Addition of radiation therapy to androgen ablation improves outcome for subclinically node-positive prostate cancer

ADULT UROLOGY

ADDITION OF RADIATION THERAPY TO ANDROGEN ABLATION IMPROVES OUTCOME FOR SUBCLINICALLY NODE-POSITIVE PROSTATE CANCER GUNAR K. ZAGARS, ALAN POLLACK,

AND

ANDREW C.

VON

ESCHENBACH

ABSTRACT Objectives. To determine the outcome for node-positive prostate cancer treated by early androgen ablation with or without prostatic radiation. Methods. Two hundred fifty-five men with lymphadenectomy-proven pelvic nodal metastases treated with early androgen ablation alone (n ⫽ 183) or with combined ablation and radiation (n ⫽ 72) between 1984 and 1998 were retrospectively reviewed for disease outcome and survival. Post-treatment disease status was based on the prostate-specific antigen levels or on the clinical and radiographic status for patients treated before 1987. Univariate and multivariate statistics were used to determine the prognostic factors and assess the influence of radiation treatment. Results. With a median follow-up of 9.4 years, the 5, 10, and 13-year overall survival rate for those treated with early ablation alone was 83%, 46%, and 21%, respectively. The freedom from relapse or rising prostate-specific antigen rate for these patients was 41%, 25%, and 19% at 5, 10, and 13 years, respectively. Distant metastasis and local recurrence occurred with a 10-year actuarial incidence of 44% and 51%, respectively. With a median follow-up of 6.2 years, the 5 and 10-year overall survival rate for those treated with radiation and ablation was 92% and 67%, respectively. The freedom from relapse or rising prostatespecific antigen rate in these men was 91% and 80% at 5 and 10 years, respectively. The superior outcome for combined ablation and radiation was substantial and statistically significant in the univariate and multivariate analyses. Conclusions. Early androgen ablation alone has little curative potential for node-positive prostate cancer. The addition of prostatic radiation to ablation resulted in substantial and significant improvement in disease control and patient survival. UROLOGY 58: 233–239, 2001. © 2001, Elsevier Science Inc.

S

urgery, radiation therapy, and androgen ablation, used individually, have proved disappointing as potentially curative strategies for nodepositive prostate cancer, particularly with prostatespecific antigen (PSA) as a sensitive index of posttherapy disease status. By 5 to 10 years after radical prostatectomy1–3 or external beam radiation,4 – 6 the disease relapses in 60% to 90% of patients; early androgen ablation is associated with a 70% to 80% This study was supported in part by grant CA 06294 awarded by the National Cancer Institute, U.S. Department of Health and Human Services. From the Departments of Radiation Oncology and Urology, University of Texas M. D. Anderson Cancer Center, Houston, Texas Reprint requests: Gunar K. Zagars, M.D., Department of Radiation Oncology, Box 97, University of Texas M. D. Anderson Cancer Center, 1515 Holcombe Boulevard, Houston, TX 77030 Submitted: February 7, 2001, accepted (with revisions): April 6, 2001 © 2001, ELSEVIER SCIENCE INC. ALL RIGHTS RESERVED

progression rate by 6 years.7,8 Although the palliative virtues and limitations of these treatments have been inconclusively debated, investigators are turning to combinations of androgen ablation and surgery or radiation in hopes of improving the outcome for these patients. Several retrospective analyses have reported that the combination of radical prostatectomy and androgen ablation is superior to surgery alone1,2 and to androgen ablation alone.9 One prospective randomized trial3 found, perhaps not definitively,10 that radical prostatectomy combined with ablation yielded superior disease control and survival compared with that achieved with radical prostatectomy alone. Retrospective studies have also reported that the combination of radiation and androgen ablation is superior to radiation alone.8,11,12 A similar benefit has been reported from subset analyses of two prospective randomized trials.6,13,14 However, few reports 0090-4295/01/$20.00 PII S0090-4295(01)01168-2 233

TABLE I. Distribution of potential prognostic factors for patients treated with androgen ablation alone versus those treated with combined ablation and radiation Patient Characteristic Age (yr) Range Median T stage T1/T2 T3 Gleason score 2–6 7 8–10 PSA (ng/mL) ⱕ4 4–10 10–20 ⬎20 Median TURP in T3 Type of ablation Orchiectomy Other Duration of follow-up (mo) Range Median

Ablation Alone (n ⴝ 183)

Ablation and Radiation (n ⴝ 72)

P Value*

35–77 65

45–74 64

0.049

23 (42) 77 (141)

