British .lournal of Urology ( I 992), 70, 304-309 01992 British Journal of Urology
Treatment of Advanced Localised Prostatic Cancer by Orchiectomy, Radiotherapy, or Combined Treatment. A Medical Research Council Study G. J. FELLOWS, P. B. CLARK, L. L. BEYNON, J. BOREHAM,C. K E E N , M. C. PARKINSON, R. PET0 and J. N. WEBB (Urological Cancer Working Party-Subgroup
on Prostatic Cancer)
Summary-A total of 277 patients with apparently localised prostatic cancer (T2-T4 NXMO) were allocated at random to receive radiotherapy alone (88), orchiectomy alone (90) and combined therapy (99) between 1980 and 1985. The main outcome measures were survival, time to appearance of metastases and treatment of local disease progression by further transurethral resection. Orchiectomy, whether alone or with radiotherapy, produced a significant delay in detection of metastases when compared with radiotherapy alone. There were no statistically significant differences between the 3 treatment groups in local disease control or in overall survival.
There is no consensus as to how apparently localised prostatic cancer should be treated. If the disease is really localised then radical prostatectomy or radiotherapy can be curative (Lepor and Walsh, 1988; Hanks, 1989). Only the latter has been practised on a large scale in the United Kingdom. Systemic therapy with cytotoxic agents does not appear to be particularly effective, but systemic hormonal therapy can often lead to prolonged regression of the primary tumour and hence palliation of its local effects (Schroder, 1990). The hormonal therapies now available include bilateral orchiectomy, oestrogens, anti-androgens and LHRH analogues. At the end of the 1970s, however, LH-RH analogues and anti-androgens were not widely available, oestrogens were known to produce cardiovascular complications and orchiectomy was therefore the standard hormonal treatment. No randomised trial of radiotherapy versus hormonal treatment had been performed. In 1980, at the suggestion of one of the authors (P.B.C.), the Medical Research Council therefore launched a multi-centre randomised trial of orchiectomy versus radiotherapy versus combined treatment (orchiecAccepted for publication 25 March 1992
304
tomy and radiotherapy) in advanced localised (T2T4 NXMO) prostatic cancer. The object was to compare the effects of these 3 treatments on the duration of survival and on the time to appearance of metastases.
Patients and Methods All patients had histologically proven carcinoma of the prostate. Sections were reviewed by 2 pathologists and ascribed a Gleason score. No patient had prior hormonal treatment or radiotherapy : surgery to relieve outflow obstruction was, however, permitted. There had to be no evidence of metastases on chest X-ray or isotope bone scan. Lymph node staging was not required. Patients were excluded if the serum acid phosphatase was above the upper limit of normal for the local laboratory. The patient’s performance status was recorded. The treatment group was allocated randomly, without stratifying for any possible prognostic variables, by telephoning the ICRF/MRC Clinical Trial Service Unit in Oxford. Orchiectomy could be total or subcapsular according to local preference. Radiotherapy involved a radical course of treatment to the prostate gland, the actual technique
305
COMPARISON OF THREE TREATMENTS FOR LOCALISED PROSTATIC CANCER
being left to the discretion of the individual radiotherapist. The design of the trial was deliberately kept as simple as possible so as not to impose an undue burden on elderly patients and to encourage as many surgeons as possible to participate. Patients were to be reviewed every 6 months until death for clinical evidence of local progression or distant metastases and for assessment of any major adverse reactions to therapy. Isotope bone scans and chest X-rays were to be performed annually or whenever metastases were suspected. Patients who died from prostatic cancer were assumed to have developed metastases midway between latest symptom-free follow-up and death if no date of onset had been reported. Thirty-two urologists in 23 centres entered a total of 277 patients into the trial between June 1980 and March 1985. Ninety patients were allocated orchiectomy alone, 88 radiotherapy alone and 99 combination therapy. The 3 groups were roughly comparable (Table 1) regarding age, performance status, T category and Gleason score and were
followed up for comparable durations, both by annual questionnaires (until September 1989), and by Central Registrar’s Office records that provide the dates and certified causes of any deaths. Followup for death is continuing through these records, but in the analyses it was censored on 30 September 1990 to allow for delay in notification. Statistical methods These are as described in the Report to the MRC Leukaemia Committee on the Design and Analysis of Randomised Trials (Peto et al., 1977), using “log rank” x2 and P values to test the statistical significance of any apparent differences in outcome, and “life-table’’ graphs to illustrate any such differences.
