate cancer (PCa)-specific mortality up to 20 years after a radical prostatectomy (RP), which can adjust the predictions according to disease-free interval., Patients and Methods: 752 patients were treated with RP for organ-confined PCa. Cox regression modeled the probability of PCa-specific mortality. The significance of the predictors was confirmed in competing risks analyses, which account for other-cause mortality., Results: The mean follow-up was 11.4 years. The 5-, 10-, 15- and 20-year actuarial rates of PCa-specific survival were 99.0, 95.5, 90.9 and 85.7%, respectively. RP Gleason sum (p < 0.001), pT stage (p = 0.007), adjuvant radiotherapy (p = 0.03) and age at RP (p = 0.004) represented independent predictors of PCa-specific mortality in the Cox regression model as well as in competing risks regression. Those variables, along with lymph node dissection status (p = 0.4), constituted the nomogram predictors. After 200 bootstrap resamples, the nomogram achieved 82.6, 83.8, 75.0 and 76.3% accuracy in predicting PCa-specific mortality at 5, 10, 15 and 20 years post-RP, respectively., Conclusions: At 20 years, roughly 20% of men treated with RP may succumb to PCa. The current nomogram helps to identify these individuals. Their follow-up or secondary therapies may be adjusted according to nomogram predictions., (Copyright (c) 2010 S. Karger AG, Basel.)

Objective: To assess the effect of adjuvant radiotherapy (aRT) on the rate of cancer-specific and overall survival after radical prostatectomy (RP) in a group of patients with a long-term follow-up, as there is controversy about the benefit of aRT after RP for prostate cancer when endpoints beyond biochemical and local recurrence are considered., Patients and Methods: Within a study cohort of 752 patients treated with RP, 118 (15.7%) received aRT; these patients were matched with controls who did not receive aRT after RP. Exact matches were made for pT stage, RP Gleason sum, surgical margin status, age (+/-10 years), year of surgery (+/-10 years) and delivery of hormonal therapy. Kaplan-Meier and life-table analyses were used to assess overall and cancer-specific survival, Results: The median (range) follow-up was 11.4 (0.1-41) years. The 10- and 20-year overall survival after RP in those with no aRT were, respectively, 81.1% and 44.8%, vs 75.5% and 40.0% in the aRT group (P = 0.1). The corresponding probabilities for cause-specific survival were, respectively, 97.3% and 89.0% vs 86.3% and 69.3% (P < 0.001). There was no statistically significant difference in the overall and cause-specific survival between the groups after matching (hazard ratio 0.9, log rank P = 0.6; and 2.1, log rank P = 0.1, respectively)., Conclusions: Our analysis showed that, in a matched case-control study, aRT has no effect on overall and cancer-specific survival. Further randomized long-term studies are necessary to confirm these results.

Objectives: To develop and internally validate a nomogram predicting the individual probability of metastatic progression after radical prostatectomy according to the length of disease-free interval., Methods: Cox regression modeled the probability of metastatic progression of prostate cancer in 752 patients treated with radical prostatectomy with a mean follow up of 11.6 years (median 11.4; range 0.1-40.5). The significance of the predictors was confirmed in competing risks analysis, which accounts for other causes of mortality. The Cox regression model-based nomogram was internally validated with 200 bootstrap resamples., Results: Eighty-five of 752 patients (11.3%) developed metastatic progression. The 5, 10, 15 and 20-year actuarial rates of metastatic progression-free survival were, respectively, 95.9, 90.5, 84.8 and 80.5%. Pathological stage T3, elevated radical prostatectomy Gleason sum and delivery of adjuvant radiotherapy represented independent predictors of metastatic progression in both Cox and competing risks regression models, and constituted the nomogram predictors along with a fourth variable describing the presence of co-morbidities. After 200 bootstrap resamples the nomogram achieved 80.2, 77.7, 77.6 and 76.0% accuracy in predicting metastatic progression at 5, 10, 15 and 20 years after radical prostatectomy., Conclusions: Metastatic progression is a sign of poor prognosis in men with prostate cancer. Our nomogram is able to accurately predict the conditional probability of metastatic progression up to 20 years after radical prostatectomy.

Background: Men who undergo radical prostatectomy (RP) are at long-term risk of biochemical recurrence (BCR). In this report, the authors have described a model capable of predicting BCR up to at least 15 years after RP that can adjust predictions according to the disease-free interval., Methods: Cox regression was used to model the probability of BCR (a prostate-specific antigen level>0.1 ng/mL and rising) in 601 men who underwent RP with a median follow-up of 11.4 years. The statistical significance of nomogram predictors was confirmed with a competing-risks regression model. The model was validated internally with 200 bootstraps and externally at 5 years, 10 years, and 15 years in 2 independent cohorts of 2963 and 3178 contemporary RP patients from 2 institutions., Results: The 5-year, 10-year, 15-year, and 20-year actuarial rates of BCR-free survival were 84.8%, 71.2%, 61.1%, and 58.6%, respectively. Pathologic stage, surgical margin status, pathologic Gleason sum, type of RP, and adjuvant radiotherapy represented independent predictors of BCR in both Cox and competing-risks regression models and constituted the nomogram predictor variables. In internal validation, the nomogram accuracy was 79.3%, 77.2%, 79.7%, and 80.6% at 5 years, 10 years, 15 years, and 20 years, respectively, after RP. In external validation, the nomogram was 77.4% accurate at 5 years in the first cohort and 77.9%, 79.4%, and 86.3% accurate at 5 years, 10 years, and 15 years, respectively, in the second cohort., Conclusions: Patients who undergo RP remain at risk of BCR beyond 10 years after RP. The nomogram described in this report distinguishes itself from other tools by its ability to accurately predict the conditional probability of BCR up to at least 15 years after surgery., (Copyright (c) 2008 American Cancer Society.)