54 (39) 46 (33)

44 (80) 22 (39) 34 (61)

28 (20) 36 (26) 36 (26)

4 (4) 26 (28) 19 (21) 52 (57) 22.0 19 (27)

4 (3) 35 (26) 30 (21) 31 (22) 12.8 9 (3)

61 (112) 39 (71)

49 (35) 51 (37)

0.09

34–201 113

15–151 74

⬍0.01

⬍0.01

0.02

0.05

0.07 0.13

KEY: PSA ⫽ prostate-specific antigen; TURP ⫽ transurethral resection of the prostate. * Based on the chi-square, Fisher exact, or Mann-Whitney tests,5 as appropriate.

appear to address the question of whether radiation therapy adds significantly to early androgen ablation. This report is a significant update, both in patient numbers and follow-up duration, of our earlier retrospective reports7,8,11 on the impact of radiation on node-positive prostate cancer treated with early androgen ablation. Our results show that local radiation appears to provide significant improvement in disease control and survival compared with that achieved by early ablation alone. MATERIAL AND METHODS Between 1984 and 1998, inclusive, 255 men with pelvic node-positive prostate cancer were treated either with early androgen ablation alone (n ⫽ 183) or with a combination of androgen ablation and external beam radiation therapy (n ⫽ 72). The preoperative evaluation included history, physical examination, and radiographic studies with a radionuclide bone scan and pelvic computed tomography scan. No patient had clinical or radiographic evidence of nodal metastatic disease. The primary tumor was classified as T1 if no tumor was palpable, T2 if the disease appeared to be confined to the prostate, and T3 if extracapsular extension was palpable. The serum PSA level was determined from 1987 onward, with lower limits of detection initially at 0.3 ng/mL and falling to 0.1 ng/mL after 1993. Each patient underwent staging pelvic lymphadenectomy as previously described.15 In brief, formal 234

pelvic node dissection was planned but was carried out under frozen section control so that the procedure could be terminated once metastatic disease was found. Permanent sections verified the metastatic disease in each case. The incomplete dissections in many patients did not permit any meaningful analysis of the influence of the extent of nodal disease on the outcome.16 The recommended treatment for node-positive disease was immediate androgen ablation; additional radiation was at the discretion of the urologist. During the period of the study, progressively more patients were referred for radiation; hence, their follow-up was shorter than that of patients treated with androgen ablation alone. Potentially significant prognostic factors for the two patient groups are summarized in Table I. The pretreatment PSA level was available for 110 men (60%) treated with androgen ablation alone and in all those treated with combined ablation and radiation. Androgen ablation consisted of orchiectomy in 147 (58%) of the 255 men and of luteinizing hormone-releasing hormone agonist or, in the early years, diethylstilbestrol and megestrol acetate in the remainder. Androgen ablation was begun at the time, or within 3 months, of lymphadenectomy. All patients treated with androgen ablation alone remained ablated for the duration of observation; 7 patients treated with combined androgen ablation and radiation terminated ablation after a minimum of 1 year and before any evidence of relapse. Radiation was begun within 3 months of lymphadenectomy and was delivered with high-energy photons using a four-field box technique to a dose of 46 Gy encompassing the prostate and periprostatic tissues, followed by a reduced four-field box (69 patients) or a six-field conformal technique (3 patients). Wide-field pelvic node raUROLOGY 58 (2), 2001

FIGURE 1. Actuarial curves for overall survival and freedom from relapse or rising PSA for 183 men treated with early androgen ablation alone. Tick marks on the survival curve are censored observations. Vertical bars are 95% confidence intervals. The age-matched expected survival curve is also shown. Survival during the first 5 years did not differ significantly from expected, but thereafter it declined steadily to less than that expected.

diation was not performed. The total doses ranged from 60 to 78 Gy (median 68). In 68 (94%) of the 72 men undergoing both androgen ablation and radiation, the androgen ablation was started before the radiation. The median duration of follow-up for all the patients alive at last contact was 8.2 years. The endpoints for this analysis were overall survival, freedom from relapse or rising PSA (no evidence of disease [NED]), local control, nodal control, and freedom from distant metastasis; all times were counted from the date of lymphadenectomy. Since some patients treated with ablation alone were followed up in the era preceding PSA determination, their disease status could only be evaluated clinically-radiographically and therefore we used the composite endpoint of relapse or a rising PSA level, whichever came first, as a uniform assessment of disease outcome. A rising PSA profile was one with at least two rising values; and for actuarial calculations, the time to the rise was taken as the average time between the nadir and the first risen value. Local recurrence was defined as the appearance of an abnormality on the digital rectal examination after initial regression, worsening palpatory findings in the absence of complete regression, or a positive biopsy pursuant to investigation of a rising PSA level. The actuarial curves were calculated using the KaplanMeier method, and tests of significance were based on the log-rank test.17 Multivariate analysis was done with the proportional hazards model,5 and logistic regression analysis was performed using standard techniques.18

