| Japanese Journal of Clinical Oncology | Pages |
Introduction
Materials And Methods
Results
Clinical Findings
Clinically Insignificant Cancers
Discussion
Acknowledgment
References
Impact of Life Expectancy and Tumor Doubling Time on the Clinical Significance of Prostate Cancer in Japan
INTRODUCTION
The incidence of prostate cancer is currently increasing and is now the ninth causeof male cancer death in Japan (1-3). The incidence of this disorder increased from 6482 in 1988 to an estimated 9000 in 1994. A total of 4262 males died of prostate cancer in 1993. The greater value of statistical data is due in part to the more sensitive detection possible through the use of the prostate-specific antigen (PSA) (4,5). Radical prostatectomy is usually indicated when the disease is organ confined. Despite the popularity and increased performance of this operation, its efficacy has yet to be adequately assessed (6,7). More data should be available to demonstrate benefits. Methods should be established to distinguish preoperatively men with clinically significant cancer requiring intervention from those possibly better served by expectant management.
For assessing the clinical significance of prostate cancer, consideration should be given to various factors (8-10). With younger patients likely not to experience the comorbidity of older patients, the rate of prostate-related mortality is greater. Both host factors and tumor characteristics are therefore important. Even a small cancer may reach a critical size in the case of a sufficiently long life span of the host. Dugan et al. have proposed a model to assess the clinical significance of prostate cancer based on cancer volume, grade, cancer volume doubling time and life expectancy (9). This model may not be directly applicable to Japanese elderly males whose life expectancy exceeds that of male populations throughout the world (3). Average life expectancy for males is 76.57 years at birth, this being 4.37 years longer than in the USA. A model should therefore be available to assess accurately the clinical significance of prostate cancer of each individual race. In the present study, this assessment was made with consideration given to patient life expectancy and the outcome of radical prostatectomy.
MATERIALS AND METHODS
Between November 1991 and September 1996, 114 Japanese males diagnosed with clinically resectable prostate cancer underwent radical prostatectomy at Kitasato University Hospital. Ten of these patients underwent preoperative hormonal manipulation and were excluded from further study.
Table 1. Projected cancer volume at death (cm3) based on patient age and cancer volume at diagnosis, cancer volume doubling time and patient life expectancy
| Doubling time (yrs) | Age at diagnosis (yrs) | Life expectancy (yrs) | Volume of cancer at diagnosis (cm3) | ||||||
| 0.25 | 0.50 | 1.00 | 1.50 | 2.00 | 3.00 | 4.00 | |||
| 1 | 60 | 20.01 | 263967.4 | 527934.7 | 1055869.4 | 1583804.1 | 2111738.8 | 3167608.3 | 4223477.7 |
| 65 | 16.22 | 19083.0 | 38166.0 | 76332.0 | 114498.0 | 152664.0 | 228995.9 | 305327.9 | |
| 70 | 12.66 | 1618.0 | 3236.0 | 6472.0 | 9708.0 | 12944.0 | 19416.1 | 25888.1 | |
| 75 | 9.50 | 181.0 | 362.0 | 724.1 | 1086.1 | 1448.2 | 2172.2 | 2896.3 | |
| 80 | 6.88 | 29.4 | 58.9 | 117.8 | 176.7 | 235.6 | 353.4 | 471.1 | |
| 2 | 50 | 28.40 | 4705.1 | 9410.0 | 18820.3 | 28230.4 | 37640.5 | 56460.8 | 75281.1 |
