British Journalof Urology (1993), 71,721-727 0 1993 British Journalof Urology

Audit and its Impact in the Management of Early Prostatic Cancer

A. RANA, G. D. CHISHOLM, S. CHRISTODOULOU, MARGARETA. MclNTYRE and R. A. ELTON

University Department of SurgerylUrology and Department of Pathology, Western General Hospitaland Medical Statistics Unit, University of Edinburgh, Edinburgh

Summary-An analysis was made of a prospective database of 614 men with newly diagnosed carcinoma of the prostate who presented between January 1978 and December 1990; 3-monthly updates were available on their clinical, haematological and biochemical parameters and 6-monthly updates on chest X-rays, bone scans and skeletal X-rays. It was found that 107 men (mean age 73.5 years) had early disease at presentation. Their management was based on regular surveillance and the treatment deferred until disease progression or development of symptoms. The audit of outcome measured various clinical events. Four patients (3.7%) developed local failure, 11 (10.3%) developed bone metastases, 3 (2.8%) died of cancer with a median survival of 6.3 years, and 34 (31.8%) died of intercurrent disease with a median survival of 2.6 years. The observed survival for 12 years of the whole group was similar to the expected survival for an age-matched population in Scotland. The standardised mortality ratio was 8 1 (95% confidence limits 57-1 12).

The fact that there are several standard methods of treatment of early cancer of the prostate (CAP) indicates that sharp divisions exist over selection of patients and choice of treatment. It is claimed that radical prostatectomy offers better “disease- free survival” in selected patients (Elder et d., 1982; Walsh and Lepor, 1987; Paulson et al., 1990; Walsh, 1990; Smithetal., 1991), whileothers prefer radical radiotherapy (Hanks et al., 1987 ; Pilepich et al., 1987; Bagshaw et al., 1990). Many patients who undergo radical prostatectomy for presumed early cancer, and are often found to have clinical understaging of their tumour, are then treated with radiotherapy. Thus radical prostatectomy and adjuvant radiotherapy have also been recom- mended to ensure yet more radical extirpation of tumour (Kwon et al., 1991).

In contrast to these ablative procedures, many centres prefer a policy of no immediate active treatment for early CAP (George, 1988; Adolfsson

~

Read at the 48th Annual Meeting of the British Association of Urological Surgeons in Bournemouth, June 1992

etal., 1992; Johanssonetal., 1992). Thisdepartment has followed a conservative approach and estab- lished a database in 1978 to monitor the outcome. Patients with early CAP are kept under regular surveillance and treated only when there is progres- sion of disease or development of symptoms. Has this approach been justified? In order to answer this question we have analysed our database of a consecutive series of 614 men with newly diagnosed CAP and examined the results in 107 men with early CAP with particular emphases on local failure, metastatic progression and overall survival com- pared with an age-matched population.

Patients and Methods

Data were collected on a prospective cohort of 614 consecutive men with newly diagnosed cancer of the prostate presenting between January 1978 and December 1990. They were classified according to the TNM system as having TO-T4, NX, MO or M1 disease (Wallace et al., 1975). T category was recorded by digital rectal examination (DRE) under anaesthesia prior to transurethral resection of the prostate (TURP) or retropubic enucleation of the

721

722 BRITISH JOURNAL OF UROLOGY

*. *. *.* **. was calculated. Kaplan-Meier (1958) estimates of

*. survival were calculated for 2 separate outcomes: 5 1..

tumour. Histological confirmation of cancer, the Results

-

Gleason sum score (Gleason, 1966) and the per- centage of cancer in the total amount of tissue removed were confirmed by one pathologist (M.A.M.). Blood samples were taken prior to DRE and serum markers were measured. Following confirmation of the diagnosis, the metastatic status was established with 99mTc-labelled bone scans, skeletal and chest X-rays. Tomography, bone biopsy and marrow examination were seldom required.

Early cancer is defined as either incidental (TO/ stage A) or localised (Tl/stage Bl/B2), non- metastatic (MO) disease with normal serum pros- tatic acid phosphatase (PAP). A total of 102 men with incidental cancer and 5 with T1 cancer fulfilled these criteria. Their mean age was 73.5 years at presentation. Following confirmation of the diag- nosis and clinical staging their treatment was deferred. They were monitored every 3 months in a dedicated prostate cancer clinic for clinical assess- ment, routine blood tests and measurement of serum markers. Chest X-rays, skeletal X-rays and bone scans were performed every 6 months (earlier if indicated). Urinary flow rates and residual volumes were assessed if outflow obstruction was suspected.

