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Keywords:

  • prostate cancer;
  • treatment;
  • radical prostatectomy;
  • hormonal therapy;
  • follow-up;
  • randomized trial

Abstract

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

Objective  To describe the outcome, assessed as the level of prostate specific antigen (PSA), of a mature (more than half the events recorded) prospective randomized study with a median follow-up of 82 months of neoadjuvant hormonal therapy before radical prostatectomy, as this has been suggested to decrease the rate of positive surgical margins (i.e. provide greater potential to completely excise the tumour).

Patient and methods  From December 1991 to March 1994, 126 patients with clinically localized prostate cancer were randomized between direct radical prostatectomy or a 3-month course of a gonadotrophin-releasing hormone analogue before surgery. The patients were followed by PSA determinations and a value of > 0.5 ng/mL used to define progression.

Results  The incidence of positive surgical margins decreased from 45.5% to 23.6% ( P  = 0.016) with hormone treatment. Despite this there was no difference in PSA progression-free survival at the last follow-up; it was 51.5% for those undergoing radical prostatectomy only and 49.8% for those who received hormonal pretreatment ( P  = 0.588).

Conclusions  Three months of neoadjuvant hormonal therapy before radical prostatectomy offers no benefit to the patient and cannot be recommended for routine clinical use.


Introduction

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

For patients with presumed localized prostate cancer, radical prostatectomy (RP) offers the possibility of cure if negative surgical margins can be achieved [1,2]. This seems to be true also in patients with more advanced pathology, i.e. poor differentiation [3] or high stage [4]. In 1944, Vallett [5] reported a patient with prostate cancer who had hormonal therapy before radical surgery to achieve better local tumour control. In a retrospective analysis, Scott and Boyd [6] found that half of treated patients survived ≥ 10 years and 29% for ≥ 15 years, with no evidence of prostate cancer, after a combination of hormonal therapy started before surgery and RP. The method of delivering hormonal therapy was either orchidectomy or oestrogen therapy, both of which were continued. The side-effects associated with the hormonal therapy, together with the morbidity of the surgery, hampered the widespread use of this combined therapy.

The introduction of LHRH analogues has allowed temporary hormonal withdrawal; this has been used as neoadjuvant hormonal therapy (NHT) before RP. Initial results from unrandomized series indicated a higher chance of achieving complete tumour excision (negative surgical margins) with the use of NHT than for historical controls [7,8]. This finding has been confirmed in randomized controlled trials, where six of seven studies to date indicated a significant lowering in the rate of positive surgical margins [9].

Thus the key question is whether this lower rate of positive surgical margins after NHT provides better disease-free survival. Several randomized studies with a short follow-up (2–4 years) have shown no difference in PSA progression between RP with or with no 3-month NHT [10–13]. The possible conclusions from these trials are hampered because there are no studies published with a follow-up of > 4 years. The aim of the present report is to describe the PSA outcome of a mature (more than half the events recorded) prospective randomized study with a median follow-up of almost 7 years.

Patients and methods

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

Five urological clinics were involved in this multicentre study. Patients with newly diagnosed, clinically localized prostate cancer were asked to participate after giving informed consent. Those who accepted were randomly assigned to NHT with monthly injections of a GnRH-analogue (triptorelin 3.75 mg intramuscular) for 3 months, followed by a retropubic RP (NHT group) or direct RP (RP group). Patients in the NHT group also received steroidal antiandrogen (cyproterone acetate 50 mg twice daily) for prophylaxis against flare 1 week before and 2 weeks after the first injection. The study protocol was approved by the ethical committee at Linköping University. There was no registration of the patients who did not accept participation in the study.

The inclusion criteria were: tumours classified as T1b-T3aNXM0, (i.e. impalpable tumour occupying > 5% of the resected specimen, or detected by needle biopsy, or palpable or visible tumours judged to be intracapsular, or with unilateral extracapsular growth, regional lymph nodes not assessed (NX), no distant metastasis (M0) [14]), of any grade, any PSA level, age < 75 years and a life expectancy of > 10 years. The disease was diagnosed by pathologists at the various hospitals and tumours graded according to the WHO [15] or Gleason system [16]. Patients were prepared to accept the expected side-effects of triptorelin and radical prostatectomy. The exclusion criterion was any former treatment against prostate cancer, except TURP. Patients underwent RP between December 1991 and March 1994.

