Paper

Prostate Cancer and Prostatic Diseases (2005) 8, 163–166. doi:10.1038/sj.pcan.4500788 Published online 15 February 2005

Long-term outcome of detectable PSA levels after radical prostatectomy

T E Ahlering1 and D W Skarecky1

1Department of Urology, UC Irvine Medical Center, Orange, California, USA

Correspondence: TE Ahlering, 101 The City Drive South, Rt. 81, Bldg 26, Orange, CA 92868, USA. E-mail: tahlerin@uci.edu

Received 8 August 2004; Revised 7 December 2004; Accepted 20 December 2004; Published online 15 February 2005.

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Abstract

Detectable prostate-specific antigen levels (PSA) following radical prostatectomy (RP) are believed to represent treatment failure. In this retrospective review, we characterize long-term PSA outcomes following RP (n=204) in a nonreferral hospital performed between 1984 and 1994. With an average follow-up of 10 y, 90 (44%) patients developed a PSA recurrence: 15 (17%) died of prostate cancer despite hormonal intervention, 39 (43%) responded to hormonal therapy with stable remission and 36 (40%) were observed without intervention. Following RP many patients may have a detectable PSA that does not require treatment. PSA doubling time (<12 months) was the best predictor of disease progression.

Keywords:

PSA, clinical recurrence

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Introduction

Much evidence exists supporting the utility of prostate-specific antigen (PSA) levels in the diagnosis, counseling and follow-up of prostate cancer.1, 2, 3 Following a radical prostatectomy (RP), a nondetectable PSA represents convincing evidence that no clinical or chemical evidence of disease exists. However, the specific relevance of a detectable PSA is controversial. Some urologists feel that a detectable PSA represents treatment failure and others report that it does not accurately predict progression to metastasis or death. Factors reported to predict patterns of recurrence and progression after RP include the interval from surgery to a detectable PSA, pathological Gleason score, seminal vesicle and lymph node involvement, margin status and PSA doubling time.4, 5, 6, 7, 8, 9 These reports add significantly to our developing knowledge, but are generally from patients with short follow-up intervals that have received no adjunctive intervention from highly selected University practices.

The purpose of this study is to provide long-term PSA outcomes of men undergoing RP between 1984 and 1994 from a nontertiary referral hospital. Men from this era had substantially more disease at the time of diagnosis and treatment, as compared to the present era, and as such present an interesting cohort to observe PSA recurrence and disease progression.

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Materials and methods

The records of all patients undergoing a radical prostatectomy at the Long Beach VA Medical Center from 1984 to 1994 were retrospectively reviewed for PSA levels and clinical outcome. After appropriate IRB approval, parameters entered into an electronic database included pertinent clinical staging factors, pathological findings and clinical follow-up. Informed consent was waived in this retrospective study (MIRB 00400). PSA values became widely available in 1990 at this institution.

The surgical technique varied slightly according to surgeon but always included a pelvic lymph node dissection and a radical prostatectomy. PSA progression was defined as a persistently detectable value greater than 0.2 ng/ml. Postoperative follow-up consisted of physical examination and serial PSA levels at least every 6 months in patients known to have PSA recurrence. Patients without a detectable PSA were followed annually after 5 y. Patients were considered dead of disease when confirmed by medical record documentation in association with hormone resistance and a rising PSA or dying with the presence of symptomatic metastasis.

Since 1984, treatment philosophy for patients with advanced or progressive disease has been primarily hormonal ablation. Patients with lymph node involvement, extensive seminal vesicle involvement, high pathological Gleason scores or a rapidly rising PSA were presented for review by a multidisciplinary group. These patients were generally managed with hormonal therapy (HT) either immediately after surgery or with the development of a rapid (doubling time <6 months) rising PSA level. The remaining patients were followed expectantly with serial PSA levels. If over the course of follow-up (generally 6–12 months) patients were found to have PSA levels rising in a geometric fashion (ie doubling on each occasion), they were referred to the Division of Hematology–Oncology and HT was instituted. HT prior to 1990 was accomplished either via bilateral orchiectomy or DES. Subsequent to 1990, it was accomplished generally via LHRH agonist therapy or occasionally via bilateral orchiectomy. Adjunctive radiotherapy was utilized in a minority of patients, 11. A two-tailed t-test was performed using Microsoft excel between group 1 and groups 2 and 3 combined.

