Long-term results of retropubic permanent 125iodine implantation of the prostate for clinically localized prostatic cancer.

PURPOSE: The historical series of retropubic prostate radioactive source implantation from the Memorial Sloan-Kettering Cancer Center has served as the framework for the current transperineal implant approaches used in the treatment of localized prostatic cancer. We report the final assessment of the 15-year outcome. MATERIALS AND METHODS: Between March 1970 and December 1987, 1,078 patients with biopsy proved adenocarcinoma of the prostate were treated at our cancer center with permanent implantation of 125iodine via a retropubic approach. In addition, all patients underwent bilateral pelvic lymphadenectomy before implantation. The clinical stages of disease were B1 in 234 patients (22%), B2 in 472 (44%), B3 in 145 (14%) and C in 227 (20%). Of the patients 733 (68%) had pathologically negative lymph nodes, whereas 345 (32%) had positive lymph nodes at lymph node dissection. Median followup was 11 years. RESULTS: Multivariate analysis identified nodal involvement, high grade disease, clinical stage B3/C and implant doses less than 140 Gy, as independent predictors of local relapse. Independent predictors of distant metastases included nodal involvement, stage B3/C disease and poorly differentiated histological status. The local recurrence-free survival rates for patients with negative nodes at 5, 10 and 15 years were 69, 44 and 24%, respectively. The distant metastases-free survival rates at 5, 10 and 15 years for patients with negative lymph nodes were 59, 36 and 21%, respectively. CONCLUSIONS: 125Iodine implantation of the prostate via the retropubic approach was associated with a greater than expected incidence of local relapse at 15 years. Technical limitations of the retropubic technique resulting in suboptimal distribution of the isotope within the prostate are believed to be the explanation for the inferior local control outcome. Although long-term results are not yet available, the 5-year results of the computer optimized transperineal prostate implantation suggest that improved implant techniques will translate into a greater likelihood of tumor control.

Intravesical bacillus Calmette-Guérin therapy prevents tumor progression and death from superficial bladder cancer: ten-year follow-up of a prospective randomized trial.

PURPOSE: Superficial bladder tumors (stage Ta, T1, and Tis) may progress to invade the bladder muscle and cause death from metastatic cancer. Transurethral tumor resection (TURB) is the standard therapy for such tumors, but surgery alone may not prevent tumor progression. Intravesical therapy is widely used as an adjunct to TURB. Bacillus Calmette-Guérin (BCG) is the most active intravesical agent, but whether BCG prevents tumor progression and death from bladder cancer is unknown. PATIENTS AND METHODS: Between 1978 and 1981, 86 high-risk patients with superficial bladder cancer were randomly assigned to receive either TURB (n = 43) or TURB plus BCG (n = 43). Adverse tumor features for progression were equally distributed between the two groups. BCG was administered weekly for 6 weeks. Patients were evaluated every 3 to 6 months thereafter for progression to muscle invasion or metastasis. Control (TURB) patients with recurrent superficial tumors were eligible for crossover to the BCG arm. All patients have been monitored until event or for a minimum of 10 years (range, 10 to 14). RESULTS: The 10-year progression-free rate was 61.9% (95% confidence interval [CI], 47.2% to 76.7%) for patients treated with BCG and 37% (95% CI, 22.9% to 53.1%) for control patients. The median progression-free interval was not reached for the BCG group and was 46 months for the control group (P = .0063). Of 18 control patients crossed over to BCG (median, 29 months), 15 did not show tumor progression. TURB plus BCG resulted in a 10-year disease-specific survival rate of 75%, compared with 55% with TURB alone (P = .03). CONCLUSION: This study shows that intravesical therapy with BCG delays tumor progression and death from tumor in patients who present with superficial bladder cancer.

Distinguishing prognostic and treatment-predictive information for localized prostate cancer.

