PSA doubling time predicts the outcome after active surveillance in screening-detected prostate cancer: Results from the European randomized study of screening for prostate cancer, Sweden section
Version of Record online: 29 SEP 2006
Copyright © 2006 Wiley-Liss, Inc.
International Journal of Cancer
Volume 120, Issue 1, pages 170–174, 1 January 2007
How to Cite
Ali, K., Gunnar, A., Jan-Erik, D., Hans, L., Pär, L. and Jonas, H. (2007), PSA doubling time predicts the outcome after active surveillance in screening-detected prostate cancer: Results from the European randomized study of screening for prostate cancer, Sweden section. Int. J. Cancer, 120: 170–174. doi: 10.1002/ijc.22161
- Issue online: 30 OCT 2006
- Version of Record online: 29 SEP 2006
- Manuscript Accepted: 23 MAY 2006
- Manuscript Received: 7 MAR 2006
- Gothenburg Medical Society
- Swedish Cancer Society. Grant Numbers: 3792-B96-01XAB, 3555
- National Cancer Institute. Grant Number: P50-CA92629
- European Union 6th Framework. Grant Number: LSHC-CT-2004-503011
- prostate cancer;
- PSA doubling time;
- radical prostatectomy
This study reports the outcome of active surveillance in men with PSA screening-detected prostate cancer (PC), and PSA doubling time (PSADT) was evaluated as a predictor of selecting patients to active treatment or surveillance. On December 31, 1994, 10,000 men were randomized to biennial PSA testing. Through to December 2004, a total of 660 men were diagnosed with PC, of whom 270 managed with initial surveillance. Of these 270 patients, 104 (39%) received active treatment during follow-up, 70 radical prostatectomy, 24 radiation and 10 endocrine treatment. Those who received active treatment during follow-up (mean 63 months) were significantly younger (62.6 vs. 65.5 years, p < 0.0001) and had a shorter PSADT (3.7 vs. 12 years, p < 0.0001). PSA relapse was observed in 9 of 70 patients who received RRP during a mean follow-up of 37 months. Seven of these nine PSA relapses were in the patients with preoperative PSADT < 2 years. None of the 37 operated patients with a PSADT > 4 years had a PSA relapse. In a Cox regression analysis adjusted for PSA, ratio-free PSA and amount of cancer in biopsy, only the preoperative PSADT was statistically significant predictor of PSA relapse in p = 0.031. The optimal candidate for surveillance is a man with early, low-grade, low-stage PC and a PSADT > 4 years. In younger men with a PSADT of less than 4 years, surveillance does not seem to be a justified alternative, and patient should be informed about the risk with such an approach. © 2006 Wiley-Liss, Inc.
Surveillance has for a long time been a treatment option in men with prostate cancer (PC). The reason for choosing surveillance and not active treatment is the slow progression rate sign in most men diagnosed with PC. Many men with early stage PC will, in the absence of active treatment, die of causes other than PC.1 Lately, 1 randomized trial data has emerged about the efficacy of active treatment versus surveillance. In the SPCG 4 study, it was shown that radical prostatectomy was superior to surveillance, but as many as 19 men needed to be treated to save 1 person from dying of PC.2 In the last report from this study, as many as 86% of the men in surveillance were still alive or died of causes other than PC, after a median follow-up of 8.3 years. Particularly in elderly men and men with a short life expectancy due to comorbidities, surveillance might be an option to avoid or postpone the side effects of treatment. Traditionally, surveillance has been followed by hormonal treatment at the time symptomatic disease occurs.3 However, in recent years, PC in many men is detected at an earlier stage and a new type of surveillance has been popularized. Klotz has shown that many men with early PC may be put on initial surveillance followed by curative-intended treatment later on.4
In a population invited to repeated PSA testing, the majority of cancers detected are in the early stage.5 As the lead-time in PSA-detected cases will add 5–10 years to the natural course of the disease, many men will not develop symptoms for many years.6 Treating all these cases could probably result in overtreatment. To avoid overtreatment, some authors have recommended initial surveillance.7 Surveillance could either be followed by curative-intended treatment at PSA progression in younger men or by hormonal manipulation in men with limited life expectancy if symptomatic disease occurs.
On the other hand, men who have been taking part in PSA screening have done so in order to avoid the development of advanced PC. This implies that, if surveillance is chosen in these cases, it must be a safe strategy. Scientific data identifying screening-detected PC who are suitable for surveillance is currently lacking.
The present study presents the outcome of initial surveillance in 270 men with PC detected by PSA screening, and evaluates the role of the PSA doubling time (PSADT) as a tool for selecting the correct patients for surveillance.