| 55 | 24.06 | 1045.5 | 2091.0 | 4182.1 | 6273.1 | 8364.1 | 12546.2 | 16728.3 | |
| 60 | 20.01 | 256.9 | 513.8 | 1027.6 | 1541.3 | 2055.1 | 3082.7 | 4110.2 | |
| 65 | 16.22 | 69.1 | 138.1 | 276.3 | 414.4 | 552.6 | 828.8 | 1105.1 | |
| 70 | 12.66 | 20.1* | 40.2 | 80.4 | 120.7 | 160.9 | 241.3 | 321.8 | |
| 75 | 9.50 | 6.7 | 13.5 | 26.9 | 40.4 | 53.8 | 80.7 | 107.6 | |
| 80 | 6.88 | 2.7 | 5.4 | 10.9 | 16.3 | 21.7 | 32.6 | 43.4 | |
| 3 | 50 | 28.40 | 176.9 | 353.8 | 707.5 | 1061.3 | 1415.1 | 2122.6 | 2630.2 |
| 55 | 24.06 | 64.9 | 129.8 | 259.6 | 389.4 | 519.1 | 778.7 | 1038.3 | |
| 60 | 20.01 | 25.5* | 50.9 | 101.8 | 152.7 | 203.7 | 305.5 | 407.3 | |
| 65 | 16.22 | 10.6 | 21.2* | 42.4 | 63.6 | 84.8 | 127.3 | 169.7 | |
| 70 | 12.66 | 4.7 | 9.3 | 18.6 | 28.0 | 37.3 | 55.9 | 74.5 | |
| 75 | 9.50 | 2.2 | 4.5 | 9.0 | 13.5 | 18.0 | 26.9 | 35.9 | |
| 80 | 6.88 | 1.2 | 2.5 | 4.9 | 7.4 | 9.8 | 14.7 | 19.6* | |
| 4 | 50 | 28.40 | 34.3 | 68.6 | 137.2 | 205.8 | 274.4 | 411.6 | 548.7 |
| 55 | 24.06 | 16.2 | 32.3 | 64.7 | 97.0 | 129.3 | 194.0 | 258.7 | |
| 60 | 20.01 | 8.0 | 16.0 | 32.1 | 48.1 | 64.1 | 96.2 | 128.2 | |
| 65 | 16.22 | 4.2 | 8.3 | 16.6 | 24.9 | 33.2 | 49.9 | 66.5 | |
| 70 | 12.66 | 2.2 | 4.5 | 9.0 | 13.5 | 17.9 | 26.9 | 35.9 | |
| 75 | 9.50 | 1.3 | 2.6 | 5.2 | 7.8 | 10.4 | 15.6 | 20.7 | |
| 80 | 6.88 | 0.8 | 1.6 | 3.3 | 4.9 | 6.6 | 9.9 | 13.2 | |
| 6 | 60 | 20.01 | 2.5 | 5.0 | 10.1 | 15.1 | 20.2* | 30.3 | 40.4 |
| 65 | 16.22 | 1.6 | 3.3 | 6.5 | 9.8 | 13.0 | 19.5 | 26.1 | |
| 70 | 12.66 | 1.1 | 2.2 | 4.3 | 6.5 | 8.6 | 13.0 | 17.3 | |
| 75 | 9.5 | 0.7 | 1.5 | 3.0 | 4.5 | 6.0 | 9.0 | 12.0 | |
| 80 | 6.88 | 0.6 | 1.1 | 2.2 | 3.3 | 4.4 | 6.6 | 8.9 | |
Clinical stage was determined in accordance with the unified tumor node metastasis (TNM) system (5,11) Briefly, stage T1a tumors were discovered incidentally based on histological findings in 5% or less of tissue resected and stage T1b tumors, in more than 5% of tissue resected. Patients with positive biopsy cores and benign-feeling glands were considered stage T1c provided sonographic findings for malignancy were unremarkable. T2a and b were palpable tumors confined within the prostate and involved only a portion of or the entire lobe, stage T2c were palpable tumors confined within the prostate and involved both lobes, stages T3a and b were palpable tumors extending through the prostatic capsule with unilateral or bilateral extension, respectively, and stage T3c were palpable tumors extending through the prostatic capsule, involving the seminal vesicles.
Radical prostatectomy was conducted here by the retropubic approach as described by Walsh (12) in all but one case who instead underwent antegrade prostatectomy by a single operator (S.E.) or under the supervision of the same surgeon. No examination was made of intraoperative frozen sections of lymph nodes in compliance with the procedures for postoperative adjuvant therapy at this hospital. All operations were therefore conducted without consideration of nodal status intraoperatively. Serum PSA was determined by Eiken polyclonal radioimmunoassay (Eiken, Tokyo, 33 patients) up to March 1993 and Dainapack IMx PSA (Dinabot, Tokyo, 71 patients) thereafter (13). Using frozen serum samples maintained at -80_C, preoperative IMx PSA was found for 28 patients. For uniformity, Eiken PSA of the remaining five patients was inter-converted as recommended by Machida et al. as follows: IMx PSA = 1.39yEiken PSA - 1.02 (13).
