Japanese Journal of Clinical Oncology

Patients

Between 1980 and 1992, 151 patients aged 75 to 89 years old were diagnosed with prostate cancer in clinical stages A2 to D2 (according to the Whitmore-Jewett classification) (4,5) at Fukui Medical University and Toyooka Public Hospital. Patients with stage A1 disease were not included in the present study, since A1 cancers were considered to be a subgroup of prostate cancer with a clinical significance distinct from others. All patients were evaluated by digital rectal examination, serum prostatic acid phosphatase measurement, bone scan, pelvic computed tomography, and since 1988, serum prostate specific antigen (PSA) level determination. The patients were divided into three groups according to the clinical stage at diagnosis (stage A2-B, C and D) for the outcome analysis (Table 1).

Table 1. Demographics of the elderly patients with prostate cancer

	Clinical stage
	A2-B (n = 55)	C (n = 46)	D (n = 50)	Total (n = 151)
Age
range	75-89	75-89	75-88	75-89
mean	80.9	80.6	80.4	80.7
Histologic grade
well differentiated	19	6	5	30
moderately differentiated	24	27	16	67
poorly differentiated	12	13	29	54
Treatment
hormone	31	37	49	117
radical prostatectomy	8	3	0	11
radiotherapy	15	5	0	20
chemotherapy	0	1	0	1
no treatment	1	0	1	2
Follow-up period
range (months)	0.5-154	1-128	0.7-143	0.5-154
mean (years)	5.8	4.1	3.5	4.5

Table 2. Follow-up results of the elderly patients with prostate cancer

Outcome	Clinical stage
	A2-B (n = 55)	C (n = 46)	D (n = 50)	Total (n = 151)
Alive	12	9	10	31
Dead	43	37	40	120
Cancer death	2 (5)a	8 (22)	22 (55)	32 (27)
Other diseaseb	36 (84)	24 (65)	11 (28)	71 (59)
Undefined	5 (12)	5 (14)	7 (18)	17 (14)

^aNumber in parentheses indicates the percentage of cases.
^bThe numbers of patients who died of cerebro- or cardiovascular disease were eight in stage A2-B, three in stage C and two in stage D.

Treatments

One hundred and seventeen patients were managed with hormonal therapy, 11 with radical prostatectomy, 20 with external radiotherapy with Cobalt 60, one with cisplatin-based chemotherapy and in two cases, no treatment (Table 2). Hormone therapy included bilateral orchiectomy in 59 cases, orchiectomy with diethylstilbestrol diphosphate in 21, diethylstilbestrol diphosphate without orchiectomy in 24, LH-RH agonist in eight, bicalutamide in four and chlormadinone acetate in one case. Radical prostatectomy was performed by retropubic approach as previously described (6). Radiotherapy to the prostate was administered at a dose of 60 to 70 Gy. Only for the three patients who had microscopic lymph node metastasis at staging pelvic lymphadenectomy, a total dose of 50 Gy was given to the whole pelvis, with an additional 10 to 20 Gy given to the prostate via reduced portals. Hormonal therapy was not administered to the patients treated by radical prostatectomy or radiotherapy until clinical disease progression was identified. For statistical analysis, the treatment methods were classified as either definitive (radical prostatectomy or radiotherapy) or non-definitive (hormonal, chemotherapy or no treatment).

Outcome Analysis

The outcome of the patients was investigated during June 1998. The latest survival information of the patients was obtained from the medical records of the two hospitals, or by telephoning the patients or their families. The average observation period was 4.5 years (ranging from 15 days to 12.8 years). The cause of death was classified as prostate cancer, other disease or undefined cause.

Statistical Method

The correlation between the stage and histologic grade was estimated by chi-square analysis. The overall and cause-specific survival rates were calculated by the Kaplan-Meier method and were analyzed according to the stage, grade and treatment method. The statistical difference of the survival rates between subgroups was evaluated with the log-rank test. Multivariate analysis of prognostic factors was performed using the Cox proportional hazard model, and the statistical significance was calculated on SPSS software (SPSS for Windows, version 6.1, SPSS Inc. Tokyo). Age-matched expected survival rates were calculated from the life table of the Japanese population (7). Relative survival rates were determined as the ratio of overall survival to expected survival.