Patients and methods
Sahlgrenska University Hospital in Gothenburg is the Swedish branch of the European Randomized Study of Prostate Cancer. From a group of 20,000 men born between January 1, 1930, and December 31, 1944, 10,000 were randomized into a screening group, and 10,000 were randomized into a control group. Patients in the screening group were invited to the first PSA testing between 1995 and 1996, and were then invited for PSA testing every second year thereafter. Men with PSA levels ≥ 3 ng/mL were offered to undergo clinical investigation, which included sextant biopsy of the prostate. Only minor corrections of the study protocol have been made so far.5
A total of 660 men were diagnosed with PC as a result of the screening procedure through to December 2004. Of these, 270 (41%) men were managed primarily with surveillance. Surveillance was defined as an active standpoint to postpone the treatment until at least 6 months after diagnosis.
The reasons for choosing surveillance were comorbidity, small-volume cancers in biopsies or patient's desire. In many cases, there was more than 1 reason for choosing surveillance. Small-volume cancers in biopsies were classified as 1 or 2 adjacent cores with a total core cancer length of less than 2 mm and where rebiopsies of the area did not reveal more cancer.8
Patients managed by surveillance were generally scheduled for follow-up visits every 6 months with PSA and clinical investigation. Patients with no signs of progression after 2 years were generally controlled at an annual basis. Rebiopsies were not mandatory during follow-up. Rebiopsies were normally recommended only in patients who had signs of T-stage progression and/or PSA progression and when the physician (and the patient) were in doubt about whether active treatment should be chosen or not. Only 34 patients were rebiopsied during the follow-up.
Bone-scans were generally not carried out in patients with PSA < 20 ng/mL and a Gleason score (GS) of < 8.
The patient's age, PSA, free/total PSA and PSA density at diagnosis were registered. The core biopsy information, including the total number of cores, number of cores with cancer, total length of cancer in the biopsy, the GS and the clinical tumor stage according to TNM classification (1992), were prospectively registered into the database. During follow-up, new information, including the PSA at the time of active treatment and the type of treatment following surveillance, were registered.
Switching to active treatment was recommended in patients with established PSA, stage or grade progression. However, in many men with stable PSA and no other signs of progression, switching to active treatment was initiated by patient's desire.
The characteristics of the entire surveillance group at diagnosis, stratified according to age group, are presented in Table I. The median age was 64.6 (51.2–70.0) years; the median PSA at diagnosis was 4.2 (3.0–27.8) ng/mL. Of the patients, 87% had T1c and none of the patients were N1 or M1.
|Number of patients||6 (2)1||44 (16)||99 (37)||121 (45)||270 (100)|
|PSA (mean/median)||4.7/3.6 [3.1–9.9]2||5.0/4.5 [3.0–15.6]||4.7/3.9 [3.0–16.4]||5.8/4.3 [3.0–27.8]||5.2/4.2 [3.0–27.8]|
|PSAD (mean/median)||0.16/0.14 [0.06–0.37]||0.16/0.14 [0.06–0.56]||0.14/0.11 [0.04–1.02]||0.16/0.13 [0.04–0.74]||0.15/0.12 [0.04–1.02]|
|Ratio-free PSA (mean/median)||11.1/8.9 [6.7–21.2]||16.5/15.7 [6.4–28.9]||19.3/18.2 [5.5–44.9]||19.6/18.5 [5.4–47.4]||18.8/17.8 [5.4–47.40]|
|T1c (no. of patients)||6||37||84||108||235 (87)|
|T2 (no. of patients)||0||7||14||13||34 (12.6)|
|T3 (no. of patients)||0||0||1||0||1 (0.4)|
Table II presents the diagnostic sextant core biopsy information: 97% of patients had Gleason 3 + 3 or less, all the patients with a GS of more than 3 + 3 were in the age group 65–70 years. Of the patients, 69% had cancer in 1 core, and only 5% had cancer in more than 3 cores. The median of the total cancer length in biopsies was 1.9 (0.05–26.3) mm.