Objectives: We hypothesized that prostate cancer-specific survival (PCaSS) could be accurately predicted in men in whom radical prostatectomy (RP) failed and who received hormonal therapy (HT) after RP failure., Methods: Between 1954 and 1994, 752 consecutive patients underwent RP without neoadjuvant therapy. Of those, 114 patients (15.2%) received HT at RP failure and represent the focus of this analysis. Cox regression models and a nomogram targeted PCaSS. The main predictor was timing of HT initiation: at prostate-specific antigen (PSA) versus local versus distant recurrence. Covariates included age at HT, pathologic T stage, surgical margin status and Gleason sum at RP, use of adjuvant or salvage radiation, and time from RP to HT., Results: Mean and median follow-up periods were 5.1 and 3.9 yr; 70 deaths were recorded, of which 45 (39.8%) were due to PCa. At 1, 5, 10, and 15 yr, the estimates of PCaSS were, respectively, 97.1%, 68.3%, 49.3%, and 30.2% (median, 9.8 yr). Younger men and those with HT initiated at the time of distant recurrence had lower PCaSS. A nomogram predicting PCaSS at 2, 3, 4, and 5 yr after RP was developed and demonstrated 66% accuracy after 200-bootstrap internal validation., Conclusion: Despite RP failure, half the patients can expect to survive for 10 yr. The nomogram can help in discriminating between those with better versus worse PCaSS, better than relying on most educated guesses.

Purpose: We report on 25-year cancer control and survival outcomes after radical prostatectomy in a single center series of patients treated during a 40-year period., Materials and Methods: Between 1954 and 1994, 787 consecutive patients underwent radical prostatectomy at Virginia Mason Medical Center in Seattle, Washington. Kaplan-Meier 25-year probabilities of prostate cancer specific, overall, prostate specific antigen progression-free, local and distant progression-free survival were determined. Multivariate Cox regression models addressed prostate cancer specific mortality., Results: Prostate cancer specific survival, overall survival, prostate specific antigen progression-free survival, local and distant progression-free survival ranged from 99.0% to 81.5%, 93.5% to 19.3%, 84.8% to 54.5%, 95.3% to 87.8% and 95.9% to 78.2%, respectively. In univariate analyses pathological stage, surgical margin status, pathological Gleason sum, delivery of hormonal therapy and radiotherapy represented statistically significant predictors of prostate cancer specific mortality (all p < or =0.001). In multivariate analyses only Gleason sum (p = 0.03) and delivery of hormonal therapy (p < 0.001) remained significant., Conclusions: This is one of the most mature radical prostatectomy series. It demonstrates that long-term biochemical cancer control outcomes after radical prostatectomy might be suboptimal. However, local and distant control outcomes are excellent, and cancer specific mortality is minimal even 25 years after surgery.

Objective: Because of efficacy demonstrated with chemotherapy in patients with metastatic disease, the National Prostate Cancer Project in 1978 initiated two protocols evaluating adjuvant therapy following surgery (Protocol 900) and irradiation (Protocol 1000) for patients with localized disease at high risk for relapse., Methods: All patients underwent staging pelvic lymph node dissection. Following definitive treatment, patients were randomized to either cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years, estramustine phosphate 600 mg/m2 orally daily for 2 years or to observation only. Accession closed in 1985 and included 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable)., Results: Nodal involvement was identified in 198 patients (49% of total): 29% in Protocol 900 and 63% in protocol 1000. Median progression-free survival (PFS) and survival have been greater for patients in Protocol 900 regardless of adjuvant, reflecting their lower pathologic stage. Median PFS is significantly greater for patients in Protocol 1000 receiving estramustine (52.2 months) compared to cyclophosphamide (35.0 months). Median PFS for patients with nodal involvement in Protocol 1000 receiving estramustine is increased (43.5 months) compared to no treatment (21.5 months). Patients with limited nodal involvement in Protocol 1000 have a longer median PFS (45.6 months) compared to patients with extensive disease (23.6 months). But in the latter group patients receiving estramustine experienced a significantly longer median PFS (43.5 months) compared to cyclophosphamide (29.1 months) or no adjuvant (13.5 months). Increased PFS with estramustine adjuvant was also noted in stage C patients (only Protocol 900) and in those with high-grade (grade 3) tumors (both protocols)., Conclusions: With now over 10 years mean follow-up for this series of patients, we conclude that adjuvant estramustine is beneficial for prostate cancer patients receiving definitive irradiation. This benefit is particularly noted in those patients with extensive nodal involvement (N+, D-1).