Demographic Characteristics of the Patients

Stage, histologic grade, treatment and follow-up period of the patients are shown in Table 1. There was no significant difference for the age at diagnosis among the three groups with different clinical stages. A positive correlation was observed between stage and histologic grade (P < 0.0001). The percentage of non-definitive treatment was higher in more advanced stages.

Clinical Outcome of the Patients

During follow-up, 120 out of 151 patients (79%) had died by June 1998 (Table 2). Although the proportion of the deceased cases was similar (78% in stage A2-B, 80% in C, and 80% in D), the cause of death was different among the three groups. The number of patients who died of prostate cancer tended to increase, while the number of those who died of other diseases tended to decrease as the stage advanced.

Table 3. Univariate analysis of prognostic factors in elderly patients with prostate cancer

	No. of cases	Overall survival (%)			Cause-specific survival (%)
		5-year	10-year	P-value	5-year	10-year	P-value
Stage
A2-B	55	67	19	A2-B vs C: 0.03	98	93	A2-B vs C: 0.008
C	46	44	12	A2-B vs D: 0.001	82	71	A2-B vs D: <0.0001
D	50	27	11		46	28	C vs D: 0.008
Histological grade
well differentiated	30	51	24		91	91	A2-B vs D: 0.004
moderately diff.	67	49	7	N.S.	85	75	C vs D: 0.01
poorly diff.	54	43	16		61	46
Treatment
definitive	31	68	18	0.03	97	89	0.007
non-definitive	120	41	13		71	62

Table 4. Multivariate analysis of prognostic factors in elderly patients with prostate cancer

Variable	Overall survival			Cause-specific survival
	Hazard ratio	95% CI	P-value	Hazard ratio	95% CI	P-value
Stagea	1.39	1.08-1.80	0.01	3.28	1.70-6.33	0.0004
Gradeb	0.91	0.61-1.35	0.63	1.65	0.76-3.56	0.21
Treatmentc	0.79	0.47-1.31	0.36	0.71	0.14-3.65	0.68

^aStage A2-B, C, D.
^bWell or moderately vs poorly differentiated.
^cDefinitive vs non-definitive treatment.

Overall and Cause-Specific Survival Rates of the Patients

Table 3 shows the results of univariate analysis for overall and cause-specific survival rates of the patients. Both the stage and treatment method were significant prognostic factors for overall and cause-specific survival rates, and grade was a significant variable only for the cause-specific survival rate of the patients. Figure 1 demonstrates the Kaplan-Meier overall survival curves for the patients with three different stages as well as the expected survival curve for an age-matched Japanese male population. The overall survival curve for the patients with stage A2-B was almost in line with the expected survival curve, but those for the patients with stage C and stage D were far below it. Multivariate analysis including the stage, grade and treatment method was then performed using the overall and cause-specific survival as endpoints. Only the stage was an independent prognostic variable for overall as well as cause-specific survival of the patients (Table 4).

Figure 1. Kaplan-Meier overall survival curves for the patients with different stages (stage A2-B, n = 55; C, n = 46; D, n = 50) and an expected survival curve for the age-matched male population.

Comparison Between Definitive and Non-Definitive Treatment in Localized Disease

The outcome of the patients with localized prostate cancer (stage A2-B) was compared between those treated definitively and those treated non-definitively. The 5- and 10-year overall survival rates for the definitively treated group (n = 23) were 78 and 25%, and those for the non-definitively treated group (n = 32) were 58 and 15%, respectively. There was no significant difference between the two groups (P = 0.10). Since the mean age of the patients treated non-definitively was higher than those treated definitively (82 ± 3.4 vs 78 ± 2.4, P < 0.0001), the relative survival rates were calculated for each group. As shown in Figs 2a and 2b, the overall survival curves of the patients treated definitively and those treated non-definitively were both in line with the corresponding expected survival curves, and the relative survival rates were similar for both groups (5 and 10-year relative survival rates were 122 and 78% for the definitively treated group, and 118 and 83% for the non-definitively treated group, respectively).

a

b

Figure 2. Overall survival curves for the patients with stage A2-B and the expected survival curves of the age-matched male population: (a) patients treated definitively (n = 23); (b) patients treated non-definitively (n = 32).

