British Journalof Urology (1992), 69, 183-187

01992 British Journal of Urology

Deferred Treatment in C IinicalIy Localised Prostatic Carcinoma J. ADOLFSSON. J. CARSTENSEN and T. LOWHAGEN Departments of Urology and Pathology, Division of Clinical Cytology, Karolinska Hospital, Stockholm; Department of Oncology, University Hospital, Linkoping, Sweden

Summary-A series of 122 patients with a cytological diagnosis of well or moderately differentiated and clinically localised (Tl-2) prostatic carcinoma were followed up without any initial anti-tumour therapy. The median observation time was 9 1 months. During follow-up the local tumour progressed to stage T3 in 6 7 patients (55%) and distant metastases developed in 17 (14%); 47 patients died (38%). 9 of them (7%) from prostatic carcinoma. The risk of dying from prostatic carcinoma was 1% after 5 years and 16% after 10 years for patients not dying from other causes.

The natural course of localised prostatic carcinoma is not yet known. Whitmore (1984) found long survival times even without progression in a selected group of patients with stage B (Tl-2) prostatic carcinoma subjected to deferred treatment. We have previously reported a small number of patients who progressed with metastases after 5 years’ observation in a group of patients with T13, low-grade, non-metastatic prostatic carcinoma receiving no initial anti-tumour therapy (Adolfsson et al., 1990). The number of patients whose death was due to prostatic carcinoma was also found to be small. Follow-up has now been extended and was made 10 years after the first patients were included. An analysis of the subgroup of patients with clinically localised (Tl-2) tumours is now presented.

Patients and Methods Between 1978 and 1982, 172 patients with newly detected low grade prostatic carcinoma were prospectively included in a surveillance study. Most patients had small tumours but those with larger tumours who were reluctant to accept therapy were also included. The patients were selected from a larger group of patients. No formal variables were Accepted for publication 22 March 1991

used in the selection and no randomisation was performed. All carcinomas were cytologically diagnosed on material obtained by transrectal fine needle aspiration biopsy. The tumours were graded according to the criteria described by Esposti (1971). Only patients with well or moderately differentiated tumours were included in the study. Local tumour stage was assessed by digital rectal examination (DRE) and the tumours were categorised according to the TNM classification (UICC, 1978). The DRE finding was recorded by means of a standard drawing and a statement in the patient’s case notes. The status of metastases was assessed by radioisotope scanning of the skeleton (bone scan) and serum acid phosphatase was measured with a tartrate-inhibited enzymatic assay. All patients had a normal bone scan and a normal value of serum acid phosphatase and were regarded as without metastases (MO). The patients were followed up by routine clinical investigation and serum acid phosphatase every third to sixth month. Bone scan was performed routinely in all patients every 12 to 18 months. If rapid local progression or development of metastases was noted, anti-tumour therapy was given. Local progression was defined as a 2 2 5 % increase in the diameter of the tumour as judged from the standard drawings and statements in the case notes. Progression of the local tumour to stage T3 was also recorded and this information was used

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in the analysis. A positive bone scan or plain X-ray was required to define progression with metastases. Cause and time of death were obtained from the case notes and from the National Swedish Death Register. Death from prostatic carcinoma was defined as death after a previous systemic progression with subsequent clinical deterioration followed by death. Patients dying of uraemia secondary to ureteric obstruction from local tumour growth were also included in this category. Death from intercurrent disease was defined as death from disease not related to prostatic carcinoma as recorded in our own files or files from the hospital where the patient died. Patients dying at home in whom no systemic progression had been documented and where the death certificate indicated a cause of death not related to prostatic carcinoma were also considered as having died from intercurrent disease. In 122 of the 172 patients the tumour was categorised as localised within the prostatic capsule (Tl-2) at diagnosis and the records of these patients were reviewed in September 1989. No patients were lost to follow-up. The 50 patients with clinically non-localised tumours (T3) were reviewed separately (unpublished data). The prognostic value of the different variables determined at the time of diagnosis was analysed using Cox’s proportional hazards regression model

(Cox, 1972). Rate ratios were estimated as eP and 95% confidence intervals as ePf1.96xSE, where 0 is the regression coefficient of the Cox model and SE the standard error of the regression coefficient. The cumulative probability of not progressing was estimated and plotted using the actuarial method described by Berkson and Gage (1950). The patients who died from intercurrent disease were also included in the analysis but were considered as censored data. The median age at diagnosis was 68 years (range 38-89) and median observation time was 91 months (range 8-127). In 13 patients the tumour was categorised as T1 and in 109 as T2. The tumour was well differentiated in 77 patients and moderately differentiated in 45.