Radical prostatectomy specimens were examined by a single pathologist (S.K.) using the whole organ step-section technique as described previously (5). Specimens were fixed in 10% formalin and sectioned at 5 mm intervals in a plane perpendicular to the long axis of the gland, from the prostatic apex to tips of seminal vesicles. Each was stained with hematoxylin and eosin. The depth and extent of capsular penetration were determined. A search for and assessment of seminal vesicle invasion and nodal involvement were made. Tumor maps were drawn up by directly tracing the outlines of tumors in the sections. Index tumor volume was computed from the maps thus obtained by the planimetry method (5). Tumor grade was assigned in accordance with the Gleason grading system. Tumor grade was considered more representative of the index tumor than entire, multiple tumors.
A mathematical model of cancer volume at death has been established by Dugan et al. (9). The most recent life tables (1990) from the Minister's Secretariat, Ministry of Health and Welfare (14), were used to determine life expectancy for each integer age. The data should be considered representative only of the Japanese race, the number of non-orientals being too small to consider. Theoretical projected prostate cancer volume at the time of expected death was obtained based on patient age and cancer volume at diagnosis, assumed cancer volume doubling time and life expectancy from the 1990 life tables (14). Prostate cancer volume doubling times of 1, 2, 3, 4 and 6 years were tabulated. The results of mathematical computation for initial cancer volumes of 0.25, 0.5, 1.0, 1.5, 2.0, 3.0 and 4.0 cm3 are summarized in Table 1. Based on these data, cancer that would reach a volume no more than 20 cm3 by the time of expected patient death and with a Gleason score less than one tenth the lowest age in any 10-year patient age interval was considered insignificant (14). The doubling time of prostate cancer has been reported to range from 1.2 months to more than 4 years (15,16). In this study, a 2-year doubling time for cancer was considered aggressive, while 3- and 4-year doubling times were typical of most diagnosed prostate cancers. Doubling times of 1 and 6 years were to show extremes. The direct outcome of radical prostatectomy was evaluated based on these findings.
For comparison of the results of clinical significance with those using other criteria, the categorization of prostate cancer by Ohori et al. (17) was used with modification. The dominant tumor nodule was taken as representative of the whole tumor. There was no indication that a group of minute tumor foci elsewhere in the gland, with total volume, for instance, of 0.05 cm3, would have a significant effect on the prognosis of a dominant tumor measuring 0.52 cm3. Categorization in this study was therefore based on the volume of the index tumor nodule, as in other studies (18,19). Index tumors less than 0.5 cm3 in volume and confined to the prostate with no primary or secondary component of Gleason grade 4 or 5 were thus considered clinically unimportant according to conventional criteria (17)
RESULTS
Clinical Findings
The mean patient age was 63.7 years (range 49-74 years). The 104 cases were classified clinically as stages T1a in 1, T1b in 4, T1c in 34, T2a in 12, T2b in 23, T2c in 13, T3a in 2, T3b in 3 and T3c in 12 patients. Twenty of these cancers were detected via the PSA-based screening program at this hospital (5) and consisted of 13 stage T1c, one T2a, four T2b, one T3a and one T3b tumors. Two cases initially diagnosed as stage T1c well differentiated adenocarcinoma showed only atypical adenomatous hyperplasia and a moderate degree of prostatic intraepithelial neoplasia in surgical specimens (pT0). One of these was found via PSA-based screening. For one patient with T1b disease, no residual tumor could be found in the prostatectomized specimen (pT0). These three cases were considered representative of clinically unimportant tumors which should be studied for more accurate assessment of the direct outcome of radical prostatectomy. Tumor volume could not be measured in two patients with stage T3c disease owing to random sectioning. These 72- and 70-year-old patients had nodal involvement and extensive extracapsular extension. Tumor grades were assigned Gleason scores 10 and 6, respectively.
