Volume 61, Issue 1, Pages 30-36 (January 2003)

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Failure after radical prostatectomy

Received 1 June 2001; accepted 17 June 2002.

Article Outline

• Predictors of failure

• Preoperative PSA

• Clinical stage

• Postoperative (specimen) Gleason score

• Pathologic stage

• Surgical margin status

• Mathematical models for outcome prediction

• Localization of recurrent or persistent disease

• Digital rectal examination

• Needle biopsy of the urethrovesical anastomosis

• PSA kinetics, pathologic stage, and specimen Gleason score

• Imaging studies

• Additional treatment for unfavorable local pathologic features for cancer recurrence

• Radiotherapy

• Adjuvant RT

• Salvage RT

• Hormonal treatment

• Conclusions

• References

• Copyright

An analysis of a large series of patients who underwent radical prostatectomy (RP) demonstrated that as many as 30% of patients will experience biochemical relapse, as represented by elevation of serum prostate-specific antigen (PSA). Most of the relapses (95%) will occur in the first 5 years. The availability of PSA as a surrogate marker for treatment failure has telescoped the time to progression. However, 10 to 15 years are necessary to ascertain the true clinical progression rate of prostate cancer after RP.1, 2

Recently, Pound et al.3 reported a 15% 5-year biochemical recurrence rate. Obek et al.4 reported a 13% biochemical recurrence rate after a mean follow-up of 2 years, Catalona and Smith5 a 22% rate at 5 years, and Kupelian et al.6 a 19% rate.

The elevation of PSA after RP precedes the clinical recurrence of prostate cancer. According to Pound et al.,3 34% of the patients with biochemical recurrence developed metastases at a median interval of 8 years if therapy at the time of biochemical recurrence was withheld. The median time to cancer-specific death in these patients was 5 years from the development of metastases. Jhaveri et al.7 reported a 90% overall 10-year survival rate after RP. In their series, no difference was found in the 10-year overall survival rate between patients with and without PSA relapse after RP. Consequently, the clinical relevance of the PSA relapse as a surrogate endpoint of RP has yet to be established, and a detectable PSA level after RP remains a therapeutic dilemma. Faced with an elevated PSA level after surgery, 50% of urologists recommend observation, 30% recommend some form of hormonal ablation, and the remainder recommend radiotherapy (RT).1 This reflects a lack of consensus in the treatment of patients with PSA relapse after RP.

Predictors of failure

Preoperative PSA

According to some, the preoperative PSA level is the most important single preoperative prognostic factor with respect to postoperative biochemical recurrence (Table I). 2, 5, 6, 8, 9

TABLE I.

Biochemical (PSA) recurrence rates after RP according to preoperative PSA level


Source	PSA (ng/mL)	Recurrence (%)
Source	PSA (ng/mL)	5 yr	10 yr
Catalona et al.5	≤10	7	—
	>10	30	—
Kupelian et al.6	≤20	40	—
	>20	70	—
Lerner et al.8	≤10	20	—
	>10	40	—
Pound et al.3	≤10	—	25
	>10	—	70
Partin et al.9	≤10	20	30 (7 yr)
	>10	50	50 (7 yr)

Key: PSA = prostate-specific antigen; RP = radical prostatectomy.

Clinical stage

The determination of the clinical stage rests on the digital rectal examination (DRE) and together with other prognostic factors is included as an important part of the nomograms predicting pathologic stage and biochemical recurrence.8, 10

Postoperative (specimen) Gleason score

The postoperative Gleason score is one of the most powerful independent prognostic factors (Table II). There is an inverse correlation between the Gleason score and the biochemical and metastasis relapse-free rate.2, 5, 8, 9, 11 According to Pound et al.,3 patients with PSA relapse after RP had a 73% chance of being free from metastases 5 years after PSA recurrence if the Gleason score was 7 or less and only a 40% chance if the Gleason score was greater than 7.

TABLE II.