These men were treated when there was progres- sion of disease and/or development of symptoms. Progression was defined as the development of metastases (Ml) or elevation of PAP to more than 2 u/l. Treatment varied from palliative radiother- apy for isolated painful metastatic sites to hormonal maniwlation for disseminated disease. Active

death, either cancer-specific or non-cancer, and disease progression. Expected survival was calcu-

*

0.25-

lated using the person-years method applied to the male population of Scotland in 1985 (Registrar General, Scotland, 1985). The patients were strati-

0.00 fied into groupsdefined by age at diagnosis, Gleason

Following deferred treatment for early cancer, 23,’ 107 patients (21.5%) developed disease progression with bony or parenchymal metastases (Ml) (1 1/23 1 and/or elevated PAP (Mla) (12/23). Three of these 23 men (13%) died with cancer and 5 (21.7%) died with intercurrent disease. The median survival of patients in the progression group was 5.8 years. Despite non-progression in 84 men, 29 (34.5%) died with intercurrent disease. None of the non-progres- sion group had cancer-related deaths and their median survival was 2.9 years. The average Gleason sum was 5-7 in the progression group and 2-4 in the non-progression group, but the percentage of cancer in the tissues was identical (5-50%) in both groups. Four men (3.7%) developed local failure, defined as active surgical intervention required for urethral or ureteric obstruction (TURP, urethrot- omy, nephrostomy or ureteric stents).

Of the total study group, 3 (2.8%) died from cancer with a median survival of 6.3 years and 34 (31 3%) died from intercurrent disease with a median survival of 2.6 years. The 3 men who died from cancer were 82, 82.6 and 86 years of age at death. The observed survival of the whole group was similar to the expected survival for an age- matched population in Scotland (Fig. 1); 45.55 deaths were expected as compared with 37 ob- served, giving a standardised mortality ratio of 81 (95% confidence limits 57-1 12).

Fifteen men were under the age of 65 at the time of presentation. The observed survival for this group was better (Fig. 2) when compared with the

-a. -. .. -*.

-.

-Observed _..._ Expected

I 0 2 4 6 8 10 12

AUDIT AND ITS IMPACT IN THE MANAGEMENT OF EARLY PROSTATIC CANCER 723

... .I.. .. ...

p value 01 log rank = 0.0938 .___.. .....

...... ......

.... Age

-----<65(n=15) .......... 265 ( " 3 2 1

0 1 I I , I , 1 0 2 4 6 8 10 12 14

Years

Fig. 2 65 years or more at presentation).

Impact of age on survival (age stratified into less than

others but the difference did not reach statistical significance ( P = 0.093).

The tumour was graded into 2 broad groups, i.e. low Gleason sum score (2-4) and high (5-10). The Gleason score was low in 26.2% and high in 73.8%. Similarly, the percentage of cancer per high power field of histologically examined specimens for incidental (TO) disease was classified as low (< 5%) and high (2 5%): this was low in 30% and high in 70%. The Gleason sum score was an excellent predictor of disease progression, with early progres- sion by high score tumours, and the difference was highly significant (P=O.OOOO) (Fig. 3). In contrast, the percentage of cancer was a poor predictor of progression (P = 0.26) (Fig. 4). Neither Gleason sum score (Fig. 5 ) nor the percentage (Fig. 6) could predict the overall survival.

A further 2 men had T1 tumours but soon developed a second cancer (hepato-cellular and

100 : b 1 j. ........ 75

25

.... .....

............ p YSIUB 01 log rank i 0.0000 ...........

..........

............... Fleason *core

-2-4 (n.79) ............ 5.10 (nsZ8)

0 ) I I I I I I 0 2 4 6 8 10 12 14

Yew5

Fig. 3 (Gleason sum stratified into low (2-4) and high (5-10)).

Impact of Gleason sum score on disease progression

1

2 2 0.6

0.5

E 0.4

Log rank x: = 1.278 p IO.258

__ Percent < 5% Percent z 5% ............

04 0 10 20 30 40 50 60 70 80

Time to progression (months)

Fig. 4 Impact of percentage of cancer tissue on disease progression (percentage stratified into c 5% or more).

l o o h ..... .........

.._.. ...... 75-

- c * - P

g JO-

H -

ii, ..................... p value 01 lop rink s 0.878

< . . , . . I ..

