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Prostate cancer disease-free survival after radical retropubic prostatectomy in patients older than 70 years compared to younger cohorts
Urologic Oncology: Seminars and Original Investigations 25 (2007) 291–297
Original article
Prostate cancer disease-free survival after radical retropubic prostatectomy in patients older than 70 years compared to younger cohorts夡 Bahaa S. Malaeb, M.D.a, Hani H. Rashid, M.D.a, Yair Lotan, M.D.b, Seyyed M. Khoddami, M.D.b, Shahrokh F. Shariat, M.D.b, Arthur I. Sagalowsky, M.D.b, John D. McConnell, M.D.b, Claus G. Roehrborn, M.D.b, Kenneth S. Koeneman, M.D.a,* a
b
Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Received 30 May 2006; received in revised form 1 August 2006; accepted 2 August 2006
Abstract Objectives: To evaluate the feasibility of radical retropubic prostatectomy (RRP) as an option for treating men older than 70 years with organ confined prostate cancer and to compare biochemical progression-free survival with younger cohorts. Materials and Methods: A total of 689 consecutive patients who were treated with RRP from 1994 to 2002 for clinically localized prostate cancer were categorized into 3 different age groups: younger than 50 years (n ⫽ 49), 50 –70 years (n ⫽ 601), and older than 70 years (n ⫽ 39). Patients older than 70 years were healthy individuals for their age. Preoperative and postoperative cancer-specific characteristics were compared among these 3 groups. Results: There was no statistical significant difference among the 3 age strata in terms of clinical parameters (prostate-specific antigen, Gleason score, clinical stage, percent and number of positive biopsy cores) and pathologic findings (surgical margin, lymph node status, extracapsular extension, lymphovascular invasion, and pathologic Gleason score). The rate of seminal vesicle invasion and prostate volume increased with advancing age (P ⫽ 0.034 and P ⬍ 0.001). In multivariate logistic regression analysis, age was not associated with seminal vesicle invasion. The 5-year prostate-specific antigen progression-free estimates for patients younger than 50, 50 –70, and older than 70 years were 82% (95% confidence interval [CI] 69% to 96%), 82% (95% CI 78% to 86%), and 65% (95% CI 43% to 86%), respectively (P ⫽ 0.349). The overall and cause-specific mortalities were not different. Conclusions: RRP could be considered a standard treatment option in men older than 70 years with localized prostate cancer. Further studies are necessary to assess the survival benefit and health-related quality of life after radical prostatectomy versus watchful waiting in patients older than 70 years. © 2007 Elsevier Inc. All rights reserved. Keywords: Radical retropubic prostatectomy; Prostate cancer; Biochemical recurrence; Watchful waiting; Life expectancy
1. Introduction Decision making in patients with prostate cancer over the age of 70 years is becoming a major area of debate because patients are living longer than in the past. With current advances in medical treatment and health awareness, as well
夡 Dr. Koeneman was supported by the Dougherty Family Chair in Uro-Oncology which made this work possible. * Corresponding author. Tel.: ⫹1-612-626-0964; fax: ⫹1-612-6240958. E-mail address: [email protected] (K.S. Koeneman).
1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2006.08.001
as the shift toward healthier lifestyles, the average life expectancy of men is on the increase. In the United States for example, the number of persons older than 65 years is expected to increase from approximately 35 million in 2000 to an estimated 71 million in 2030 [1]. This increase will be paralleled in other countries. Prostate cancer, being primarily a disease of older men, will reflect this trend through an increase in the number of patients diagnosed over the age of 65 years. It is not uncommon these days that urologists are faced with a 70 –75-year-old, healthy patient newly diagnosed with prostate cancer, with all pretreatment indices pointing toward organ-confined disease. Decision making in
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this group is still left to the discretions and algorithms of the treating physician, and questions arise whether this age group is being denied definitive treatment, leading to a compromise of its health status and life expectancies. The 10-year life expectancy requirement governs the decision making for physicians faced with strong evidence of organ-confined disease in an elderly patient. Although surgeons treat their patients with prostate cancer in a case by case basis, this rule is widely accepted secondary to the belief that prostate cancer develops and progresses slowly compared to other tumors, thus raising the need for a rather long life expectancy to be able to show the survival benefit of intervention with curative intent [2]. Johansson et al. [3] recently published their results in JAMA, showing it took more than 15 years for their patients with localized prostate cancer who underwent watchful waiting before they had statistically significant worsening progression-free survival, metastasis-free survival, and prostate cancer specific survival. However, the fact is that the origin of the “10-year rule” is poorly documented in literature and does not consider tumor-specific characteristics (grade, stage, prostatespecific antigen [PSA] level). In addition, for those patients who are offered curative treatment, modalities such as external beam radiation, brachytherapy, and cryotherapy are discussed rather than open radical surgery because of the perceived morbidities of surgery [4,5]. It is possible that older patients would prefer the risk and side effect profile of surgical treatment versus other treatment modalities morbidity but are never given the option, nor are even the risks and benefits discussed fairly and intelligently with them. Therefore, the question is why not offer surgical treatment to patients older than 70 years with localized prostate cancer? The fact is that, to our knowledge, no contemporary literature specifically and solely asks this question, and compares the outcome of patients with localized prostate cancer in different age groups. In an effort to add to the existing limited data on treatment of localized prostate cancer in patients older than 70 years, as well as assess the feasibility and outcome of radical retropubic prostatectomy (RRP) in this age group, we analyzed data from a cohort of 689 consecutive patients with clinically localized prostate cancer [6 – 8]. Patients older than 70 years were “selected” by their surgeons as “fit” for radical prostatectomy and represented, in general, healthy individuals for their age.