Pathological Findings
In Table 2 are presented the pathological features of tumors in the 104 patients treated with radical prostatectomy. The 104 cases were classified pathologically as pT0 in 3, pT2N0 in 47, pT3a,bN0 in 14, pT3cN0 in 27 and pT2-3N1 in 13 patients. Total and index tumor volumes averaged 7.2 + 9.0 and 6.8 + 9.0 cm3 (range 0.00-44.0 cm3), respectively. Overall 50 (48.1%, 50/104, including three with pT0 disease) had pathologically organ confined disease. Extracapsular extension, seminal vesicle involvement, microscopic nodal involvement and positive surgical margin were evident in 47.1, 36.5, 12.5 and 34.6% of the patients, respectively. In patients with clinically localized cancer (<T3), confinement to the prostate was observed in 57.5% (50/87). Tumor grade was classified postoperatively as well (Gleason sum 2-4) or moderately (Gleason sum 5 or 6) differentiated in 19 (18.3%) or 27 (26.0%) patients, respectively. Thirty-three (31.7%) and 22 (21.2%) patients had poorly differentiated tumors with Gleason sums of 7 and 8-10, respectively. A primary or secondary component of Gleason grade 4 or 5 was present in each of 56 (53.8%) patients.
Thirteen (12.5%) of the present patients had either pT0 disease (n = 3) or well to moderately differentiated tumors less than 0.5 cm3, pathologically confined to the gland (n = 10). One small (0.2 cm3) moderately differentiated tumor had a positive surgical margin without features of pT3 disease. All three pT0 cases in the present study may be considered clinically insignificant and two .pT3 with no tumor volume data as significant.
Clinically Insignificant Cancers
By the criteria of Dugan et al. (9), 5 (4.8%) of the 104 specimens were shown to be clinically insignificant for an assumed tumor doubling time of 2 years (Table 3). For 3-, 4- and 6-year doubling times, 11 (10.6%), 16 (15.4%) and 28 (26.9%) of the 104 cases had clinically insignificant cancers, respectively.
Table 2. Correlation of clinical stage with final pathological findings
| Final pathological findings | |||||||||
| Clinical stage | No. patients No. (%) | PSA (ng/ml) mean ± | Index TV (cm3) mean ± | Gleason sum mean±SD | Organ confined No. (%) | ECE No. (%) |
SVI No. (%) |
Nodal inv. No. (%) |
Positive margin No. (%) |
| T1a | 1(1.0) | 0.8 | 0.1 | 2 | 1(100.0) | 0(0.0) | 0(0.0) | 0(0.0) | 0(0.0) |
| T1b | 4(3.9) | 3.7±2.8 | 2.4±3.5 | 6.0±1.0 | 3(75.0) | 1(25.0) | 1(25.0) | 0(0.0) | 2(50.0) |
| T1c | 34(32.7) | 11.4±18.0 | 3.9±7.0 | 5.3±2.0 | 24(70.6) | 10(29.4) | 5(14.7) | 2(5.9) | 9(26.5) |
| T2a | 12(11.5) | 16.9±24.9 | 4.2±4.8 | 5.8±1.8 | 8(66.7) | 3(25.0) | 3(25.0) | 1(8.3) | 3(25.0) |
| T2b | 23(22.1) | 10.8±10.3 | 2.5±1.6 | 6.3±1.1 | 14(60.9) | 8(34.8) | 4(17.4) | 1(4.3) | 6(26.1) |
| T2c | 13(12.5) | 17.0±23.4 | 13.4±10.1 | 7.4±1.0 | 0(0.0) | 10(76.9) | 11(84.6) | 3(23.1) | 5(38.5) |
| T3a | 2(1.9) | 30.5±26.4 | 13.4±6.2 | 8.5±2.1 | 0(0.0) | 2(100.0) | 1(50.0) | 0(0.0) | 1(50.0) |
| T3b | 3(2.9) | 15.8±17.4 | 21.6±19.5 | 8.0±1.0 | 0(0.0) | 3(100.0) | 3(100.0) | 1(33.3) | 2(66.7) |
| T3c | 12(11.5) | 38.7±36.7 | 18.2±9.3 | 7.8±1.6 | 0(0.0) | 12(100.0) | 10(83.3) | 5(41.7) | 8(66.7) |
| Total | 104(100.0) | 16.0±22.5 | 6.8±9.0 | 6.3±1.9 | 50(48.1) | 49(47.1) | 38(36.5) | 13(12.5) | 36(34.6) |