In 1978 the National Prostate Cancer Project launched two protocols evaluating adjuvant therapy following surgery (Protocol 900) or irradiation (Protocol 1,000) for clinically localized prostate cancer. All patients underwent staging pelvic lymphadenectomy. Following definitive treatment, patients were randomized to either cyclophosphamide 1 gram/m2-IV every 3 weeks for 2 years, estramustine phosphate 600 mg/m2-po daily for up to 2 years, or to observation only. Patient accession closed in 1985 and includes 184 to Protocol 900 (170 evaluable) and 253 to Protocol 1,000 (233 evaluable). Lymph node involvement was identified in 198 patients (49% of total), 29% in Protocol 900, 63% in Protocol 1,000. Median progression-free survival (PFS) for patients with nodal involvement in Protocol 1,000 receiving estramustine phosphate adjuvant was longer (37.3 mo) compared to cyclophosphamide (30.9 mo) and to no treatment (20.9 mo). Median PFS for patients with limited nodal disease in Protocol 1,000 was longer (39.9 mo), regardless of adjuvant, compared to extensive nodal disease (20.7 mo). However for patients with extensive nodal involvement, those receiving adjuvant estramustine phosphate experienced a significantly longer median PFS (32.8 mo) compared to adjuvant cyclophosphamide (22.7 mo) and no adjuvant (12.9 mo). We conclude that adjuvant estramustine phosphate is of benefit in prostate cancer patients with extensive pelvic node involvement receiving irradiation as definitive treatment.

Purpose: The American Urological Association convened the Prostate Cancer Clinical Guidelines Panel to analyze the literature regarding available methods for treating locally confined prostate cancer, and to make practice policy recommendations based on the treatment outcomes data insofar as the data permit., Materials and Methods: The panel searched the MEDLINE data base for all articles from 1966 to 1993 on stage T2 (B) prostate cancer and systematically analyzed outcomes data for radical prostatectomy, radiation therapy and surveillance as treatment alternatives. Outcomes considered most important were survival at 5, 10 and 15 years, progression at 5, 10 and 15 years, and treatment complications., Results: The panel found the outcomes data inadequate for valid comparisons of treatments. Differences were too great among treatment series with regard to such significant characteristics as age, tumor grade and pelvic lymph node status. The panel elected to display, in tabular form and graphically, the ranges in outcomes data reported for each treatment alternative., Conclusions: In making its recommendations, the panel presented treatment alternatives as options, identifying the advantages and disadvantages of each, and recommended as a standard that patients with newly diagnosed, clinically localized prostate cancer should be informed of all commonly accepted treatment options.

Total prostatectomy in the properly selected patient will provide disease-free survival rates comparable to the expected survival in similarly aged men for up to 30 years of observation (Figure 4). Patients who undergo total prostatectomy accept a very small risk of long-term permanent complications or mortality, and effective treatment is available for most complications. The morbidity and costs associated with hormone refractory metastatic prostate cancer are significant, with bone pain and anemia from bone marrow invasion, bladder dysfunction (retention, incontinence, and hematuria), urinary tract infection, anorexia, and uremia from obstructed ureters being common sequelae in the months before death. In the properly selected patient, minimal risk is incurred from total prostatectomy, the potential complications are well defined and manageable, and long-term disease-free survival is seen in most patients.

Background: In 1978, the National Prostatic Cancer Project launched two protocols evaluating adjuvant therapy after surgery (Protocol 900) or irradiation (Protocol 1000) for clinically localized prostate cancer. All patients underwent staging pelvic lymphadenectomy., Methods: After definitive treatment, the patients were randomized either to receive cyclophosphamide 1 g/m2 intravenously every 3 weeks for 2 years or estramustine phosphate 600 mg/m2 orally daily for up to 2 years or to undergo observation only. Patient accession closed in 1985 and includes 184 patients in Protocol 900 (170 evaluable) and 253 in Protocol 1000 (233 evaluable)., Results: Lymph node involvement was identified in 198 patients (49% of total), 29% in Protocol 900 and 63% in Protocol 1000. The median progression-free survival (PFS) and survival were greater for patients in Protocol 900 compared with 1000, regardless of the adjuvant therapy. This reflected the greater proportion of patients with lower pathologic stage disease in the surgically treated group. The median PFS was significantly greater for all patients in Protocol 1000 receiving estramustine phosphate adjuvant (48.2 months) compared with patients randomized to receive cyclophosphamide (35.6 months). The median PFS for patients with nodal involvement in Protocol 1000 who received estramustine phosphate adjuvant was prolonged significantly (37.3 months) compared with no treatment (20.9 months). The median PFS for patients with limited nodal disease in Protocol 1000 was longer (39.9 months), regardless of the adjuvant therapy, compared with those with extensive nodal disease (20.7 months). However, in the latter patient group, those receiving adjuvant estramustine phosphate had a significantly longer median PFS (32.8 months) compared with those receiving adjuvant cyclophosphamide (22.7 months) or no adjuvant therapy (12.9 months)., Conclusion: Adjuvant estramustine phosphate was beneficial in patients with prostate cancer and pelvic node involvement who received irradiation as definitive treatment.