2. Materials and methods A total of 689 consecutive patients underwent RRP with bilateral lymph node dissection for clinically localized prostate cancer at 1 of 2 teaching hospitals of the University of Texas Southwestern Medical Center during the period of July 1994 to December 2002. Studies were undertaken with the approval and oversight of the Institutional Review Board for the Protection of Human Subjects. The operating
surgeon assigned the clinical stage according to the 1992 American Joint Committee on Cancer/tumor-nodes-metastasis system. The serum total PSA was measured by Tandem-E assay (Hybriteck Inc., San Diego, CA). The percentage of positive biopsy cores was defined as: (number of positive biopsy cores/total number of biopsy cores) ⫻ 100. 2.1. Pathologic examination Staff pathologists from our institution examined all prostatectomy specimens pathologically, as described elsewhere in accordance with the guidelines of the College of American Pathologists, and a detailed description is found in earlier reports [6 –9]. Multiple, oriented quadrant sections from the entire prostate were processed (approximately 25–30 blocks). The 1997 American Joint Committee on Cancer/tumor-nodesmetastasis system was used for pathologic staging. Grading of the primary tumor was performed according to the Gleason system. Clinical parameters measured were age, preoperative PSA, Gleason score, number and percentage of positive biopsy cores, number of lymph nodes dissected, number of positive lymph nodes, extracapsular extension, lymphovascular invasion, seminal vesicle invasion, surgical margin status, and whether the tumor was organ confined or not. To ensure validity of the outcomes, 2 clinicians read pathology reports, while blinded to patient clinical parameters and the finding of the other reviewer. Inter-reader reliability measured using the intra-class correlation coefficient was more than 0.95 for all pathologic parameters. 2.2. Postoperative follow-up Patients generally were scheduled to have a digital rectal examination and serum total PSA evaluation postoperatively every 3 months for the first year, at least semiannually from the second through the fifth year, and annually thereafter. Biochemical progression was defined as a sustained increase, on ⱖ2 occasions, of serum total PSA ⱖ0.2 ng/ml and was assigned to the date of the first value ⱖ0.2 ng/ml. Patients who received adjuvant radiation therapy before biochemical progression because of clinical or pathologic characteristics were considered to have disease progression from the date of the first value ⱖ0.2 ng/ml. For patients who had biochemical progression, post-progression serum T-PSA doubling time was calculated using the formula: total PSA doubling time ⫽ [ln (2) ⫻ Time]/[ln (final total PSA) ⫺ ln (initial total PSA)]. All patients had at least 3 total PSA measurements available after biochemical progression. 2.3. Statistical analysis The chi-square test was used to evaluate the association between categorical variables. Differences in continuous variables across categorical variables were assessed using the Kruskal-Wallis test. The Spearman rank correlation co-
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Table 1 Clinical and pathological variables compared among the 3 different age groups. No. pts (%)
a
Clinical stage (No. pts, %) T1 T2 Biopsy Gleason sum (No. pts, %)a 2–6 7 8–10 Extracapsular extension (No. pts, %)a Negative Positive Seminal vesicle involvement (No. pts, %)a Negative Positive Surgical margin status (No. pts, %)a Negative Positive Pathology Gleason sum (No. pts, %)a 2–6 7 8–10 Lympho-vascular invasion (No. pts, %)a Negative Positive Perineural invasion (No. pts, %)a Negative Positive Regional lymph node metastases (No. pts, %)a Negative Positive Number positive biopsy cores (median, range)b Percent positive biopsy cores (median, range)b Total prostate volume (median, range; cc)b Preoperative serum PSA (median, range; ng/mL)b Preoperative serum percent free PSA (median, range; ng/mL)b
689 477 (69.2%) 212 (30.8%) 681 451 (66.2%) 188 (27.6%) 42 (6.2%) 687 480 (69.9%) 207 (30.1%) 687 624 (90.8%) 63 (9.2%) 687 548 (79.8%) 139 (20.2%) 687 282 (41.0%) 334 (48.6%) 71 (10.3%) 628 594 (94.6%) 34 (5.4%) 628 249 (39.6%) 379 (60.4%) 686 674 (98.3%) 12 (1.7%) 2 (1–15) 25 (1–100) 45 (12–210) 6.0 (1–99.3) 21.6 (1.1–98.6)
Age strata ⬍50 years
50–69.9 years
ⱖ70 years
49 37 (75.5%) 12 (24.5%) 49 35 (71.4%) 12 (24.5%) 2 (4.1%) 49 36 (73.5%) 13 (26.5%) 49 46 (93.9%) 3 (6.1%) 49 42 (85.7%) 7 (14.3%) 49 20 (40.8%) 24 (49.0%) 5 (10.2%) 40 39 (97.5%) 1 (2.5%) 40 14 (35.0%) 26 (65.0%) 49 49 (100.0%) 0 (0.0%) 1 (1–12) 17 (5–83) 39 (16–119) 5.7 (1–36.9) 21.2 (5.6–87.4)
601 419 (69.7%) 182 (30.3%) 593 392 (66.1%) 165 (27.8%) 36 (6.1%) 599 418 (69.8%) 181 (30.2%) 599 547 (91.3%) 52 (8.7%) 599 474 (79.1%) 125 (20.9%) 599 246 (41.1%) 293 (48.9%) 60 (10.0%) 555 523 (94.2%) 32 (5.8%) 555 226 (40.7%) 329 (59.3%) 598 586 (98.0%) 12 (2.0%) 2 (1–15) 25 (1–100) 46 (12–210) 6.0 (1–99.3) 21.5 (1.7–98.6)
39 21 (53.8%) 18 (46.2%) 39 24 (61.5%) 11 (28.2%) 4 (10.3%) 39 26 (66.7%) 13 (33.3%) 39 31 (79.5%) 8 (20.5%) 39 32 (82.1%) 7 (17.9%) 39 16 (41.0%) 17 (43.6%) 6 (15.4%) 33 32 (97.0%) 1 (3.0%) 33 9 (27.3%) 24 (72.7%) 39 39 (100%) 0 (0.0%) 2 (1–6) 25 (6–83) 64 (27–116) 6.0 (2.1–32.0) 26.6 (6.2–97.1)
P value 0.07
0.749
0.781
0.034
0.509
0.872
0.559
0.254
0.407 0.407 0.225 0.421 ⬍0.001 0.673 0.279
Extracapsular extension, surgical margin status, pathology Gleason sum, and seminal vesicle involvement were not available in 2 patients. Biopsy Gleason sum was not available in 8 patients. Lymph node status was not available in 3 patients. Lympho- vascular invasion and perineural invasion were not available in 61 patients. a Chi-square test. b Kruskal Wallis test.
efficient was used to compare ordinal and continuous variables. Logistic regression was used for multivariate analysis of binary outcome variables. Clinical stage was evaluated as T1 versus T2. Biopsy and prostatectomy Gleason sum were evaluated as grades 4 – 6 versus grade 7 versus grades 8 –10. Statistical significance in this study was set as P ⱕ 0.05. All reported P values are 2 sided. All analyses were performed with SPSS (version 13.0; SPSS, Inc., Chicago, IL) for Windows (Microsoft, Corp., Redmond, WA).