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Results

Table 1 presents data on the overall outcome of the 204 patients included in this review. Based on PSA recurrence and treatment outcomes, three groups were identified from the 90 patients with PSA elevation. Although not the focus of this paper, baseline information regarding the 114 patients without PSA recurrence has been included.


Group 1: Prostate cancer deaths. The 15 patients had PSA and clinical progression despite hormonal intervention and died of prostate cancer. This represents 7% of the 204 RP patients and 17% of the men with an elevated PSA.

Of the 15 patients, five (33%) had immediate hormonal intervention and the remaining 10 were started subsequently (range 2.6–6.4 y). The decision for immediate intervention was largely left to the Division of Hematology/Oncology and generally was related to grade and volume of disease. These patients with apparent higher volume disease lived on average only 6.5 y following surgery (range 2.9–8.8 y) compared to 8.4 years (range 5.5–12.1 y) for men started subsequently.

Group 2: Clinical disease progression. A total of 39 patients developed rapid progression of their PSA levels and were treated with hormonal ablation. Of these, 10 (26%) patients died of other causes. The remaining 29 patients continue on therapy and have stable PSA levels and no clinical evidence of disease progression.

Group 3: Observation of PSA progression. A total of 36 patients developed an elevated PSA level that progressed slowly, in a linear fashion thus far, and none of these patients have received adjunctive therapy. Only patients experiencing a geometric rise in their PSA levels were referred to the Division of Hematology/Oncology for HT. Of these, 14 (39%) patients died of other causes.

The only clinical factor that had statistical significance for predicting cancer-specific death in our patients (Group 1) was PSA doubling time and average secondary Gleason value (P<0.01). For the entire group, 94 (46%) have died. In all, 79 (39%) died of other causes and 15 (7%) of prostate cancer. Presently, 90 men (44%) have developed PSA progression and only 26% have received further treatment.

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Discussion

The utility of PSA in the diagnosis and treatment of prostate cancer is well documented. For example, expanded PSA testing through the 1990s has increased the percentage of men with organ confined disease.10, 11, 12, 13 Similarly the 10-y actuarial risk of non-PSA recurrence in a highly selected University practice has changed from 67% (1982–1988) to 80% (1989–1991).14 Although the significance of a nondetectable PSA following RP is well established, the exact clinical significance of a PSA recurrence is controversial. The controversy revolves around the definition of 'treatment failure'. Although PSA elevation following RP most likely represents disease recurrence, there is a question as to whether this represents 'treatment failure' if the patient never requires further treatment intervention. Many urologists and oncologists fear the consequences of a detectable PSA after RP as if it dooms the patient to death from prostate cancer.

There is little information regarding the long-term PSA and clinical outcomes of patients treated primarily with surgery and adjunctive hormonal therapy in nonreferral hospitals. Gerber et al15 reported in 1996 on 2758 men treated for localized prostate cancer with RP. This was a pooled analysis from eight high volume academic centers and no information regarding PSA status was reported. Lu-Yao and Yao16 in 1997 reported long-term survival of prostate cancer derived from nearly 60 000 patients using SEER data. No information was available on the PSA status of these patients or the use of adjunctive therapies. As evidence grows regarding the benefits of early institution of HT especially in patients with locally advanced disease, physicians are faced with little information regarding the timing of its application.17, 18, 19 Of particular interest is the outcome of patients with a PSA recurrence that is simply observed.