The study was initially designed and powered to examine whether a 3-month course of NHT had any effect on the rate of positive surgical margins (i.e. if the cancer could be excised completely). All removed prostates were assessed by central pathological review by one pathologist (S.L.). The results from this first part of the study showed that the rate of positive surgical margins was significantly lower after NHT (23.6% vs 45.5%; P= 0.016; [17]).

The present report describes an ad-hoc protocol in which all patients were followed with a clinical examination and measurements of serum PSA level. All patients randomized (randomization stratified by T1 vs T2/T3 per centre) were included in the final analysis (intention-to-treat). The cumulative risk of progression was calculated with the Kaplan-Meier estimates and differences between the groups assessed by the Mantel-Cox log-rank test. Patients who were not in progression were censored at their last visit, or at death if they died from unrelated causes with no known progression; the trial profile is described in Fig. 1.

image

Figure 1. The study design. *Two patients continued with hormonal therapy only, one for a newly diagnosed aortic stenosis and one by preference. One patient chose external beam radiation instead of surgery.

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Patients were followed at regular intervals and PSA estimated using monoclonal antibody-based assays and a reference value of < 4 ng/mL. Values of > 0.5 ng/mL were defined as indicating biochemical progression (PSA relapse). This threshold (> 0.5 ng/mL) is in accord with a recent report including 2782 patients, where different thresholds for the definition of biochemical failure after RP were assessed [18]. The institution of any external beam radiation or hormonal therapy after surgery was based on individual clinical judgement and not as part of the protocol.

Results

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

There were no differences between the groups in age, pretreatment serum PSA level, tumour classification and tumour grade (Table 1). All patients were followed according to the ad hoc protocol, in which they were carefully evaluated for toxicity of the NHT that was used. Except for the expected effects of androgen withdrawal, no unexpected severe toxicity, e.g. fluid retention or thrombo-embolic complications, were noted.

Table 1.  The pretreatment characteristics of the 126 randomized patients, and the adjuvant therapy given against prostate cancer during the follow-up, with the patient status at the last visit
VariableNHT (63)RP (63)
  • *

    One PSA value missing.

Mean (range):
Age, years67 (50–77)66 (54–77)
PSA, ng/mL12.0 (1.5–210.0)11.2 (0.8–130.0)
T-stage, n
T1b–T1c1015
T2a1010
T2b–T3a4338
PSA groups*(n), ng/mL
0–9.92530
10–19.92220
20–49.91310
> 50 3 2
Tumour grade, n
1/ Gleason 2–4 2 1
2/Gleason 5–62622
3/Gleason 7–103540
Adjuvant therapy
radiotherapy1010
hormonal therapy1917
Status at last visit
Tumour-free2834
PSA progression only2118
Metastases 3 2
Dead from prostate cancer 3 3
Dead from other causes 8 6

Adjuvant therapy given during the follow-up and the status of the patients at the last visit indicated that the fate of the patients was equal in both groups (Table 1). The median (range) follow-up was 82 (8–104) months; there was no difference in crude survival among the groups (Fig. 2a). PSA progression-free survival was also equal between the groups, irrespective of whether an intention-to-treat analysis was used (Fig. 2b) or if only the subgroup of patients who underwent RP was analysed (Fig. 2c).

imageimageimage

Figure 2. a, Crude survival (126 patients; P  = 0.513), b, progression-free survival (126 patients; P  = 0.588) and c, progression-free survival in node-negative patients who underwent RP (112 patients; P  = 0.633), for the NHT group (open green circles) and the RP group (closed red circles).

Discussion

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

The present results indicate that there is no advantage in using the combination of a 3-month course of NHT and RP over RP alone. Initial results from unrandomized series indicated a greater chance of complete tumour excision (negative surgical margins) with the use of NHT then in historical controls [7,8,19]. These results provoked several randomized series; in five of six studies the lower incidence of cancer growth in the surgical margin after NHT was confirmed (Table 2) [20–23] but Dalkin et al.[24] were unable to detect a difference, although this was also the smallest study, including only 56 patients.

Table 2.  Surgical margins; the outcome of randomized studies with 3 months of NHT before RP
StudyN% positive marginsSignificant?
NHTRP
[20]2542746Yes
[21]161 834Yes
[22]2821848Yes
[17]1112341Yes
[23]1922865Yes
[24] 561814No

PSA is a reliable surrogate endpoint in trials in prostate cancer involving RP. After surgery a PSA value of > 0.4 ng/mL (monoclonal assay) is a good marker for persistent or relapsing disease, with ≈ 80% of patients needing therapy or having a continuous rise after reaching this threshold [18]. However, the median time from elevation of serum PSA until clinical progression (metastatic disease) was on average 8 years in another series, during which the patient was left with no adjuvant treatment [25].