3. Results The number of patients in the age groups of younger than 50, 50 –70, and older than 70 years were 49 (7.1%), 601
(87.2%), and 39 (5.7%), respectively. Median age in patients younger than 50 years was 47.8 (range 33.1– 49.9). Median age in patients between 50 and 69.9 years was 60.9 (range 50.2– 69.9). Median age in patients 70 years or older was 71.6 (range 70.0 –75.2). Clinical and pathologic characteristics of the 689 patients with prostatectomy and association with age strata are shown in Table 1. No significant difference was noted among the 3 groups with respect to biopsy Gleason score, preoperative PSA, percent-free PSA, number of positive biopsy cores, percent-positive biopsy, and number of lymph nodes taken during surgery. Mean PSA values were 7.54, 7.91, and 8.07 for the 3 age groups younger than 50, 50 –70, and older than 70 years, respectively (no significant difference, P ⫽ 0.405). Patients older than 70 years were more likely to have seminal vesicle invasion (P ⫽ 0.034) and higher total prostate volume (P ⬍
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100
PSA Progression-Free Probability
90
Below 50 years
80 50-69.9 years
70 60 50 40 30
Log rank tests
P value
Pooled over strata < 50 years vs 50-69.9 years < 50 years vs 70 years 50-69.9 years vs 70 years
0.3494 0.9499 0.3685 0.1548
20
Age
10
Below 50 years 50-69.9 years 70 years and older
70 years and older
3 yr. ± SE
5 yr. ± SE
82.3 ± 6.7 % 87.3 ± 1.5 % 82.9 ± 7.2 %
82.3 ± 6.7 % 82.3 ± 2.1 % 64.6 ± 10.9 %
0 0
20
40
60
80
100
120
Months after Surgery Fig. 1. Kaplan-Meier curves showing PSA progression-free survival in each of the 3 age groups.
0.001) than patients aged 50 – 69.9 years or those younger than 50 years. Age analyzed as continuous variable was correlated with total prostate volume (rho ⫽ 0.305, P ⬍ 0.001) and preoperative serum total PSA (rho ⫽ 0.187, P ⫽ 0.024), but not preoperative serum percent free PSA (rho ⫽ 0.040, P ⫽ 0.404). In preoperative multivariate logistic regression analysis, clinical stage (odds ratio [OR] 2.573, P ⫽ 0.002), biopsy Gleason sum (OR 2.790, P ⬍ 0.001), and preoperative serum total PSA (OR 1.055, P ⬍ 0.001), but not age stratified as younger than 50 versus 50 – 69.9 versus 70 years or older (P ⫽ 0.115), were significantly associated with an increased risk of seminal vesicle invasion. Overall, only 13.5% of patients (93 of 689) had biochemical disease progression with a median postoperative follow-up of 32.6 months (range 1.0 –113). Mean postoperative follow-up was 39 months. The overall PSA progression-free survival was 85.4% ⫾ 1.6% (standard error) at 3 years and 80.9% ⫾ 2.1% at 5 years. Using the log-rank test, we found that there was no statistically sig-
nificant risk of PSA progression across age strata (P ⫽ 0.3494; Fig. 1). There were 11 patients who did not undergo additional treatment after disease progression at last follow-up. A total of 27 patients underwent local salvage radiation therapy at our institution, and 59 underwent hormonal therapy as primary treatment of prostate cancer progression. PSA doubling time calculation could be performed for 78 patients who had PSA progression before the administration of salvage therapy. PSA doubling time between PSA failure and initiation of salvage therapy was not different across age strata (P ⫽ 0.214). A staging evaluation, including bone scan or ProstaScint scan (CYTOGEN Corp., Princeton, NJ), was performed at our institution for 76 patients who had biochemical progression after radical prostatectomy. As evidenced by imaging studies, bone metastases developed in 14 patients. All 14 patients were between 50 and 69.9 years of age. Development of metastasis was not associated with age strata (P ⫽ 0.351). Overall survival data were available for all 689 patients. Of the 689 patients, 7 (1%) were dead from any cause at
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analysis. There were 4 patients between 50 and 69.9 years of age who died. In this age group, 2 patients died of prostate cancer after having PSA progression and distant metastases within 20.5 and 39.1 months of their surgery, and 2 died of cardiovascular events within 28.7 and 47.3 months of the surgery without having PSA progression. There was 1 patient younger than 50 years who died of a cerebrovascular event 48.2 months after surgery. Two patients older than 70 years died of cardiovascular events 12.6 and 57.9 months after surgery.
