PROGNOSIS OF PATIENTS WITH LYMPH NODE POSITIVE PROSTATE CANCER FOLLOWING RADICAL PROSTATECTOMY: LONG-TERM RESULTS

PROGNOSIS OF PATIENTS WITH LYMPH NODE POSITIVE PROSTATE CANCER FOLLOWING RADICAL PROSTATECTOMY: LONG-TERM RESULTS

0022-5347/04/1726-2252/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION Vol. 172, 2252–2255, December 2004 Printed in U...

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0022-5347/04/1726-2252/0 THE JOURNAL OF UROLOGY® Copyright © 2004 by AMERICAN UROLOGICAL ASSOCIATION

Vol. 172, 2252–2255, December 2004 Printed in U.S.A.

DOI: 10.1097/01.ju.0000143448.04161.cc

PROGNOSIS OF PATIENTS WITH LYMPH NODE POSITIVE PROSTATE CANCER FOLLOWING RADICAL PROSTATECTOMY: LONG-TERM RESULTS SIAMAK DANESHMAND,* MARCUS L. QUEK, JOHN P. STEIN, GARY LIESKOVSKY, JIE CAI, JACEK PINSKI, EILA C. SKINNER AND DONALD G. SKINNER From the Departments of Urology, Preventive Medicine (JC) and Medical Oncology (JP), Kenneth Norris Jr. Comprehensive Cancer Center, University of Southern California Keck School of Medicine, Los Angeles, California

ABSTRACT

Purpose: We determined the prognostic factors that affect recurrence and survival in patients with lymph node positive prostate cancer. Materials and Methods: Between 1972 and 1999, 1,936 patients underwent radical retropubic prostatectomy and pelvic lymph node dissection for clinically organ confined prostate cancer. A total of 235 patients (12.1%) were found to have disease metastatic to the lymph nodes (stage D1). Of the patients 69% received no adjuvant treatment. We reviewed the tumor stage (TNM), Gleason score, number and percent of involved lymph nodes (lymph node density), preoperative prostate specific antigen when available and adjuvant treatment. Overall survival and recurrence-free survival were estimated using Kaplan-Meier plots. Results: Followup was 1 to 24 years (median 11.4). Overall median survival was 15 years. Overall clinical recurrence-free survival at 5, 10 and 15 years was 80%, 65% and 58%, respectively. Patients who had 1 or 2 positive lymph nodes had a clinical recurrence-free survival of 70% and 73% at 10 years, respectively, vs 49% in those who had 5 or more involved lymph nodes (p ⫽ 0.0031). When stratified by lymph node density, patients with a lymph node density of 20% or greater were at higher risk for clinical recurrence compared to those with a density of less than 20% (relative risk ⫽ 2.32, p ⬍0.0001). On stratified log rank test only prostate cancer T stage, and the number and percent of positive lymph nodes correlated with recurrence-free and overall survival. Conclusions: Local tumor bulk and the number/percent of involved lymph nodes significantly affect disease progression and the survival rate. Radical prostatectomy may offer long-term survival in patients who have limited tumor bulk and nodal involvement. KEY WORDS: prostate, prostatic neoplasms, lymph nodes, neoplasm metastasis, prostatectomy

Lymph node metastasis in prostate cancer is generally considered a poor prognostic indicator. The reported incidence of lymph node metastasis in clinically localized prostate cancer has decreased dramatically in the last decade to 4% to 6% in most recent series due to earlier detection with prostate specific antigen (PSA) screening.1, 2 Treatment of these patients is controversial, in particular the benefit of radical prostatectomy when positive lymph nodes are found on frozen section. Retrospective reviews indicate that patients with lymph node positive prostate cancer may in fact have meaningful survival.3– 8 Ten-year cancer specific survival in larger series is 47% to 78% in patients treated with radical prostatectomy with immediate hormonal therapy3, 5, 7 and 57% to 62% in patients treated with radical prostatectomy without immediate hormonal treatment.8, 9 Few groups have examined the number of positive lymph nodes or lymph node density (LND), that is the number of positive lymph nodes divided by the total number of lymph nodes removed.3, 8, 10 In this study we determined the influence of the number of positive lymph nodes on long-term recurrence and survival in a large series of patients who underwent radical prostatectomy and bilat-

eral pelvic lymph node dissection for clinically organ confined prostate cancer at a single institution. MATERIALS AND METHODS

