The purpose of this study was to investigate the clinical outcomes of postoperative radiotherapy (PORT) patients who underwent radical prostatectomy for localized prostate cancer.
Localized prostate cancer patients who received PORT after radical prostatectomy between 2001 and 2012 were identified retrospectively in a multi-institutional database. In total, 1,117 patients in 19 institutions were included. Biochemical failure after PORT was defined as prostate-specific antigen (PSA) ≥ nadir+2 after PORT or initiation of androgen deprivation therapy (ADT) for increasing PSA regardless of its value.
Ten-year biochemical failure-free survival, clinical failure-free survival, distant metastasis-free survival, overall survival (OS), and cause-specific survival were 60.5%, 76.2%, 84.4%, 91.1%, and 96.6%, respectively, at a median of 84 months after PORT. Pre-PORT PSA ≤ 0.5 ng/ml and Gleason’s score ≤ 7 predicted favorable clinical outcomes, with 10-year OS rates of 92.5% and 94.1%, respectively. The 10-year OS rate was 82.7% for patients with a PSA > 1.0 ng/mL and 86.0% for patients with a Gleason score of 8-10. The addition of long-term ADT (≥ 12 months) to PORT improved OS, particularly in those with a Gleason score of 8-10 or ≥ T3b.
Clinical outcomes of PORT in a Korean prostate cancer population were very similar to those in Western countries. Lower Gleason score and serum PSA level at the time of PORT were significantly associated with favorable outcomes. Addition of long-term ADT (≥ 12 months) to PORT should be considered, particularly in unfavorable risk patients with Gleason scores of 8-10 or ≥ T3b.
Radical prostatectomy (RP) is frequently recommended as curative treatment for patients with localized prostate cancer. Although RP provides excellent cancer control, approximately one-third of patients experience recurrence during long-term follow-up [
Nevertheless, long-term outcome data after PORT in patients who undergo RP are still limited and the natural history of those men is not fully understood. In addition, the optimal management of PORT in men with prostate cancer is still under investigation. Only a few analyses about the delivery of PORT, for example regarding the timing of radiotherapy (RT), total dose, field size, or a combination of other treatments, have been performed. There is a lack of consensus on the definition of biochemical failure after PORT, so most studies have had to use their own definition to evaluate the clinical endpoint. Due to the long interval before prostate cancer shows clinically evident recurrence after biochemical failure [
This study included patients who were treated with PORT from January 2001 to December 2012 at 19 KROG member institutions. Inclusion criteria were patients who received PORT either adjuvant or salvage after RP for histologically confirmed localized adenocarcinoma of the prostate, and who completed the entire PORT schedule until December 2012. Patients who had evidence of distant metastases, prior pelvic radiation or prostate brachytherapy, previous or concurrent cytotoxic chemotherapy for prostate cancer, insufficient follow-up after PORT (< 12 months), or a history of another malignancy were excluded. We identified 1,117 patients with prostate cancer, drawn from 19 institutions, who met the study inclusion criteria. The patients were followed up through June 2018. The routine postoperative follow-up generally included a digital rectal examination and serum PSA measurements every 3 months during the first 2 years, every 6 months over the next 3 years, and annually thereafter.
All patients underwent RP. The most common type of RP was retropubic RP (n=575), followed by robotic-assisted RP (n=365), transperineal RP (n=104), and laparoscopic RP (n=73). When PORT was given, radiation was delivered to the prostate bed only (n=456), and in addition to the seminal vesicular bed (n=226), true pelvis (including regional lymph nodes) (n=18), whole pelvis (including common iliac lymph nodes) (n=414), and whole pelvis plus para-aortic area (n=3). The dose fractionation scheme consisted of conventional fractionation (n=842), hypofractionation (n=274), and mixed conventional and hypofractionation (n=1). To adjust for different dose fractionation, the total equivalent dose was calculated in 2 Gy fractions for prostate cancer (α/β ratio=2.0). A median RT dose of 66.7 Gy (interquartile range [IQR], 64.6 to 70.0) was delivered to the clinical target volume (CTV). The RT techniques used at each institution were three-dimensional (3D)-conformal RT (n=568), intensity-modulated RT (n=530), two-dimensional-RT (n=7), proton beam therapy (n=5) and a combination of 3D-conformal RT and intensity-modulated RT (n=7). Androgen deprivation therapy (ADT) was administered before the PORT referral (n=106) or concurrently with PORT (n=579). Adjuvant PORT was defined as PORT given when PSA < 0.2 ng/mL within 1 year from RP, and with no history of ADT. Salvage PORT was defined as PORT given for biochemical or clinical failure after PORT.
