Clinical characteristics and pathologic findings in patients eligible for active surveillance who underwent radical prostatectomy

Urologic Oncology: Seminars and Original Investigations 30 (2012) 402– 407

Original article

Clinical characteristics and pathologic findings in patients eligible for active surveillance who underwent radical prostatectomy Sarah J. Drouin, M.D.,a,c Eva Comperat, M.D., Ph.D.,b,c Olivier Cussenot, M.D., Ph.D.,c Marc-Olivier Bitker, M.D.,a Alain Haertig, M.D.,a Morgan Rouprêt, M.D., Ph.D.a,c,* a

Department of Urology of GHU EST, Assistance-Publique Hôpitaux de Paris, Paris, France Department of Pathology of GHU EST, Assistance-Publique Hôpitaux de Paris, Paris, France c Faculté de Médecine Pierre et Marie Curie, University Paris VI, Paris, France and CeRePP, Centre d’Etudes et de Recherche sur les Pathologies Prostatiques, Paris, France

b

Received 12 March 2010; received in revised form 9 April 2010; accepted 12 April 2010

Abstract Objective: To analyze clinical characteristics and pathologic findings in patients eligible for active surveillance (AS) who underwent radical prostatectomy (RP). Materials and methods: We collected data from 495 patients who underwent RP during an 8-year period. We have then selected those who would have been eligible for AS according to 2 different sets of published criteria. Group 1 used broader criteria: clinical stage ⱕ T2b, Gleason score of seven or less and PSA ⱕ 15 ng/ml. Group 2 used more restrictive criteria: age ⬍ 75 years, PSA ⬍ 10 ng/ml, clinical stage T1c or T2a, Gleason score of 6 or less, at least 10 biopsies available and a tumor length of less than 3 mm in 2 biopsy cores. Results: Overall, 207 patients (41.8%) were included in group 1 and 43 (8.7%) in group 2. The median follow-up was 31 (3–108) and 32 (3– 84) months in groups 1 and 2, respectively. We recorded 132 cases (63.8%) of pT2c in group 1 and 31 in group 2 (72.1%). Extracapsular extension was noted in 37 (17.9%) and 2 (4.7%) specimens from groups 1 and 2, respectively. In groups 1 and 2, a biochemical failure occurred in 47 patients (22.7%) and 6 (14%), respectively. The Gleason score at biopsy was underestimated in 54 (26%) and 9 (21%) of patients in groups 1 and 2, respectively. Conclusion: Overall, 21% to 26% of patients eligible for AS had upgraded Gleason scores at prostatectomy and actually had a more significant disease with a potentially aggressive behavior. Therefore, based on criteria, certain tumors currently selected for AS may be significant and may require radical treatment. © 2012 Elsevier Inc. All rights reserved. Keywords: Prostate cancer; Active surveillance; Radical prostatectomy; Prostate-specific antigen; Biochemical recurrence; Prognosis

1. Introduction Prostate cancer incidence has been continuously increasing during the past 20 years [1]. The introduction of PSA screening and the ease of sampling prostate tissue with transrectal ultrasound-directed prostate biopsy have contributed not only to this phenomenon but also to an increase of small, localized prostate cancers considered as being “low risk” [2]. Some of these cancers would have remained undetected throughout life without systematic screening [3]. At present, the gold standard management of newly diagnosed prostate cancer remains active treatment. However, * Corresponding author. Tel.: ⫹0033660544166; fax: ⫹0033142177112. E-mail address: [email protected] (M. Rouprêt). 1078-1439/$ – see front matter © 2012 Elsevier Inc. All rights reserved. http://dx.doi.org/10.1016/j.urolonc.2010.04.004

systematic curative treatment in these small tumors has been criticized and considered as over-treatment by several authors [4]. Indeed, some retrospective studies suggest that low-grade prostate cancer without radical treatment might have a low risk of cancer specific mortality or even clinical progression [5,6]. Moreover, a radical treatment can be a source of decreased quality of life due to erectile dysfunction or urinary incontinence and can be much more aggressive than the behavior of the disease itself in certain cases [7]. Consequently, the concept of active surveillance (AS) has progressively emerged as a real alternative treatment for these “favorable” tumors. Nevertheless, one study supports a clinical advantage for surgery over “watchful waiting” [8]. However, watchful waiting has to be distinguished from AS. Watchful waiting does not involve close monitoring of