|Number of patients with|
|1 core with cancer||2 (33)1||25 (57)||71 (71)||87 (72)||185 (69)|
|2–3 cores with cancer||3 (50)||14 (32)||24 (24)||29 (24)||70 (26)|
|4–6 cores with cancer||1 (17)||5 (11)||4 (4)||5 (4)||15 (5)|
|Total cancer length in core biopsy, mean/median (mm)||9.0/6.2 [2.7–26.3]2||4.6/2.5 [0.05–19.7]||3.2/1.7 [0.1–23.7]||3.0/1.7 [0.1–18.0]||3.4/1.9 [0.05–26.3]|
|Number of patients with|
|Gleason score 2+2||0||1 (2.5)||0||2 (1.6)||3 (1)|
|Gleason score 3+2||0||1 (2.5)||3 (3)||3 (2.5)||7 (3)|
|Gleason score 3+3||6 (100)||42 (95)||96 (97)||107 (88.5)||251 (93)|
|Gleason score 3+4||0||0||0||9 (7.4)||9 (3)|
PSA doubling time (PSADT) was calculated based on PSA measurements at least 3 months apart. PSADT was estimated for each patient as the reciprocal of the slope from regression of log-2 PSA on time.9 We used the PSA at diagnosis and the latest PSA value before any active treatment was received or at last follow-up for the patients still in surveillance.
In patients having radical prostatectomy, the technique was as previously described.10 No neoadjuvant endocrine treatment was given. PSA relapse in the radical retropubic prostatectomy (RRP) group was defined as 2 consecutive PSA elevations above 0.2 ng/mL.
Radiation therapy was given as external beam radiation in 8 patients with 70 Gy. Fourteen patients were treated using combination therapy with high dose rate Iridium implants combined with external radiation. Two patients were treated with seed implants. The majority of radiated patients received hormonal therapy for 6 months, starting 3 months before radiation. PSA relapse in radiated patients was defined according to the ASTRO criteria.
The 2 endpoint of the study were to evaluate if PSADT could predict the patients who would switch to active treatment during the follow-up and the power of PSADT as a predictor of PSA relapse after RRP.
Differences in continuous prognostic markers (PSA, ratio-free to total PSA, PSA-density, PSADT, total cancer length in biopsies and age) between groups were tested by the Mann Whitney method. The Kaplan–Meier estimates were used for calculating time to active treatment (patients were considered censored at time of last follow-up or death due to other causes) and to calculate PSA-free survival in men treated with RRP.
The influence of possible preoperative prognostic covariates on PSA-free survival after RRP was tested in a Cox regression model. A p-value of < 0.05 was regarded as significant. All analysis was performed using the SAS statistical program.
The mean follow-up time was 63 (11–120) months. During this time period, 104 (39%) patients changed from surveillance to active treatment with RRP in 70 (67%) patients, radiation therapy in 24 (23%) patients and hormonal therapy in 10 (10%) patients. During the follow-up, another 10 patients had been treated due to urinary obstructive symptoms; 3 with TURP, 1 with TUMT and 6 with 5α-reductase inhibitors. Of the patients in the age group 50–54 at diagnosis, only 16.7% continued surveillance compared with 77.7% in the age group 65–70 (Table III).
|Radical prostatectomy||4 (66.7)1||19 (43.2)||35 (35.4)||12 (9.9)||70 (25.9)|
|Radiotherapy||1 (16.7)||5 (11.4)||9 (9.1)||9 (7.4)||24 (8.9)|
|Hormonal treatment||0||1 (2.3)||3 (3)||6 (5.0)||10 (3.7)|
|LUTS treatment2||0||3 (6.8)||2 (2)||5 (4.1)||10 (3.7)|
|Continuing surveillance||1 (16.7)||16 (36.4)||50 (50.5)||89 (73.6)||156 (57.8)|
|Total||6 (100)||44 (100)||99 (100)||121 (100)||270 (100)|
The distribution of different prognostic markers in those who received active treatment and those who were still under surveillance is presented in Table IV. Patients who received active treatment were significantly younger (p < 0.0001), had a lower free PSA ratio (p = 0.007) and a higher amount of cancer in the biopsies (p = 0.033). The median PSADT in patients still under surveillance was 12.0 years compared with 3.7 years (p < 0.0001) in those who changed to active treatment. There was no statistical significant difference in PSA at diagnosis or PSA density between the 2 groups. Figure 1 illustrates the time to active treatment stratified for different PSADT intervals.