RESULTS EARLY ANDROGEN ABLATION ALONE The overall survival rate of the 183 men treated with androgen ablation alone was 83%, 46%, and 21% at 5, 10, and 13 years, respectively (Fig. 1). The NED rate declined after the first year to 41%, 25%, and 19% at 5, 10, and 13 years, respectively UROLOGY 58 (2), 2001

(Fig. 1). One hundred twenty-six men (69%) had a relapse or rising PSA level. In 71 of the 126, a rising PSA level was found with relapse in one or more local, nodal, or metastatic sites; in 24, a rising PSA level occurred without other evidence of disease; and in 31, a local, nodal, or distant relapse was found before any post-treatment PSA values were available. Biopsy confirmation of local recurrence was obtained in 54 (71%) of the 76 men whose disease failed locally; in 12 men with clinical local recurrence, biopsy was not indicated because of prior or concurrent metastatic relapse; and 9 men refused biopsy. The actuarial local control rate was 71%, 49%, and 40% at 5, 10, and 13 years, respectively. The actuarial freedom from metastasis rate was 81%, 56%, and 44% at 5, 10, and 13 years, respectively. Thus, the local and metastatic failure was approximately equal in incidence. Only 5 patients had pelvic nodal relapse, yielding a 10-year nodal control rate of 96%. No pretreatment factors (age, T stage, Gleason score, PSA, prior transurethral resection of the prostate [TURP]) correlated significantly with local control either in univariate or multivariate analysis (data not shown). For distant metastasis, Gleason score and prior TURP in T3 disease were the only significant correlates, and both remained significant in the multivariate analysis. Gleason scores of 2 to 7 were associated with a 63% freedom from metastasis rate at 10 years compared with a rate of 40% for Gleason scores of 8 to 10 (P ⫽ 0.01). Patients with T3 tumors who did not undergo TURP before lymphadenectomy had a 58% rate of freedom from metastasis at 10 years compared with 39% for those who underwent the procedure (P ⬍0.01). No TURP effect was found for T1/T2 disease. The small number of nodal failures precluded any meaningful statistical analysis for this endpoint. For the NED endpoint, T stage, Gleason score, and TURP in T3 disease were significant in the univariate analysis, but only the Gleason score and TURP in T3 disease were independent factors in the multivariate analysis. The NED rate was 42% and 21% at 10 years for T1/T2 versus T3 tumors, respectively (P ⫽ 0.04); it was 30% and 17% at 10 years for Gleason scores of 2 to 7 versus Gleason scores of 8 to 10, respectively (P ⫽ 0.01); and it was 23% and 11%, respectively, at 10 years for patients with T3 tumors who underwent TURP versus those with T3 tumors who did not (P ⫽ 0.02). Overall survival significantly correlated with Gleason score and TURP in T3 disease. At 10 years, the survival rate for patients with Gleason score 2 to 7 tumors was 50% compared with a survival rate of 38% for those with Gleason score 8 to 10 tumors (P ⬍0.01). For patients with T3 disease who underwent TURP, the 10-year survival rate was 39% compared with 46% for those 235