Results There was no statistically significant difference between the 3 treatment groups in overall survival (Fig. 1, Table 2) or in the need for further treatment (usually transurethral resection) for local progres-
Table 1 Number of Patients Studied according to Possible Prognostic Variables, Duration of Follow-up and Allocated Treatment Group Allocated treatment group ~~
Total no. ofpatients Age at randomisation
(years) < 65 65-14 15 T category T2 T3 T4 Not known Gleason score Low (4-6) Medium (7) High (8-10) Not known Performance status Fully active Restricted activity Not known FONOW-UP* Disease progression Median/maximumyears Death Median/maximumyears
+
Radiotherapy
Orchiectomy
Combination
88
90
99
15 54 19
18 53 19
20 50 29
39 35 I I
35 36 13 6
45 31 8 9
24 19 29 16
20 30 25 15
24 26 40 9
71 11 6
I0 11 9
14 15 10
4.1/8.3
4.0/8.3
4.5/8.1
4.3/9.8
4.6/10.2
5.2/ 10.2
* Follow-up for local and distant disease progression was concluded on 30.9.89;follow-up for death was censored on 30.9.90, but is continuing through Central Registrar’sOffice records.
306
BRITISH JOURNAL OF UROLOGY Combination Orchiectomy only Radiotherapy only
................................
-- - - - - - -- - -- - -
----.
..........\........ .------.-
al
n
25
I
-
- - - - - - -.
Numbers of patients at risk (radiotherapy only, orchiectomy only, combination)
(81,86,95) (75,79,84)
(65,63,72)
(52,49,64) (39,42,52)
(27,38,42) (18,28,25)
0
I
0
2
1
3
4
5
6
7
Time since randomisation in years
Fig. 1 Overall (all cause) mortality.
sion (Fig. 2, Table 2). However, the incidence of distant metastases was significantly (x2*= 13.27, 2P
Treatment of Advanced Localised Prostatic Cancer by Orchiectomy, Radiotherapy, or Combined Treatment. A Medical Research Council Study G. J. FELLOWS, P. B. CLARK, L. L. BEYNON, J. BOREHAM,C. K E E N , M. C. PARKINSON, R. PET0 and J. N. WEBB (Urological Cancer Working Party-Subgroup
on Prostatic Cancer)
Summary-A total of 277 patients with apparently localised prostatic cancer (T2-T4 NXMO) were allocated at random to receive radiotherapy alone (88), orchiectomy alone (90) and combined therapy (99) between 1980 and 1985. The main outcome measures were survival, time to appearance of metastases and treatment of local disease progression by further transurethral resection. Orchiectomy, whether alone or with radiotherapy, produced a significant delay in detection of metastases when compared with radiotherapy alone. There were no statistically significant differences between the 3 treatment groups in local disease control or in overall survival.
There is no consensus as to how apparently localised prostatic cancer should be treated. If the disease is really localised then radical prostatectomy or radiotherapy can be curative (Lepor and Walsh, 1988; Hanks, 1989). Only the latter has been practised on a large scale in the United Kingdom. Systemic therapy with cytotoxic agents does not appear to be particularly effective, but systemic hormonal therapy can often lead to prolonged regression of the primary tumour and hence palliation of its local effects (Schroder, 1990). The hormonal therapies now available include bilateral orchiectomy, oestrogens, anti-androgens and LHRH analogues. At the end of the 1970s, however, LH-RH analogues and anti-androgens were not widely available, oestrogens were known to produce cardiovascular complications and orchiectomy was therefore the standard hormonal treatment. No randomised trial of radiotherapy versus hormonal treatment had been performed. In 1980, at the suggestion of one of the authors (P.B.C.), the Medical Research Council therefore launched a multi-centre randomised trial of orchiectomy versus radiotherapy versus combined treatment (orchiecAccepted for publication 25 March 1992
304
tomy and radiotherapy) in advanced localised (T2T4 NXMO) prostatic cancer. The object was to compare the effects of these 3 treatments on the duration of survival and on the time to appearance of metastases.