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patients, and in the case of progression, no curative treatment is offered to patients. The main objective of AS is to withhold radical treatment at the cost of a stringent follow-up [9]. Predictive tools such as nomograms are currently available to predict indolent outcome and are used to select patients who are likely to be candidates for AS [10,11]. On the other hand, there is a risk that certain patients with significant tumors will remain misclassified under AS criteria [12,13]. The most common criteria used to define cancers amenable to AS are the Gleason, PSA, and clinical stage criteria. The other parameters include pathologic characteristics of biopsy: total positive cores or tumor length of biopsy [14,15]. Following the development of the AS concept, inclusion criteria became more and more stringent to improve patient selection. The variability of the criteria has demonstrated the lack of cut-off definitions to establish low-risk disease. The aim of this study was to assess the efficiency of 2 different selection criteria by a retrospective analysis of prostatectomy specimens of patients who would have been eligible for AS.

2. Materials and methods 2.1. Inclusion criteria We reviewed our surgical database for all consecutive patients treated by radical prostatectomy (RP) for localized prostate cancer between 2000 and 2008 at our institution. Overall, 495 men underwent RP during this period. According to recent literature, different inclusion AS criteria have been proposed [4,16 –19]. In the current study, we chose to use 2 different published AS criteria, broader criteria to include the largest population in group 1 and stringent criteria to select a smaller population in group 2. For group 1, we used the criteria defined by Choo et al. [16]: clinical stage ⱕ T2b, a Gleason score of 7 or less, and PSA ⱕ 15 ng/ml. For group 2, the criteria came from a French national protocol (SurACaP) currently open in France [20]. These criteria were based on biopsy results and were defined as follows: age under 75 years, PSA ⬍ 10 ng/ml, clinical stage ⱕ T2a, a Gleason score of 6 or less, 10 or more biopsies available, 1 or 2 positive cores, and less than 3 mm of cancer in each core. Evidently, patients included in the second group were also included in the first one. The clinical stage was confirmed by digital rectal examination (DRE) and assigned according to the 2002 TNM staging system. All patients underwent prostate biopsies according to a protocol previously described by the French national committee of urologic oncology [21]. All biopsies were performed at our institution and evaluated by 1 senior uropathologist. Prostate biopsies were not routinely repeated if the patients were referred. 2.2. Operative technique The surgical procedures were either open retropubic prostatectomy performed by 2 surgeons or video-assisted

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prostatectomy (i.e., laparoscopic and robot-assisted) performed by an experienced operator. 2.3. Pathologic findings RP specimens were fixed intact in 10% neutral buffered formalin and then sectioned transversely at regular intervals. Tumor differentiation was quantified by the surgical Gleason score, high (2 to 6), moderate (7), and poor (8 to 10), according to the WHO consensus conference recommendations. Surgical margins were positive when tumor foci were found by microscopy in the absence of macroscopically visible abnormalities. The positive margin length was given by the greatest tumor length in millimeters reaching the ink in the permanent sections. The prostate specimen was fixed in formalin and examined by permanent section analysis. We defined upgrading as any increase in Gleason score between the biopsy and prostatectomy specimen. All prostatectomy specimens were evaluated by 2 senior uropathologists. 2.4. Follow-up All patients were seen at 3 and 6 months after surgery and at least once a year thereafter. In the current study, biochemical recurrence of the disease was defined as a single measurement of a PSA level ⬎ 0.2 ng/ml at least 3 months after RP.

3. Results 3.1. Population Overall, we identified 207 (41.8%) and 43 (8.7%) patients who underwent RP and would have been eligible for AS in groups 1 and 2, respectively. The main characteristics are fully detailed in Table 1. The mean patient age at diagnosis was comparable in both groups (62.1 and 61.9 years). The mean PSA at diagnosis was higher in group 1 than in group 2 (10.3 vs. 6.45 ng/ml), and the PSA density was also higher in group 1 (0.2 vs. 0.13 ng/ml/cm3). We recorded a majority of patients at the T1c clinical stage in both groups: 131 (63.3%) and 38 (88.4%) patients in groups 1 and 2, respectively. 3.2. Biopsy findings The pathologic results are given in Table 2. A majority of patients in both groups had of Gleason scores of 6 (3⫹3), namely 144 (69.6%) patients in group 1 and 41 (95.3%) in group 2. In group 1, we also recorded 52 (25%) men with a Gleason score of 7. A mean of 10.2 (range 4 to 19) and 11.4 biopsy cores (range 10 to 19) were obtained in groups 1 and 2, respectively. Of the 43 patients from group 2, 27 (63%) had 1 positive core, and 16 (37%) 2 positive cores. The