Biochemical (PSA) recurrence and metastasis rate after RP according to postoperative Gleason score


Source	pGS	R (%)	M+ (%)	Follow-up (yr)
Lerner et al.8	6	25	—	5
	7	40	—	5
	>7	55	—	5
Kupelian et al.6	<7	20	—	5
	≥7	55	—	5
Pound et al.2	≤7	20	5	5
		35	15	10
	>7	55	25	5
		70	60	10
Partin et al.9	≤6	15	—	5
		30	—	10
	7	40	—	5
		50	—	10
	>7	45	—	5
		85	—	10
Epstein et al.11	≤6	5	—	4
		15	—	10
	7	25	—	4
		50	—	10
	>7	40	—	4
		65	—	10

Key: pGS = postoperative Gleason score; R = recurrence; M = metastasis; other abbreviations as in Table I.

Pathologic stage

There is an inverse correlation between the pathologic stage and biochemical recurrence-free rate (Table III). 2, 5, 11, 12, 13 The extent of capsular penetration also has prognostic importance, with focal capsular penetration conferring a 65% 7-year biochemical progression-free rate and extensive capsular penetration only 40%.2, 13

TABLE III.

Biochemical recurrence and metastasis rate after RP according to pathologic stage


Source	pT Stage	R (%)		M (%)
Source	pT Stage	5 yr	10 yr	5 yr	10 yr
Kupelian et al.6	pT2	15	—	—	—
	pT3a-b	52	—	—	—
Pound et al.2	pT2	5	10	1	1
	pT3a-b	20	35	2	10
	pT3c	50	70	8	23
	N+	75	—	5	32
Epstein et al.11	pT2	2	15	—	—
	pT3a-b	22	42	—	—
Stein et al.12	pT2	—	15	—	—
	pT3a-b	—	40	—	—

Abbreviations as in Table II.

Surgical margin status

Between 30% and 40% of the patients with positive surgical margins (SMs) develop recurrence after RP. In a review of several large series, Wieder and Soloway14 noted that 28% of patients after RP had positive SMs and that SM status represents a significant independent prognostic factor for biochemical recurrence.

Obek et al.4 reported that patients with positive SMs had a fourfold biochemical recurrence rate compared with patients with negative SMs (28% versus 7%, respectively).

Grossfeld et al.15 showed that patients with positive SMs have three times the biochemical relapse risk of patients with negative SMs.

The site and the number of positive SMs are also important. Positive SMs at the bladder neck or at the posterolateral border of the prostate, as well as multiple positive SMs, are independently associated with a shorter time to recurrence.4, 14

Mathematical models for outcome prediction

Since it became evident that no single decisive prognostic factor could be identified, efforts have been made to design mathematical models that would evaluate the joint effect of the most significant individual prognostic factors and would permit the approximation of a patient’s outcome.

Partin et al.10 developed a nomogram using preoperative PSA, Gleason score, and clinical stage. The clinician or patient can derive the estimated pathologic stage of the tumor. This was an important step in providing the patient with the data necessary for informed decision making and the clinician in considering among the therapeutic alternatives. Kattan et al.16 produced a validated (nomogram) mathematical model based on all the above-mentioned prognostic factors. Using this model one can approximate the 7-year biochemical recurrence-free rate probability after RP.

Localization of recurrent or persistent disease

Differentiating local recurrence from distant progression may be important if one contemplates additional treatment.

Digital rectal examination

The DRE is not very reliable for detecting recurrent or persistent prostate cancer. However, serial examinations in the context of a detectable postoperative and rising PSA level may be helpful. The DRE is virtually never abnormal if the PSA level is undetectable.17, 18

Most of the RP series with long-term follow-up have a clinical local recurrence rate (DRE diagnosed) of less than 5%.6, 17, 18, 19, 20 It is difficult to obtain a true incidence of local recurrence because of the limitations of the direct diagnostic methods when the PSA value is elevated and the DRE is normal.

Needle biopsy of the urethrovesical anastomosis

The probability of obtaining a positive biopsy on the basis of a detectable postoperative PSA level with or without an abnormal DRE is 30% to 50%.21, 22 If multiple sets of biopsies are performed, the probability of obtaining a positive biopsy may be higher.22, 23 Clinical parameters that predict a positive biopsy are a PSA level greater than 1 ng/mL and Stage pT3.23, 24 Urethrovesical anastomosis biopsy is not routinely performed. Recently, Koppie et al.25 reviewed a series of 67 patients that received salvage RT for PSA relapse after RP. No difference in the biochemical relapse rate after RT was noted between patients who underwent RT as determined by a positive urethrovesical anastomosis biopsy and those for whom the decision was made only on the basis of a rising PSA. A negative biopsy does not rule out local recurrence and a positive biopsy does not exclude systemic disease.