4. Discussion This study tries to prove the feasibility of operating on older men diagnosed with prostate cancer in terms of biochemical progression-free survival. Patients in this study over the age of 70 years did not differ statistically significantly from the 2 other groups with respect to their preoperative parameters. All patients had evidence for localized disease and underwent radical prostatectomy after the same surgical decision making protocol. Thus, the patients older than 70 years were “selected” and represented, in general, very healthy individuals for their age. Patients with significant medical comorbidities such as cardiac, pulmonary, stroke, and morbid obesity issues were generally instructed not to undergo surgical intervention. The most important determinants of biochemical failure are pretreatment PSA, Gleason score, the presence of extracapsular extension, and positive surgical margins on pathology [10 –12]. There was no statistical difference in Gleason score, organ-confined status, margin status, lymphovascular invasion, extracapsular extension, and lymph node status. Because the same parameters were used to assess the possibility of organconfined disease among for the 3 different age groups, no difference was expected in the surgical outcome. Although biochemical progression rates where slightly higher in patients older than 70 years, this did not reach statistical significance. This result could possibly be attributed to the relatively small sample size of patients older than 70 and younger than 50 years, as opposed to the age group 50 –70 years, however, a 2-tailed statistical analysis was used that considered the small sample size. Another possibility was that patients older than 70 years did have a higher percentage of T2 (vs. T1) tumors, higher percentage Gleason grade 7–10, and higher mean PSA. Although these tumor factors were not statistically significant, this could have slightly skewed the outcomes toward biochemical progression. Third, “host” factors such as altered immune status of men older than 70 years may be a biologic reason for a slightly higher PSA progression rate. Finally, the follow-up period might not be long enough, and, with time, statistically significant differences might be seen. In that regard, only longer follow-up will answer that question. Radical surgery appears to offer an effective treatment option for older patients and should be considered in a
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certain subset of patients. However, increasing age is associated with decreased frequency of treatment with curative intent being in the form of RRP or radiation therapy, even when tumor characteristics (Gleason score and PSA), comorbidity, and life expectancy are all adjusted for [13,14]. The results of the study performed by Alibhai et al. [15] suggest that age may be improperly weighed when treating men with localized prostate carcinoma. Younger men with a less than 10-year life expectancy because of a serious comorbidity were offered curative treatment, while men older than 70 years with more than 10 years of life expectancy were not. For patients with a high-grade tumor, Gleason 8 –10, significant benefits are noted in both survival as well as quality adjusted survival with potentially curative therapy in men up to the age of 80 years. The survival benefit decreased with an increase in coexisting morbidity, such that 75-year-old men with moderate comorbidity and 80-year-old men with even mild comorbidity had a similar outcome to watchful waiting [16]. This study argued for wider consideration of potentially curative therapy for older men with high-grade disease. Schwartz et al. [17] showed that in 276 patients, with approximately half of them over the age of 70 years and all with no or mild comorbidities, that age, comorbidity, and Gleason score were independent predictors of suboptimal treatment. The group that most frequently was suboptimally treated included men in their 70s with moderately or poorly differentiated tumors and no-to-mild comorbidity. Most subjects in this group were offered watchful waiting with resultant losses in health outcome and life expectancy relative to those achievable with optimal treatment. In addition, patients with prostate cancer die of their disease versus other causes if the tumor burden is significant enough. Albertsen et al. [18] showed that patients with prostate cancer who underwent watchful waiting had a higher chance of mortality from the disease if high-grade tumors were present. The mortality from prostate cancer in men aged 70 –74 years increased from 7% for Gleason score 2– 4, to 11% for Gleason 5, 32% for Gleason 6, 40% for Gleason 7, and 60% for Gleason 8 –10. This result implies that certain types of prostate cancers in patients older than 70 years should have some form of curative treatment or risk dying of the disease. However, an age bias is present and is attributed to the fact that clinicians are less likely to offer aggressive treatment to older men because of the increased risk of short-term as well as long-term treatmentrelated adverse side effects [19,20], and, of course, shorter life expectancy in general (i.e., some men die with their prostate cancer, not of it). Finally, Bill-Axelson et al. [21] followed 695 men with early prostate cancer with a mean age of 64.7 years and randomly assigned them into either watchful waiting (348) or RRP. Over an 8.2-year median follow-up, they showed that a statistically significantly higher percentage of patients died of prostate cancer in the watchful waiting (14.4%) versus RRP (8.6%) group, with increased risk seen after 10
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years. This benefit lay mostly in reduction of the risk of metastasis and local tumor progression [21]. Although our patient population did not have the high-risk disease that some of the aforementioned studies’ patients had, the suggestion is that surgery should be feasible in older patients with localized prostate cancer, assuming prudent clinicians appropriately select them. A major limitation of this study is the lack of data in the database on incontinence and impotence rates after surgery within the 3 different groups. One issue with operating on patients older than 70 years is the theoretical increased risk of morbidity. In truth, these issues of specific treatmentrelated morbidity in men older than 70 years remain very poorly studied or not studied at all in this cohort. Indeed, specific studies examining patients older than 70 years and evaluating cancer outcomes in surgical series are extremely limited, and only 1 other article could be found addressing this issue in any fashion [22]. In the series by Freedland et al. [22], of the SEARCH Database Study, 1753 men treated with radical prostatectomy between 1988 and 2002, from 5 institutions were examined. Patients older than 70 years had significantly higher PSA failure rates than men 51–70 years or men younger than 50 years. A number of articles have addressed the question of men younger than 50 years and generally found better cancer-specific outcomes [23,24]. Older patients are commonly given other treatment options such as brachytherapy and external beam radiation because of biases and a lack of these data. It is unclear at this time if new advances with laparoscopic and robotic- assisted radical prostatectomies will improve these side effects. Tewari et al. [25] published results from a nonrandomized prospective trial comparing 100 open RRP versus 200 robotic-assisted prostatectomies at their institution. They showed a quicker return of continence (44 vs. 160 days) and erections (180 vs. 440 days) in the robot versus open surgery group. The reduced morbidity of this surgery could make operating on patients older than 70 years more of a rule than an exception. Future studies should try to address both the questions and limitations that occur from this study to assess truly the practicality of performing RRP on patients older than 70 years.
5. Conclusions Our study failed to show a statistically significant difference in the biochemical recurrence among patients older than 70 years when compared to 2 younger age groups. Whether there is truly a significant difference or not requires a prospective study with a larger number of patients older than 70 years. This issue is problematic and limited by the fact that these patients are often not offered curative surgical treatment. In the meantime, our results serve as a primary report for the feasibility of RRP in patients older than 70 years with no or mild comorbidity.