OBJECTIVES: To distinguish the concepts of prognostic and treatment-predictive information for localized prostate cancer. METHODS: We defined a prognostic factor as one that identifies subgroups associated with differing outcomes in untreated patients. A treatment-predictive factor identifies patients with differing outcomes as a consequence of treatment and is best identified in a large, randomized trial. Outside of such a trial, a treatment-predictive factor can be identified in prognostic subgroups or after adjustment for prognostic factors. RESULTS: The distinctions between prognostic and treatment-predictive factors are illustrated by hypothetical examples. CONCLUSIONS: The practical implication of the distinctions is that prognostic information may not provide reliable treatment-predictive information, that is, additional information may be needed before selection of patients for different treatments can be based on prognostic information. Determination of the relative treatment effect in any prognostic subgroup of patients requires a comparative setting. Until now, identified prognostic factors for localized prostate cancer at best can give guidance for clinical decisions on which patients should not be offered local aggressive therapy if the aim of the therapy is to cure the patient of the disease.

Significance of normal serum prostate-specific antigen in the follow-up period after definitive radiation therapy for prostatic cancer.

PURPOSE: To determine the prognostic significance of a normal serum prostate-specific antigen (PSA) level in patients with prostatic cancer with long-term follow-up evaluation after radiotherapy. MATERIALS AND METHODS: PSA information was available in 403 patients (38%) who were treated with pelvic lymph node dissection and retropubic radioactive iodine-125 implantation. One hundred eighty-two patients had a normal serum PSA level (< or = 4.0 ng/mL) the first time this test was conducted during the follow-up period, designated PSA-1. RESULTS: Among patients with PSA-1 values < or = 1.0 ng/mL, the 5-year PSA relapse-free survival rate was 85% compared with 27%, respectively, among those with PSA values in the higher range of normal (P < .00001). Multivariate analysis demonstrated that only a PSA-1 value greater than 1.0 to < or 4.0 (P < .00001) and grade II/III histology (P = .009) had a negative impact on continued PSA relapse-free survival. The only independent variable identified by a multivariate analysis to affect local relapse-free survival (LRFS) was a PSA-1 value greater than 1.0 to < or = 4.0 ng/mL (P < .004), while high-grade histology (P < .0001) and local failure (P < .001) were the only significant variables to affect distant metastases-free survival (DMFS). CONCLUSION: Patients with PSA values < or = 1.0 ng/mL are significantly less likely to have a subsequent relapse after therapy than those with levels greater than 1.0 to < or = 4.0 ng/mL. Continuously maintained PSA levels of < or = 1.0 ng/mL after treatment may serve as an end point for early evaluation of the efficacy of experimental radiotherapy protocols in prostate cancer.

Expectant management of clinically localized prostatic cancer.

Among approximately 4,000 prostatic cancer registrations 75 patients with clinical stage B histologically proved prostatic cancer receiving no therapy for at least 1 year after diagnosis were identified and managed expectantly. Of the patients 29 had stage B1, 37 stage B2 and 9 stage B3 lesions. Eight patients ultimately elected definitive radiation treatment. First evidence of tumor progression was local in more than 90% of the cases. Overall median intervals were 78 months to local progression, 186 months to metastasis, 108 months to initiation of any treatment and 156 months to death. The rate of tumor progression was often consistent with protracted survival. Prostatic cancer and co-morbidity were each significant forces of mortality.

The role of pelvic lymphadenectomy and radical cystectomy for lymph node positive bladder cancer. The Memorial Sloan-Kettering Cancer Center experience.

BACKGROUND: The impact of pelvic lymph node dissection (PLND) on the survival of patients with lymph node positive bladder cancer is controversial. METHODS: The authors retrospectively analyzed the long term and disease free survival among 140 patients with lymph node positive disease having radical cystectomy and bilateral PLND at the Memorial Sloan-Kettering Cancer Center between 1980 and 1988. They also sought to identify prognostic variables for recurrence and survival. RESULTS: Of the 140 patients, 36 (25.7%) were found to be tumor free, with 22 (15.7%) followed longer than 5 years. Regression analysis identified P-category as the only prognostic parameter influencing survival. Patients with tumors confined to the bladder (< or = P3a) had a 52.6% 5-year survival rate compared with 23.4% among those with extravesical (> or = P3b) tumors. N-category was a significant predictor for recurrence but not survival. CONCLUSIONS: As judged from this analysis, radical cystectomy and a systematic PLND alone can provide favorable outcome in some patients with regional nodal metastases from bladder cancer. The survival advantage is most pronounced in patients with low stage primary tumors. Stage migration and patient selection may have biased these findings.