Table 3. Patients with clinically insignificant prostate cancer as determined according to the criteria of Dugan et al. (9)
| No. patients with insignificant cancer | ||||||
| Doubling time (yrs) | ||||||
| No. patients | ||||||
| No. (%) | 2 | 3 | 4 | 6 | ||
| Age at diagnosis (yrs): | 45-49 | 1(1.0) | 0 | 0 | 0 | 0 |
| 50-59 | 20(19.2) | 1 | 2 | 2 | 4 | |
| 60-69 | 69(66.3) | 3 | 8 | 12 | 20 | |
| 70- | 14(13.5) | 1 | 1 | 2 | 4 | |
| Preop. PSA (ng/ml): | -4.0 | 21(20.2) | 2 | 4 | 5 | 10 |
| 4.1-10.0 | 44(42.3) | 3 | 6 | 8 | 14 | |
| 10.1- | 39(37.5) | 0 | 1 | 3 | 4 | |
| Clinical stage: | T1a | 1(1.0) | 1 | 1 | 1 | 1 |
| T1b | 4(3.8) | 1 | 1 | 2 | 2 | |
| T1c | 34(32.7) | 3 | 5 | 8 | 16 | |
| T2a | 12(11.5) | 0 | 3 | 4 | 4 | |
| T2b | 23(22.1) | 0 | 1 | 1 | 5 | |
| T2c-T3 | 30(28.9) | 0 | 0 | 0 | 0 | |
| Gleason score: | 2-4 | 19(18.3) | 2 | 8 | 10 | 16 |
| 5 | 15(14.4) | 0 | 0 | 3 | 8 | |
| 6 | 12(11.5) | 0 | 0 | 0 | 1 | |
| 7 | 33(31.7) | 0 | 0 | 0 | 0 | |
| 8-10 | 22(21.2) | 0 | 0 | 0 | 0 | |
| No tumor | 3(2.9) | 3 | 3 | 3 | 3 | |
The clinical stages of 28 patients with insignificant tumors for an assumed 6-year doubling time wereT1a in 1 (3.6%), T1b in 2 (7.1%), T1c in 16 (57.1%), T2a in 4 (14.3%) and T2b in 5 (17.9%) (Fig. 1, Table 3). Approximately half of these insignificant cancers were clinically stage T1c disease, while no clinical stage T2c-T3 cancers were clinically insignificant. Except for three pT0 cases, all cancers were well to moderately differentiated adenocarcinoma. Clinically insignificant cancers were present in 4 of 21 patients less than 60 years old, in 20 of 69 patients aged 60-69 years and in 4 of 14 patients over 70 years old. Prediction of insignificant cancer by preoperative serum PSA level was not possible because PSA was 34.0 ng/ml in 10, 4.1-10.0 ng/ml in 14 and >10.0 ng/ml in 4. Tumor volume was >0.5 cm3 in 17 of 28 insignificant cancers, whereas three moderately differentiated cancers <0.5 cm3 were considered to be clinically significant. The PSA-based screening program detected 14 clinically significant and five insignificant cancers (three T1c, one T2a and one T2b). However, tumor volume exceeded 0.5 cm3 in all five insignificant tumors and the T2a cancer remained clinically insignificant for the assumed doubling times of 3 and 4 years.
Figure With pathologically confined prostate cancer with negativc surgical margin assumed as an indicator of curability, only 37.6% of the patients (38/101 excluding 3 with pT0 but including 2 with pT3 without tumor volume data as significant cancer) were considered potentially curable by surgery alone (Fig. 2). For a 2-year doubling time and excluding clinically insignificant cancer based on current criteria, only 36.4% (36/99) of the significant cancers were considered potentially curable and for a 3-year doubling time, 32.3% (30/93). At 4- and 6-year doubling times, only 30.7% (27/88) and 25.0% (19/76) were found potentially curable, respectively. Had radical prostatectomy not been indicated for 17 clinical stage T3 patients and 13 with nodal involvement, potentially curable surgery for clinically significant cancers would have been possible for 48.0% (36/75), 43.5% (30/69), 42.2% (27/64) and 36.5% (19/52), assuming 2-, 3-, 4 and 6-year doubling times, respectively.