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Original article
Prostate cancer disease-free survival after radical retropubic prostatectomy in patients older than 70 years compared to younger cohorts夡 Bahaa S. Malaeb, M.D.a, Hani H. Rashid, M.D.a, Yair Lotan, M.D.b, Seyyed M. Khoddami, M.D.b, Shahrokh F. Shariat, M.D.b, Arthur I. Sagalowsky, M.D.b, John D. McConnell, M.D.b, Claus G. Roehrborn, M.D.b, Kenneth S. Koeneman, M.D.a,* a
b
Department of Urology, University of Minnesota, Minneapolis, MN 55455, USA Department of Urology, University of Texas Southwestern Medical Center, Dallas, TX 75390, USA Received 30 May 2006; received in revised form 1 August 2006; accepted 2 August 2006
Abstract Objectives: To evaluate the feasibility of radical retropubic prostatectomy (RRP) as an option for treating men older than 70 years with organ confined prostate cancer and to compare biochemical progression-free survival with younger cohorts. Materials and Methods: A total of 689 consecutive patients who were treated with RRP from 1994 to 2002 for clinically localized prostate cancer were categorized into 3 different age groups: younger than 50 years (n ⫽ 49), 50 –70 years (n ⫽ 601), and older than 70 years (n ⫽ 39). Patients older than 70 years were healthy individuals for their age. Preoperative and postoperative cancer-specific characteristics were compared among these 3 groups. Results: There was no statistical significant difference among the 3 age strata in terms of clinical parameters (prostate-specific antigen, Gleason score, clinical stage, percent and number of positive biopsy cores) and pathologic findings (surgical margin, lymph node status, extracapsular extension, lymphovascular invasion, and pathologic Gleason score). The rate of seminal vesicle invasion and prostate volume increased with advancing age (P ⫽ 0.034 and P ⬍ 0.001). In multivariate logistic regression analysis, age was not associated with seminal vesicle invasion. The 5-year prostate-specific antigen progression-free estimates for patients younger than 50, 50 –70, and older than 70 years were 82% (95% confidence interval [CI] 69% to 96%), 82% (95% CI 78% to 86%), and 65% (95% CI 43% to 86%), respectively (P ⫽ 0.349). The overall and cause-specific mortalities were not different. Conclusions: RRP could be considered a standard treatment option in men older than 70 years with localized prostate cancer. Further studies are necessary to assess the survival benefit and health-related quality of life after radical prostatectomy versus watchful waiting in patients older than 70 years. © 2007 Elsevier Inc. All rights reserved. Keywords: Radical retropubic prostatectomy; Prostate cancer; Biochemical recurrence; Watchful waiting; Life expectancy
1. Introduction Decision making in patients with prostate cancer over the age of 70 years is becoming a major area of debate because patients are living longer than in the past. With current advances in medical treatment and health awareness, as well
夡 Dr. Koeneman was supported by the Dougherty Family Chair in Uro-Oncology which made this work possible. * Corresponding author. Tel.: ⫹1-612-626-0964; fax: ⫹1-612-6240958. E-mail address: [email protected] (K.S. Koeneman).
1078-1439/07/$ – see front matter © 2007 Elsevier Inc. All rights reserved. doi:10.1016/j.urolonc.2006.08.001
as the shift toward healthier lifestyles, the average life expectancy of men is on the increase. In the United States for example, the number of persons older than 65 years is expected to increase from approximately 35 million in 2000 to an estimated 71 million in 2030 [1]. This increase will be paralleled in other countries. Prostate cancer, being primarily a disease of older men, will reflect this trend through an increase in the number of patients diagnosed over the age of 65 years. It is not uncommon these days that urologists are faced with a 70 –75-year-old, healthy patient newly diagnosed with prostate cancer, with all pretreatment indices pointing toward organ-confined disease. Decision making in
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this group is still left to the discretions and algorithms of the treating physician, and questions arise whether this age group is being denied definitive treatment, leading to a compromise of its health status and life expectancies. The 10-year life expectancy requirement governs the decision making for physicians faced with strong evidence of organ-confined disease in an elderly patient. Although surgeons treat their patients with prostate cancer in a case by case basis, this rule is widely accepted secondary to the belief that prostate cancer develops and progresses slowly compared to other tumors, thus raising the need for a rather long life expectancy to be able to show the survival benefit of intervention with curative intent [2]. Johansson et al. [3] recently published their results in JAMA, showing it took more than 15 years for their patients with localized prostate cancer who underwent watchful waiting before they had statistically significant worsening progression-free survival, metastasis-free survival, and prostate cancer specific survival. However, the fact is that the origin of the “10-year rule” is poorly documented in literature and does not consider tumor-specific characteristics (grade, stage, prostatespecific antigen [PSA] level). In addition, for those patients who are offered curative treatment, modalities such as external beam radiation, brachytherapy, and cryotherapy are discussed rather than open radical surgery because of the perceived morbidities of surgery [4,5]. It is possible that older patients would prefer the risk and side effect profile of surgical treatment versus other treatment modalities morbidity but are never given the option, nor are even the risks and benefits discussed fairly and intelligently with them. Therefore, the question is why not offer surgical treatment to patients older than 70 years with localized prostate cancer? The fact is that, to our knowledge, no contemporary literature specifically and solely asks this question, and compares the outcome of patients with localized prostate cancer in different age groups. In an effort to add to the existing limited data on treatment of localized prostate cancer in patients older than 70 years, as well as assess the feasibility and outcome of radical retropubic prostatectomy (RRP) in this age group, we analyzed data from a cohort of 689 consecutive patients with clinically localized prostate cancer [6 – 8]. Patients older than 70 years were “selected” by their surgeons as “fit” for radical prostatectomy and represented, in general, healthy individuals for their age.