PSA kinetics, pathologic stage, and specimen Gleason score

If the PSA does not reach an undetectable level after RP or becomes detectable in the first year after RP, the recurrent disease is most probably systemic. After surgery, a PSA velocity of greater than 0.75 ng/mL/yr and a PSA doubling time (PSADT) of less than 6 to 10 months have been shown to correlate with systemic relapse. Conversely, if the PSA velocity is less than 0.75 ng/mL/yr or the PSA becomes detectable more than 1 to 2 years after RP and the PSADT is greater than 1 year, the clinical relapse is more likely to be local. Positive SMs and Stage pT3a-b correlate with local recurrence and pT3c (seminal vesicle invasion) and positive lymph nodes with systemic relapse.19, 20, 21, 26

The post-RP specimen Gleason score has been shown to correlate with the site of clinical relapse. A Gleason score of 7 or less correlates with local relapse and a Gleason score greater than 7 with systemic relapse.2, 3 Patients with a Gleason score of 7 or less and with a PSADT of less than 10 months have a 65% chance of metastases at 5 years after PSA relapse compared with only 25% if the PSADT is greater than 10 months.3

Imaging studies

Computed tomography in the context of a rising PSA after RP has limited value unless the PSA level is high.27

Bone scanning may be part of the evaluation of a patient whose PSA becomes detectable after RP. However, some investigators suggest the bone scan will be negative until the PSA level reaches 30 ng/mL.3, 21

The radiolabeled anti-prostate-specific membrane antigen antibody scan (ProstaScint or indium-111 capromab pendetide scan) was approved by the Food and Drug Administration for the evaluation of post-RP patients with biochemical relapse. At the time of the approval, the sensitivity, specificity, and overall accuracy was 62%, 72%, and 68%, respectively.28 Patients with a PSA relapse after RP in whom the ProstaScint scan is positive for extraprostatic fossa sites have a 30% response rate to salvage RT as opposed to a 70% response rate in patients with a negative ProstaScint scan for extraprostatic fossa sites.29 With good expertise and together with other clinical data, the ProstaScint scan may provide diagnostic and prognostic information for patients with a rising PSA after RP and may refine the selection for salvage RT of patients with PSA relapse.

Additional treatment for unfavorable local pathologic features for cancer recurrence

Radiotherapy

RT can be administered as adjuvant treatment 3 to 6 months after RP in patients with unfavorable pathologic features such as extracapsular disease (pT3) or positive SMs or as salvage therapy at the time of biochemical or clinical recurrence.

Adjuvant RT

Patients with pathologic adverse features such as multiple and/or extensive positive SMs or positive SMs at the prostate base but with small probability of concomitant systemic disease may benefit from adjuvant RT.30 The biochemical recurrence-free rate with adjuvant RT in patients with positive SMs is between 70% and 90% at 5 years and 60% at 10 years.14, 30, 31 On the other hand, because only 30% to 40% of patients with positive SMs eventually develop recurrence after surgery without additional treatment, 60% to 70% of patients with positive SMs would receive adjuvant RT unnecessarily.14 With respect to pT3 cases, it seems that better local control is achieved with adjuvant RT (90% versus 60% at 5 years) and the biochemical relapse rate also seems to be lower (90% versus 40% at 5 years)12, 32, 33, 34, 35 (Table IV).

TABLE IV.

Biochemical recurrence rate after adjuvant RT according to pT stage


Source	Indication (pT)	R(%)	Follow-up (yr)
Petrovich et al.33	pT3a-c	50	10
Leibovich et al.30	SM+	20	5
Valicenti et al.35	pT3c	15	3
Valicenti and Gomella37	pT3a-b	11	5
Vicini et al.32	pT3a-c	33	5
Grossfeld et al.36	SM+	20	4
Morris et al.31	SM+ and pT3c	12	3

Key: RT = radiotherapy; R = recurrence; SM = surgical margin.

Grossfeld et al.15, 36 recently published a decision analysis model and pointed out that patients with multiple positive SMs, Gleason score of 7 or less, and negative seminal vesicle invasion were most likely to benefit from adjuvant RT.

Leibovich et al.30 demonstrated in a matched group analysis that adjuvant RT in patients with positive SMs significantly reduces the biochemical and clinical relapse rate (12% versus 41% and 0% versus 16%, respectively).