|Total||Continued surveillance||Active treatment||Active treatment (all)||p-value (active treatment vs. surveillance)|
|PSA at diagnosis||5.2 (4.2)1||5.2 (4.1)||4.9 (4.2)||5.0 (3.9)||8.2 (7.0)||5.3 (4.2)||0.41|
|Ratio-free PSA (%)||18.8 (17.8)||19.9 (19.3)||17.3 (16.7)||17.0 (15.7)||15.5 (13.9)||17 (16)||0.007|
|PSA-density||0.15 (0.12)||0.15 (0.12)||0.15 (0.12)||0.16 (0.13)||0.21 (0.17)||0.16 (0.13)||0.52|
|TCL2 in biopsy||3.4 (1.9)||2.9 (1.6)||3.2 (2.0)||6.9 (4.6)||6.4 (6.6)||4.3 (2.5)||0.003|
|Age||63.8 (64.5)||64.8 (65.5)||61.6 (62)||63.0 (64.3)||64.4 (65.5)||62.1 (62.6)||<0.0001|
|PSA at treatment||–||–||6.7 (5.9)||7.7 (5.4)||11.9 (9.9)||7.4 (5.9)||–|
|Time to treatment||–||–||28.4 (21.0)||21.2 (15.4)||36.6 (24.6)||–||–|
The mean time from diagnosis to RRP was 28.4 (7.6–95) months. The mean PSA at diagnosis was 4.9 (3–13), and the mean PSA at the time of treatment was 6.7 (3.3–15) in the RRP group. The median PSADT in the RRP group was 3.8 years compared with 7.0 years for the entire surveillance population. The corresponding data for patients who received radiation or hormonal therapy are presented in Table IV.
The pathological assessment of RRP specimens resulted in an upgrading of the GS in 15 (21%) patients, from GS 3 + 2 to 5 + 3 in 1 case, from GS 3 + 3 to 4 + 3 in 1 case and from GS 3 + 3 to 3 + 4 in 13 cases. Downgrading was observed in 9 (13%) patients, from GS 3 + 3 to 3 + 2 in 8 cases and to 3 + 1 in 1 case. The pathologic stage was pT2 in 60 (86%) patients and pT3 in 10 (14%) cases. Two cases had seminal vesicle invasion. The positive margin rate was 23%.
During a mean follow-up of 37 months, 9 (13%) of the patients in the RRP group had a PSA relapse. Of the 9 patients who had relapsed, 7 had a preoperative PSADT of less then 2 years and the other 2 had a PSADT between 2 and 4 years. There was not a single PSA relapse in the patients with a preoperative PSADT more than 4 years (Fig. 2).
The result of the Cox regression analysis, including PSA at diagnosis, free to total PSA and total length of cancer in biopsy, confirmed that the preoperative PSADT was significantly correlated with PSA relapse after RRP (p = 0.031, Table V)
|Variable1||Parameter estimate2||Standard deviation||Risk ratio||p-value|
|TCL3 in biopsy||0.14||0.12||1.15||0.26|
In patients who received radiation therapy, 1 patient had relapsed. Among the 10 patients who received delayed hormonal treatment, none so far had reached a hormone insensitive stage.
During the follow-up, 14 patients in the study population died from reasons other than PC. None of these patients had received active treatment. At the most recent PSA assessment, only 5 patients had a PSA exceeding 20 ng/mL, and all of these patients were still in the surveillance group. In spite of the fact that not all the patients had undergone a bone scan, there was no patient who clinically manifested with bone metastasis or other metastasis during the follow-up.
In this study, we observed wide distribution of PSADT very similar to other reports.7 A majority of men have a very long PSADT, and the number of men that have a short doubling time is relatively few. The rate of men with a PSADT exceeding 4 years was 67 %. It was obvious that men with a short PSADT were the ones who rapidly switched to active treatment (Fig. 1). Many men who initially chose surveillance will discontinue surveillance, because of PSA progression. In 1 study of men younger than 70 years, 57.3 and 73.2% had discontinued surveillance after 2 and 4 years, respectively.11 In the present study, 50% were still on surveillance after 7 years (Fig. 1). One reason for this difference could be that the patients in our study were detected in an ambitious screening programme, and many very early cancers were detected. Another explanation could be that treatment traditions differ. In Scandinavia, surveillance has been a common alternative for a long time in men with asymptomatic PC.12
In this study, apart from PSADT, age at diagnosis influenced the decision to continue surveillance. The majority of younger men discontinued surveillance, while almost 75% of men in the age group 65–70 years at diagnosis were still under surveillance at last follow-up (Table III). As younger men in general have a long life expectancy and according to this and other studies they discontinue surveillance early, it seems questionable to offer these men surveillance. Although follow-up in this study was up to 10 years, the long-term results with surveillance are still obscure. As these men were detected by PSA-screening, a lead-time on an average of 10 years will be added before clinical symptoms are to be expected. The risk with progression after 10 years is therefore difficult to judge and, as long as such data are missing, it seems questionable to put men with very long life expectancy on long-term surveillance. Conversely, postponing the side-effects of active treatment and the complexity in assessment of different curative treatment options are the two major motives that younger men declare as a reason for choosing the initial surveillance. This period of the initial surveillance is resulting in huge anxiety in these patients. They want to know if this period of surveillance can reduce their chance of cure later on. The lack of reliable prognostic markers is the reason that a limited PSA raise usually leads to change to the active treatment in these patients. For these younger men, it is important to recognize the possible risks associated with such a strategy, if there are subgroups of men in which surveillance is truly associated with increased risk. A few studies have focused on this and have not reported any major increased risk for these patients who have delayed curative treatment.13 In a previous study, we could conclude that, in selected patients, an average surveillance of 2 years did not reduce the chance of cure by radical prostatectomy.14
One problem in selecting patients for active surveillance is the lack of reliable prognostic factors in early PCs. The GS is generally assumed to be the best prognostic factor, but the problem is that, in a screening situation, more than 70% of detected cancers are Gleason 3 + 3.15 It is also well known that the Gleason grading based on core biopsies is unreliable.16 In the present study, 21% of the patients who were later operated were upgraded and 13% were downgraded.