Time to recurrence and follow-up were calculated from the first day of PORT. Biochemical failure after PORT was defined as serum PSA level ≥ nadir+2.0 ng/mL or the initiation of salvage ADT regardless of the PSA value, based on the result of a pooled analysis conducted using the Radiation Therapy Oncology Group (RTOG) 0534 protocol [
KROG 18-01 was approved by the institutional review boards of each participating hospital and performed in accordance with the ethical principles of the Declaration of Helsinki and the International Conference on Harmonization guideline E6: Good Clinical Practice. Written informed consent was waived due to retrospective nature of the study.
The patient characteristics are summarized in
The median follow-up duration was 84 months (IQR, 67 to 108 months) from the first day of PORT and 103 months (IQR, 79 to 130 months) from RP. Overall, the estimated 10-year BCFFS, CFFS, DMFS, OS, and CSS were 60.5%, 76.2%, 84.4%, 91.1%, and 96.6%, respectively (
The results of the univariate analysis of prognostic factors are shown in
The results of the multivariate analysis for prognostic factors are summarized in
In general, long-term radiation-related toxicity was acceptable during the observation period (
This study analyzed the long-term outcomes of PORT in Korean patients with prostate cancer who underwent RP. The estimated 10-year OS and CSS rates were 91% and 97%, respectively, and were comparable to or higher than those reported for western countries. Previous large retrospective series reported 10-year OS rates of 77%-89% and 10-year CSS rates of 82%-90% after PORT [
In the prognostic factor analysis, a lower Gleason score and the use of PORT at a lower PSA level were strongly associated with a favorable outcome on all endpoints. The survival disadvantage related to higher pre-PORT PSA level was only seen when the value was ≥ 1.0 ng/mL. A pre-PORT PSA level of 0.5-1.0 ng/mL was a significant predictor of poor BCFFS, CFFS, and DMFS outcomes, but was not predictive of OS or CSS. Stephenson et al. [
Approximately 7% of patients in this study receiving adjuvant PORT demonstrated significantly better BCFFS and CFFS compared to patients who received salvage PORT (
The prescribed RT dose of ≥ 70 Gy significantly improved BCFFS, but not the other endpoints, in our study. Although primary RT for localized prostate cancer has sufficient data supporting dose-escalated RT [
The optimal CTV for PORT remains an unresolved issue. In particular, whether CTV should include regional nodes or not remains controversial, particularly in high-risk patients. In the present study, elective nodal irradiation was a significant predictor for decreased CFFS and DMFS in univariate analysis; however, the results were non-significant in multivariate analysis. The discrepancy might have been due to confounding factors, such as selection bias in retrospective analyses, particularly in relation to baseline characteristics (
When combined with RT in prostate cancer, the major benefits of ADT are control of subclinical distant metastasis and some local effects [
In the RTOG 9601 trial, a
Approximately 4% and 1% of patients suffered from severe genitourinary and gastrointestinal toxicity in this study. Late genitourinary toxicity ≥ grade 3 after PORT has been reported as 7%-10% cases in other studies [
A limitation of this study was its retrospective nature, which may have led to unknown selection biases. However, we attempted to minimize potential bias in the analysis by using a large sample size and a multivariate analysis, to account for variables potentially affecting the outcomes. In addition, given the fact that pre-PORT PSA values are a significant prognostic factor predicting OS and DSS, there could be a lead-time bias when calculating survival from the day of the first PORT instead of the day of RP. To eliminate this lead-time bias, we re-calculated the survivals from the day of RP. In this analyses, pre-PORT PSA was consistently a significant factor predicting OS (p=0.003) and CSS (p < 0.001) (
In conclusion, the clinical outcomes of PORT in a Korean population with prostate cancer were very similar to those published in Western countries. Gleason score and lower serum PSA level at the time of PORT were significantly associated with favorable outcomes in all clinical endpoints. Adding long-term ADT (≥ 12 months) to PORT should be considered in patients with an unfavorable prognosis with Gleason scores of 8-10 or ≥ T3b. Further studies are warranted to refine treatments based on their unique risks and benefits.