who did not (P ⫽ 0.06). In multivariate analysis, only the Gleason score correlated with survival (P ⬍0.01). One hundred thirty-two patients had PSA estimations after treatment and within 12 months of ablation. PSA became undetectable within 1 year in 67 (51%). In the other 65 men, the nadir PSA values ranged from 0.4 to 25 ng/mL (median 0.9). The achievement of an undetectable PSA level within 1 year was a powerful correlate with disease outcome. The 10-year freedom from relapse or rising PSA rate was 45% for patients with an undetectable postablation PSA level versus 14% for those with a detectable postablation PSA value (P ⬍0.01). Local control at 10 years was 76% for those with undetectable postablation PSA levels and 37% for those with detectable postablation PSA levels (P ⬍0.01); metastatic control at 10 years was 80% for those with undetectable postablation PSA levels compared with 52% for those with detectable PSA levels (P ⬍0.01). The beneficial effect of an undetectable post-treatment PSA level was, however, not significant for overall survival—56% versus 41% for undetectable versus detectable PSA levels, respectively (P ⫽ 0.24). Multivariate logistic regression analysis revealed that the achievement of an undetectable post-treatment PSA level was significantly influenced only by the pretreatment PSA value (P ⬍0.01)—the higher the initial PSA level, the less likely was it to become undetectable within 1 year. EARLY ANDROGEN ABLATION AND RADIATION THERAPY The overall survival rate of the 72 men treated with androgen ablation and radiation was 92% and 67% at 5 and 10 years, respectively, and was not significantly different than that of an age-matched normal cohort (Fig. 2). All the men in this group were followed up with sequential PSA values, and the endpoint of relapse or rising PSA was equivalent to that of a rising PSA, since no patient developed clinical-radiographic evidence of disease relapse without first developing a rising PSA level. Ten men (14%) developed rising PSA levels; seven were found to have bone metastasis, one had local recurrence and metastasis, one had isolated local recurrence, and one remained without evidence of disease apart from a rising PSA value. The NED rate was 91% and 80% at 5 and 10 years, respectively (Fig. 2). The freedom from metastasis rate was 93% and 85% at 5 and 10 years, respectively. No patient developed pelvic nodal metastases. In view of the small number of endpoint events, meaningful statistical analyses could only be performed for NED, metastatic relapse, and survival. For metastatic relapse, the Gleason score was the only significant variable. The 8-year freedom from 236

FIGURE 2. Actuarial curves for overall survival and freedom from relapse or rising PSA for 72 men treated with androgen ablation and radiation therapy. Tick marks on the survival curve are censored observations. Vertical bars are 95% confidence intervals. Also shown is the age-matched expected survival curve.

metastasis rate was 93% and 66% for Gleason scores of 2 to 7 and 8 to 10, respectively (P ⬍0.01). For relapse or rising PSA, the T stage and Gleason score correlated with outcome in both univariate and multivariate analyses. The 8-year freedom from rising PSA rate was 91% and 71% for T1/T2 versus T3 disease, respectively (P ⫽ 0.05). The 8-year freedom from rising PSA rate was 97% and 52% for Gleason scores of 2 to 7 versus 8 to 10, respectively (P ⬍0.01). In multivariate analysis, the Gleason score predominated (P ⫽ 0.007), but the T stage contributed significantly (P ⫽ 0.032). No factor correlated with overall survival. All 72 men had post-treatment PSA values, and 64 (89%) achieved undetectable values within 1 year. In the remaining 8 men, the nadir PSA values ranged from 0.4 to 1.8 ng/mL (median 0.8). The small number of patients with persistently detectable PSA values precluded definitive statistical analysis. ANDROGEN ABLATION ALONE COMPARED WITH COMBINED ABLATION AND RADIATION The comparative outcomes for patients treated with ablation alone versus ablation and radiation are summarized in Tables II and III and in Figure 3. For all endpoints except nodal control, patients treated with both modalities fared substantially and significantly better than those treated with ablation alone. To correct for imbalances in the potential prognostic factors between the treatment groups (Table I), multivariate proportional hazards regression analysis was performed and revealed that the addition of radiation was a signifiUROLOGY 58 (2), 2001

TABLE II. Outcome according to treatment 10-Year Actuarial Percentage Endpoint

Ablation Alone

Ablation and Radiation

P Value

49 96 56 25 46

89 100 85 80 67

⬍0.001 0.233 0.006 ⬍0.001 0.008

Local control Nodal control Freedom from metastasis Freedom from relapse or rising PSA Survival KEY: PSA ⫽ prostate-specific antigen.

TABLE III. Proportional hazards multivariate analysis for various endpoints for all patients Endpoint and Significant Variables Freedom from relapse or rising PSA Radiation therapy Gleason score ⬍8 vs. 8–10 T1/T2 vs. T3 Freedom from metastasis Gleason score ⬍8 vs. 8–10 Radiation therapy Overall survival Radiation therapy Gleason score ⬍8 vs. 8–10

Chi-Square

df

P Value

Relative Risk (CI)

45.35 6.88 4.20

1 1 1

⬍0.0001 0.0087 0.0404

6.0 (3.1–11.5) 1.6 (1.1–2.3) 1.6 (1.0–2.5)

10.68 8.89

1 1

0.0011 0.0029

2.2 (1.4–3.4) 2.7 (1.3–5.6)

7.47 7.16

1 1

0.0063 0.0074

2.1 (1.2–3.9) 1.7 (1.2–2.5)

KEY: df ⫽ degrees of freedom; P value ⫽ likelihood ratio P value; CI ⫽ 95% confidence interval for relative risk; PSA ⫽ prostate-specific antigen.