DISCUSSION

The average values for the life expectancy of Japanese men at 75 years old were 8.3 years in 1980 and 9.5 years in 1990, and those at 89 years old were 3.5 and 3.6 years, respectively (7). In the present study, we thus analyzed the long-term treatment results of elderly patients whose average life expectancy at diagnosis had been between 3 and 10 years. Our major concern in this selected age group of patients was to solve the following question: To what extent did the presence of prostate cancer have an impact on the survival of the patients with limited life expectancy in relation to the three clinicopathologic factors: stage of disease, histologic grade and treatment method?

A univariate analysis demonstrated that all three factors were significant prognostic indicators for cause-specific survival, while stage and treatment method were significant prognostic factors for overall survival of the patients. However, when multivariate analysis was performed including the three factors, stage was shown to be the only significant variable for cause-specific as well as overall survival of the patients. These results indicated that the presence of an advanced prostate cancer disease had an apparently negative influence on the survival of the elderly patients. Therefore, it might be concluded that the advanced-stage prostate cancer patients need treatment regardless of age. Furthermore, the present results support the recent opinion advocating the detection and treatment of prostate cancer at an earlier stage and at a younger age, since we unfortunately do not have any effective treatment method for the patients with advanced stage now.

On the other hand, the long-term results of patients with localized prostate cancer were almost satisfactory. It has generally been considered that definitive treatment such as radical prostatectomy or radiotherapy should be offered to the patients who are expected to live at least 10 years or longer (8-10). The benefit of definitive treatment in elderly patients whose life expectancy is less than 10 years, thus, is questionable, although the recent data indicate that there was, in fact, a large number of elderly patients who received definitive treatment (11-13). To date, there has been no prospective randomized study comparing definitive and non-definitive treatments in elderly patients with prostate cancer (14,15). In the present study, we therefore compared the treatment results of localized prostate cancer between the definitive and non-definitive treatment groups.

Among the patients with stage A2-B disease, there was no significant difference in the overall survival rates between the definitively and non-definitively treated groups. Furthermore, the relative survival rates were quite similar between the two groups. Although the present study was a non-randomized comparison of a relatively small number of cases and the mean age of the non-definitive treatment group was higher than the definitive treatment group, it supports the general assumption that the superiority of definitive local treatment over non-definitive treatment is not apparent when the patients have a limited life expectancy, at least in terms of survival.

The limitation of this retrospective analysis may be that we could not assess the various factors related to the patients' quality of life either at the time of diagnosis or during follow-up. For example, performance status of the patients, which was not included in the multivariate analysis, might be an important prognostic factor especially in such an elderly population. Furthermore, there might have been other cancer-related or treatment-related morbidity which we were not able to evaluate (16).

We therefore consider that future possible clinical trials, such as those comparing definitive versus non-definitive or no-treatment for localized disease or those comparing immediate versus deferred endocrine treatment for advanced disease, must be designed to assess the quality of life (17) rather than the survival of elderly patients with prostate cancer.

In conclusion, we have analyzed the long-term follow-up results of elderly patients with prostate cancer in Japan, which have not been reported in detail previously. Stage was the most important prognostic factor for survival of the patients. Since effective treatments are still lacking for advanced-stage patients, efforts for earlier detection and treatment at a younger age, in addition to a development of new agents or strategies for advanced prostate cancer, are needed to solve the problem.

References

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Received September 30, 1998; accepted November 25, 1998
For reprints and all correspondence: Hiroshi Kanamaru, Department of Urology, Fukui Medical University, Matsuoka, Fukui 901-1193, Japan. E-mail: urohk{at}fmsrsa.fukui-med.ac.jp

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