2. Materials and methods A total of 689 consecutive patients underwent RRP with bilateral lymph node dissection for clinically localized prostate cancer at 1 of 2 teaching hospitals of the University of Texas Southwestern Medical Center during the period of July 1994 to December 2002. Studies were undertaken with the approval and oversight of the Institutional Review Board for the Protection of Human Subjects. The operating
surgeon assigned the clinical stage according to the 1992 American Joint Committee on Cancer/tumor-nodes-metastasis system. The serum total PSA was measured by Tandem-E assay (Hybriteck Inc., San Diego, CA). The percentage of positive biopsy cores was defined as: (number of positive biopsy cores/total number of biopsy cores) ⫻ 100. 2.1. Pathologic examination Staff pathologists from our institution examined all prostatectomy specimens pathologically, as described elsewhere in accordance with the guidelines of the College of American Pathologists, and a detailed description is found in earlier reports [6 –9]. Multiple, oriented quadrant sections from the entire prostate were processed (approximately 25–30 blocks). The 1997 American Joint Committee on Cancer/tumor-nodesmetastasis system was used for pathologic staging. Grading of the primary tumor was performed according to the Gleason system. Clinical parameters measured were age, preoperative PSA, Gleason score, number and percentage of positive biopsy cores, number of lymph nodes dissected, number of positive lymph nodes, extracapsular extension, lymphovascular invasion, seminal vesicle invasion, surgical margin status, and whether the tumor was organ confined or not. To ensure validity of the outcomes, 2 clinicians read pathology reports, while blinded to patient clinical parameters and the finding of the other reviewer. Inter-reader reliability measured using the intra-class correlation coefficient was more than 0.95 for all pathologic parameters. 2.2. Postoperative follow-up Patients generally were scheduled to have a digital rectal examination and serum total PSA evaluation postoperatively every 3 months for the first year, at least semiannually from the second through the fifth year, and annually thereafter. Biochemical progression was defined as a sustained increase, on ⱖ2 occasions, of serum total PSA ⱖ0.2 ng/ml and was assigned to the date of the first value ⱖ0.2 ng/ml. Patients who received adjuvant radiation therapy before biochemical progression because of clinical or pathologic characteristics were considered to have disease progression from the date of the first value ⱖ0.2 ng/ml. For patients who had biochemical progression, post-progression serum T-PSA doubling time was calculated using the formula: total PSA doubling time ⫽ [ln (2) ⫻ Time]/[ln (final total PSA) ⫺ ln (initial total PSA)]. All patients had at least 3 total PSA measurements available after biochemical progression. 2.3. Statistical analysis The chi-square test was used to evaluate the association between categorical variables. Differences in continuous variables across categorical variables were assessed using the Kruskal-Wallis test. The Spearman rank correlation co-
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Table 1 Clinical and pathological variables compared among the 3 different age groups. No. pts (%)
a
Clinical stage (No. pts, %) T1 T2 Biopsy Gleason sum (No. pts, %)a 2–6 7 8–10 Extracapsular extension (No. pts, %)a Negative Positive Seminal vesicle involvement (No. pts, %)a Negative Positive Surgical margin status (No. pts, %)a Negative Positive Pathology Gleason sum (No. pts, %)a 2–6 7 8–10 Lympho-vascular invasion (No. pts, %)a Negative Positive Perineural invasion (No. pts, %)a Negative Positive Regional lymph node metastases (No. pts, %)a Negative Positive Number positive biopsy cores (median, range)b Percent positive biopsy cores (median, range)b Total prostate volume (median, range; cc)b Preoperative serum PSA (median, range; ng/mL)b Preoperative serum percent free PSA (median, range; ng/mL)b
689 477 (69.2%) 212 (30.8%) 681 451 (66.2%) 188 (27.6%) 42 (6.2%) 687 480 (69.9%) 207 (30.1%) 687 624 (90.8%) 63 (9.2%) 687 548 (79.8%) 139 (20.2%) 687 282 (41.0%) 334 (48.6%) 71 (10.3%) 628 594 (94.6%) 34 (5.4%) 628 249 (39.6%) 379 (60.4%) 686 674 (98.3%) 12 (1.7%) 2 (1–15) 25 (1–100) 45 (12–210) 6.0 (1–99.3) 21.6 (1.1–98.6)
Age strata ⬍50 years
50–69.9 years
ⱖ70 years
49 37 (75.5%) 12 (24.5%) 49 35 (71.4%) 12 (24.5%) 2 (4.1%) 49 36 (73.5%) 13 (26.5%) 49 46 (93.9%) 3 (6.1%) 49 42 (85.7%) 7 (14.3%) 49 20 (40.8%) 24 (49.0%) 5 (10.2%) 40 39 (97.5%) 1 (2.5%) 40 14 (35.0%) 26 (65.0%) 49 49 (100.0%) 0 (0.0%) 1 (1–12) 17 (5–83) 39 (16–119) 5.7 (1–36.9) 21.2 (5.6–87.4)
601 419 (69.7%) 182 (30.3%) 593 392 (66.1%) 165 (27.8%) 36 (6.1%) 599 418 (69.8%) 181 (30.2%) 599 547 (91.3%) 52 (8.7%) 599 474 (79.1%) 125 (20.9%) 599 246 (41.1%) 293 (48.9%) 60 (10.0%) 555 523 (94.2%) 32 (5.8%) 555 226 (40.7%) 329 (59.3%) 598 586 (98.0%) 12 (2.0%) 2 (1–15) 25 (1–100) 46 (12–210) 6.0 (1–99.3) 21.5 (1.7–98.6)
39 21 (53.8%) 18 (46.2%) 39 24 (61.5%) 11 (28.2%) 4 (10.3%) 39 26 (66.7%) 13 (33.3%) 39 31 (79.5%) 8 (20.5%) 39 32 (82.1%) 7 (17.9%) 39 16 (41.0%) 17 (43.6%) 6 (15.4%) 33 32 (97.0%) 1 (3.0%) 33 9 (27.3%) 24 (72.7%) 39 39 (100%) 0 (0.0%) 2 (1–6) 25 (6–83) 64 (27–116) 6.0 (2.1–32.0) 26.6 (6.2–97.1)
P value 0.07
0.749
0.781
0.034
0.509
0.872
0.559
0.254
0.407 0.407 0.225 0.421 ⬍0.001 0.673 0.279
Extracapsular extension, surgical margin status, pathology Gleason sum, and seminal vesicle involvement were not available in 2 patients. Biopsy Gleason sum was not available in 8 patients. Lymph node status was not available in 3 patients. Lympho- vascular invasion and perineural invasion were not available in 61 patients. a Chi-square test. b Kruskal Wallis test.
efficient was used to compare ordinal and continuous variables. Logistic regression was used for multivariate analysis of binary outcome variables. Clinical stage was evaluated as T1 versus T2. Biopsy and prostatectomy Gleason sum were evaluated as grades 4 – 6 versus grade 7 versus grades 8 –10. Statistical significance in this study was set as P ⱕ 0.05. All reported P values are 2 sided. All analyses were performed with SPSS (version 13.0; SPSS, Inc., Chicago, IL) for Windows (Microsoft, Corp., Redmond, WA).