The present randomization procedure resulted in well-balanced groups before surgery for known risk factors for progression (Table 1). Even if further therapy was left to the clinician, both groups received the same number of such treatments (Table 1) and thus this factor should not have affected the comparisons between the groups.

Comparing the present PSA progression-free survival with other reports, all of which have a shorter follow-up, the results agree completely. Klotz et al.[11] followed 213 patients randomized between RP or a 12-week course of cyproterone acetate before surgery. With a follow-up of 36 months the risk of PSA progression was no different from the control arm (30.1% vs 40.2%; P = 0.323). The follow-up of the USA T2b [12] trial showed no difference in PSA relapse after 42 months. Also, the largest study so far, the European multicentre study, including 402 patients, failed to detect any difference in PSA progression-free survival after a median follow-up of 4 years (26.4% vs 32.5%; P = 0.19) [13].

Two larger unrandomized series are available for comparison. Fair and Betancourt [26] recently updated the Memorial Sloan-Kettering experience with NHT. In that unrandomized study 520 patients received NHT for 3–11 months and were compared with 1413 patients operated upon with no pretreatment; the median follow-up was 34 months. Extensive subgroup analysis showed no difference in overall disease-free survival, nor in any subset of the patients [26]. The same negative result was reported by Meyer et al.[27], who followed 680 men, of whom 292 received NHT with no randomization. After a median follow-up of 38 months there was no difference in PSA failures between the groups, despite a lower incidence of positive surgical margins after NHT.

That 3 months of NHT was associated with a significant decrease in positive surgical margins, but that this did not translate into better biochemical control, is somewhat contradictory. The reasons are multifactorial but probably mostly related to the severe histopathological changes induced by the hormonal deprivation [28,29]. We earlier described more severe hormone-induced histopathological changes in those patients who had negative margins after NHT than in those who had positive margins despite the treatment. Wrongly, we interpreted these finding as down-staging [17]; however, these extensive regressive changes can mislead the pathologist when evaluating the margin status, even if the pathologist is experienced in evaluating these cases. Bazinet et al.[30] showed that cytokeratin staining may be used to better assess the margin status after hormonal therapy; the rate of positive margins increased from 13% to 22% with the use of cytokeratin staining when compared to routine staining with haematoxylin and eosin. This information was not available when the margin status was evaluated in the present series.

The general discussion is only valid for a comparatively short (6–12 week) course of NHT; recently, Gleave et al.[31] updated their study including 156 men who received 8 months of NHT. After a median follow-up of 54 months, the overall PSA recurrence rate was low, at 12.2%. The same group also presented a randomized study comparing 3 and 8 months of NHT. The preliminary results indicate that the rate of positive surgical margins may be significantly less, from 17% to 5% [32]; no follow-up results are yet available from this study.

The two unrandomized studies discussed above assessed the duration of NHT in their subgroup analysis and found conflicting results. Meyer et al.[27] found an advantage for the longer treatment when combined antiandrogen and LHRH were used, while there was no such difference in the Sloan-Kettering series [26].

The main weakness of the present study is that it was designed and powered to evaluate differences in the surgical margins, as shown in Table 2. Thus the study cannot stand alone but must be judged with other similar reports. When comparing the present well-balanced groups, the progression-free survival curves cross over and there is no tendency to differ between the groups. We consider that the results from the present study, with the other reports, support our conclusion, i.e. a 3-month course of a GnRH-analogue before RP does not affect the subsequent risk of PSA progression and thus it cannot be recommended for clinical use. Current studies will show whether longer hormonal pretreatment will give better results.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

Financial support was received from Ferring Pharmaceuticals, Malmö, Sweden during the conduct of treatment but not during the follow-up.

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Authors

  1. Top of page
  2. Abstract
  3. Introduction
  4. Patients and methods
  5. Results
  6. Discussion
  7. Acknowledgements
  8. Authors

G. Aus, MD, Associate Professor.

P.-A. Abrahamsson, MD, Professor.

G. Ahlgren, MD, PhD.

J. Hugosson, MD, Professor.

S. Lundberg, MD.

M. Schain, MD.

S. Schelin, MD.

K. Pedersen, MD, PhD.

Abbreviation
NHT

neoadjuvant hormonal treatment

RP

radical prostatectomy.

Gunnar Aus, Department of Urology, Sahlgrens University Hospital, S-413 45 Göteborg, Sweden. e-mail: gunnar.aus@vgregion.se