Valicenti and Gomella37 in a matched pair analysis of patients with pT3 disease concluded that adjuvant RT improved the 3-year biochemical relapse-free rate from 48% to 86%. A radiation dose greater than 61 Gy correlated with significantly better results.34 Early adjuvant RT in patients with positive seminal vesicles (Stage pT3c) and with an undetectable post-RP PSA level rendered 86% of the patients disease free 3 years after RT. Of the patients with pT3c disease not receiving adjuvant RT, only 38% remained disease free.35

Salvage RT

Rogers et al.38 reported a 48% 3-year second PSA relapse-free rate after RT in patients with biopsy-proved local recurrence after RP (Table V). A Gleason score of 7 or less and a pre-RT PSA level less than 4 ng/mL were predictors for durable RT results.38

TABLE V.

Biochemical recurrence rate after salvage RT at biochemical and/or clinically diagnosed local recurrence after RP*


Source	Recurrence (%)	Follow-up	Comment
Grossfeld et al.15	54	39 mo	Review paper
Vicini et al.32	84	5 yr	—
Tiguert et al.40	36	4 yr	If pre-RT PSA <2 ng/mL and no pT3c or N+, 18% recurrence rate vs. 60% if PSA >2 ng/mL and pT3c and N+
	50	36 mo	pT3c
Schild et al.42	50	5 yr	If pre-RT PSA <1 ng/mL, 25% recurrence rate
			If pre-RT PSA >1 ng/mL, 75% recurrence rate
			Dose >64 Gy
Garg et al.43	32	3 yr	If pre-RT PSA <2 ng/mL, 22% recurrence rate
			If pre-RT PSA >2 ng/mL, 70% recurrence rate
Morris et al.31	32	3 yr	—

Abbreviations as in TABLE I, TABLE IV.

PSA level at RT is an important prognostic factor with respect to outcome.

According to Pisansky et al.,39 salvage RT rendered 46% of the patients biochemically relapse free at 5 years. Seminal vesicle invasion, Gleason score, and, most importantly, the pre-RT PSA level were significant prognostic factors for the post-RT PSA relapse-free rate.39

The pre-RT PSA is the most important single parameter determining the success of salvage RT according to Tiguert et al.40 A PSA level less than 2 ng/mL correlated with a 74% 4-year second biochemical relapse-free rate versus only 22% if the pre-RT PSA was greater than 2 ng/mL. Patients with positive seminal vesicle invasion had a 50% chance of being free of a second PSA relapse if the pre-RT PSA was less than 2 ng/mL.40

Nudell et al.41 and others also showed that if the PSA level was less than 1 ng/mL, patients with biochemical recurrence after RP treated with salvage RT had the same second biochemical relapse-free rate as patients treated with adjuvant RT.42, 43

The American Society for Therapeutic Radiology and Oncology Consensus Panel concluded that prospective randomized studies are necessary for an actual consensus regarding the issue of salvage RT for a rising PSA level after RP. However, it seems reasonable to defer RT until biochemical failure is evident and initiate it before the PSA reaches 1.5 ng/mL, especially if the patient fulfills the clinical and pathologic criteria for local recurrence. The RT dose should be at least 64 Gy.44 At present, there is no standard role for concomitant hormonal therapy in patients who undergo salvage RT for a rising PSA after RP. In this setting, the use of hormones together with RT is still investigational.44

Hormonal treatment

Most information on androgen deprivation therapy (ADT) is on patients with clinically detectable metastases or with positive lymph nodes and not with PSA recurrence without clinically detectable cancer.

Luteinizing hormone-releasing hormone agonists or orchiectomy with or without antiandrogen agents are considered the most effective form of hormonal therapy for metastatic prostate cancer. In the context of biochemical evidence of recurrent or persistent cancer only after RP, extrapolation of the mentioned data must be made carefully. According to the data from general oncology on systemic cancer, a low volume and good performance status are considered prerequisites for better results with adjuvant systemic therapy. Patients with systemic recurrence suggested only by a rising PSA could be the patients with the optimal tumor–volume situation for ADT.45, 46

In their recent report of patients with positive lymph nodes at the time of RP, Messing et al.47 reported significantly better cancer-specific survival in patients who were treated with ADT immediately after surgery. In these patients, the median PSA level before surgery was 19 ng/mL, and 80% of the patients had an undetectable PSA level after surgery. This information may support early ADT in some patients with biochemical recurrence after RP.