An established ethics committee and institutional review board approved computerized database was used to report clinical and pathological information and outcomes. Between 1972 and 1999, 1,936 patients underwent radical retropubic prostatectomy and pelvic lymph node dissection for clinically organ confined prostate cancer at our institution. The limits of pelvic lymph node dissection included all lymphatic tissue along the external iliac vein from the lymph node of Cloquet distal to the bifurcation of the common iliac vein proximal, including all lymphatic tissue in the obturator fossa. In this cohort 235 patients (12.1%) were found to have disease metastatic to the lymph nodes on final pathological analysis (stage D1). Table 1 shows the era in which patients underwent operation. The 2 senior surgeons (GL and DGS) performed 91% of the prostatectomies in this cohort. To identify factors that affect prognosis we reviewed tumor stage using the 1992 TNM staging system, Gleason grade, number and percent of involved lymph nodes (lymph node density), preoperative PSA when available, margin status and neoadjuvant or adjuvant treatment. Adjuvant and neoadjuvant therapy. The use of neoadjuvant and adjuvant therapy (used from 1981 to 1999) was recorded in each case. Adjuvant therapy consisted of a lutein-

Accepted for publication July 2, 2004. Database received ethics committee and institutional review board approval. * Correspondence: Division of Urology (L588), Oregon Health and Science University, 3181 Southwest Sam Jackson Park Rd., Portland, Oregon 97239 (e-mail: [email protected]). 2252

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PROGNOSIS OF LYMPH NODE POSITIVE PROSTATE CANCER TABLE 1. Patients with positive lymph nodes with time Yrs

No. Pos Lymph Node Pts

No. Prostatectomies

% Pos Lymph Nodes

1972–1975 1976–1980 1981–1985 1986–1990 1991–1995 1996–1999 Overall

2 3 36 59 97 38 235

9 16 121 309 832 649 1,936

22 19 30 19 12 6 12.1

izing hormone releasing hormone agonist used alone or in combination with an antiandrogen, surgical castration, an estrogen derivative and/or postoperative radiation started within 3 months of surgery. In patients who did not receive immediate adjuvant therapy hormonal ablative therapy was initiated if there was symptomatic progression or if PSA reached an arbitrary predefined limit at treating physician discretion or by patient choice. Pathological findings. All radical prostatectomy specimens were evaluated by the same pathological protocol. Multiple sections were obtained from the prostate and staging was performed according to the 1992 TNM classification of the American Joint Committee on Cancer. The lymph nodes from pelvic lymph node dissection were totally embedded for histological evaluation. Tumor grading was performed according to the Gleason system. Clinical outcomes. Patients were followed every 4 to 6 months in year 1, every 6 months in years 2 and 3, and then yearly thereafter. At each visit physical examination, serum PSA measurement and chest x-ray were performed. Bone scan was done only if there was symptomatic progression or an increase in PSA. Clinical outcomes were measured by time to clinical recurrence and overall survival. Time to clinical recurrence or recurrence-free survival was calculated as the time from radical prostatectomy to the date of the first documented clinical recurrence based on physical examination, chest x-ray, computerized tomography or bone scan. Patients who died prior to clinical recurrence were censored at death. Survival was calculated as time from radical prostatectomy to the date of death. All deaths regardless of cause were counted as events. Patients who were alive were censored at the date of last contact. Serum PSA was measured with the ultra-sensitive Tosoh assay (Tosoh, Foster City, California) with PSA recurrence defined as a serum PSA of 0.05 ng/ml or greater. Followup PSA data were analyzed for 222 of the 235 patients. In 8 patients PSA was not reported or it was unknown, 1 had clinical recurrence but no PSA recurrence and in 4 PSA never became undetectable after surgery. Statistical methods. Kaplan-Meier plots were used to estimate overall 5 and 10-year survival, and recurrence-free survival in the different groups. The log rank test (overall and stratified) were used to compare differences in survival or recurrence in subgroups. Pearson’s chi-square test was used to examine the association between important clinical variables. All p values reported in the analyses are 2-sided. RESULTS

Followup was 1 to 24 years (median 11.4) and 30 patients had more than 15 years of followup. Table 2 lists the characteristics and pathological subgroups of the 235 patients. Most patients (69%) received no adjuvant or neoadjuvant treatment, while 17% received postoperative diethylstilbestrol and 14% received radiation therapy and/or other hormonal therapy. Of the patients 54 did not receive any hormonal therapy at any time during the clinical course. PSA was 20 ng/ml or less in 39% of the patients and 20 ng/ml or greater in 26%, while 35% were treated in the pre-PSA era and, thus, had no PSA measured preoperatively. The median number of lymph nodes removed during pelvic lymphadenectomy was 19 (range 2 to 62). Two-thirds of the

TABLE 2. Characteristics of patients with pathological stage D1 prostate cancer % No. pts Age: Younger than 60 60–70 Older than 70 Preop PSA (ng/ml): Less than 4 4–10 10–20 Greater than 20 Not available Adjuvant treatment: None Diethylstilbestrol Other 1992 AJCC pathological stage: T2b T2c T3a T3b T3c T4a T4b Gleason grade: 2–4 5–6 7 8–10 Not available Margin status: Pos Neg Not available