In this third cooperative chemotherapy trial of the National Prostatic Cancer Project 165 patients with histologically confirmed, relapsing clinical stage D prostatic cancer were randomized to receive either imidazole-carboxamide, procarbazine or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on initial therapy were crossed over or randomized to receive an alternate drug. There were 129 patients available for comparison of treatments. The objective response rates (partial regression plus stable disease) were 26% for cyclophosphamide, 27% for imidazole-carboxamide and 14% for procarbazine. Subjective responses were noted in pain relief, improvement in performance status and weight gain. Procarbazine was associated with excessive toxicity, resulting in many patients (28%) discontinuing therapy within the first 3 weeks and closure of this particular arm of the study. The regimen of initial imidazole-carboxamide therapy with a later cross-over to cyclophosphamide when the disease continues to progress is associated with the longest increase in survival. Imidazole-carboxamide and cyclophosphamide appear to be active agents in advanced prostatic cancer and are worthy of continued use in this disease.

Non-specific granulomatous prostatitis is an inflammatory response of a foreign body type to extravasated prostatic fluid. Its significance is incident to its frequent confusion with carcinoma of the prostate. Noteworthy is the rapidity of onset of irritative and obstructive symptoms in a relatively younger age group than one generally sees in carcinoma of the prostate. Tissue diagnosis in those suspected of carcinoma of the prostate should be established by needle biopsy and conservative measures used for at least 4 weeks in the treatment of obstructive symptoms to allow the inflammatory response to subside before intervening surgically . Most patients frequently have associated benign prostatic hyperplasia with persistent obstructive symptoms and significant residual urine. Transurethral resection of the prostate has been performed in this study without postoperative complications.

In summary, the completed NPCP clinical trials have demonstrated that treatment with single antitumor agents and some combinations provide potential benefit to men with metastatic disease, both in those who have failed conventional hormonal therapy as well as those with newly diagnosed metastatic lesions. A summary of overall objective response rates in trials conducted on hormone-refractory patients is shown in Tables 17 and 18. In addition to demonstrating that chemotherapy can elicit a favorable response in patients with relapsing stage D disease, the NPCP has demonstrated that patients who respond to chemotherapy survive significantly longer than nonresponders. Furthermore, it has been demonstrated in these patients that objective partial regressions have been seen only with chemotherapy. Active single agents in prostatic cancer include methotrexate, cis-platinum, Estracyt, cyclophosphamide, 5-FU, DTIC, and streptozotocin. Finally, there may be some benefit in terms of response rate and survival when adding chemotherapy to conventional hormone therapy in patients with previously untreated stage D disease.

Patients with advanced prostate carcinoma that had been stabilized by orchiectomy (ORCH) or hormone therapy for at least 3 months, were randomized to either diethylstilbestrol (DES) alone or DES plus Cytoxan or DES plus Emcyt. A total of 188 patients were randomized between July, 1976 and February, 1982 of which 161 were evaluable for objective response to treatment. Objective response rates, response duration, or survival experiences were not demonstrably different between treatment arms, either for all patients or within good or poor prognosis groups determined by initial pain or acid phosphatase level. Subjective improvements in performance status were small for each treatment. Pain relief was somewhat greater in the chemotherapy-hormone combinations than in the DES/ORCH, but the advantage was not statistically significant. Side effects were primarily nausea and vomiting and leukopenia, mostly in the DES + Cytoxan arm. The duration of stabilization prior to entry did not influence response overall, although there were opposing trends within each of the two chemotherapy arms. The premise for combining antitumor agents with hormones before hormone failure is still felt to be a more logical approach than waiting for the ultimate hormone failure, and a combination of hormones plus two antitumor agents is being evaluated in a subsequent ongoing trial where a more rigid design limits the duration of the preentry period of hormone stabilization.

Optimal management of men with diffuse incidental prostatic cancer (Stage A2) is an unresolved issue. Current forms of therapy include radical prostatectomy, external beam radiation therapy, and no treatment. Long-term results with curative therapy have been unreported because of the relatively recent substaging of Stage A into incidental and diffuse disease. The results of radical prostatectomy in 25 patients with Stage A2 prostatic cancer were reviewed. Incontinence was the most serious complication and occurred in four patients (16%). Pathologically, 24 patients (96%) had residual carcinoma present in the radical prostatectomy specimen. In 22 men (88%) the tumor was entirely confined to the prostate. Two patients (8%) demonstrated seminal vesicle invasion, and one (4%) had capsular penetration. In follow-up metastatic disease has developed in one patient, and another died without evidence of cancer. The remaining patients are alive without evidence of disease. Since 88% of men with Stage A2 disease have their tumor entirely confined to the prostate, radical prostatectomy offers an excellent chance of long-term cure, as in Stage B prostatic cancer.

Several exciting new forms of therapy for metastatic prostatic cancer have been introduced recently. Luteinizing hormone-releasing hormone (LH-RH) agonists paradoxically inhibit pituitary release of luteinizing hormone, resulting in a fall of serum testosterone to castrate levels within two to four weeks. These drugs have no cardiovascular side effects. A nonsteroidal antiandrogen, flutamide, may be as effective as orchiectomy in men with untreated metastatic disease and has the advantage of preserving potency in most men. In recent reports, combining the LH-RH agonist with an antiandrogen resulted in "total medical castration," which may substantially improve objective response rates and patient survival. Ketoconazole, an antifungal drug, also rapidly inhibits testicular and adrenal androgen synthesis and decreases plasma testosterone to castrate levels within 72 hours. In men with hormone-resistant disease, combination chemotherapy may produce an objective response rate of 50%. In men with severely painful bony metastasis, an inexpensive drug used in Paget's disease, etidronate disodium, may be palliative.