3. Results The number of patients in the age groups of younger than 50, 50 –70, and older than 70 years were 49 (7.1%), 601
(87.2%), and 39 (5.7%), respectively. Median age in patients younger than 50 years was 47.8 (range 33.1– 49.9). Median age in patients between 50 and 69.9 years was 60.9 (range 50.2– 69.9). Median age in patients 70 years or older was 71.6 (range 70.0 –75.2). Clinical and pathologic characteristics of the 689 patients with prostatectomy and association with age strata are shown in Table 1. No significant difference was noted among the 3 groups with respect to biopsy Gleason score, preoperative PSA, percent-free PSA, number of positive biopsy cores, percent-positive biopsy, and number of lymph nodes taken during surgery. Mean PSA values were 7.54, 7.91, and 8.07 for the 3 age groups younger than 50, 50 –70, and older than 70 years, respectively (no significant difference, P ⫽ 0.405). Patients older than 70 years were more likely to have seminal vesicle invasion (P ⫽ 0.034) and higher total prostate volume (P ⬍
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100
PSA Progression-Free Probability
90
Below 50 years
80 50-69.9 years
70 60 50 40 30
Log rank tests
P value
Pooled over strata < 50 years vs 50-69.9 years < 50 years vs 70 years 50-69.9 years vs 70 years
0.3494 0.9499 0.3685 0.1548
20
Age
10
Below 50 years 50-69.9 years 70 years and older
70 years and older
3 yr. ± SE
5 yr. ± SE
82.3 ± 6.7 % 87.3 ± 1.5 % 82.9 ± 7.2 %
82.3 ± 6.7 % 82.3 ± 2.1 % 64.6 ± 10.9 %
0 0
20
40
60
80
100
120
Months after Surgery Fig. 1. Kaplan-Meier curves showing PSA progression-free survival in each of the 3 age groups.
0.001) than patients aged 50 – 69.9 years or those younger than 50 years. Age analyzed as continuous variable was correlated with total prostate volume (rho ⫽ 0.305, P ⬍ 0.001) and preoperative serum total PSA (rho ⫽ 0.187, P ⫽ 0.024), but not preoperative serum percent free PSA (rho ⫽ 0.040, P ⫽ 0.404). In preoperative multivariate logistic regression analysis, clinical stage (odds ratio [OR] 2.573, P ⫽ 0.002), biopsy Gleason sum (OR 2.790, P ⬍ 0.001), and preoperative serum total PSA (OR 1.055, P ⬍ 0.001), but not age stratified as younger than 50 versus 50 – 69.9 versus 70 years or older (P ⫽ 0.115), were significantly associated with an increased risk of seminal vesicle invasion. Overall, only 13.5% of patients (93 of 689) had biochemical disease progression with a median postoperative follow-up of 32.6 months (range 1.0 –113). Mean postoperative follow-up was 39 months. The overall PSA progression-free survival was 85.4% ⫾ 1.6% (standard error) at 3 years and 80.9% ⫾ 2.1% at 5 years. Using the log-rank test, we found that there was no statistically sig-
nificant risk of PSA progression across age strata (P ⫽ 0.3494; Fig. 1). There were 11 patients who did not undergo additional treatment after disease progression at last follow-up. A total of 27 patients underwent local salvage radiation therapy at our institution, and 59 underwent hormonal therapy as primary treatment of prostate cancer progression. PSA doubling time calculation could be performed for 78 patients who had PSA progression before the administration of salvage therapy. PSA doubling time between PSA failure and initiation of salvage therapy was not different across age strata (P ⫽ 0.214). A staging evaluation, including bone scan or ProstaScint scan (CYTOGEN Corp., Princeton, NJ), was performed at our institution for 76 patients who had biochemical progression after radical prostatectomy. As evidenced by imaging studies, bone metastases developed in 14 patients. All 14 patients were between 50 and 69.9 years of age. Development of metastasis was not associated with age strata (P ⫽ 0.351). Overall survival data were available for all 689 patients. Of the 689 patients, 7 (1%) were dead from any cause at
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analysis. There were 4 patients between 50 and 69.9 years of age who died. In this age group, 2 patients died of prostate cancer after having PSA progression and distant metastases within 20.5 and 39.1 months of their surgery, and 2 died of cardiovascular events within 28.7 and 47.3 months of the surgery without having PSA progression. There was 1 patient younger than 50 years who died of a cerebrovascular event 48.2 months after surgery. Two patients older than 70 years died of cardiovascular events 12.6 and 57.9 months after surgery.