;1 WaaPnearPra".78) ............ 5-10 (".28)

01 I 1 I I 0 2 4 6 8 10 12 14

Yew8

Fig. 5 Impact of Gleason sum score on survival

1

0 9 'k 0.8-

:z 0.7- 2 y, 0.6-

0

0

5 0.5- P

2 0.4-

Log rank xy = 0.7004 p =0377

- Percent I 5% Percent z 5%

0 10 20 30 40 50 60 70 80 90 100 110 120 130 140

Survival lime (months)

Fig. 6 Impact of percentage of cancer tissue on survival

724 BRITISH JOURNAL OF UROLOGY

bronchogenic) and succumbed without progression of their prostatic cancer. They have been excluded from statistical analysis.

Discussion

Early cancers of the prostate are classified either by the TNM system (Wallace et al., 1975) as TO and T1, or stage Al , A2, B1 and B2 by the Whitmore- Jewett system (Whitmore, 1956; Jewett, 1975; Benson and Olsson, 1989). T2 (stage B2) cancer is difficult to differentiate clinically from T3 (stage C) (Benson and Olsson, 1989). Clinical understaging has been reported in 60 to 66% of these tumours and this explains the poor prognosis in clinical B2 tumours (Elder et al., 1982; Lange and Narayan, 1983). To fulfil the criteria for early cancer of the prostate, further investigations must exclude bony or parenchymal metastases (M 1). The prognostic significance of high serum PAP (DO disease) was highlighted by Whitesel et al. (1984) and therefore a normal serum PAP is also mandatory. Thus the present study varies slightly from previously re- ported series from this centre (Beynon et al., 1983; Goodman et al., 1988) because we have now excluded patients with overt bony metastases or elevated PAP from incidental (TO) cancer, although their primary tumour might have been the inciden- tal diagnosis. Pelvic lymph node dissection was not carried out and hence the nodal status remains NX.

The diagnosis of prostatic cancer at an early stage should provide an opportunity for successful eradication of the tumour and an aggressive and ablative approach might seem to be the logical course of action. The present study, however, has demonstrated a comparable outcome from the conservative approach of watchful waiting.

Smith et al. (1991) reported one of the largest series of patients treated with radical prostatectomy for early cancer of the prostate with confirmed node-negative disease and followed up for a minimum of 10 years; 22% died from recurrent metastatic cancer. Whilst their rate of cancer deaths for stage A disease (3%) was identical to that in the present study, only 18% of their patients died from causes unrelated to prostate cancer compared with 31.8% (34/107) in the present series. We attribute this to their younger age group (average age 64 years) and to the general selection criteria for major surgical procedures such as pelvic lymph node dissection and radical prostatectomy. The median time to death from prostate cancer was 6.5 years compared with 6.3 years in the present series with deferred treatment and unknown nodal status.

Treatment failure (i.e. progression to metastatic disease (Ml) or elevation of serum PAP (Mla) or biopsy-confirmed local recurrence following radical prostatectomy in node-negative disease) varied from 12 to 60%, depending on whether the tumour was organ-confined or margin-positive on final histological examination (Paulson et al., 1990). Post-operative radiotherapy did not seem to alter the survival of such margin-positive cancers (Anscher and Prosnitz, 1987).

Walsh (1990) recommended radical prostatec- tomy for Al , A2 and B 1 cancers with node-negative disease. Elder et al. (1982) and Walsh and Lepor (1987) claimed best results following radical pros- tatectomy in B1 cancers. Their 15-year cancer-free survival rate was 51%, with the average age of their patients being 61 years at presentation. Thus it seems that only half of their B1 cancer patients survived up to the age of 76 years, while the other half were either dead or had active disease progression despite radical tumour ablative surgery. With deferred treatment for similar cancer, no patient in the present series, irrespective of nodal status, died from prostate cancer under the age of 82.

A major surgical procedure is not appropriate in a substantial number of patients with early CAP who are elderly and have high risk factors. Radiotherapy may, therefore, be a suitable alter- native. A nationwide overview of early cancer of the prostate with radical radiotherapy in the United States was reported by Pilepich et al. (1987). Within 5 years the probability of developing distant metastases (Ml) was just under 10% for the Stanford series. The age of the patients was not mentioned, but in the series in Stanford reported by Bagshaw et al. (1990), the average age was 63 years at presentation. It has been reported that 60 to 70% of patients die within 3 years and all by 7 to 8 years from metastatic failure following radical radiother- apy (Hanks et al., 1987). Thus 10% of patients would develop distant metastases by the age of 68 and die from cancer by the age of 76 despite radical ablative treatment. In contrast, only 2.8% of men died from cancer and 11% progressed to M1 disease in this centre with no node dissection surgery and no radical ablative treatment.