There were 121 men with hormonally refractory metastatic cancer of the prostate who were randomized to receive estramustine phosphate or vincristine, or the combination of these 2 agents. All patients had received prior radiation therapy (greater than 2,000 rad). There were 90 patients who could be compared for response. The objective response rates (partial regression or stabilization of disease) for the 3 treatment groups were 26 per cent for estramustine phosphate, 24 per cent for estramustine phosphate plus vincristine and 15 per cent for vincristine. Subjective parameters varied little among the 3 regimens. The median duration of response for those responding to estramustine phosphate was similar (20 weeks) to that for vincristine (22 weeks) and greater than that for the combination (13 weeks). The probability of survival did not differ significantly for patients randomized to each of the 3 regimens. The addition of vincristine to estramustine phosphate did not enhance the response rate achieved by estramustine phosphate alone and vincristine alone produced the lowest response rate. Estramustine phosphate continues to be the most active agent in previously irradiated patients with hormonally refractory metastatic cancer of the prostate.

Several treatment options currently are available for the patient with clinically localized carcinoma of the prostate and each has its proponents. Comparison of results between institutions becomes necessary to determine the relative value of these treatments, keeping in mind the absence of a suitable control group in any series. Such inter-institutional treatment comparisons are possible only if the patient compositions are similar in terms of age, grade and extent of disease. Comparisons of patients with stage B disease frequently are made because most urologists agree that these patients have palpable disease confined to the prostate and no evidence of metastasis. At our clinic willing patients with clinically localized adenocarcinoma of the prostate who have an expected 15-year survival are treated preferentially with total prostatectomy. We summarize our experience with total prostatectomy in 215 consecutive patients, including 213 who were available for followup. There were 16 patients with clinical stage A, 195 with clinical stage B and 2 with clinical stage C disease. Of these patients 207 underwent radical perineal prostatectomy and there were no operative deaths. Patients did not receive adjuvant hormonal therapy unless disease recurred. Of the 110 patients who have undergone the operation within the last 5 years 98 per cent are alive. Actual survival and survival free of disease, respectively, for the entire series were 55 and 48 per cent at 15 years, 75 and 67 per cent at 10 years, and 94 and 86 per cent at 5 years, compared to 55 and 48, 74 and 67, and 95 and 90 per cent, respectively, for the 195 patients with clinical stage B disease. We believe these results demonstrate that in terms of local control of the disease, over-all survival and survival free of disease total prostatectomy remains the optimal treatment for patients with clinically localized carcinoma of the prostate.

Estramustine has been shown previously to be an effective drug in the treatment of metastatic prostatic cancer, demonstrating significant objective and subjective responses in long-term non-randomized trials and in other randomized trials. In this study prednimustine alone has shown a minimal over-all objective response rate of 12.9 percent of the cases, although with marked subjective improvement of pain relief and patient performance status. The combination of prednimustine with estramustine did not result in improvement of objective or subjective response parameters. The effects in terms of responses or in terms of toxicity for either agent were not additive when they were given in combination. Cross-over for those patients whose disease progressed on prednimustine therapy to estramustine had some benefit in over-all survival. Prednimustine alone or in combination with estramustine may be used safely and could improve markedly the quality of life for irradiated patients with advanced prostatic cancer who failed on hormonal treatment and have too poor a bone marrow reserve to be treated by other currently available myelosuppressive agents.

We report on 121 patients with adenocarcinoma of the prostate who underwent lymphangiography and, when indicated, subsequent fine needle aspiration biopsy of lymph nodes. The clinical staging correlation with this procedure reveals an assumed falsely negative rate of 5 to 15 per cent. The falsely positive rate is 0. This procedure is essentially without morbidity and has allowed us to stage more confidently prostatic cancer and make appropriate therapeutic recommendations.

The National Prostatic Cancer Project has randomized this study for endocrine-resistant prostatic cancer patients for treatment with standard hormonal or other therapies compared to 5-fluorouracil and cyclophosphamide. Both agents were found at the probability level of 0.05 to have a significant advantage over standard treatment in terms of objective response, subjective improvement and minimal toxicity. Additional chemotherapy protocols are currently under way. This randomized trial is the first report of such a national study completed to date. We are much encouraged by this program and believe that additional agents now under consideration will provide additionally encouraging results.

Local clinical control of the primary disease was evaluated in 209 patients with stage C adenocarcinoma of the prostate treated with definitive external beam radiation therapy and followed for a minimum of 2 years. Of these patients 92 per cent required no further prostatic operations for obstruction. Prostatectomy before therapy did not necessarily prevent later prostatic obstruction from occurring. Of 129 patients who had only a needle biopsy before irradiation 90 per cent had improvement of the obstructive and/or irritative symptoms as tumor regression occurred with therapy and these patients did not require a later prostatic operation for obstruction. Stricture formation occurred in 8 per cent of the patients and was not influenced by the type of preirradiation prostatic operation done. If transurethral resection was reuqired after irradiation it was technically more difficult but the morbidity was acceptable. The incidence of hematuria and incontinence was far less than that reported in non-irradiated patients with this disease. Most tumors exhibited a down-grading effect after irradiation. There were no deaths attributable to the treatment. Over-all, 83 per cent of the 209 patients had no urinary complaints after completion of therapy. From a urological viewpoint, good clinical local control is achieved in the patient with stage C adenocarcinoma of the prostate treated with external beam radiation therapy.