To assist these men with early PC in their treatments decision making, the question was raised if the preoperative PSADT could be a prognostic marker of PSA relapse after RRP. The rationale is based on the association between PSA and the volume of PC.17 The usefulness of PSADT is further demonstrated by the fact that several studies have suggested PSADT to be constant over the time.9 These data suggest that PSADT could be used as a proxy for growth rate in PC and is measurable even in early PCs. In a study of 200 patients, none of the traditional prognostic factors, grade, stage or PSA at base line was correlated to the PSADT. In the same report, one third of the patients had a PSADT > 10 years. PSADT, therefore, seems to have a potential as a tool in the management of patients who select surveillance. The authors conclude that a PSADT < 2 years can identify the patients at high risk of local progression, in spite of otherwise favorable traditional prognostic factors.18 The importance of PSA kinetic in prognosis has also been analyzed in men undergoing radical prostatectomy. Preoperative PSA velocity has been identified as a risk factor for progression after RRP19 and also for later PC-specific mortality.20 In a recently published paper from Freedland et al., 379 patients with biochemical recurrence after RRP were observed, and the main outcome was PC mortality. The PSADT was the strongest risk factor for PC-specific mortality.21
In this study, we analyzed the risk of PSA recurrence in those patients who received RRP, as an active treatment following surveillance. Of the patients in our study who received RRP, 9 cases of PSA relapse were observed; 7 of these patients had a preoperative PSADT < 2 years and another 2 cases had a PSADT of < 4 years. There was not a single PSA relapse after RRP in the group of patients with PSADT > 4 years (Fig. 2). The power of PSADT as a prognostic marker of PSA relapse was tested in a Cox regression model adjusted for PSA at diagnosis, free to total PSA and total length of cancer in biopsy (Table V). The PSADT was the only statistically significant predictor of PSA relapse after RRP. Accordingly, men with short PSADT had a high risk of disease progression after radical prostatectomy. This group might have had a better chance of cure if they were treated immediately.
One problem is that PSADT is not always established at the time of diagnosis, and thus not available when deciding whether active treatment or surveillance should be chosen. Studies so far have not shown that a limited surveillance in selected patients compromise their chance of cure even if the curative treatment is postponed for up to 2 years.13, 14 The results from the present study question whether this is an appropriate approach in the subgroup of patients with a short PSADT. If PSADT is not available at the time of diagnosis, close surveillance is warranted.
Even if it could be questioned whether men with a short PSADT are candidates for surveillance, it is obvious from this study that men with a PSADT longer than 4 years were excellent candidates for this strategy. In the patients with a PSADT > 4 years, who later received radical prostatectomy, no PSA relapses have been observed so far in this study. Overall, the present results from surveillance, with a mean follow-up of 63 months, were very encouraging, with no patients who had developed clinical signs of metastasis, and only 5 of 270 patients who at last follow-up had a PSA exceeding 20 ng/mL.
PSADT seems to be a useful, reliable and discriminating prognostic marker of disease progression and active treatment during the follow-up of patients with screening-detected early PC who opt for initial active surveillance.
Younger, screen-detected men who opt for an initial period of surveillance with a PSADT > 4 years still have an excellent chance of cure by RRP. However, patients with a short PSADT (<4 years) should be informed about the risk for disease progression.
Our sincere thanks to Mrs. Catrin Bergqvist (statistician/PhD).
- 9Clinical observations on the doubling time of prostate cancer. Eur Urol 1993; 23 ( Suppl 2): 60–3., , .