A Multi-Institutional Evaluation of Active Surveillance for Low Risk Prostate Cancer

Results 

Between 1991 and 2007, 262 patients meeting the inclusion criteria enrolled in AS at the 4 institutions (table 1). Median (IQR) age was 64 (58, 69) years and median PSA was 4.9 ng/ml, with 212 (81%) patients having an initial PSA of 7 ng/ml or less and 218 (83%) having clinical stage T1c or lower. Total positive cores combined before AS was 2 or less in 178 (78%) patients and AS commenced in 2001 or later for 197 (78%). The median (IQR) time between diagnostic biopsy and the second restaging biopsy was 6.0 months (3.7, 10.5). Median (IQR) followup was 29 months (15, 52) and 50 (19%) patients had more than 5 years of followup.

Table 1. Patient characteristics

		University of Miami	University of British Columbia	Memorial Sloan-Kettering Cancer Center	Cleveland Clinic Foundation	Overall
	No. pts	61	34	146	21	262
	Yrs	1992–2007	1994–2007	1991–2007	2000–2006
	Median (IQR) age	62 (56,68)	66 (63,68)	64 (58,69)	68 (64,71)	69 (58,64)
	No. family history(%)	13 (21)	4 (12)	27 (19)	2 (10)	46 (18)
	No. ng/ml PSA(%):
	Less than 4	18 (30)	12 (35)	54 (37)	4 (19)	88 (34)
	4–7	30 (49)	16 (47)	66 (45)	12 (57)	124 (47)
	7.1–10	13 (21)	6 (18)	26 (18)	5 (24)	50 (19)
	No. clinical stage(%):
	T1a/b	4 (7)	5 (15)	10 (7)	1 (5)	20 (8)
	T1c	47 (77)	20 (59)	112 (77)	19 (90)	198 (75)
	T2a	5 (8)	9 (26)	24 (16)	1 (5)	39 (15)
	Not available	5 (8)	0	0	0	5 (2)
	No. biopsy Gleason score(%):
	2–5	10 (16)	16 (47)	3 (2)	1 (5)	30 (12)
	6	51 (84)	18 (53)	143 (98)	20 (95)	232 (88)
	No. biopsy cores(%):
	12–20	25 (41)	27 (79)	35 (24)	0	87 (33)
	Greater than 20	12 (20)	1 (3)	66 (45)	20 (95)	99 (38)
	Not available	24 (39)	6 (18)	45 (31)	1 (5)	76 (29)
	No. total pos cores(%):
	1–2	41 (67)	19 (56)	105 (72)	13 (62)	178 (68)
	3–5	7 (11)	11 (32)	25 (17)	7 (33)	50 (19)
	Not available⁎	13 (21)	4 (12)	16 (11)	1 (5)	34 (13)
	Median(IQR) estimated cc prostate size†	40 (30,54)	50 (35,62)	49 (33,66)	36 (29,56)	45 (31,61)
	No. diagnosis yr(%):
	Before 2000	8 (13)	22 (66)	34 (23)	1 (5)	65 (25)
	2001–2004	19 (31)	6 (18)	78 (54)	12 (57)	115 (44)
	2005–2007	34 (56)	6 (18)	34 (23)	8 (38)	82 (31)
	No. active treatment(%)	3 (5)	5 (15)	29 (20)	6 (29)	43 (16)
	Median (IQR) mos followup	21 (13,38)	44 (19,84)	25 (13,43)	30 (15,39)	29 (15,52)

⁎ Transurethral prostate resection (20 patients) or not available from repeat biopsy (14 patients). † Available for 216 patients (82%) via ultrasound or MRI.

After initiating AS 157 (60%) patients had at least 1 further followup biopsy. Of all patients on AS for a minimum of 18 months (172, 65%), 56 (33%) had 1 followup biopsy, 38 (22%) had 2 and 17 (10%) had at least 3. Of patients entering AS since 2000 with at least 18 months followup (131, 50%) 100 (76%) had at least 1 followup biopsy.

A total of 19 patients had grade progression (Gleason 7 or greater) on surveillance biopsy representing 7% of all patients and 12% of those having a biopsy after starting AS. A total of 15 patients underwent active treatment and 4 declined. Those declining active treatment were followed for 10, 14, 22 and 25 months without evidence of metastases.