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Table 1 Patient characteristics at baseline

Number of patients Age (year) Mean Range BMI Mean Range PSA (ng/ml) Mean Range Follow-up after prostatectomy (month) Mean Range Clinical stage (%) T1c T2a T2b

Table 3 Pathological findings and PSA outcomes Group 1

Group 2

207

43

62.1 49–82

61.9 52–73

25.2 23–30

25 23–29

10.3 4–15 31 3–108 131 (63.3) 37 (17.9) 39 (18.8)

6.45 3.1–9.9 32 3–84 38 (88.4) 5 (11.6) —

mean tumoral length in the cores was much higher in group 1 than in group 2 (9.8 vs. 1.6 mm).

Prostate volume (g) Mean Range Gleason score (%) 6 7 (3⫹4) 7 (4⫹3) 8 9 pTNM (%) pT0 pT2a pT2b pT2c pT3a pT3b-pT4 Surgical margins status (%) Positive Negative Biochemical recurrence (%) Yes No

Group 1 (n ⫽ 207)

Group 2 (n ⫽ 43)

45.6 17–107

53 30–158

126 (60.9) 58 (28) 12 (5.8) 7 (3.4) 3 (1.4)

35 (81.4) 6 (14) 1 (2.3) — —

1 (0.5) 15 (7.2) 22 (10.6) 132 (63.8) 26 (12.6) 11 (5.3)

1 (2.3) 3 (7) 6 (13.9) 31 (72.1) 2 (4.7) 0

13.5 86.5

7 93

47 (22.7) 160 (77.3)

6 (14) 37 (86)

3.3. Pathologic findings The pathologic results are given in Table 3. Of the 16 patients who had 2 positive cores with stringent criteria, 7 (43.8%) had bilateral localization. Of the 207 patients qualifying for AS in group 1, the Gleason score was upgraded in 54 (26%) cases. Thirty-six (66.7%) were upgraded from Gleason 5 or 6 to Gleason 7. We found 7 (3.4%) and 3 patients (1.4%) with Gleason 8 and 9, respectively. Overall, 12 (5.8%) patients were downgraded, and 83.3% of them were downgraded from Gleason 7 to 6 In the second group, 9 (21%) patients were upgraded to Gleason 7. We did not find any Gleason scores of 8 or 9. No patients were downgraded except 1 who was pT0. We found 132 (63.8%) and Table 2 Pathological findings in prostate biopsies

Number of biopsies Mean Range Number of positive cores (%) Mean 1 2 ⬎2 Tumor length in biopsy (mm) Mean Range Gleason score (%) 5 6 7

Group 1 (n ⫽ 207)

Group 2 (n ⫽ 43)

10.2 4–19

11.5 10–19

2.4 112 (54) 60 (29) 35 (17)

1.4 27 (63) 16 (37) —

9.8 0.7–55

1.6 0.7–2.8

11 (5.3) 144 (69.6) 52 (25.1)

2 (4.7) 41 (95.3) —

31 (72.1%) pT2c, 26 (12.6%) and 2 (4.7%) pT3a, and 11 (5.3%) and none pT3b scores in groups 1 and 2, respectively. Of the cases, 37 (17.9%) and 2 (4.7%) had extracapsular extension in groups 1 and 2, respectively. We found 11 (5.3%) seminal vesicle invasions in group 1 and none in group 2. 3.4. Oncologic outcomes Overall, there were positive margins in 28 (13.5%) and 3 patients (7%) in groups 1 and 2, respectively. The mean follow-up was comparable in both groups (31 vs. 32 months). Biochemical failure occurred in 47 patients (22.7%) in group 1, and 6 patients (14%) in group 2. All of the patients who experienced biological recurrence (PSA ⬎ 0.2 ng/ml) received adjuvant treatment (radiotherapy or hormono-radiotherapy). In group 1, 7 (3.4%) patients died, 3 of them from prostate cancer. In group 2, 2 patients (4.7%) died from other causes than prostate cancer and none from prostate cancer. The pathologic findings and biological outcomes are summarized in Table 3.