4. Discussion This study tries to prove the feasibility of operating on older men diagnosed with prostate cancer in terms of biochemical progression-free survival. Patients in this study over the age of 70 years did not differ statistically significantly from the 2 other groups with respect to their preoperative parameters. All patients had evidence for localized disease and underwent radical prostatectomy after the same surgical decision making protocol. Thus, the patients older than 70 years were “selected” and represented, in general, very healthy individuals for their age. Patients with significant medical comorbidities such as cardiac, pulmonary, stroke, and morbid obesity issues were generally instructed not to undergo surgical intervention. The most important determinants of biochemical failure are pretreatment PSA, Gleason score, the presence of extracapsular extension, and positive surgical margins on pathology [10 –12]. There was no statistical difference in Gleason score, organ-confined status, margin status, lymphovascular invasion, extracapsular extension, and lymph node status. Because the same parameters were used to assess the possibility of organconfined disease among for the 3 different age groups, no difference was expected in the surgical outcome. Although biochemical progression rates where slightly higher in patients older than 70 years, this did not reach statistical significance. This result could possibly be attributed to the relatively small sample size of patients older than 70 and younger than 50 years, as opposed to the age group 50 –70 years, however, a 2-tailed statistical analysis was used that considered the small sample size. Another possibility was that patients older than 70 years did have a higher percentage of T2 (vs. T1) tumors, higher percentage Gleason grade 7–10, and higher mean PSA. Although these tumor factors were not statistically significant, this could have slightly skewed the outcomes toward biochemical progression. Third, “host” factors such as altered immune status of men older than 70 years may be a biologic reason for a slightly higher PSA progression rate. Finally, the follow-up period might not be long enough, and, with time, statistically significant differences might be seen. In that regard, only longer follow-up will answer that question. Radical surgery appears to offer an effective treatment option for older patients and should be considered in a
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certain subset of patients. However, increasing age is associated with decreased frequency of treatment with curative intent being in the form of RRP or radiation therapy, even when tumor characteristics (Gleason score and PSA), comorbidity, and life expectancy are all adjusted for [13,14]. The results of the study performed by Alibhai et al. [15] suggest that age may be improperly weighed when treating men with localized prostate carcinoma. Younger men with a less than 10-year life expectancy because of a serious comorbidity were offered curative treatment, while men older than 70 years with more than 10 years of life expectancy were not. For patients with a high-grade tumor, Gleason 8 –10, significant benefits are noted in both survival as well as quality adjusted survival with potentially curative therapy in men up to the age of 80 years. The survival benefit decreased with an increase in coexisting morbidity, such that 75-year-old men with moderate comorbidity and 80-year-old men with even mild comorbidity had a similar outcome to watchful waiting [16]. This study argued for wider consideration of potentially curative therapy for older men with high-grade disease. Schwartz et al. [17] showed that in 276 patients, with approximately half of them over the age of 70 years and all with no or mild comorbidities, that age, comorbidity, and Gleason score were independent predictors of suboptimal treatment. The group that most frequently was suboptimally treated included men in their 70s with moderately or poorly differentiated tumors and no-to-mild comorbidity. Most subjects in this group were offered watchful waiting with resultant losses in health outcome and life expectancy relative to those achievable with optimal treatment. In addition, patients with prostate cancer die of their disease versus other causes if the tumor burden is significant enough. Albertsen et al. [18] showed that patients with prostate cancer who underwent watchful waiting had a higher chance of mortality from the disease if high-grade tumors were present. The mortality from prostate cancer in men aged 70 –74 years increased from 7% for Gleason score 2– 4, to 11% for Gleason 5, 32% for Gleason 6, 40% for Gleason 7, and 60% for Gleason 8 –10. This result implies that certain types of prostate cancers in patients older than 70 years should have some form of curative treatment or risk dying of the disease. However, an age bias is present and is attributed to the fact that clinicians are less likely to offer aggressive treatment to older men because of the increased risk of short-term as well as long-term treatmentrelated adverse side effects [19,20], and, of course, shorter life expectancy in general (i.e., some men die with their prostate cancer, not of it). Finally, Bill-Axelson et al. [21] followed 695 men with early prostate cancer with a mean age of 64.7 years and randomly assigned them into either watchful waiting (348) or RRP. Over an 8.2-year median follow-up, they showed that a statistically significantly higher percentage of patients died of prostate cancer in the watchful waiting (14.4%) versus RRP (8.6%) group, with increased risk seen after 10
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years. This benefit lay mostly in reduction of the risk of metastasis and local tumor progression [21]. Although our patient population did not have the high-risk disease that some of the aforementioned studies’ patients had, the suggestion is that surgery should be feasible in older patients with localized prostate cancer, assuming prudent clinicians appropriately select them. A major limitation of this study is the lack of data in the database on incontinence and impotence rates after surgery within the 3 different groups. One issue with operating on patients older than 70 years is the theoretical increased risk of morbidity. In truth, these issues of specific treatmentrelated morbidity in men older than 70 years remain very poorly studied or not studied at all in this cohort. Indeed, specific studies examining patients older than 70 years and evaluating cancer outcomes in surgical series are extremely limited, and only 1 other article could be found addressing this issue in any fashion [22]. In the series by Freedland et al. [22], of the SEARCH Database Study, 1753 men treated with radical prostatectomy between 1988 and 2002, from 5 institutions were examined. Patients older than 70 years had significantly higher PSA failure rates than men 51–70 years or men younger than 50 years. A number of articles have addressed the question of men younger than 50 years and generally found better cancer-specific outcomes [23,24]. Older patients are commonly given other treatment options such as brachytherapy and external beam radiation because of biases and a lack of these data. It is unclear at this time if new advances with laparoscopic and robotic- assisted radical prostatectomies will improve these side effects. Tewari et al. [25] published results from a nonrandomized prospective trial comparing 100 open RRP versus 200 robotic-assisted prostatectomies at their institution. They showed a quicker return of continence (44 vs. 160 days) and erections (180 vs. 440 days) in the robot versus open surgery group. The reduced morbidity of this surgery could make operating on patients older than 70 years more of a rule than an exception. Future studies should try to address both the questions and limitations that occur from this study to assess truly the practicality of performing RRP on patients older than 70 years.
5. Conclusions Our study failed to show a statistically significant difference in the biochemical recurrence among patients older than 70 years when compared to 2 younger age groups. Whether there is truly a significant difference or not requires a prospective study with a larger number of patients older than 70 years. This issue is problematic and limited by the fact that these patients are often not offered curative surgical treatment. In the meantime, our results serve as a primary report for the feasibility of RRP in patients older than 70 years with no or mild comorbidity.
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