Patient and cancer characteristics associated with an increased chance of discontinuing AS included total number of positive cores from both pre-AS biopsies (p = 0.002) and cancer identified on repeat biopsy before AS (HR 2.23, 95% CI 1.23–4.06, p = 0.007) (table 2). Age, PSA, clinical stage, prostate volume and total number of biopsy cores sampled were not associated with the likelihood of remaining on AS.

Table 2. Predictors of discontinuing active surveillance

		No. Pts (%)	Hazard Ratio (95% CI)	p Value
	PSA (log) (per ng/ml)	—	1.02 (0.90–1.15)	0.7
	Age (per yr)	—	0.99 (0.95–1.03)	0.8
	Clinical stage:
	T1a/b	20 (7)	0.91 (0.32–2.57)	0.9
	T1c	198 (76)	Referent
	T2a	39 (15)	0.87 (0.36–2.07)
	Prostate vol cc (ultrasound or MRI):
	Less than 30	52 (24)	Referent	0.6
	30–50	74 (34)	0.59 (0.23–1.53)
	Greater than 50	90 (42)	0.75 (0.32–1.71)
	Repeat biopsy with Ca:
	No	159 (61)	Referent
	Yes	103 (39)	2.23 (1.23–4.06)	0.007
	Total cores from both biopsies (per core)	—	1.02 (0.99–1.06)	0.25
	Total pos cores from both biopsies:
	1–2	178	Referent	0.002
	3–4	42	1.4 (1.11–1.94)
	5–6	8	6.3 (1.72–15.36)

During the course of the study 43 (16%) patients elected active treatment, and the 2 and 5-year probability of remaining on AS was 91% and 75%, respectively (see figure). The reasons for stopping active surveillance were most commonly upgrading (35%) or higher volume of cancer (16%) on surveillance biopsy, or a change in patient preference (14%) (table 3). The active treatment choices were RP for 26 (60.5%), radiation therapy for 13 (30%), cryotherapy for 1 (2.5%) and androgen deprivation for 3 (7%).

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Actuarial estimate of remaining on active surveillance

Table 3. Reasons for ceasing active surveillance and electing treatment

		No. (%)
	Gleason 7 or greater on surveillance biopsy	15 (35)
	Surveillance biopsy with more than 3 cores or more than 50% in single core	7 (16)
	Change in pt preference	6 (14)
	Increasing PSA without worsening biopsy features	2 (5)
	MRI findings	2 (5)
	Voiding symptoms	1 (2)
	Bone metastases	1 (2)
	Up staging via digital rectal examination	1 (2)
	Unknown	12 (28)

Overall greater than 100% as some patients had multiple reasons.

For the 26 patients who chose to undergo RP Gleason 7 cancer, positive surgical margin, extracapsular extension and lymph node involvement were present in 13 (50%), 2 (8%), 4 (15%) and 1 (4%), respectively. Of the 13 men with Gleason 7 prostate cancer identified at radical prostatectomy 9 (69%) had a biopsy between the start of active surveillance and surgery. Of those 9 patients 3 (33%) had evidence of Gleason 7 disease on biopsy before surgery.

The patient with lymph node metastases had 1 of 28 nodes involved and is currently without biochemical recurrence at 24 months after RP. Following RP 23 patients were free of biochemical recurrence at a median followup of 19 months since surgery, 2 had a biochemical recurrence following surgery but were without evidence of cancer progression following salvage radiation therapy and 1 had a biochemical recurrence 60 months after surgery with the most recent PSA 0.6 ng/ml. All 3 patients with a biochemical recurrence had a positive surgical margin. After radiation therapy all 13 patients were without biochemical recurrence (PSA nadir plus 2 ng/ml) at a median followup of 31 months. Following androgen deprivation 2 of 3 patients maintained an undetectable PSA. The other patient receiving androgen deprivation was 73 years old at diagnosis with a PSA of 3.4 ng/ml, Gleason 6 cancer in 1 of 20 cores from 2 separate biopsy sessions and disease staged as clinical T1c. However, he never underwent a biopsy after initiating active surveillance and had a PSA of 6.5 ng/ml 3 years later (PSA doubling time of 3.4 years). However, 38 months after starting active surveillance PSA was 24 ng/ml and a bone scan revealed multifocal bone metastases in the thoracic and lumbar spine. Androgen deprivation was initiated and he has since been lost to followup.