4. Discussion Several active monitoring protocols have been proposed to avoid the risk of overtreatment of indolent prostate cancer. Only prospective randomized studies would produce acceptable results to acknowledge the role of AS in the management of selected cases of localized prostate cancer. Large randomized trials such as the ProtecT study are cur-

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rently ongoing [17], and these results are urgently needed and highly anticipated. However, inclusion criteria of AS protocols have evolved greatly over the time, and there is a large discrepancy between those proposed initially (i.e., no longer applicable today) and those currently updated and applied. For instance, the criteria defined by the ProtecT study were a PSA ⱕ 20 ng/ml and clinical stage T1 or T2N0M0. In contrast, the Epstein criteria were a PSA density ⬍ 0.15 ng/ml/cm3, a Gleason score of 6 or less, fewer than 3 positive biopsy cores, and 50% or less involvement of any core with cancer [10,17]. Thus, certain studies recorded 91.6% of disease cases as organ-confined depending on the selected criteria [10,22]. The rate of low-risk prostate cancer is continually increasing, and accurately selecting the patients with an indolent disease is the real challenge and still a matter of debate. In this study, we chose to analyze pathologic findings in prostate specimens of patients who would have been eligible for 2 different AS criteria. The rate of patients included was 41.8% in the first group and 8.7% in the second from among the 495 reviewed patients. These results have different explanations. First, the small number of patients in our group 2 might be explained by the criteria used for RP. Indeed, AS criteria included men ⬍ 75 years. There were very few patients ⬎ 70 years in the surgical database we reviewed. Then, the criteria of the second group were much more stringent than those for the first group, including the number and length of positive cores and lower Gleason scores, clinical stages, and PSA cut-offs. Obviously, the more stringent criteria resulted in fewer patients eligible for AS. However, more stringent criteria seemed to decrease the risk of misclassification. The rate of undergraded patients decreased from 26% to 21% with stringent criteria. Accordingly, the risk of positive margins and biochemical failure decreased in group 2. Our data are in line with other studies that compared different AS criteria in patients who underwent RP (Table 3). In other studies, the rate of upgraded tumor at prostatectomy ranged from 9.7% to 55.4% and decreased with the stringency of criteria [19,23–25]. The less stringent the biopsy criteria were, the higher the patient inclusion and misclassification rates were [19,23,25]. Thus, the accuracy of the Gleason score is still very questionable. On one hand there is an intra- and interobservers discrepancy in the assessment of the score, on the other hand there is always an important gap between biopsy and pathological scores [19,23,25]. Perhaps, it would be interesting to propose that at least 2 uropathologists, experts in the field, assess systematically the Gleason score to reduce this discrepancy. Using inclusion criteria based only on PSA, DRE findings, and Gleason scores was insufficient to define cancer with a low risk of progression. The number of positive cores and the tumor length limited to 3 mm are probably the most stringent criteria [24,26]. However, these criteria appear to be the best predictors of disease recurrence after RP. Therefore, we strongly advocate inclusion of limited positive