FIGURE 3. A comparison of outcomes for patients treated with androgen ablation alone versus those treated with ablation and radiation. Vertical bars are 95% confidence intervals. Freedom from disease means absence of any relapse or rising PSA.

cant determinant of outcome for all endpoints (Table III). The Gleason score also remained an independent determinant of outcome for all endpoints. The pretreatment PSA level was not a significant covariate for any endpoint. In view of the unequal duration of follow-up for the two treatment groups, we compared the outcomes for patients accrued after 1987 when the PSA value was available. One hundred one men UROLOGY 58 (2), 2001

underwent androgen ablation alone (median follow-up 8.8 years) and 68 underwent both modalities (median follow-up 6.1 years). At 8 years, the outcomes for those undergoing androgen ablation alone compared with those undergoing both modalities were as follows: an NED rate of 30% and 78% (P ⬍0.001); freedom from metastasis rate of 46% and 83% (P ⬍0.001); and survival rate of 57% and 78% (P ⫽ 0.039), respectively. 237

COMMENT Our experience with early androgen ablation for node-positive disease (Fig. 1) is consistent with the limited data available in published reports19,20 and confirms that such treatment has little curative potential. It is noteworthy that the survival rate did not fall significantly below that expected for 5 years after treatment and only thereafter steadily declined, emphasizing the need for long follow-up to evaluate the differential survival effects of therapy. The major determinants of relapse and survival were the Gleason score and the performance of TURP in T3 disease. We previously noted this TURP effect,1 but whether it results from the procedure itself or reflects the adverse disease that necessitated such surgery is unclear. The performance of TURP has dramatically declined in recent years, and it is doubtful that the issue it raises remains of much clinical relevance today. The outcome for our patients treated with androgen ablation and radiation is most comparable to that reported from the Mayo Clinic after radical prostatectomy and androgen ablation2,9 and to that observed in the combined modality arm of the randomized trial reported by Messing et al.3 DeKernion et al.1 reported a 5-year survival rate and disease-free rate of approximately 80% and 68%, respectively, after combined prostatectomy and ablation. Studies of radiation and androgen ablation reported 5-year survival rates of 70%,6 75%,13 and 94%.12 The freedom from relapse rate at 5 years after radiation and ablation for node-positive disease have been reported as 55%13 and 78%.12 These variations in outcome almost certainly reflect disease and patient selection factors and highlight the need for prospective randomized trials to evaluate definitively the relative merits of different treatment strategies. In the absence of definitive randomized studies, our retrospective analysis has the merit of comparing two treatment modalities used in the same institution, and multivariate analysis makes allowance for the differences in distribution of certain prognostic factors between the two differently treated groups of patients. To our knowledge, this series is the largest reported cohort of node-positive patients treated with early androgen ablation or with combined radiation and ablation and followed up for a reasonable time. Although we cannot be certain, the differences in treatment effect summarized in Tables II and III and in Figure 3 appear to be real. The addition of local radiation to early androgen ablation resulted in substantial and significant benefits for freedom from relapse, freedom from metastasis, and freedom from local recurrence and translated into a significant survival benefit. Our results for the combined modality treatment are similar to 238

