This study aimed to examine the causes of death in Korean patients who underwent radical prostatectomy for prostate cancer and investigate the relationship between comorbidity and mortality.
We conducted a retrospective multicenter cohort study including 4,064 consecutive patients who had prostate cancer and underwent radical prostatectomy between January 1998 and June 2013. The primary endpoint of this study was all-cause mortality, and the secondary endpoints were cancer-specific mortality (CSM) and other-cause mortality (OCM). Charlson comorbidity index (CCI) was calculated to assess the comorbidities of each patient.
Of 4,064 patients, 446 (11.0%) died during follow-up. The cause of death was prostate cancer in 132 patients (29.6%), other cancers in 121 patients (27.1%), and vascular disease in 57 patients (12.8%) in our cohort. The overall 10-year CSM rate was lower than the OCM rate (4.6% vs. 10.5%). The 10-year CSM rate was lower than the OCM rate in low- to intermediate-risk group patients (1.2% vs. 10.6%), whereas they were similar in high-risk group patients (11.8% vs. 10.1%). In the multivariable analysis, CCI was independently associated with all-cause mortality after radical prostatectomy, regardless of age and pathologic features.
Death from prostate cancer was rare in Korean men who underwent radical prostatectomy. Clinicians should be aware of the possibility of overtreatment of low-risk prostate cancer in men with significant comorbidity. Our findings may help to facilitate counseling and plan management in this patient group.
Prostate cancer remains the most commonly diagnosed cancer in men worldwide [
Medical comorbidity is common among the aging population with cancer, and this affects treatment efficacy [
In this multicenter study, we aimed to evaluate the causes of death after radical prostatectomy for prostate cancer in a Korean cohort. We also assessed the impact of comorbidity on mortality after radical prostatectomy.
To focus on survival outcomes after radical prostatectomy, patients who had received neoadjuvant or adjuvant therapy, had not achieved undetectable prostate-specific antigen (PSA) after surgery, or had inadequate clinical information were excluded from the analysis. The records of 4,064 men with prostate cancer who underwent radical prostatectomy (3,210 patients in Asan Medical Center and 854 patients in the National Cancer Center) between January 1998 and June 2013 were reviewed. Patient data, including demographic and clinical characteristics, treatment-related variables, and survival outcomes, were evaluated retrospectively. For the assessment of comorbidities among the enrolled patients, the Charlson comorbidity index (CCI) and age-adjusted CCI of each patient were calculated [
The levels of PSA were followed up postoperatively at 3-month intervals for the first 2 years, 6-month intervals for the third and fourth years, and annually thereafter. Biochemical recurrence was defined as two consecutive rises in the PSA level of ≥ 0.2 ng/mL after radical prostatectomy. The decision on secondary treatment modalities after biochemical recurrence, including salvage radiotherapy, androgen deprivation therapy, or surveillance, was based on patient’s or physician’s discretion. Abdominopelvic computed tomography and bone scanning were routinely performed at the time of biochemical relapse after radical prostatectomy and biochemical progression after secondary treatment. Radiographic progression was evaluated using computed tomography or magnetic resonance imaging for soft-tissue disease and bone scanning for bone disease. Survival was measured from the date of radical prostatectomy until the date of death. The cause of death was determined according to medical records.
Four-tier National Comprehensive Cancer Network (NCCN) risk groups defined by the guidelines were as follows: low risk: stage T1-T2a, Gleason score (GS) ≤ 6, and PSA < 10 ng/mL; favorable intermediate risk: one intermediate-risk factor (IRF, that is, stage T2b-T2c or GS 7 or PSA 10-20 ng/mL), GS 6 or 3+4, and < 50% biopsy cores positive; unfavorable intermediate risk: two or three IRFs, GS 4+3, and ≥ 50% biopsy cores positive; high risk: stage T3a or GS 8–10 or PSA > 20 ng/mL [
Clinical and pathological data were expressed as frequencies and means. Survival outcomes were determined using the Kaplan-Meier method and compared with log-rank tests. Significant prognostic factors for survival were assessed by multivariate analysis using the Cox proportional hazard model with stepwise backward elimination approach. Competing risk regression was performed to test the association of predictor variables after accounting for prostate CSM and OCM. All statistical tests were two-tailed, with a significance level of 0.05. All statistical analyses were performed using SAS ver. 9.4 (SAS Institute Inc., Cary, NC) and R ver. 3.5.2 (R Foundation for Statistical Computing, Vienna, Austria).