Supplementary materials are available at Cancer Research and Treatment website (
The adverse effect according to the RT dose and RT field
Overall survival and cancer-specific survival from the day of RP according to pre-PORT PSA level. RP, radical prostatectomy; PORT, postoperative radiotherapy; PSA, prostate-specific antigen.
Conflict of interest relevant to this article was not reported.
Kaplan-Meier estimates of biochemical failure-free survival (BCFFS), clinical failure-free survival (CFFS), distant metastasis-free survival (DMFS), overall survival (OS) and cancer-specific survival (CSS) of all patients.
Kaplan-Meier estimates of biochemical failure-free survival (BCFFS), clinical failure-free survival (CFFS), distant metastasis-free survival (DMFS), overall survival (OS), and cancer-specific survival (CSS) according to pre-postoperative radiotherapy prostate-specific antigen (PSA) level (A) and Gleason score (B). RT, radiation treatment.
Effect of long-term androgen deprivation therapy (ADT) on overall survival in patients receiving postoperative radiotherapy (PORT). HR, hazard ratio; CI, confidence interval; PSA, prostate-specific antigen.
Biochemical failure (BCF)–free survival (BCFFS) rates according to the biochemical failure definition. PSA, prostate-specific antigen; ADT, androgen deprivation therapy.
Patient characteristics
Variable | No. (%) (n=1,117) |
---|---|
≤ 67 | 575 (51) |
> 67 | 542 (49) |
≤ 20 | 791 (71) |
> 20 | 326 (29) |
2-6 | 85 (8) |
7 | 596 (53) |
8-10 | 433 (39) |
T2 | 335 (30) |
T3a | 422 (38) |
≥ T3b | 355 (32) |
N0-Nx | 1,051 (94) |
N1 | 65 (6) |
Negative | 379 (34) |
Positive | 725 (66) |
< 0.2 | 415 (37) |
0.2 to < 0.5 | 346 (31) |
0.5 to < 1.0 | 192 (17) |
≥ 1.0 | 164 (15) |
Adjuvant | 81 (7) |
Salvage | 1,036 (93) |
< 64 | 245 (22) |
64-67 | 322 (29) |
≥ 67 to < 70 | 122 (11) |
≥ 70 | 425 (38) |
Surgical bed only | 670 (64) |
Including regional lymphatic | 381 (36) |
Pre-PORT |
|
No | 1,011 (91) |
Yes | 106 (9) |
Concurrent ADT |
|
No | 538 (48) |
Short-term (< 12 mo) | 178 (16) |
Long-term (≥ 12 mo) | 295 (26) |
PORT, postoperative radiotherapy; PSA, prostate-specific antigen; EQD2, equivalent dose in 2 Gy fractions; RT, radiotherapy; ADT, androgen deprivation therapy.
Patients with N(+) were excluded,
A history of ADT use longer than 6 months before PORT including perioperative ADT,
ADT given within 6 months before PORT to any time after PORT as the (neo)adjuvant, therapy but not as salvage therapy for biochemical failure after PORT.
Univariate analysis of prognostic factors of BCFFS, CFFS, DMFS, OS, and CSS
Variable | No. | BCFFS |
CFFS |
DMFS |
OS |
CSS |
|||||
---|---|---|---|---|---|---|---|---|---|---|---|
10-Year | p-value |
10-Year | p-value | 10-Year | p-value | 10-Year | p-value | 10-Year | p-value | ||
≤ 20 | 791 | 61.1 | 0.214 | 77.3 | 0.582 | 85.5 | 0.227 | 90.9 | 0.891 | 96.5 | 0.691 |
> 20 | 326 | 57.3 | 73.5 | 81.3 | 91.3 | 97.1 | |||||
≤ 7 | 681 | 67.9 | < 0.001 | 82.3 | < 0.001 | 88.8 | < 0.001 | 94.1 | 0.001 | 98.8 | < 0.001 |