those reported from the Mayo Clinic for radical prostatectomy and androgen ablation.2,9 A final issue that arises is the overall clinical impact of this study given that fewer patients now present with nodal disease because of earlier diagnosis.3 We have previously argued that patients with unfavorable local-regional prostate cancer by virtue of high T stage, high Gleason grade, or high PSA value are the only group with a significant risk of nodal disease, but that a negative lymphadenectomy does not convert their disease into a favorable category.8 Regardless of the findings at lymphadenectomy, such patients should be treated with combined radiation and androgen ablation and thus, staging lymphadenectomy becomes irrelevant. The outcome for unfavorable Nx disease managed with radiation and ablation is similar to that reported here for node-positive patients treated in the same way.8 CONCLUSIONS Early androgen ablation as the sole treatment for node-positive prostate cancer has limited, if any, curative potential. The addition of local radiation to ablation results in substantial and significant improvements in disease control and patient survival. Aggressive control of the primary tumor aids in eradication of future metastatic clones and contributes to patient survival. REFERENCES 1. DeKernion JB, Neuwirth H, Stein A, et al: Prognosis of patients with stage D1 prostate carcinoma following radical prostatectomy with and without early endocrine therapy. J Urol 144: 700 –703, 1990. 2. Zincke H, Bergstralh EJ, Larson-Keller JJ, et al: Stage D1 prostate cancer treated by radical prostatectomy and adjuvant hormonal treatment: evidence for favorable survival in patients with DNA diploid tumors. Cancer 70(suppl): 311–323, 1992. 3. Messing EM, Manola J, Sarosdy M, et al: Immediate hormonal therapy compared with observation after radical prostatectomy and pelvic lymphadenectomy in men with node-positive prostate cancer. N Engl J Med 341: 1781–1788, 1999. 4. Hanks GE, Buzydlowski J, Sause WT, et al: Ten-year outcomes for pathologic node-positive patients treated in RTOG 75-06. Int J Radiat Oncol Biol Phys 40: 765–768, 1998. 5. Lee RJ, and Sause WT: Surgically staged patients with prostate carcinoma treated with definitive radiotherapy—15 year results. Urology 43: 640 – 644, 1994. 6. Granfors T, Modig H, Damber J-E, et al: Combined orchiectomy and external radiotherapy versus radiotherapy alone for nonmetastatic prostate cancer with or without pelvic lymph node involvement: a prospective randomized study. J Urol 159: 2030 –2034, 1998. 7. Zagars GK, Sands ME, Pollack A, et al: Early androgen ablation for stage D1 (N1 to N3, M0) prostate cancer: prognostic variables and outcome. J Urol 151: 1330 –1333, 1994. 8. Zagars GK, Pollack A, and von Eschenbach AC: Management of unfavorable locoregional prostate carcinoma with radiation and androgen ablation. Cancer 80: 764 –775, 1997. UROLOGY 58 (2), 2001

9. Ghavamian R, Bergstralh EJ, Blute ML, et al: Radical prostatectomy plus orchiectomy versus orchiectomy alone for pTxN⫹ prostate cancer: a matched comparison. J Urol 161: 1223–1228, 1999. 10. Eisenberger MA, and Walsh PC: Early androgen deprivation for prostate cancer? N Engl J Med 342: 1837–1838, 1999. 11. Sands ME, Pollack A, and Zagars GK: Influence of radiotherapy on node-positive prostate cancer treated with androgen ablation. Int J Radiat Oncol Biol Phys 31: 13–19, 1995. 12. Whittington R, Malkowicz SB, Machtay M, et al: The use of combined radiation therapy and hormonal therapy in the management of lymph node-positive prostate cancer. Int J Radiat Oncol Biol Phys 39: 673– 680, 1997. 13. Lawton CA, Winter K, Byhardt R, et al: Androgen suppression plus radiation versus radiation alone for patients with D1 (pN⫹) adenocarcinoma of the prostate (results based on a national prospective randomized trial, RTOG 85-31). Int J Radiat Oncol Biol Phys 38: 931–939, 1997. 14. Pilepich MV, Caplan R, Byhardt RW, et al: Phase III trial of androgen suppression using goserelin in unfavorable-prog-

UROLOGY 58 (2), 2001

nosis carcinoma of the prostate treated with definitive radiotherapy: report of Radiation Therapy Oncology Group protocol 85-31. J Clin Oncol 15: 1013–1021, 1997. 15. McDowell GC, Johnson JW, Tenney DM, et al: Pelvic lymphadenectomy for staging clinically localized prostate cancer: indications, complications and results in 217 cases. Urology 35: 476 – 482, 1990. 16. Cadeddu JA, Partin AW, Epstein JI, et al: Stage D1 (T1–3, N1–3, M0) prostate cancer: a case-controlled comparison of conservative treatment versus radical prostatectomy. Urology 50: 251–255, 1997. 17. Harris EK, and Albert A: Survivorship Analysis for Clinical Studies. New York, Marcel Dekker, 1991, pp 5–125. 18. Hosmer DW, and Lemeshow S: Applied Logistic Regression. New York, John Wiley & Sons, 1989, pp 25–173. 19. van Aubel OG, Hoekstra WJ, and Schroder FH: Early orchiectomy for patients with stage D1 prostatic carcinoma. J Urol 134: 292–294, 1985. 20. Kramolowsky EV: The value of testosterone deprivation in stage D1 carcinoma of the prostate. J Urol 139: 1242– 1244, 1988.

239