Single and combination chemotherapy was compared in a clinical trial for men with advanced, metastatic prostate cancer who had received prior pelvic irradiation and had had progression of disease despite hormonal therapy. The 149 patients were randomized to receive estramustine phosphate or cis-platinum alone or in combination. Of the 149 patients 25 (17 per cent) were excluded from the study but 124 were evaluated for response and survival. Entry variables were distributed similarly among patients in each treatment arm. There were no complete or partial responders but there were nearly twice as many patients whose disease was stabilized (33 per cent) on the combination regimen compared to estramustine phosphate (18 per cent) and about a third more than for cis-platinum (21 per cent). Analysis of survival revealed some advantage for patients on combination therapy. Major toxicities for all treatments were nausea and vomiting (62 to 88 per cent) and accompanying anorexia (72 to 95 per cent). Azotemia developed in 45 per cent of the patients receiving combination therapy. In addition an elevation in serum creatinine occurred in 22 per cent of the patients receiving combination therapy and in 17 per cent of those receiving cis-platinum alone. Myelosuppression occurred infrequently.

The response and duration of survival were evaluated for patients with stage D relapsing prostatic cancer who were randomized to cyclophosphamide (Cytoxan),5-fluorouracil (5-FU) or standard therapy, or to subsequent chemotherapies. The chemotherapies on initial randomization were superior to the standard therapy in the number of responders and duration of response. Survival was longer for responders (stable or partial regression) on chemotherapy by comparison to responders (stable only) on standard therapy. The survival for patients receiving initial and crossover chemotherapy was significantly improved for patients who responded to therapy. Chemotherapy of advanced relapsing stage D prostatic cancer is more beneficially treated by specific chemotherapy as shown in this randomized study.

Clinical and pathological staging furnishes valuable information upon which the clinician can base his treatment and compare results. Staging refinements occur as we learn more about the natural history of the disease and the efficacy of our treatment. We observed that clinical stage B patients with minimal (less than twice normal) elevation of the serum acid phosphatase have similar pathologic stage B (75%) and disease-free survival rates following total prostatectomy as stage B patients with normal acid phosphatases. Intraglandular crystalloids were found in 26% of clinical stage B patients treated by total prostatectomy, and none of this subgroup of patients has had a recurrence of disease. Pathologic staging frequently confirms the presence of a greater extent of tumor than was clinically anticipated. In general, prognosis for patients with a small tumor mass will be more favorable than that for patients with a large tumor mass. Staging permits the estimation of prognosis of groups of patients with similar tumor burdens; however, the survival of an individual within any such group is unpredictable.

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.

In this clinical trial of men with advanced prostatic cancer no longer responsive to hormone therapy 189 were randomized to receive estramustine phosphate, methotrexate or cis-platinum. Response evaluations were done in 158 cases. Objective response rates (complete, partial or stabilization of disease) were 34 per cent for estramustine phosphate, 36 per cent for cis-platinum and 41 per cent for methotrexate. Subjective parameters indicated a substantial advantage for pain improvement with methotrexate or cis-platinum over estramustine phosphate. Probabilities of continued response indicated some advantage for methotrexate and median response durations at this time were twice as long for methotrexate (32 weeks) as for cis-platinum (16 weeks), with estramustine phosphate intermediate (23 weeks). Survival rates for the original treatment randomization groups were not different at this time. Side effects of estramustine phosphate consisted primarily of nausea and vomiting and/or anorexia but to a lesser extent than with cis-platinum. These effects were somewhat less for methotrexate, for which the major side effects were stomatitis and leukopenia, as well as hepatic toxicity reflected by elevated serum glutamic oxaloacetic transaminase levels. Other side effects of cis-platinum were less than for methotrexate (no stomatitis), except for signs of renal toxicity (elevations in blood urea nitrogen and serum creatinine), which were greater. Methotrexate had a relatively high level of activity against metastatic, progressive, hormone nonresponsive prostatic cancer, with side effects that were substantial but manageable.

This cooperative study was sponsored by the National Prostatic Cancer Project to determine the usefulness of serum acid phosphatase levels as a predictive indicator with regard to performance status, sites of metastases, response to treatment, and survival in patients with advanced prostatic carcinoma. The results indicate that survival was significantly shorter for those patients who had elevation of thier on-study (pretreatment) total serum acid phosphatase ler cent reduction of primary tumor mass, relief of pain, and acid phosphatase activity. No correlation could be demonstrated between serum acid phosphatase and performance status, site of metastases, and other criteria of response to therapy. It is concluded that this test as currently determined spectrophotometrically at this stage of disease and if employed alone is not sufficient to allow for total evaluation of the response of therapy. It is, however, helpful when used in correlation with the previously mentioned positive factors.