The study protocol was approved by the institutional review board of Asan Medical Center and National Cancer Center, Korea (AMC 2017-1036 and NCC 2018-0123). Informed consent was waived.
The clinical and pathological characteristics of the 4,064 men with prostate cancer who underwent radical prostatectomy in the two study centers, along with the baseline comorbidities, are summarized in
The 10-year all-cause mortality rate was 15.5% in the overall population (
The 10-year CSM rate was lower than the OCM rate in patients with pT2 (1.0% vs. 10.6%) and pT3a (5.4% vs. 10.2%) cancers. However, in patients with pT3b cancers, the 10-year CSM rate was higher than the OCM rate (20.1% vs. 10.4%). The 10-year CSM rate was lower than the OCM rate in patients with pathologic GS of ≤ 7 (1.5% vs. 10.3%). In patients with pathologic GS of 8-10, there was a trend toward having a higher 10-year CSM rate than OCM rate (14.8% vs. 11.3%). A comparison between CSM and OCM according to the preoperative NCCN risk groups and age-adjusted CCI is shown in
In the multivariable analyses, CCI was significantly associated with overall mortality after radical prostatectomy, regardless of age and pathologic features (
Treatment decisions for men with non-metastatic prostate cancer are mostly influenced by age and clinical cancer characteristics [
The number of prostate cancer survivors is expected to increase continuously because of demographic changes and advances in treatment methods. Considering the heterogeneity of prostate cancer characteristics and comorbidities according to different geographical and ethnic populations [
In 2018, the mortality rates of the two top causes of death per 100,000 people in Korea were 154.3 for malignant neoplasms and 122.7 for circulatory system diseases [
The over-diagnosis and overtreatment of non-metastatic prostate cancer have become a major health care issue [
We acknowledge several limitations to this study. First, this study was retrospective in nature and could not eliminate the biases inherent to observational studies. Moreover, the lack of prospective standardized protocols for primary and salvage treatment may have introduced biases. Second, the study population may not be representative of all Korean men who undergo radical prostatectomy. Thus, the generalizability of our data from referral centers may be limited. Third, incomplete data on the statistics of the cause of death is another main limitation. These data on the cause of death solely depend on medical records; because of loss to follow-up, the causes of death in 95 patients (21.3%) were unknown. Few patients had evidence of prostate cancer recurrence until the last follow-up (biochemical recurrence: 17/95 [17.9%] and distant metastasis: 0/95 [0%]), suggesting that there may be a larger number of patients who died from other causes than the present data have shown. Fourth, we could not conduct comprehensive geriatric assessment (CGA) in this retrospective study. While CCI provides a quantitative approach to enumerate comorbid conditions, CGA is a multidisciplinary and comprehensive tool for evaluating elderly patients, which may be more appropriate for predicting survival and radical treatment selection. Lastly, the duration and severity of each comorbidity were not taken into consideration.
In conclusion, we have demonstrated that mortality from prostate cancer was rare in Korean men who underwent radical prostatectomy. Physicians should be aware of the possibility of overtreatment for low-risk prostate cancer in men with significant comorbidity. These findings may help to facilitate counseling and plan management in this patient group.
Supplementary materials are available at Cancer Research and Treatment website (
Survival outcomes according to comorbidities and CAPRA-S score. CCI, Charlson comorbidity index.
Cause-specific mortality outcomes according to preoperative National Comprehensive Cancer Network risk group.
Conflicts of interest relevant to this article was not reported.