The effects of local and regional treatment on the metastatic outcome in prostatic carcinoma with pelvic lymph node involvement.

PURPOSE: The effect of local and regional treatment on the development of distant metastases in patients with localized node negative and node positive carcinoma of the prostate is examined. METHODS AND MATERIALS: Distant metastases-free survival was evaluated in 1078 patients with Stage B-C node negative (733 patients) or node positive (345 patients) carcinoma of the prostate, staged with pelvic lymph node dissection and treated with retropublic 125I implantation at the Memorial Sloan-Kettering Cancer Center between 1970 and 1985. RESULTS: The 15-year actuarial distant metastases-free survival rate for the entire group of patients was 27%. Lymph node involvement was the most significant covariate affecting distant metastases-free survival, although local failure, stage, and grade were also independent variables. Distant metastases-free survival varied with the extent of lymph node involvement (N0 vs. N1, p < 0.0001; N1 vs. N2, p < 0.0001). However, the difference between N1 and N2 patients was due to a faster rate of development of distant metastases in N2 patients. The ultimate 10-year distant metastases-free survival rate was similar for the two patient groups (11% for N1 and 9% for N2). Local failure correlated with the metastatic outcome in patients with B-C/N0 disease (p < 0.00001), but not in N1 or N2 patients. Although distant metastases-free survival in locally controlled N1 patients was improved compared to N2 patients (p = 0.004), when stratified by primary tumor stage and grade, the differences were no longer significant. CONCLUSION: Essentially all node positive patients with carcinoma of the prostate will develop distant metastatic disease if followed for sufficiently long periods of time. This is consistent with the hypothesis that in such patients distant micrometastatic dissemination already exists at the time of initial diagnosis. The data suggest that clinical trials designed to test whether improvements in local therapy impact on survival should be restricted to node negative patients. The data also raise concerns regarding the therapeutic value of elective whole pelvic irradiation.

Impact of transurethral resection on the long-term outcome of patients with prostatic carcinoma.

Between March 1970 and December 1987, 1,078 patients with adenocarcinoma of the prostate were treated with pelvic lymph node dissection and permanent 125iodine implantation. Before implantation, 257 patients (27%) underwent transurethral resection of the prostate, while 702 (73%) did not and their diagnosis was established by needle biopsy. A total of 119 patients (10%) underwent hormonal therapy before implantation and they were excluded from the present analysis. Clinical stage and pathological grade were similar in both groups. A higher percentage of patients in the transurethral resection group had nodal metastases at implantation. Positive lymph nodes were found in 121 patients (47%) in the transurethral resection group versus 199 (26%) who did not undergo resection (p < 0.001). The actuarial 5, 10 and 15-year distant metastasis-free survival rates among the patients who underwent transurethral resection of the prostate were 79%, 42% and 16%, respectively, compared to 86%, 52% and 27%, respectively, in the group without transurethral resection (p < 0.0001). Similarly, the actuarial disease-free and local relapse-free survival rates were significantly inferior in the transurethral resection group. A negative impact of transurethral resection of the prostate could be demonstrated among patients with grade I/II tumors. However, when stratified for nodal status, no difference in outcome in any clinical parameter was noted between the groups with and without transurethral resection of the prostate. Specifically, distant metastasis-free survival among transurethral resection group patients with negative nodes was 78%, 57% and 47% at 5, 10 and 15 years, respectively, compared to 80%, 59% and 47%, respectively, among the patients with negative nodes who did not undergo transurethral resection of the prostate (p = 0.38). Similarly, the differences between the 2 groups among patients with positive lymph nodes were not significant. When stratified by the clinical stage, grade and nodal status, the negative impact of transurethral resection of the prostate could not be demonstrated in any combination. A multivariate analysis failed to demonstrate transurethral resection of the prostate to be an independent variable in predicting the metastatic, local control or disease-free survival outcome. In conclusion, the long-term results in these pathologically staged cases indicate that transurethral resection of the prostate does not impact negatively on the clinical outcome.

Recent results of management of palpable clinically localized prostate cancer.