Between 1954 and 1978, 148 patients underwent radical perineal prostatectomy for adenocarcinoma clinically confined to the prostate gland. This report is based on 45 of these patients with microscopic extension of disease beyond the gland and a minimum 5-year followup. Of the patients 22 received adjuvant external beam radiation therapy and 23 did not. The groups were comparable with regard to significant prognostic variables. Patient selection was by surgeon preference. Local recurrences were seen in 1 of 22 patients (5 per cent) receiving adjuvant radiotherapy and 7 of 23 (30 per cent) undergoing an operation alone (p less than 0.05). Of 8 patients with local recurrence 7 died of the disease. Delayed radiotherapy of a local recurrence generally was not effective in controlling the disease. Of the 11 patients who died of prostatic cancer with a mean followup of 9.2 years 3 received adjuvant radiotherapy and 8 did not. Severe but nonfatal long-term complications were seen in 14 per cent of the irradiated patients and 6 per cent of those treated with an operation alone. Most of the complications occurred in the earlier years of the study in patients who received 60cobalt radiotherapy. When clinical stage B cancer of the prostate is found to be pathological stage C following radical perineal prostatectomy, adjuvant radiotherapy can decrease the incidence of subsequent local recurrence. The potential risk of adjuvant radiation therapy should be weighed and its use considered, particularly in patients whose tumor extends to the surgical margins or who have seminal vesicle invasion.

The fate of the first 52 patients with clinically localized prostate cancer who underwent total perineal prostatectomy at our clinic and have been followed for a minimum of 15 years is reviewed to evaluate the long-term impact of this operation on the disease. None of these patients received any adjuvant therapy. Nine patients (17 per cent) had recurrence and 5 (10 per cent) died of disease during this interval. The actual observed over-all survival at 15 years was 64 per cent, the actuarial survival was 67 per cent and the cause-specific survival was 90 per cent.

The alkaline phosphatase isoenzymes in 105 patients with stage D carcinoma of the prostate who entered the National Prostatic Cancer Study were analyzed and these values were correlated to clinical response. Only patients with at least 3 measurements of alkaline phosphatase were evaluated. In 91% of patients with metastatic bone disease, bone alkaline phosphatase was elevated. Those patients with higher pre-treatment levels of alkaline phosphatase generally showed a poorer response to therapy. The results of alkaline phosphatase isoenzyme estimation indicate that these biological markers may be used in the evaluation of patients with metastatic prostatic cancer to predict and monitor their response to chemotherapy. The evaluation of bone and liver alkaline phosphatase isoenzymes in earlier stages also may be valuable.

In the 36 months since its inception, the National Prostatic Cancer Project treatment subgroup has randomly assigned over 360 patients with progressive advanced prostatic cancer who were no longer responsive to endocrine manipulation to either one of four different clinical studies. The initial study demonstrated a clear superiority for 5-fluorouracil (5-FU) and cyclophosphamide over continued conventional therapy. Beneficial responses were documented and are associated with increased survival rates and relief from pain and other symptoms. A proportionately larger number of patients obtained clinical benefit (stable and partial regression) on cyclophosphamide than on standard or 5-FU therapy. The criteria for evaluation of patients are supported by the survival data, ie, responders have survived for a longer period of time than those patients who continued in progression. Preliminary data from the subsequent protocols have documented a 30% response (stable and partial regression) in patients receiving oral estramustine phosphate and definite responses in patients treated with DTIC; Too few patients have been treated with Leo 1031 to offer total response rates at this time, although the early results are promising. These clinical studies have firmly established a place for chemotherapy in the management of prostatic cancer. New trials will introduce single- and multiple-drug chemotherapy at earlier phases of the clinical course of prostatic cancer patients.

Several chemotherapeutic drugs have been shown to be potentially effective in the patient with metastatic hormone refractory prostate cancer. Individual patients who respond to these chemotherapy agents survive longer than nonresponders, but overall objective response rates for the entire group have been disappointingly small, the length of response short, and there has been no overall survival advantage. Combination chemotherapy has not yet been shown to be superior to single-agent chemotherapy in controlled phase III clinical trials. If chemotherapy drugs are administered to such patients, it is desirable to give them as part of protocols designed to gather reliable data on their risks and benefits.

Radical prostatectomy in patients who have had prior transurethral resection of the prostate has been reported to result in significant morbidity. From 1974 to 1982, 30 patients who had had previous transurethral resection of the prostate underwent radical perineal prostatectomy for localized prostatic cancer. Operative time and blood loss were similar to a group of patients who had not had prior transurethral resection of the prostate. Over-all, 3 patients (10 per cent) had total incontinence and 3 (10 per cent) had stress incontinence requiring a pad or device. No patient undergoing radical prostatectomy less than 4 weeks or more than 4 months after transurethral resection of the prostate had postoperative incontinence. When radical perineal prostatectomy was performed between 4 weeks and 4 months after transurethral resection of the prostate the incidence of incontinence was 50 per cent. Five patients experienced prolonged perineal urinary drainage, all but 1 of whom healed spontaneously. Of the 6 patients with incontinence 3 had prolonged drainage. No patient had a rectal injury and there was no operative mortality. Two patients died without cancer and 1 has evidence of disease recurrence. We conclude that radical prostatectomy may be performed safely with acceptable morbidity following transurethral resection of the prostate and that if 4 weeks has elapsed since resection it might be advantageous to wait 4 months before performing radical surgery to lessen the risk of incontinence.