This work was supported by a career development award (NCCCDA2019-06) from the National Cancer Center, Korea.
Survival outcomes of the overall population.
Survival outcomes according to the preoperative National Comprehensive Cancer Network risk group.
Survival outcomes according to comorbidities and preoperative National Comprehensive Cancer Network risk group. CCI, Charlson comorbidity index.
Clinical and pathological characteristics of patients
Total (n=4,064) | |
---|---|
65.1 | |
< 50 | 74 (1.8) |
50-60 | 763 (18.8) |
60-70 | 2,055 (50.6) |
70-80 | 1,154 (28.4) |
≥ 80 | 18 (0.4) |
24.7 | |
Hypertension | 1,759 (43.3) |
Diabetes mellitus | 638 (15.7) |
Other malignancy | 141 (3.5) |
Heart disease | 190 (4.7) |
Cerebrovascular disease | 113 (2.8) |
Liver cirrhosis | 50 (1.2) |
End-stage renal disease | 6 (0.1) |
Chronic obstructive pulmonary disease | 112 (2.7) |
Charlson comorbidity index | |
0 | 2,993 (73.6) |
1 | 380 (9.4) |
2 | 543 (13.4) |
≥ 3 | 148 (3.6) |
13.0 | |
Low | 1,280 (31.5) |
Favorable intermediate | 1,041 (25.6) |
Unfavorable intermediate | 483 (11.9) |
High | 1,260 (31.0) |
Unknown | 129 (3.2) |
6 | 909 (22.4) |
3+4 | 1,368 (33.6) |
4+3 | 857 (21.1) |
8 | 343 (8.4) |
9-10 | 458 (11.3) |
T2 | 2,573 (63.4) |
T3a | 989 (24.3) |
T3b-T4 | 502 (12.3) |
224 (5.5) | |
1,309 (32.2) |
Values are presented as number (%) unless otherwise indicated. NCCN, National Comprehensive Cancer Network.
Causes of death after radical prostatectomy
Cause of death | Total (n=446) |
---|---|
132 (29.6) | |
219 (49.1) | |
Other malignancy | 121 (27.1) |
Lung | 25 (5.6) |
Liver | 11 (2.5) |
Colon, rectum, and anus | 8 (1.8) |
Stomach | 19 (4.2) |
Biliary tract and pancreas | 29 (6.5) |
Hematopoietic malignancy | 12 (2.7) |
Bladder | 7 (1.6) |
Others | 10 (2.2) |
Vascular disease | 57 (12.8) |
Coronary heart disease | 31 (7.0) |
Cerebrovascular disease | 26 (5.8) |
Chronic pulmonary disease | 22 (4.9) |
Chronic liver disease | 5 (1.1) |
Other causes | 14 (3.1) |
95 (21.3) |
Values are presented as number (%).
Multivariable Cox regression analyses for evaluating the risk of overall mortality
Variable | No. (event) | Univariable |
Multivariable |
||
---|---|---|---|---|---|
HR (95% CI) | p-value | HR (95% CI) | p-value | ||
4,064 (447) | 1.087 (1.070-1.105) | < 0.001 | 1.081 (1.063-1.098) | < 0.001 | |
4,064 (447) | 0.945 (0.912-0.978) | 0.002 | - | - | |
0-1 | 3,803 (370) | 1 (reference) | 1 (reference) | ||
≥ 2 | 261 (77) | 3.236 (2.531-4.138) | < 0.001 | 2.964 (2.292-3.834) | < 0.001 |
4,064 (447) | 1.007 (1.005-1.010) | < 0.001 | 1.004 (1.000-1.008) | 0.048 | |
T2 | 2,499 (206) | 1 (reference) | < 0.001 | 1 (reference) | < 0.001 |
T3a | 942 (105) | 1.372 (1.085-1.736) | 0.008 | 1.102 (0.860-1.412) | 0.444 |
T3b-N1 | 623 (136) | 2.750 (2.214-3.415) | < 0.001 | 2.194 (1.706-2.821) | <0.001 |
Missing=129 | |||||
≤ 3+4 | 2,277 (186) | 1 (reference) | < 0.001 | 1 (reference) | < 0.001 |
4+3 | 857 (77) | 1.196 (0.916-1.560) | 0.188 | 1.003 (0.766-1.314) | 0.982 |
8-10 | 801 (165) | 2.447 (1.984-3.018) | < 0.001 | 1.546 (1.222-1.957) | < 0.001 |
Negative | 2,755 (267) | 1 (reference) | - | ||
Positive | 1,309 (180) | 1.405 (1.163-1.698) | < 0.001 | - | - |
HR, hazard ratio; CI, confidence interval.