BACKGROUND: There is uncertainty regarding if, when, and how localized prostate cancer should be managed. METHODS: To examine evidence of a beneficial effect of aggressive treatment on metastatic failure and disease-specific mortality in clinically localized prostate cancer, the authors compiled data from the literature since 1980 regarding radical prostatectomy, external radiation therapy, and deferred treatment. RESULTS: The weighted mean of reported disease-specific survival at 10 years was 93% for radical prostatectomy, 83% for deferred treatment, and 74% for external radiation therapy. To broaden the database we have also computed, from the recorded number of patients who died of prostate cancer and the number of person-years at risk, a calculated disease-specific survival at 10 years of 93% for radical prostatectomy, 83% for deferred treatment, and 62% for external radiation therapy. The data suggest a favorable treatment effect with regard to disease-specific mortality for radical prostatectomy, but not for external radiation therapy at 10 years of follow-up. This observation must be tempered by the absence of convincing randomized trials and by the possibility of selection biases in the reviewed studies. CONCLUSIONS: As judged from our analysis, clinically localized prostate cancer often has a protracted course associated with a significant competing mortality and marginal benefit from radical prostatectomy at 10 years in terms of the endpoints used.

Conservative approaches to the management of localized prostatic cancer.

BACKGROUND: The management of early stage prostatic cancer is controversial. METHODS: Pertinent literature concerning the conservative management of early stage prostatic cancer by early endocrine therapy (EET) or by deferred treatment (DT) was reviewed. RESULTS: EET has not been systematically studied. Available evidence suggests that early stage prostatic cancer often progresses slowly and that DT results in a cancer-specific mortality of approximately 80% at 10 years. CONCLUSIONS: EET warrants clinical investigation. DT is a management option, at least in patients with a life expectancy of 10 years or less.

The role of neoadjuvant hormonal manipulation in localized prostatic cancer.

BACKGROUND: Although hormonal manipulation is standard therapy for patients with metastatic prostatic cancer, its use in localized disease in combination with surgical extirpation of the gland has not been investigated thoroughly and systematically. METHODS: The authors report their initial pilot studies using preoperative neoadjuvant endocrine therapy. RESULTS: Although marked reduction in serum prostate-specific antigen (PSA) levels occurred in all patients, the PSA level after endocrine manipulation did not predict the pathologic stage. In addition, immunohistochemical staining of the radical prostatectomy specimen for PSA, in several patients with a zero serum PSA level, after endocrine therapy revealed intense PSA staining in the cancer cells but not in benign epithelium. The effects on tumor downstaging were inconclusive. Overall, only 33% of patients had organ-confined disease, but in some patients, complete tumor regression (PO) occurred. CONCLUSIONS: Neoadjuvant hormonal therapy in prostatic cancer, although definitely not standard therapy, bears investigation. In addition to the effect on the "index" cancer, it also provides an opportunity to evaluate the effect of hormonal agents on microfocal ("early") cancer and known precursors of malignant change. Therefore, it may provide a means of assessing agents of potential use in the development of chemopreventive strategies.

Conservative management of localized prostatic cancer.

Radical prostatectomy (RP), irradiation (RT), early endocrine therapy (EET), and expectant treatment (DT) are strategies for the management of clinically localized prostatic cancer. EET has not been systematically studied, but warrants prospective exploration. DT in uncontrolled studies results in disease-specific survival rates at 10 years that appear comparable to those achieved following RP or RT and may be considered a management option in patients with limited life expectancy. Serial observations in untreated patients provide a clinical indication of the rate of tumor progression, but better indicators of growth rate, metastatic potential, and responsiveness to a particular therapy are needed. Decision analysis may ultimately provide a practical supplement to clinical judgment in the choice of treatment.

The effect of local control on metastatic dissemination in carcinoma of the prostate: long-term results in patients treated with 125I implantation.