Results In 67/122 patients (55%) the tumour had progressed to clinical stage T3. Cytological grade was of prognostic importance regarding progression to T3 when analysed together with local stage in a Cox’s multivariate analysis (Table 1). The patients with T2 tumours had a tendency to progress to stage T3 earlier than those with T1 tumours but this difference was not statistically significant (Table 1). In all, 17/122 patients (14%) progressed with

Table 1 Prognostic Value of Cytological Grade and Tumour Stage MI (17)

T3 (67) Variable category Grade Well differentiated (77) Moderately differentiated (45) Tumour stage TI (13) T2(109)

Rate ratio

95% confidence interval

Rate ratio

9S% confidence inierval

1.O

-

1.o

-

1.9

I .2-3.1*

1.2

0.4-3.2

1.o

-

1.5

0.6-3.6

I .o I .o

-

0.2-4.5

* P< 0.05. Numbers in parentheses are numbers of patients

Table 2 Patients’ Progress during Follow-up

5 years At follow-up

MI

Dead from prostatic carcinoma

Dead from iniercurreni disease

Alive

9 17

2 9

21

99

38

75

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DEFERRED TREATMENT IN CLINICALLY LOCALISED PROSTATIC CARCINOMA

metastases during follow-up (Table 2). Thirteen of these patients developed metastases before treatment and 4 after treatment had commenced. Neither grade nor stage had any significant prognostic importance regarding progression with metastases (Table 1). During follow-up 47 patients (38%) died, 9 (7%) from prostatic carcinoma and 38 (31%) from disease not related to prostatic carcinoma (Table 2). Of the patients who died from prostatic carcinoma 8 died after systemic progression followed by clinical deterioration and 1 died of uraemia secondary to ureteric obstruction due to local growth of the tumour. The number of deaths related to prostatic carcinoma was too small to permit a Cox analysis. When the patients who died from intercurrent disease were censored in the analysis, the risk of developing metastases for patients alive at 5 and 10 years was found to be 8 and 28% respectively (Table 3) (Fig. 1). Similarly, the risk of dying from prostatic carcinoma was 1% after 5 years and 16% after 10 years (Table 3) (Fig. 2).

At the time of the review a total of 55 patients (45%) had been treated because of local and/or distant progression of their prostatic carcinoma. Such progression occurred at a steady rate throughout the observation period and there was no subgroup of patients with early rapid progress (Figs 1 and 2). At the time of follow-up, endocrine treatment had been given to 36 patients, 12 had received external radiation therapy to the prostate, 3 had been implanted with lZsI seeds and 4 had been subjected to radical prostatectomy. Discussion Two series on deferred treatment of localised prostatic carcinoma have been published. George (1988) reported 120 patients with clinically localised prostatic carcinoma of all grades. The median follow-up time was not given but is assumed to have been approximately 4 years since the patients were included in the study between 1980 and 1986, and follow-up probably took place during 1987.

Table 3 Probability of Progression

5 years 10 years

Progression to T3

MI

Death from prostatic carcinoma

0.52 k0.05 0.69f0.05

0.08 k0.03 0.28k0.09

0.01 k0.009 0.16+0.07

Values are means fSE

100 80 60 Q

%

*

40

0

Non-met. T1-2

I 0

2

4 6 8 Observation time (years)

10

Fig 1 Relative number of patients with localised low-grade prostatic carcinoma remaining stage T12 and non-metastasised during the follow-up period (median 7.5 years). Numbers in parentheses are number of patients at risk.

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%.

40

-

20

-

0

*

I

0

2

I

I

4 6 Observation time (years)

I

I

8

10

Crudesurv.

Fig. 2 Relative crude survival of patients with localised low-grade prostatic carcinoma and relative survival when patients dead of intercurrent disease have been censored from the analysis. Median followup period=7.5 years. Numbers in parentheses are number of patients at risk.

Johansson et af. (1989) reported 223 patients with TO-2 tumours of all grades (9 patients with poorly differentiated tumours) with a mean follow-up of 6.5 years. In the present series, 122 patients with T1-2, well or moderately differentiated prostatic carcinomas were followed up for a median period of 7.5 years. In most patients the tumour seemed to progress locally with time. George (1988) reported a local progression rate of 84%, and in the present series 55% progressed to stage T3. We found that the cytological grade of the tumour had a prognostic value for progression to stage T3. There was a tendency for T2 tumours to progress faster than T1 lesions. The difference was, however, not statistically significant and this was probably due to the low number of patients with T1 tumours. The lower local progression rate in the present series may be explained by the selection of patients with well and moderately differentiated tumours. George (1988) also included patients with poorly differentiated tumours and these can be expected to progress at a higher rate, as shown by Esposti (1971). Local progression by itself is difficult to evaluate and compare between different investigators because of variations in the criteria used to evaluate this parameter. In the series of George (1988), 13 patients developed metastases during the observation period. This represents 12% (13/105) of the eligible patients (105 patients, since 15 patients were not