Many advocates of radical ablative treatment exclude from statistical consideration a number of patients who undergo pelvic lymph node dissection and are found to have node-positive disease. For patients with small-volume, low-grade tumours and node-negative disease, any form of treatment may appear successful. If one is more selective and offers

AUDIT AND ITS IMPACT IN THE MANAGEMENT OF EARLY PROSTATIC CANCER 725

such treatment to younger men with stable cardio- vascular and excellent performance status, their 10- or 15-year projected survival would appear even more impressive, but this must represent a lead- time bias. It is clear that the “patient likely to benefit from radical prostatectomy is the one with a localised tumour that progresses somewhat slowly if inexorably” (Smith et al., 1991).

George (1988) reported a series of 120 men with localised disease who were managed conservatively. During a 7-year study period, 11% developed bone metastasis and 4% died from cancer. Precise anatomical staging and histological grading were, however, not taken into consideration. In another series of deferred treatment for Tl-T2 CAP, Adolfsson et al. (1 992) reported a cancer death rate of 7% and distant metastasis of 14% over a median observation period of 7.5 years. Similarly, Johans- son et al. (1992) studied the natural history of untreated TO-T2NXMO tumours. The 10-year, disease-specific survival rate was 86% and the cancer death rate was only 8.5%. The relative risks of dying from prostate cancer were 58.4 and 2.5 times higher in men with poorly and moderately differentiated tumours respectively when compared with patients with well differentiated tumours. Thus any claim of superiority for one particular type of treatment in a series which includes mostly well or moderately differentiated tumours is suspect if there are no untreated controls. It is, therefore, not surprising that Kwon et al. (1991) reported their best results with radical prostatectomy and adjuvant radiotherapy in patients with early cancer of the prostate. All of their patients had confirmed node- negative disease and normal PAP, and only 1.3% had high grade tumour.

The age of the patient and the tumour stage or grade have been reported to correlate well (Alex- ander et al., 1989). In this centre, men with early prostatic cancer present at an average age of 73.5 years. With a policy of no immediate active treatment, their 12-year survival rate has been no different from that of an age-matched healthy population. Only a few men (n = 15) were under the age of 65 at presentation and none has yet developed bone metastasis or died from prostate cancer although we are continuing with their long-term follow-up. In the present series, a Gleason sum proved to be an excellent predictor of disease progression, and yet it could not predict survival because of a higher incidence of non-cancer deaths. On the other hand, tumour percentage could predict neither progression nor survival.

Local disease progression is difficult to assess

accurately, more so after radical ablative treatment. Most of these progressions are silent. Moreover, digital rectal examination alone is an unreliable method of assessing local disease.

Following radiation therapy for cancer of the prostate, asymptomatic patients with no evidence of cancer on digital rectal examination underwent multiple transrectal biopsies using a spring-loaded automatic-firing biopsy gun under ultrasound guid- ance. On average, eight 15-mm biopsy cores were obtained from each patient through clinically normal prostatic tissue and residual cancer was present in 91% (Kabalin et al., 1989). Similarly, digitally-guided biopsies were negative in 43 men but multiple core biopsies under ultrasound guid- ance revealed cancer in 23 (53%) (Hodge et al., 1989). These results have led to serious doubts about the validity of “disease-free survival” claimed with radical ablative treatment (Steineck et al., 1991). In a series of patients with localised prostate cancer managed conservatively, the local tumour progres- sion rate was as high as 84% and yet the cancer death rate was only 4% (George, 1988). Thus local progression, if asymptomatic and not associated with metastases, has minimal prognostic signifi- cance. Only one patient in the present series had his tumour diagnosed with needle core biopsy ; the majority underwent TURP for associated bladder outflow symptoms. Local tumour assessment as the parameter of progression is not recommended following TURP (Newling, 1990). Moveover, when the primary tumour has been deliberately left in situ under the policy of deferred treatment, the correct interpretation of local failure can be difficult. We believe that if the patient develops urethral or ureteric obstruction and requires active surgical intervention, it is more logical to regard these events as local failure. This takes account of iatrogenic local complications such as stricture, incontinence, etc, following tumour resection or radical extirpation. It also avoids the gross inaccur- acies of digital rectal examination and the need for multiple needle passes through asymptomatic tis- sues, which involves the risk of tumour dissemina- tion along the needle track (Bastacky et al., 1991). Two of our patients required a repeat TURP and 2 others required urethrotomy for benign urethral strictures which were attributed to instrumentation during the original tumour resection.