Figure
Frequently detected clinically silent prostate cancer in autopsy studies suggests benign natural history of the disease in some men, but a more aggressive and potentially lethal nature in others. The benefits of and decision making for any treatment require a thorough knowledge of the natural history and clinical significance of this malignancy. Factors that should be considered for assessing the clinical significance of prostate cancer include both host features and tumor characteristics (8-10).
The most important morphological prognosticators in radical prostatectomy specimens are pathological stage, surgical margin status, histological grade and tumor volume. Based on the lifetime probability of a diagnosis of prostate cancer and volume distribution of unsuspected prostate cancers in cystoprostatectomy specimens, Stamey et al. consider the largest prostate cancer <0.5 cm3 in volume possibly to be clinically insignificant (19). Ohori et al. consider total tumor volume <0.5 cm3, Gleason primary or secondary grades 1-3 and organ-confined as clinically insignificant (17). Humphrey et al. maintain that carcinomas are potentially insignificant if the neoplasm is well differentiated (Gleason score 2-4) and the total tumor volume is <0.5 cm3 (20). Epstein et al. define prostate cancer as clinically insignificant only if dominant tumor volume is <0.2 cm3 or minimal (0.2-0.5 cm3) for low or intermediate grade (Gleason score <7) and confined to the prostate (18). Hence these definitions of insignificant cancer were made arbitrarily based on histopathological data of specimens removed at surgery and only for selected cases in radical surgery. They therefore may not be representative of the whole population with prostate cancer. Although these tumors may be pathologically significant, whether they would progress if left untreated remains unclarified.
Table 4. Differences in the incidence of clinically insignificant cancer for Japanese and American male populations for an assumed cancer doubling time of 6 years according to clinical stage
Prostate cancer is slowly progressive and occurs in persons with life expectancy made short due to other diseases (21). The assignment of any cancer to an unimportant category must therefore be based on the age, health and life expectancy and features of the cancer itself (8,9,16,17). Dugan et al. consider prostate cancer to be clinically insignificant if the adjusted Gleason score is low and the tumor volume will not exceed 20 cm3 by the time of expected patient death (9). Most prostate cancers would metastasize and occupy the greater part of the prostate gland at this volume, thus giving rise to urinary obstructive symptoms, and they would therefore be considered clinically significant. With these definitions and findings considered, clinically insignificant cancers in the 337 prostatectomy specimens were 0.3, 3.9, 7.4 and 14.5% for cancer volume doubling times of 2, 3, 4 and 6 years, respectively. Accordingly, most men treated by radical prostatectomy may be concluded to have clinically significant cancer. Dugan et al. have yet to report outcome results for their surgery (9). The present model may not be directly applicable to other populations owing todifferences in the methods of patient recruitment and staging, nor may it be applicable to elderly Japanese males since they have a longer life expectancy than other male populations in the world (3). The average life expectancy for Japanese males at birth is 1-6 years longer than that in western countries. Small cancers should, at least in theory, grow to a critical size in a population with longer life expectancy. A model for accurately assessing clinical significance of prostate cancer for each individual race and population is therefore essential and should be established. The estimated volume of prostate cancer at the time of expected patient death appears greater in Japanese than American patients (Table 1) (9). The use of index rather than total tumor volume in this study has made actual differences even more pronounced. Four additional classes of prostate cancer were considered clinically significant based on the present criteria for Japanese males (Table 1). Prostate cancer of 0.25 cm3 found at the age of 70 may be significant, should cancer volume doubling time be 2 years. Similarly, 0.25 cm3 tumors at the age of 60 and 0.5 cm3 tumors at the age of 65 would be significant for a tumor doubling time of 3 years. Prostate cancer of 2.0 cm3 at the age of 60 is probably significant for a cancer volume doubling time of 6 years. None of these tumors was significant according to Dugan et al. (9). However, 4.0 cm3 tumors with a doubling time of 3 years cannot reach 20 cm3 at the time of patient expected death if the patient is already 80 years old. The longer life expectancy of elderly Japanese males, especially those who are younger, is the reason for the present findings. Distinct differences in the incidence and mortality of prostate cancer suggest this disease in western populations to be more aggressive biologically (l-3,22-25). Current findings may be interpreted