The investigators of the National Prostatic Cancer Treatment Group (NPCTG) have entered 212 patients with surgically confirmed stage D-1 prostate cancer in studies to determine the efficacy of adjuvant therapy after either definitive surgery (Protocol 900) or definitive radiotherapy (Protocol 1000). Follow-up indicates that this group represents 70% of all patients with recurrent disease. Because patients with less than 20% nodal involvement were found to have a statistically significant better progression-free-survival (PFS) than those with greater than 20% nodal involvement, we examined the exact anatomic sites of nodal metastases. The status of obturator, external iliac, internal iliac, and common iliac nodes was compared to PFS and overall survival in 198 patients with D-1 disease in both protocols. Results demonstrate no significant difference in either PFS or overall survival relative to anatomic sites of positive nodes. These data suggest that although minimal pelvic nodal metastasis is consistent with improved PFS, there is no predictable anatomic distribution of disease consonant with that better prognosis.

This is the fifth completed randomized clinical trial of the National Prostatic Cancer Project. There were 125 patients with histologically confirmed relapsing clinical stage D prostatic cancer randomized to receive hydroxyurea, methyl-chloroethyl-cyclohexy-nitrosourea or cyclophosphamide. All patients had received and failed previous hormonal therapy. Patients whose disease progressed after 12 weeks on the initial therapy were crossed over or randomized to receive an alternate drug. There were 98 patients available for comparison of treatments. Objective responses included patients with complete or partial regression as well as stable disease. The response rates were 35 per cent for cyclophosphamide, 30 per cent for methyl-chloroethyl-cyclohexy-nitrosourea and 15 per cent for hydroxyurea. Subjective response parameters included improvement in performance status and relief of pain. Pain was improved in a fifth of the patients on each treatment area. Methyl-chloroethyl-cyclohexy-nitrosourea and hydroxyurea showed activity in advanced prostatic cancer patients but at the expense of excessive toxicity. Cyclophosphamide continues to be the most active single agent in this type of patient, particularly with regard to duration of response and survival. There was a statistically demonstrable advantage for cyclophosphamide over hydroxyurea and a marginal advantage over methyl-chloroethyl-cyclohexy-nitrosourea in survival experience.

The outcome for the first 57 successive patients who underwent total perineal prostatectomy for clinically localized prostate cancer at the Virginia Mason Clinic and who have been followed up for a minimum of 15 years is reviewed for evaluation of the long-term impact of this operation on the disease. Twenty percent of the patients had pathologic stage C disease. Recurrence developed in 11 of the 55 patients (20%) who could be evaluated, and death from prostate cancer occurred in 6 (11%) during this interval. The actual observed overall survival at 15 years or more was 60%, the actuarial survival 67%, and the cause-specific survival 89%. The current morbidity of this operation was evaluated by review of the last 50 consecutive patients who underwent this procedure and had follow-up of at least 6 months. Operative time averaged 140 minutes, and blood loss averaged 660 ml; 22% of the patients required a transfusion. Average postoperative hospitalization was 5 days. Two patients required a temporary colostomy for unrecognized rectal injury, and 2 developed a stricture requiring more than one dilation. Three patients (6%) wear pads for mild stress incontinence. One patient died of a cerebral vascular accident.

A total of 125 patients with progressing advanced prostatic cancer were entered into a chemotherapy study comparing cyclophosphamide, 5-fluorouracil, and standard therapy. Parameters of response were studied in 110 patients who could be evaluated. Thirty-six patients (33 per cent) were considered to have an objective response, that is becoming stable (29 patients) or in partial regression (7 patients). Negative response parameters (predictors of a poor response to chemotherapy or standard theraphy leading to progress) included (1) bone marrow evidence of prostatic cancer, (2) abnormal liver scan, (3) prior radiation therapy (indirectly through increased toxicity to chemotherapy), and (4) lack of bilateral orchiectomy prior to randomization. Positive indicators (predictors of good responses) included (1) reduction of primary tumor mass, especially after administration of 5-fluorouracil or cyclophosphamide, and (2) hemoglobin values. There were more objective responders to cyclophosphamide than standard therapy whether the hemoglobin was initially normal or low. Indeterminate parameters of response included weight gain, presence of bony or soft tissue metastases, relief of pain, performance status, excretory urography, and biochemical determinations of liver and renal function.

Estramustine has been shown previously to be an effective drug in the treatment of metastatic prostatic cancer, demonstrating significant objective and subjective responses in long-term non-randomized trials and in other randomized trials. In this study prednimustine alone has shown a minimal over-all objective response rate of 12.9% of the cases, although with marked subjective improvement of pain relief and patient performance status. The combination of prednimustine with estramustine did not result in improvement of objective or subjective response parameters. The effects in terms of responses or in terms of toxicity for either agent were not additive when they were given in combination. Cross-over for those patients whose disease progressed on prednimustine therapy to estramustine had some benefit in over-all survival. Prednimustine alone or in combination with estramustine may be used safely and could improve markedly the quality of life for irradiated patients with advanced prostatic cancer who failed on hormonal treatment and have too poor a bone marrow reserve to be treated by other currently available myelosuppressive agents.