235 21 62 17 3 18 18 26 35 69 17 14 3 9 14 9 51 16 Less than 1 Less than 1 14 35 48 2 44 55 1

patients had 1 (46%) or 2 (22%) positive lymph nodes, while 18% had 5 or more positive lymph nodes. LND was defined as the number of positive lymph nodes divided by the total number of lymph nodes removed. Lymph node density was less than 10% in 49% of patients, 10% to 20% in 24% and greater than 20% in 27% (table 3). About 89% of the patients had disease outside of the prostate capsule. The surgical margin was positive in 44% of patients. At followup 143 of 235 patients (61%) were alive, including 21 with more than 15 years of followup, and 146 (62%) had recurrent prostate cancer. Median survival in the entire cohort was 15 years. Overall clinically recurrence-free survival at 5, 10 and 15 years was 80%, 65% and 58%, respectively. Patients who had 1 or 2 positive lymph nodes had an overall survival of 94% and 96% at 5 years, and 75% and 74% at 10 years, respectively. Patients with more than 5 involved lymph nodes had 5 and 10-year overall survival of 76% and 49%, respectively (p ⬍0.005, fig. 1). Clinical recurrence-free survival in patients with 1 or 2 lymph nodes was 89% and 81% at 5 years, and 70% and 73% at 10 years, respectively. However, in patients with 5 or more involved lymph nodes clinical recurrence-free survival at 5 and 10 years was 62% and 49%, respectively (p ⫽ 0.042, fig. 2). When stratified by LND, patients with a LND of 20% or greater were at higher risk for clinical recurrence compared to those with a density of less than 20% (relative risk ⫽ 2.31,

TABLE 3. Patients with positive lymph nodes stratified by number of positive lymph nodes and LND % No. pos lymph nodes: 1 2 3–4 5 or Greater % LND: 10 or Less 10–20 20 or Greater

46 22 15 18 49 24 27

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PROGNOSIS OF LYMPH NODE POSITIVE PROSTATE CANCER

FIG. 1. Overall survival in 235 patients with stage D1, lymph node positive prostate cancer following radical prostatectomy and lymph node dissection stratified by number of positive lymph nodes (LN⫹).

FIG. 4. PSA recurrence-free survival in patients with lymph node positive prostate cancer following radical prostatectomy and lymph node dissection.

clinical recurrence-free and PSA recurrence-free survival was 74%, 69% and 40%, respectively, at 10 years. On the stratified log rank test only prostate cancer T stage, and the number and percent of positive lymph nodes correlated with recurrence-free and overall survival. DISCUSSION

FIG. 2. Clinical recurrence-free survival in 235 patients with stage D1, lymph node positive prostate cancer following radical prostatectomy and lymph node dissection stratified by number of positive lymph nodes (LN⫹).

p ⫽ 0.0001). In patients with LND less than 20% the mean 10-year clinical recurrence free survival rate ⫾ SE was 72% ⫾ 4% compared to 47% ⫾ 7% in those with a LND 20% or greater (p ⫽ 0.0001, fig. 3). PSA recurrence-free survival at 5, 10 and 15 years was 54%, 39% and 21%, respectively. Median PSA recurrence-free survival was 6.1 years (fig. 4). In the 163 patients who received no adjuvant or neoadjuvant therapy overall,

FIG. 3. Clinical recurrence-free survival in patients with stage D1, lymph node positive prostate cancer following radical prostatectomy and lymph node dissection stratified by positive LND, that is number of positive lymph nodes divided by total number of lymph nodes removed.

Several studies have suggested that patients treated with combined radical prostatectomy and androgen ablation therapy have significant improvement in cause specific survival compared to those receiving androgen ablation alone.5, 11, 12 Furthermore, the incidence of local complications, including stricture formation, bleeding or cancer regrowth requiring dilation or surgical intervention (transurethral prostatectomy), are significantly lower in patients who undergo radical prostatectomy compared to those treated with hormonal therapy alone.12 Several retrospective studies have shown that patients with lymph node positive prostate cancer in fact have meaningful long-term survival.3– 8 In their large series of 790 patients with lymph node positive prostate cancer from the Mayo Clinic Seay et al reported overall cause specific survival probabilities of 79% and 60% at 10 and 15 years, respectively.7 Patients with diploid tumors who received adjuvant ablative therapy had cause specific survival probabilities at 5, 10 and 15 years of 94%, 86% and 83% compared to 97%, 83% and 49%, respectively, in those not receiving immediate androgen ablation therapy. They found that the impact of androgen ablation therapy in their series became significant only after 10 years. In nondiploid cases androgen ablation therapy did not impact disease specific survival. In a series from Johns Hopkins Pound et al followed 1,623 men with clinically localized prostate cancer after radical prostatectomy.13 Patients with lymph node micrometastasis had a 10-year metastasis-free survival rate of 68% without any adjuvant therapy. Similarly Zwergel et al from the University of Saarland, Germany recently reported a series of 147 patients with lymph node positive prostate cancer (treated with hormonal ablation in 92%) followed a median of 41.9 months.6 They found a cancer specific survival rate of 74% and 58% at 10 and 15 years, respectively. Our data are consistent with these series, showing an overall clinical recurrence-free survival rate of 65% and 58% at 10 and 15 years, respectively. Few groups looking at progression and survival in lymph node positive prostate cancer have considered the number or percent of positive lymph nodes.3, 8, 10, 12 Our analysis of 235 patients with lymph node positive disease showed an excellent long-term prognosis with a median survival of 15 years. Patients with limited lymph node disease had a significantly better prognosis than those with a larger nodal tumor burden even