8-10 | 433 | 46.9 | 66.7 | 77.5 | 86.0 | 93.0 | |||||
pT2 | 344 | 71.6 | < 0.001 | 84.0 | < 0.001 | 89.0 | < 0.001 | 91.8 | < 0.001 | 97.7 | 0.026 |
pT3a | 422 | 61.4 | 79.9 | 89.0 | 96.2 | 98.3 | |||||
≥ pT3b | 355 | 47.6 | 65.4 | 75.3 | 85.1 | 94.2 | |||||
Negative | 379 | 59.7 | 0.200 | 75.2 | 0.689 | 83.8 | 0.919 | 90.3 | 0.604 | 96.1 | 0.639 |
Positive | 725 | 60.2 | 76.7 | 84.7 | 91.6 | 97.1 | |||||
0 to < 0.5 | 761 | 66.0 | < 0.001 | 81.2 | < 0.001 | 87.6 | < 0.001 | 92.5 | 0.003 | 97.7 | < 0.001 |
0.5 to < 1.0 | 192 | 59.0 | 71.0 | 87.0 | 92.6 | 97.9 | |||||
≥ 1.0 | 164 | 35.9 | 59.0 | 66.3 | 82.7 | 89.9 | |||||
Salvage | 1,036 | 59.7 | 0.013 | 75.5 | 0.035 | 83.9 | 0.094 | 90.5 | 0.053 | 96.7 | 0.150 |
Adjuvant | 81 | 71.1 | 86.0 | 90.9 | 98.0 | N/A | |||||
< 70 | 692 | 55.8 | 0.004 | 76.0 | 0.866 | 82.7 | 0.051 | 90.3 | 0.486 | 96.7 | 0.713 |
≥ 70 | 425 | 67.6 | 76.0 | 86.3 | 92.3 | 96.5 | |||||
Surgical bed | 670 | 61.5 | 0.149 | 81.1 | 0.012 | 90.3 | < 0.001 | 91.3 | 0.556 | 97.1 | 0.286 |
Regional | 381 | 61.0 | 71.4 | 76.4 | 91.3 | 96.0 | |||||
No | 538 | 52.4 | < 0.001 | 73.5 | 0.022 | 86.2 | 0.368 | 90.2 | 0.030 | 96.2 | 0.215 |
Short-term | 178 | 60.8 | 78.2 | 81.7 | 87.8 | 96.4 | |||||
Long-term | 295 | 75.8 | 86.6 | 88.9 | 97.0 | 99.0 |
BCFFS, biochemical failure-free survival; CFFS, clinical failure-free survival; DMFS, distant metastasis-free survival; OS, overall survival; CSS, cancer-specific survival; PSA, prostate-specific antigen; PORT, postoperative radiotherapy; EQD2, equivalent dose in 2 Gy fractions; RT, radiation treatment; ADT, androgen deprivation therapy.
Biochemical progression was defined as PSA > nadir+2 or initiation of salvage ADT after PORT,
Log-rank test.
Multivariate analysis of prognostic factors of BCFFS, CFFS, DMFS, OS, and CSS
Variable | BCFFS |
CFFS |
DMFS |
OS |
CSS |
|||||
---|---|---|---|---|---|---|---|---|---|---|
HR (95% CI) | p-value |
HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | HR (95% CI) | p-value | |
≤ 20 | Reference | Reference | Reference | Reference | Reference | |||||
> 20 | 0.89 (0.67-1.19) | 0.448 | 0.73 (0.49-1.09) | 0.129 | 0.64 (0.40-1.04) | 0.074 | 0.70 (0.37-1.33) | 0.278 | 0.61 (0.21-1.76) | 0.361 |
≤ 7 | Reference | Reference | Reference | Reference | Reference | |||||
8-10 | 1.80 (1.40-2.31) | < 0.001 | 1.87 (1.32-2.66) | < 0.001 | 2.27 (1.46-3.53) | < 0.001 | 2.12 (1.21-3.71) | 0.008 | 4.90 (1.66-14.40) | 0.004 |
pT2 | Reference | Reference | Reference | Reference | Reference | |||||
pT3a | 1.41 (1.03-1.93) | 0.032 | 1.20 (0.75-1.91) | 0.436 | 1.18 (0.64-2.14) | 0.586 | 0.49 (0.23-1.06) | 0.073 | 0.66 (0.14-3.07) | 0.599 |
≥ pT3b | 2.33 (1.67-3.25) | < 0.001 | 2.78 (1.75-4.40) | < 0.001 | 2.34 (1.31-4.18) | 0.004 | 1.57 (0.82-3.03) | 0.171 | 3.06 (0.89-10.46) | 0.074 |
Negative | Reference | Reference | Reference | Reference | Reference | |||||
Positive | 0.84 (0.65-1.08) | 0.188 | 0.90 (0.63-1.29) | 0.573 | 1.02 (0.65-1.61) | 0.917 | 0.88 (0.50-1.54) | 0.665 | 0.88 (0.33-2.36) | 0.811 |