Overall of the 43 patients undergoing postponed treatment 41 (95%) are currently without evidence of metastases at a median of 23 months following treatment. There were 3 deaths in the cohort but none from prostate cancer.

Discussion 

Our study provides an overview of a multi-institutional retrospective experience with AS in men with low risk prostate cancer at diagnosis who are also candidates for other treatment options such as radiation or surgery due to estimated life expectancy. We provide further short-term evidence that for highly select patients AS appears to be safe, durable and associated with a low but finite risk of disease progression.

The ultimate success of any AS program relies on accurate disease characterization at diagnosis. By specifying strict clinical and pathological inclusion criteria and requiring a restaging biopsy before commencing AS, we identified a cohort of men with a low risk of disease progression and an estimated 5-year biochemical recurrence risk of less than 5% if they elected immediate prostatectomy. The rate of AS discontinuation in our study was approximately 5% per year, lower than that of similar series, and reflects our more restrictive entry criteria, particularly a second prostate biopsy before starting AS.5, 9, 12

The ability to predict relative disease indolence is imperfect as evidenced by the modest accuracy of pretreatment predictive tools intended for that purpose, by the 2 patients diagnosed with metastases (bone metastases during AS and another with lymph node metastases at RP) and by the 67% of patients with Gleason 7 disease at RP showing lower grade cancer on biopsy.13 Therefore, it is imperative that all men electing an AS program be counseled on the low but real risk of potentially life threatening cancer progression. To minimize this risk we strongly believe that a restaging biopsy before initiating AS is mandatory as it excludes up to 30% of patients considered for AS based on the initial diagnostic biopsy, minimizes the risk of a Gleason grade sampling error and predicts the likelihood of remaining on AS. Berglund et al have shown that of 104 patients being considered for AS after a diagnostic biopsy with criteria identical to those in this study 27% will be excluded from consideration of AS because of up staging or upgrading at re-biopsy.14 Additional support for the restaging biopsy is that Gleason upgrading on surveillance biopsy is the most common reason for discontinuing AS and is most likely a result of inaccurate assessment before AS rather than cancer progression.15 When comparing our data to those of another well-defined cohort of 407 men undergoing AS, median followup (29 vs 26 months), proportion of patients having at least 1 surveillance biopsy (60% vs 59%) and frequency of recommended surveillance biopsies were similar.15 However, the absolute proportion of patients with upgrading on surveillance biopsy was less (7% vs 19%), suggesting that our strategy of restaging biopsy before AS may be one way of minimizing progression while on AS. For these reasons we believe the diagnostic biopsy may lead to a patient being an AS candidate, but findings on the restaging biopsy ultimately determine and finalize eligibility.

Multiple lines of overlapping evidence confirm the increased incidence of men being diagnosed with low risk prostate cancer, the highly unlikely progression to metastases and increased interest in observational or minimally invasive management approaches. The lead time bias afforded by intensive PSA screening leads to an increased detection rate of biologically indolent cancer, and is estimated to be 3 to 12 years depending on different modeling techniques, screening intervals and biopsy indications.16, 17 In addition, since the introduction and widespread use of PSA, rates of prostate cancer identified on autopsy have decreased, suggesting an increased detection and presumptive treatment of cancers not likely to have clinical manifestations.18 Nearly 50% of men in the United States diagnosed with prostate cancer (Cancer of the Prostate Strategic Urologic Research Endeavor) and 30% of European men (European Randomized Study of Screening for Prostate Cancer) meet variable low risk or indolent cancer criteria at diagnosis, consistent with other estimated rates of over diagnosis (23% to 50%).2, 3 Finally, many treated men are not likely to benefit from an intervention. A population based assessment by Miller et al estimated that up to 50% of men with low risk prostate cancer (well differentiated cancers in men of any age or moderately differentiated tumors in men older than 70 years) are overtreated.13 In the European Randomized Screening for Prostate Cancer trial 49% of men with clinical stage T1c-T2a, PSA less than 20 ng/ml, Gleason 6 or less, less than 50% positive cores and less than 20 mm total cancer who underwent RP had pathologically indolent features (total tumor volume less than 0.5 cc, confined to the prostate and no Gleason grade 4 or 5).3 Despite the data suggesting lead time bias, diagnosis of autopsy detected cancers, over diagnosis and overtreatment, it is estimated that AS is used as a treatment strategy in only 10% of patients with newly diagnosed prostate cancer.2 Our data indicate further consideration of AS for appropriately selected patients.