The study evaluates the effect of the locally recurring tumor on the incidence of metastatic disease in early stage carcinoma of the prostate. The probability of distant metastases was studied in 679 patients with Stage B-C/N0 carcinoma of the prostate treated at MSKCC between 1970 and 1985 (median follow-up of 97 months). Patients were staged with pelvic lymph node dissection and treated with retropubic 125I implantation. The actuarial distant metastases free survival (DMFS) for patients at risk at 15 years after initial therapy was 37%. Cox proportional hazard regression analysis of covariates affecting the metastatic outcome showed that local failure, used in the model as a time dependent variable, was the most significant covariate, although stage, grade, and implant volume were also found to be independent variables. The relative risk of metastatic spread subsequent to local failure was 4-fold increased compared to the risk without evidence of local relapse. The 15-year actuarial DMFS in 351 patients with local control was 77% compared to 24% in 328 patients who developed local relapses (p less than 0.00001). The relation of distant spread to the local outcome was observed regardless of stage, grade, or implant dose. Even stage B1/N0-Grade I patient with local control showed a 15-year actuarial DMFS of 82%, compared to 22% in patients with local relapse; p less than 0.00001). The median local relapse-free survival (LRFS) in the 268 patients with local recurrences who did not receive hormonal therapy before distant metastases were detected was 51 months, compared to a median of 71 months for DMFS in the same patients (p less than 0.001), consistent with the possibility that distant dissemination may develop secondary to local failure. Furthermore, distant metastases in patients with local control, apparently already existing as micrometastases before treatment, were detected earlier (median DMFS of 37 months) than in patients with local relapse (median DMFS of 54 months; p = 0.009). These data suggest that the existence and re-growth of local residual disease in localized prostatic carcinoma promotes an enhanced spread of metastatic disease, and that early and complete eradication of the primary tumor is required if a long term cure is to be achieved, although the clinical expression of secondary metastases may not become apparent for 6.5 years or more in one-half of the patients.

Expectant management of localized prostatic cancer.

Seventy-five patients with clinical Stage B histologically proven prostatic cancer accumulated over a 40-year period and receiving no therapy for at least 1 year after histologic diagnosis were retrospectively reviewed. Twenty-nine patients had Stage B1 lesions, 37 had B2, and nine had B3 lesions; median follow-up for these patients was 124, 120, and 96 months, respectively. Five ultimately received pelvic lymph node dissection with iodine-125 implantation, 23 had transurethral resection of the prostate, and 18 had endocrine therapy. Of those tumors which progressed, 18 of 19 (95%) B1, 26 of 29 (90%) B2, and four of four (100%) B3 lesions demonstrated local progression first. Six of 29 (21%) B1, 17 of 37 (46%) B2, and two of nine (22%) B3 tumors developed recognized distant metastasis. Actuarial survival at 15 years was 67%, 39%, and 63% for patients with B1, B2, and B3 lesions, respectively. These data indicate the varied and potentially protracted course of patients with clinical Stage B prostatic cancer.

'Local recurrence' and 'disease-free survival'. Doubtful parameters when comparing non-randomized studies of prostate cancer.

We reviewed recent literature on studies with external radiation of prostatectomy for localized prostate cancer considering the definitions of 'local recurrence' and 'disease-free survival' and the reporting of patients lost to follow-up. Among studies evaluating external radiation, 5/71 (29%) mention that prostate biopsy is used for some patients in determining local recurrence, versus 6/11 (55%) for prostatectomy. Several studies, 15/28 (54%), present figures for disease-free survival without giving a definition of the parameter. In the majority of the reports no comments are made relative to patients lost to follow-up. Three authors consider patients lost to follow-up as dead with disease. Considerations regarding 'local recurrence' and 'disease-free survival' warrant caution in the interpretation of data based on such parameters. In a comparison of non-randomized studies of localized prostate cancer, cancer-specific survival with prostate cancer death defined as 'death wtih diagnosed distant metastases' may be a robust parameter.

Natural history of low-stage prostatic cancer and the impact of early detection.

An expanding and increasingly older population, a rising incidence of prostate cancer, and uncertainties regarding treatment effectiveness have made this disease a target of special concern. The natural history of the cancer must be a consequence of host-tumor interactions, but little is known for sure about this subject. The growth rate of the tumor is determined by many factors, including genetic instability. At present, tumor grade, volume, and ploidy are the most useful techniques for judging the growth rate and metastatic potential. Stage A1 tumors generally are indolent, whereas stage A2 tumors are more aggressive. The natural history of stage B lesions is not well documented. The author asks two questions (Is cure necessary in those in whom it may be possible? Is cure possible in those in whom it may be necessary?) and reviews the problems inherent in screening for prostate cancer at this time.