0 to < 0.5 | Reference | Reference | Reference | Reference | Reference | |||||
0.5 to < 1.0 | 1.51 (1.10-2.05) | 0.009 | 1.71 (1.12-2.60) | 0.012 | 1.74 (1.00-3.04) | 0.050 | 1.28 (0.62-2.62) | 0.491 | 1.40 (0.35-5.51) | 0.623 |
≥ 1.0 | 2.91 (2.15-3.94) | < 0.001 | 2.30 (1.49-3.54) | < 0.001 | 3.14 (1.89-5.20) | < 0.001 | 1.98 (1.03-3.78) | 0.039 | 4.33 (1.50-12.49) | 0.007 |
Salvage | Reference | Reference | Reference | Reference | Reference | |||||
Adjuvant | 0.44 (0.25-0.76) | 0.003 | 0.49 (0.22-1.08) | 0.078 | 0.66 (0.54-1.33) | 0.396 | 0.15 (0.02-1.17) | 0.071 | N/A | 0.977 |
< 70 | Reference | Reference | Reference | Reference | Reference | |||||
≥ 70 | 0.76 (0.59-0.98) | 0.038 | 1.15 (0.81-1.62) | 0.428 | 0.85 (0.54-1.33) | 0.489 | 0.73 (0.41-1.31) | 0.295 | 1.06 (0.41-2.73) | 0.889 |
Surgical bed | Reference | Reference | Reference | Reference | Reference | |||||
Regional | 0.81 (0.62-1.05) | 0.124 | 1.02 (0.70-1.47) | 0.912 | 1.52 (0.97-2.37) | 0.063 | 0.95 (0.53-1.72) | 0.888 | 0.80 (0.29-2.21) | 0.681 |
No | Reference | Reference | Reference | Reference | Reference | |||||
Short-term | 0.71 (0.52-0.97) | 0.033 | 0.73 (0.47-1.14) | 0.169 | 1.21 (0.72-2.04) | 0.466 | 1.03 (0.54-1.95) | 0.919 | 0.95 (0.32-2.83) | 0.933 |
Long-term | 0.25 (0.17-0.36) | < 0.001 | 0.36 (0.22-0.60) | < 0.001 | 0.66 (0.37-1.17) | 0.163 | 0.21 (0.07-0.61) | 0.004 | 0.14 (0.01-1.14) | 0.067 |
BCFFS, biochemical failure-free survival; CFFS, clinical failure-free survival; DMFS, distant metastasis-free survival; OS, overall survival; CSS, cancer-specific survival; PSA, prostate-specific antigen; PORT, postoperative radiotherapy; EQD2, equivalent dose in 2 Gy fractions; RT, radiation treatment; ADT, androgen deprivation therapy.
Biochemical progression was defined as PSA > nadir+2 or initiation of salvage ADT after PORT,
Cox proportional hazards model.
The most severe types of radiation-related toxicity observed during follow-up
Grade 1 | Grade 2 | Grade 3 | Total | |
---|---|---|---|---|
Genitourinary | ||||
No. of patients (%) | 171 (15) | 145 (13) | 44 (4) | 352 (32) |
Median interval from PORT (mo) | 1.3 | 27.5 | 51.9 | 8.2 |
Gastrointestinal | ||||
No. of patients (%) | 182 (16) | 48 (4) | 9 (1) | 241 (22) |
Median interval from PORT (mo) | 2.3 | 1.3 | 10.7 | 1.3 |
Evaluated by Radiation Therapy Oncology Group toxicity criteria. PORT, postoperative radiotherapy.
Comparison of baseline characteristics between two different groups regarding RT field
Variable | Prostate bed only | Prostate bed+elective nodal RT | p-value |
---|---|---|---|
≤ 20 | 535 (80) | 224 (59) | < 0.001 |
> 20 | 136 (20) | 154 (41) | |
≤ 7 | 486 (73) | 168 (45) | < 0.001 |
8-10 | 184 (27) | 208 (55) | |
T2 | 246 (37) | 84 (22) | < 0.001 |
T3a | 261 (39) | 144 (38) | |
≥ T3b | 161 (24) | 148 (39) | |
< 0.2 | 483 (72) | 237 (63) | < 0.001 |
0.5 to < 1.0 | 123 (18) | 58 (15) | |
≥1.0 | 65 (10) | 83 (22) |
Values are presented as number (%). RT, radiation treatment; PSA, prostate-specific antigen; PORT, postoperative radiotherapy.
Chi-square test.