Covariates were chosen based on backward selection.
Cause-specific hazard model for prostate cancer-specific mortality and other-cause mortality
Variable | Prostate cancer-specific mortality |
Other-cause mortality |
|||||||||
---|---|---|---|---|---|---|---|---|---|---|---|
No. (event) | Univariable |
Multivariable |
No. (event) | Univariable |
Multivariable |
||||||
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | ||||
4,064 (133) | 1.030 (1.003-1.058) | 0.028 | 1.018 (0.990-1.047) | 0.208 | 4,064 (314) | 1.116 (1.094-1.139) | < 0.001 | 1.112 (1.090-1.135) | < 0.001 | ||
4,064 (133) | 0.974 (0.915-1.038) | 0.421 | - | - | 4,064 (314) | 0.932 (0.894-0.972) | 0.001 | - | - | ||
0-1 | 3,803 (124) | 1 (reference) | 1 (reference) | 3,803 (246) | 1 (reference) | 1 (reference) | |||||
≥ 2 | 261 (9) | 1.127 (0.573-2.218) | 0.729 | 1.265 (0.614-2.605) | 0.524 | 261 (68) | 4.303 (3.288-5.630) | < 0.001 | 3.832 (2.928-5.016) | < 0.001 | |
4,064 (133) | 1.013 (1.010-1.015) | < 0.001 | 1.006 (1.002-1.010) | 0.002 | 4,064 (314) | 0.997 (0.990-1.004) | 0.371 | - | - | ||
T2 | 2,499 (17) | 1 (reference) | < 0.001 | 1 (reference) | < 0.001 | 2,499 (189) | 1 (reference) | 0.783 | - | - | |
T3a | 942 (28) | 4.430 (2.425-8.094) | < 0.001 | 2.383 (1.268-4.479) | 0.007 | 942 (77) | 1.097 (0.841-1.430) | 0.494 | - | - | |
T3b-N1 | 623 (88) | 21.818 (12.979-36.676) | < 0.001 | 7.554 (4.264-13.382) | < 0.001 | 623 (48) | 1.051 (0.765-1.443) | 0.760 | - | - | |
≤ 3+4 | 2,277 (9) | 1 (reference) | < 0.001 | 1 (reference) | < 0.001 | 2,277 (177) | 1 (reference) | 0.593 | - | - | |
4+3 | 857 (21) | 6.723 (3.079-14.681) | < 0.001 | 4.282 (1.938-9.458) | < 0.001 | 857 (56) | 0.915 (0.677-1.236) | 0.563 | - | - | |
8-10 | 801 (94) | 29.26 (14.765-57.987) | < 0.001 | 11.627 (5.675-23.825) | < 0.001 | 801 (71) | 1.098 (0.833-1.446) | 0.507 | - | - | |
Negative | 2,755 (53) | 1 (reference) | - | 2,755 (214) | 1 (reference) | - | - | ||||
Positive | 1,309 (80) | 3.168 (2.239-4.483) | < 0.001 | - | - | 1,309 (100) | 0.970 (0.765-1.231) | 0.805 | - | - |
HR, hazard ratio; CI, confidence interval.
Covariates were chosen based on backward selection included age and Charlson comorbidity index at treatment.