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cores and tumor length as criteria to refine patient selection [27]. However, inclusion is the price to pay to avoid a worse disease progression than initially predicted. To minimize this risk, a restaging biopsy might be efficient. Indeed, it has been shown that 27% of patients being considered for AS would not be selected after further rebiopsy due to upstaging or upgrading [27]. For patients eligible for AS, some teams advocate repeated wide area sampling of the prostate using ultrasound needle-directed biopsies to decrease the odds that the initial biopsy underestimated the extent of disease [28]. In a current French protocol, a scheme of at least a 10 core biopsies is requested [19]. Indeed, an extended template of ⬎ 10 cores might improve the concordance between prostate biopsy and final pathologic results at prostatectomy [29]. However, it might not be enough. A recent study has demonstrated that in cases of more than 20 initial biopsy cores, there were fewer upgraded cores on re-biopsy [30]. It appears obviously that re-biopsy is the best way to limit the misclassification of patients currently. The addition of further techniques might improve the predictive accuracy of the existing criteria. For example, it has been shown that the use of MRI could be helpful to estimate prostate volume as a marker of biochemical prostate modifications [14]. Because prostate volume has been shown to correlate with the risk of deferred treatment, it might be taken into account in new inclusion criteria. We acknowledge that there are several limitations to extrapolating conclusions of AS criteria efficiency from trends observed in patients who underwent immediate surgery. However, our goal was to provide contemporary results from a large number of prostate cancer patients as a reflection of clinical practice. We have demonstrated that some of these patients did not actually have an insignificant disease and underwent biochemical failure even with immediate surgery and stringent criteria. We also showed that the use of more stringent criteria decreased the rate of misclassified tumors. Other studies have addressed this problem with larger populations but it was either a multicenter recruitment or a very long period of inclusion (⬎10 years), which leads to bias of interpretation in Gleason score and in discrepancy of criteria over time (Table 4). Despite initially encouraging data, current AS results are still limited due to the lack of long-term follow-up [31]. Patients should present indolent disease and follow-up for at least 10 years to estimate the results of AS. Answers from largescale prospective ongoing studies are awaited to define the best criteria for patient selection for AS. Under ideal circumstances, radical treatment will be reserved for men with a high risk of cancer progression. If an indolent disease could be proved, AS could be instituted safely. But even with multiple and stringent criteria, it is likely that some tumors will still be misclassified with clinical and pathologic criteria. The need for novel biomarkers to predict the biological behavior of individual tumors remains. Lastly, many patients might have a recurrence after radical surgery, and still die from a non-prostate cancer-related

406

Bastian et al. [22] Conti et al. [23]

Study period (year)

Total population of RP

3 11

237 1097

TNM

Gleason

PSA (ng/ml)

PSA density

Number of biopsies required

Positive biopsy

Tumor length

Gleason upgraded at RP (%)

237 (100) 331 (30) 236 (22) 904 (82) 42 (4) 950 (87) 61 (6.9) 85 (9.7)

T1c T1-T2 T1 T1-T2 T1 T1-T2 T1c T1-T2

— ⱕ7 ⱕ6 ⱕ7 ⱕ6 ⱕ7 ⱕ6 ⱕ6

— ⱕ15 ⱕ10 ⱕ20 — — — ⱕ10

⬍0.15 — — — ⱕ0.15 — ⱕ0.15 ⬍0.2

— ⱖ6

ⱕ2 ⱕ3 ⱕ1/3 — ⱕ2 — ⱕ2 ⱕ2

ⱕ50% ⱕ50% ⱕ50% — ⱕ50% — ⱕ50% —

9.7 31 35 29 23 87 28.2 27.9

1080

549 (51)

ⱕT2a

ⱕ6

ⱕ10

—

—

—

23

468

64 (19) 80 (23.9) 122 (37.8) 3959 (92.8) 3536 (82.9) 2330 (54.6) 207 (41.8) 43 (8.7)

T1c T1c T1c T1c ⱕT2b* T1c ⱕT2b* ⱕT2a

ⱕ6 ⱕ6 ⱕ6 ⱕ7 ⱕ7* — ⱕ7* ⱕ6

ⱕ10 ⱕ10 ⱕ10 — ⱕ15* — ⱕ15* ⱕ10

— — — —

—

ⱕ2 ⱕ2 ⬍33% —

⬍3 mm ⬍50% — —

— — —

— —

— — ⱕ2

— — ⱕ3 mm

48.3 53.6 55.4 — — — 26 21

Suardi et al. [24]

6.5

Louie-Johnsun et al. [31] Ploussard et al. [19]

8

Thaxton et al. [25]

23

4625

9

495

Current study

7.5

874

Proportion of qualified patients for AS (%)

* Criteria from Choo et al. J Urol 2002;167:1664 [16].

AS criteria

ⱖ12 (if ⱕT2 and PSAⱕ20 ng/ml) or ⱖ6 (if ⱖT3 or PSA⬍20 ng/ml) — ⱖ21

Extracapsular extension (%)

Positive margins (%)

Biochemical failure (PSA ⬎ 0.2 ng/ml)

8.4 14 11 18 7 19 5.9 3.3

0 — — — — — — —

— — — — — — — —

5

8

1.1

11.2 14.3 17.5 18 17 15 17.9 4.7

18 19.6 20.9 19 18 16 13.5 7

5.6 6.25 4.5 4 11 8 22.7 14

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Table 4 Main criteria and results from recent studies

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