On the other hand, with the recently reported survival rates after RP, the wide use of ADT in patients with a postoperative elevated PSA could be challenged if we consider survival as the endpoint of the therapy.3, 7 In the general clinical situation, however, many patients are psychologically stressed by elevated PSA levels, and they may pursue means to reduce it.46

Because of the side effects of long-term ADT, such as diminished libido and erectile function, vasomotor hot flushes, asthenia, loss of muscle mass, anemia, and changes in bone density, intermittent ADT or nonsteroidal, antiandrogen monotherapy may be an alternative.

Intermittent androgen suppression or cyclic hormonal therapy aims to delay progression to androgen-independent tumor cell clones and enable recovery of the apoptotic potential of the prostate cancer cells.48 At the same time, it improves the quality of life through the reduction of the androgen suppression side effects. The “on therapy time” is reduced to 50%. Goldenberg et al.49 and Zerbib and Conquy50 reported an improved quality of life in 90% and 80%, respectively, of the patients with metastatic prostate cancer receiving intermittent hormone therapy. Therapy cycles of at least 6 to 9 months with luteinizing hormone-releasing hormone agonists are recommended. Initially with locally advanced and metastatic prostate cancer, therapy was given until the PSA level reached its nadir and was restarted when the PSA reached 10 to 20 ng/mL.51 In the cases of biochemical recurrence after RP, the patients are empirically re-administered hormonal therapy when the PSA reaches 4 to 5 ng/mL.52

Nonsteroidal antiandrogen monotherapy with bicalutamide (Casodex 150 mg/day) has been recently evaluated and found to have the same effect as castration on patients free of metastases with locally advanced disease.53 Given the minimal tumor burden associated with PSA recurrence after RP, antiandrogen monotherapy seems a reasonable choice.52

Finasteride (5-alpha-reductase inhibitor) has been evaluated alone and in combination with flutamide.54, 55 The reduction in the levels of dihydrotestosterone caused by finasteride increase the availability of the dihydrotestosterone receptors for the antiandrogen agent, causing a synergism between the two drugs that may result in a 90% reduction of the PSA.52

In which patients, when and if at all, an aggressive adjuvant or salvage approach is justified at the time of PSA relapse is still debatable.

Patients with clinically localized prostate cancer and with PSA relapse after RP have a good overall survival rate, comparable at 10 years of follow-up with patients without biochemical recurrence. Salvage RT can be contemplated if the clinical and pathologic parameters suggest a high probability of local recurrence. RT should be implemented preferably when the PSA level is still less than 1.5 ng/mL. The ProstaScint scan may have a role in further refining the selection of patients for salvage RT. Other options, such as continuous or intermittent hormonal therapy and follow-up only (deferred hormonal therapy) should be carefully discussed with the patient because of the recently published landmark data that underscored the good 10-year overall survival of patients undergoing RP for clinically localized prostate cancer.

Conclusions

An elevated or detectable PSA level after RP for prostate cancer signifies in the great majority of the cases recurrent or persistent disease. The time lag between the biochemical and clinical manifestation of the disease may be as long as 5 to 8 years, followed by an additional 5-year median time to metastases and another 5-year median time to cancer-specific death. RT may be beneficial as adjuvant or early salvage treatment if the PSA level is less than 1.5 ng/mL and for patients with a high probability of local recurrence. Early salvage RT is a more acceptable option than adjuvant RT, saving 70% of patients with adverse pathologic features unnecessary treatment. Hormonal therapy at the time of biochemical relapse is justified in selected patients.

These statements are correct if the biochemical recurrence-free status is the measure of the treatment’s success. In most patients, however, the clinical relevance of these facts with respect to, and measured by, an improved cancer-specific and overall survival together with an acceptable quality of life has yet to be studied.

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a Department of Urology, Soroka Medical Center, Ben Gurion University, Beer Sheva, Israel

b Department of Urology, University of Miami School of Medicine, Miami, Florida, USA

Reprint requests: Mark S. Soloway, M.D., Department of Urology, University of Miami School of Medicine, P.O. Box 016960 (M814), Miami, FL 33101, USA

PII: S0090-4295(02)01918-0

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