However, multiple limitations of our study should be considered. Based on the modest followup in our study (median 29 months) and in others (median 22 to 64 months) caution should be exercised in extrapolating these findings to justify AS as a long-term management strategy.4, 5, 12, 19 Extended followup is mandatory to answer this question, particularly since the Scandinavian Prostate Cancer Group analyzed men with untreated, localized and primarily palpable prostate cancer.20 They found local progression and metastases frequently occur 10 to 20 years after the diagnosis, and cancer specific mortality rates 15 years after diagnosis are tripled compared to the first 15 years of followup. Our data simply provide an observational experience which will continue to provide insights into the natural history of low risk prostate cancer, generalized rates of delayed treatment given the variable practice patterns, overall cancer specific success rates and causes of death. Although one of the strengths of our study is the multi-institutional cohort, this has also led to variations in the intensity of followup, diagnostic and restaging biopsy strategies, frequency of surveillance biopsies, pathological assessment and indications for treatment. Thus, the generalizing of our findings to include other populations should be done with caution. While the most common reason for discontinuing AS in our series was the result of a surveillance biopsy, in other AS series it was patient preference or an increasing PSA alone, highlighting the variable nature of currently available series and the need for prespecified study methodology. Ongoing prospective randomized trials such as START (Standard Treatment Against Restricted Treatment, National Cancer Institute of Canada) and ProtecT (Prostate Testing for Cancer and Treatment, National Health Service in the United Kingdom) will provide larger scale and sounder evidence regarding the role and limitations of AS. During the course of our study the best available clinical and pathological data were used to establish inclusion criteria. It is hoped that more accurate predictors of tumor biology, such as advances in imaging (eg MRI) or genetic assessment (eg ERG, TMPRSS2), may ultimately improve the patient selection process for AS. Lastly the impact of lead time bias should be considered when interpreting our findings. It is possible that patients meeting criteria for AS but undergoing active treatment within 6 months (excluded from our study) had higher risk features and, if included in analysis, would have led to less favorable outcomes for the entire cohort.

Our view on AS is not one of disregard for men with low risk cancer features but rather a strategy that encourages initial observation, frequent monitoring based on serial prostate biopsies and, if needed, the implementation of active therapy while disease is still at a highly curable stage. The short-term effectiveness of delayed treatment is exemplified by 42 of the 43 patients currently without evidence of disease after RP (26), radiation (13) or cryotherapy (1), or with an undetectable PSA after androgen deprivation (2). Similarly Warlick et al found that in 38 patients electing radical prostatectomy 12 to 73 months after starting an AS program, the pathological outcomes did not significantly differ from those of 150 men with similar cancer characteristics who chose immediate surgery at diagnosis.4 These findings highlight many of the hallmark features and purported benefits of AS in that most men will not require an intervention, and those who do will have benefited from a period when quality of life and cancer related outcomes do not appear to be compromised.

Conclusions 

Active surveillance with judicious monitoring for appropriately selected patients with low risk prostate cancer appears to be safe, durable and associated with a low risk of systemic progression. Restaging biopsy before considering active surveillance appears essential since cancer detected on restaging biopsy and a higher number of cores with cancer are associated with a lower likelihood of remaining on active surveillance. With selective inclusion criteria 91% and 75% remain on active surveillance at 2 and 5 years, respectively, and short-term cancer control following active treatment is encouraging. Prospective randomized trials against primary treatment will ultimately determine the efficacy and role of active surveillance.