It becomes apparent that those who advocate radical ablative treatment for early CAP have not produced sufficient evidence to prove that their results are better than the results associated with a conservative approach. Attempts have been made

726 BRITISH JOURNAL OF UROLOGY

Table Cause of Death in Patients with Early Cancer of the Prostate (n = 37)

Acute Acute cardiovascular chest Acute G.I . Second Prostate Hepatic condition condition bleed cancer cancer failure

24 3 3 3 3 1

to resolve this debate about the optimum manage- ment for early CAP with prospective randomised trials. The second VACURG study was the appro- priate method, with randomisation between radical prostatectomy plus placebo and placebo alone. There was no significant difference in survival between these 2 arms (Byar et al., 1981 ; Graversen et al., 1990). Paulson et al. (1982) undertook a randomised study comparing radical prostatectomy with radical radiotherapy for early disease. Within 5 years, their treatment failure rates were 10 and 30% respectively, with a statistically significant advantage in favour of surgery. Walsh (1982) questioned the validity of VACURG reports on the grounds that bone scan and lymph node staging were not performed prior to radical prostatectomy. In placebo group too, however, those investigations were not performed. Thus their 2 arms of treatment were indeed comparable. The report by Paulson et al. (1982) has been criticised by a group of radiotherapists (Pilepich et al., 1987), who pointed out that radiotherapy results were much better in their own centres than where the trial was conducted by Paulson et al. (1982). There were also unex- plained variations between the total number of patients in the 2 arms of their treatment (41 for radical prostatectomy and 56 for radical radiother- apy) with 7 crossovers. Thus the controversy persists despite painstaking prospective randomised trials.

The true incidence of prostatic cancer is far greater than is clinically encountered today (Ka- balin et al., 1989a and b). If an effective screening programme unmasked the total number of subclin- ical cancers, approximately 40% of men around the age of 64 would seek advice from specialists. Selection of treatment could then impose a great dilemma. It is therefore essential to study the natural history of the disease and to judge the clinical outcome of different forms of management with particular reference to local failure, metastatic progression and comparative survival with an age- matched population. The present study has endea- voured to do so.

In conclusion, data from this study have shown that patients with early cancer of the prostate are

10 times more likely to die from a condition unrelated to prostatic cancer (Table), with cardio- vascular disease being the main cause of death (65%). It must be questioned whether lymph node dissection and radical ablative treatment could have improved their survival. The role of serum prostatic specific antigen in patients with early CAP is also under close evaluation. The manage- ment policy in this study was based on surveillance. We recommend that patients with early CAP should be followed up regularly in a dedicated prostate cancer clinic. Deferred treatment must not be adopted with complacency. A small proportion of patients will eventually require active surgical intervention for local failure, and hormonal manip- ulation for disseminated disease. With this ap- proach of watchful waiting, the 12-year observed survival rate has matched the expected survival for men of similar age in Scotland. This outcome supports our view that pelvic lymph node staging is not justified if a policy of conservative manage- ment is adopted. For further improvement of their survival, we strongly recommend careful monitor- ing of patients’ cardiovascular status. We reiterate that only a large database and longer follow-up should influence decision-making and justify the selection of one approach when there are already several alternatives. Such audit is cheaper and more effective in addressing our clinical dilemmas than some of the controversial randomised experimental trials.

Acknowledgement We are grateful to Mrs Elizabeth Brunton for secretarial assistance.

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60,526-527.

The Authors A. Rana, MS, FRCS(Glas), FRCS(I), DUrol(Lond), Registrar,

G. D. Chisholm, CBE, ChM, PPRCSE, FRCS, Professor,

S. Christodoulou, MD, Honorary Registrar, University Depart-

Margaret A. McIntyre, FRCPath, Consultant Histopathologist. R. A. Elton, PhD, Senior Lecturer, Medical Statistics Unit.

Requests for reprints to: A. Rana, University Department of Surgery/Urology, Western General Hospital, Edinburgh EH4 2xu.

University Department of Surgery/Urology.

University Department of Surgery/Urology.

ment of Surgery/Urology.