followed up with bone scans). Johansson et al. (1989) reported that 9% of their patients (20/223) developed metastases and in the present series the corresponding rate was 14% (17/122). The slightly higher rate in this series may be due to the longer observation time. With regard to the survival of patients with localised prostatic carcinoma, Whitmore (1984) reported long follow-up times even without progression in a group of patients with stage B (Tl-2) tumours. This finding is supported by the findings of both the present and the studies of George (1988) and Johansson et al. (1989). Of our 122 patients with localised prostatic carcinoma, 47 (38%) had died at the time of follow-up and only 9 (7%) had died from prostatic carcinoma. The finding that the majority of the deaths were due to unrelated disease is consistent with the studies of George (1988), who reported 52 deaths ( 4 3 3 , of which 5 (4%) were from prostatic carcinoma, and Johansson et af. (1989), who reported 83 deaths (3779, of which 16 (7%) were from prostatic carcinoma. The rates of metastatic and fatal disease which we found were influenced by the fact that many patients died from intercurrent disease during the observation period. If those patients who died of intercurrent disease during follow-up were treated as censored observations in the analysis, the rate of metastatic and fatal disease remains as shown in Figures 1 and 2. Therefore, according to our results,

DEFERRED TREATMENT IN CLINICALLY LOCALISED PROSTATIC CARCINOMA

the risk of developing metastases for the patients who were alive at 5 years was 8% and 28% at 10 years. Similarly, for patients not dying of any other disease, the risk of dying of prostatic carcinoma would be 1% before 5 years and 16% before 10 years. Owing to the high rate of intercurrent deaths, however, the risk of dying from any cause during the observation period (median 7.5 years) was 38% for the patients in the present study. The difference between the risk of dying from prostate cancer when deaths from intercurrent disease have been censored and the risk of dying from any cause represents the intercurrent mortality in the series, as illustrated in Figure 2. In our previous report we concluded that patients with prostatic carcinoma subjected to deferred treatment progressed slowly during the first 5 years of observation (Adolfsson et al., 1990). When comparing the extended follow-up of our patients with localised disease with the reports of George (1988) and Johansson et al. (1989), the natural course of localised, low grade prostatic carcinoma seems to be a slow but steady local progression with a low rate of metastatic disease and an even lower rate of fatal disease within the first 10 years after diagnosis. The risk of dying from intercurrent disease seems to be considerably higher than the risk of dying from prostatic carcinoma for this category of patients.

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References Adolfsson, J., Ronstrom, L., Carstensen, J. et al. (1990). The natural course of low-grade, non-metastatic prostatic carcinoma. Br. J. Urol., 65,611414. Berkson, J. and Gage, R. P. (1950). Calculations of survival rates for cancer. Proc. Staff. Meet. Mayo Clin., 25,27&274. Cox, D. R. (1972). Regression models and life tables. J. R. Statist. SOC.( B ) , 34, 181-220. Esposti, P. L. (1971). Cytologic malignancy grading of prostate carcinoma by transrectal aspiration biopsy. Scand. J. Urol. Nephrol., 5, 199-209. George, N. J. R. (1988). Natural history of localised prostatic carcinoma managed by conservative therapy alone. Lancet, 11,494497. Johansson, J-E., Anderson, S-E., Krusemo, U. B. ef al. (1989). Natural history of localised prostatic cancer. Lancet, I, 799803. UICC Union Internationale contre le Cancer (1978). TNM Classification of Malignant Tumours. Third edition. Geneva : International Union against Cancer. Whitmore, W. F. (1984). Natural history and staging of prostate cancer. Urol. Clin. North Am., 11,205-220.

The Authors J . Adolfsson, MD, PhD, Senior Registrar, Department of Urology, Karolinska Hospital. J. Carstensen, PhD, Statistician and Associate Professor, Department of Oncology, Linkoping University Hospital. T. Lowhagen, MD, Associate Professor, Department of Pathology, Division of Clinical Cytology, Karolinska Hospital.

Acknowledgement This study was supported by a grant from the Research Funds of the Karolinska Institute, Stockholm, Sweden.

Requests for reprints to: J. Adolfsson, Department of Urology, Karolinska Hospital, Box 60500, S-104 01 Stockholm, Sweden.

Deferred treatment in clinically localised prostatic carcinoma.

A series of 122 patients with a cytological diagnosis of well or moderately differentiated and clinically localised (T1-2) prostatic carcinoma were fo...
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