Patients and Methods All patients had histologically proven carcinoma of the prostate. Sections were reviewed by 2 pathologists and ascribed a Gleason score. No patient had prior hormonal treatment or radiotherapy : surgery to relieve outflow obstruction was, however, permitted. There had to be no evidence of metastases on chest X-ray or isotope bone scan. Lymph node staging was not required. Patients were excluded if the serum acid phosphatase was above the upper limit of normal for the local laboratory. The patient’s performance status was recorded. The treatment group was allocated randomly, without stratifying for any possible prognostic variables, by telephoning the ICRF/MRC Clinical Trial Service Unit in Oxford. Orchiectomy could be total or subcapsular according to local preference. Radiotherapy involved a radical course of treatment to the prostate gland, the actual technique
305
COMPARISON OF THREE TREATMENTS FOR LOCALISED PROSTATIC CANCER
being left to the discretion of the individual radiotherapist. The design of the trial was deliberately kept as simple as possible so as not to impose an undue burden on elderly patients and to encourage as many surgeons as possible to participate. Patients were to be reviewed every 6 months until death for clinical evidence of local progression or distant metastases and for assessment of any major adverse reactions to therapy. Isotope bone scans and chest X-rays were to be performed annually or whenever metastases were suspected. Patients who died from prostatic cancer were assumed to have developed metastases midway between latest symptom-free follow-up and death if no date of onset had been reported. Thirty-two urologists in 23 centres entered a total of 277 patients into the trial between June 1980 and March 1985. Ninety patients were allocated orchiectomy alone, 88 radiotherapy alone and 99 combination therapy. The 3 groups were roughly comparable (Table 1) regarding age, performance status, T category and Gleason score and were
followed up for comparable durations, both by annual questionnaires (until September 1989), and by Central Registrar’s Office records that provide the dates and certified causes of any deaths. Followup for death is continuing through these records, but in the analyses it was censored on 30 September 1990 to allow for delay in notification. Statistical methods These are as described in the Report to the MRC Leukaemia Committee on the Design and Analysis of Randomised Trials (Peto et al., 1977), using “log rank” x2 and P values to test the statistical significance of any apparent differences in outcome, and “life-table’’ graphs to illustrate any such differences.
Results There was no statistically significant difference between the 3 treatment groups in overall survival (Fig. 1, Table 2) or in the need for further treatment (usually transurethral resection) for local progres-
Table 1 Number of Patients Studied according to Possible Prognostic Variables, Duration of Follow-up and Allocated Treatment Group Allocated treatment group ~~
Total no. ofpatients Age at randomisation
(years) < 65 65-14 15 T category T2 T3 T4 Not known Gleason score Low (4-6) Medium (7) High (8-10) Not known Performance status Fully active Restricted activity Not known FONOW-UP* Disease progression Median/maximumyears Death Median/maximumyears
+
Radiotherapy
Orchiectomy
Combination
88
90
99
15 54 19
18 53 19
20 50 29
39 35 I I
35 36 13 6
45 31 8 9
24 19 29 16
20 30 25 15
24 26 40 9
71 11 6
I0 11 9
14 15 10
4.1/8.3
4.0/8.3
4.5/8.1
4.3/9.8
4.6/10.2
5.2/ 10.2
* Follow-up for local and distant disease progression was concluded on 30.9.89;follow-up for death was censored on 30.9.90, but is continuing through Central Registrar’sOffice records.
306
BRITISH JOURNAL OF UROLOGY Combination Orchiectomy only Radiotherapy only
................................
-- - - - - - -- - -- - -
----.
..........\........ .------.-
al
n
25
I
-
- - - - - - -.
Numbers of patients at risk (radiotherapy only, orchiectomy only, combination)
(81,86,95) (75,79,84)
(65,63,72)
(52,49,64) (39,42,52)
(27,38,42) (18,28,25)
0
I
0
2
1
3
4
5
6
7
Time since randomisation in years
Fig. 1 Overall (all cause) mortality.
sion (Fig. 2, Table 2). However, the incidence of distant metastases was significantly (x2*= 13.27, 2P