otherwise. The model proposed here does not consider unidentified tumor factors involved in the development of clinically significant tumors. Cancers may remain clinically silent as long as there are no further malignant changes essential for tumor progression, regardless of host longevity (24). The definition of clinical significance of prostate cancer based only on assumptions on fixed tumor doubling time, life expectancy and other estimates may be problematic. Current findings and the definition for the clinical significance of prostate cancer should therefore be evaluated further for confirmation of validity. Pathologically confined prostate cancer of <0.5 cm3 with well to moderately differentiated histology was found in 13 (12.5%) of the present patients. These were considered unimportant on being assessed based on the conventional definition (17). With patient life expectancy and tumor doubling time taken into consideration, 4.8-26.9% of the tumors were considered clinically insignificant. Approximately half of these insignificant cancers were clinically stage T1c, irrespective of tumor doubling time. The incidence of clinically insignificant cancer almost doubled in our study compared with that by Dugan et al. (9) (Table 4). This may be attributed to the greater proportion of insignificant cancer in stage T1c disease in this study. The absence of insignificant cancer in T2c disease may have been due to the small number of patients in this category in our study. Insignificant tumors were found in 8.8-47.1% of all stage T1c depending on tumor doubling times. The incidence of insignificant stage T1c tumors <0.5 cm3 has been reported as 10-26% (18,26). The actual incidence of insignificant tumors may be greater especially for longer doubling times, as has been observed for most well to moderately differentiated tumors (9,15,16,19). Many stage T1c tumors with favorable histology may therefore be treated better conservatively than by definitive therapy. Radical prostatectomy, when performcd on men with life expectancy of .15 years with actually organ-confined, clinically significant cancer, is acceptable and effective. However, it is curative only if all the tumor present is removed. No patient in the present study with clinical stage T3 tumor had organ-confined disease pathologically. In 57.5% of those with clinically localized disease (<T3), pathologically confined disease was noted. With pathologically confined prostate cancer with negative surgical margin assumed as an indication of curability, 37.6% (38/101) were considered potentially curable by surgery alone. Only one in 3-4 clinically significant tumors could be considered curable by radical prostatectomy, with life expectancy and tumor doubling time taken into consideration in the present study. Had radical surgery not been indicated for 17 clinical stage T3 disease and 13 with nodal involvement, possibly curable clinically significant tumors would have been 36.5-48.9%, depending on tumor doubling time. The other patients may have undergone unnecessary, potentially harmful intervention in response to cancer detection. Unfortunately, this may be an over-estimation of what is possible by radical prostatectomy since clinical failure (local or distant) occurs at 10-26% even for lesions pathologically confined to the prostate following radical prostatectomy (27). For two (4.9%) patients with pathologically organ confined disease, biochemical failure was noted at a mean follow-up of 25.1 months after surgery. Additional such incidences may be observed with longer follow-up. Those for whom radical prostatectomy is indicated have less comorbidity than patients undergoing other treatments or whose expected life expectancy may exceed that of the general population (28,29). Some clinically insignificant tumors may in turn appear significant.Tumor doubling time and patient life expectancy were found in this study to be significant determinants of the clinical significance of prostate cancer, particularly in elderly males with a greater risk of mortality. The pathological significance of a tumor cannot directly be expressed as clinical significance. The outcome of radical prostatectomy was found to be less satisfactory with these factors taken into consideration. Many stage T1c patients may be better candidates for expectant management especially if their histology is comparatively more favorable. The inability to predict tumor volume accurately prior to treatment may limit the extent to which the present definition of prostate cancer significance is clinically applicable. In consideration of the effects of other diseases, the present conclusions may be considered only preliminary and additional research should be conducted.
This work was supported in part by a grant from the Ministry of Health and Welfare of Japan (7-42).
DISCUSSION
ACKNOWLEDGMENT
REFERENCES
Received April 4, 1997; accepted June 20, 1997
For reprints and all correspondence: Shin Egawa, Department of Urology, Kitasato University School of Medicine, 1-15-1 Kitasato, Sagamihara, Kanagawa 228, Japan
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