Our study reports the experience of a large nonreferral VA hospital between the years 1984 and 1994. Because of the era, one would expect that patients undergoing RP would be older and have higher preoperative PSA levels than the present era. This is indeed reflected in the average age (65.8 y) and preoperative PSA (>15 ng/ml). Further, patients generally did not receive adjunctive radiation therapy, rather HT was the secondary treatment offered. HT intervention was not always executed exactly the same way, but it is accurate to state that patients were started 'early.' The philosophy of the institution over the years has been reasonably consistent in that patients were only started on HT when the PSA began to rise rapidly (geometrically) or if they had high volume disease pathologically (ie positive lymph nodes or seminal vesicles, or high Gleason score). It has not been the policy of the institution to wait until bone metastasis to begin HT.

A total of 204 patients had an RP and to date, 90 patients have (44%) developed a PSA recurrence; 54 or 26% of the entire group required HT (Figure 1). For patients with PSA recurrence, 60% have required HT whereas 40% have been observed without intervention. All of the 11 patients treated with RT came from Group 1 or 2. In all, 15 died of prostate cancer, which constitutes 7% of the entire group or 17% of the patients who developed a PSA recurrence. During the period of observation, 79 of the 204 patients (39%) died of other causes. These results are noteworthy in that a PSA recurrence does not invariably lead to a prostate cancer death and further many patients are safely managed with observation. Our findings give long-term support to the nearly identical short-term results reported by Koch et al.20 With increased application of PSA, patients undergoing RP are younger and they have less disease and lower average preoperative PSA levels. In fact, the average PSA for patients undergoing an RP at our institution is 8.7 ng/ml (data not shown). This, of course, would favorably impact both the PSA recurrence rate and the need for hormonal intervention.

Figure 1.
Figure 1 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

Percentages of Groups 1, PSA rise – treatment failure; 2, PSA rise – treatment responders; 3, PSA rise – no treatment; and 4, no PSA progression after after radical prostatectomy.

Full figure and legend (65K)

Although not the focus of this outcome oriented study, factors that predict a more aggressive cancer were evaluated and are nearly identical to those reported previously. Preoperative PSA, Gleason score, time to first PSA elevation were factors that demonstrated a weak trend to predict progression. Like others, we found that a short PSA doubling time was the best predictor of disease progression.7, 8, 21, 22 Similarly, we found that a long doubling time (>18 months) was most consistent with observing a patient with a PSA recurrence. Figure 2 is a representational graph of the three groups' PSA over time. Figure 2 was generated by utilizing the respective average time to first PSA elevation and the average PSADT for each of the Groups in Table 1. And, as reported by Soergel and associates,23 developing a formula and defining enough points to calculate accurately PSADT was elusive. Interestingly, the VA lab services can electronically graph all PSA levels over time, instantaneously. This allowed us to visually identify when an individual was progressing from a linear to geometric rate of progression (Figure 2). Lastly we found, as previously noted by Koch et al,20 the factors that significantly identified patients at increased risk of short PSADT and disease progression and death was Gleason score (total and secondary).

Figure 2.
Figure 2 - Unfortunately we are unable to provide accessible alternative text for this. If you require assistance to access this image, please contact help@nature.com or the author

A representational graph of the progression for the three groups based on different rates of PSA doubling. Group 1 (PSADT=6 months) generally requires earlier HT, short-term relief of PSA but subsequent failure. Group 2 (PSADT=11 months) has a slower PSA rise prior to hormonal intervention, and is maintained for much greater periods on HT. Group 3 (PSADT=30 months) will have slowly rising PSA values and may not reach a threshold for hormonal intervention for a decade or more.

Full figure and legend (59K)

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Conclusions

We present long-term follow-up that PSA recurrence following RP (even in this high risk/volume group of patients) has variable biological significance. For physicians managing patients with PSA recurrence, PSADT and Gleason score (total and secondary) appear to be important predictors of aggressive behavior. For the era 1984 to 1994, the overall PSA recurrence rate in a nontertiary practice was 44%. Of these patients, 40% with recurrence had a doubling time greater than 12 months and had not yet required further intervention (average follow-up of 10 years) but continue to require careful monitoring.

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References

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