PROGNOSIS OF LYMPH NODE POSITIVE PROSTATE CANCER

without immediate adjuvant treatment. In patients with 1 or 2 positive lymph nodes recurrence-free survival was more than 70% at 10 years. In the Mayo Clinic series Cheng et al found that patients with a single lymph node metastasis had 5 and 10-year cancer-specific survival rates of 99% and 94%, respectively, following radical prostatectomy and immediate androgen ablation.3 This was comparable to 5 and 10-year tumor specific survival in patients with negative lymph nodes. Burkhard et al analyzed the records of 460 patients with clinically organ confined prostate cancer with a median PSA of 11.0 ng/ml and found that 25% had positive lymph nodes following meticulous pelvic lymph node dissection.14 Surprisingly 12% of patients with PSA below 10.0 ng/ml had positive lymph nodes. In a recently published study the same group stratified their results according to the number of positive lymph nodes.8 They found that the number of lymph node metastases was significantly related to progression and cancer specific death using univariate Cox regression analysis (p ⬍0.001). The probability of PSA relapse, symptomatic progression, and cancer specific death increased with each additional lymph node involved. This is an important natural history cohort since none of the patients received immediate adjuvant hormonal therapy. In our study 69% of the patients received no neoadjuvant or adjuvant therapy. Hormonal therapy was generally initiated if there was symptomatic progression (based on physical examination, chest x-ray, computerized tomography or bone scan) or if PSA reached an arbitrary predefined limit at the discretion of the treating physician. Overall and clinical recurrence-free survival in this group was 74% and 69%, respectively, at 10 years. Although there was considerable selection bias in this group, this still represents a large group of patients with promising survival rates despite no treatment with immediate androgen ablation. The timing of androgen deprivation in patients with lymph node positive prostate cancer has been the topic of discussion.15, 16 Messing et al and the Eastern Cooperative Oncology Group performed a prospective, randomized trial to answer this question.9 In their study they found that after a median of 7.1 years there was a significant difference in survival following immediate androgen ablation. Patients who did not receive immediate hormonal ablation had a relatively low cancer specific survival of 78% at 5 years compared to more than 90% in other series,7, 11 including ours. That trial has been criticized for the small number of patients accrued and the possibly unequal distribution of patients in the delayed therapy group.15 However, the impact of hormonal treatment on health related quality of life (HRQOL) should be considered in clinical decision making. Long-term androgen ablation can have a significant negative impact on HRQOL. Patients treated with androgen deprivation show a significantly worse sexual, emotional and physical function, experience more hot flashes and have worse overall HRQOL than patients receiving no therapy.17 In our series patients with a single lymph node metastasis or a LND of less than 10% had a clinical recurrence-free survival rate of greater than 70% at 10 years. It can be argued that progression and recurrence could be delayed even further in this cohort if they were uniformly treated with immediate hormonal deprivation. This study was limited by its retrospective nature and the fact that not all patients were treated uniformly, hence, the existence of a selection bias. It does not answer the question of whether immediate androgen deprivation prolongs survival in patients with lymph node positive disease following radical prostatectomy. Nevertheless, this large series with long-term followup shows excellent long-term survival in a population of patients typically considered to have a poor prognosis. Given promising survival in patients with a minimal nodal burden and the negative impact of long-term hormonal ablation, some patients may be considered for observation. Future molecular marker studies may be able to provide better prognostic indicators in this group.

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CONCLUSIONS

Our long-term analysis of 235 patients with stage D1 prostate cancer shows that local tumor bulk (T stage), and the number and percent of involved lymph nodes significantly predict disease progression and survival. The data suggest that radical prostatectomy and pelvic lymph node dissection may offer long-term survival in select patients who have limited tumor bulk and nodal involvement.

REFERENCES

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