Research ArticleExperimental Studies

Postoperative Radiotherapy for Localized Prostate Cancer: Clinical Significance of Nadir Prostate-specific Antigen Value within 12 Months

KAZUHIKO OGAWA, KATSUMASA NAKAMURA, TOMONARI SASAKI, HIROSHI ONISHI, MASAHIKO KOIZUMI, MASAYUKI ARAYA, NOBUTAKA MUKUMOTO, MICHIHIDE MITSUMORI, TERUKI TESHIMA and the Japanese Patterns of Care Study Working Subgroup of Prostate Cancer
Anticancer Research November 2009, 29 (11) 4605-4613;

Abstract

Aim: To analyze retrospectively the results of postoperative radiotherapy for localized prostate cancer and to investigate the clinical significance of nadir prostate-specific antigen (PSA) value within 12 months (nPSA12) as an early estimate of clinical outcome after radiotherapy. Patients and Methods: Seventy-six patients with localized prostate cancer treated with postoperative radiotherapy were retrospectively reviewed. Total radiation doses ranged from 50 to 70 Gy (median: 60 Gy), and the median follow-up period for all 76 patients was 47.9 months (range, 12.4-101.3 months). Results: The 5-year actuarial overall survival, progression-free survival, biochemical relapse-free survival (BRFS) and local control rates in all 76 patients after radiotherapy were 86.1%, 77.8%, 80.0% and 92.2%, respectively. Distant metastases and/or regional lymph node metastases developed in 11 patients (14%) after radiotherapy, while local progression was observed in only 5 patients (7%). Of all 76 patients, the median nPSA12 in patients with biochemical failure and that in patients without biochemical failure were 1.16 ng/ml and 0.05 ng/ml, respectively. The 5-year BRFS rates in patients with low nPSA12 (<0.5 ng/ml) and those with high nPSA12 (≥0.5 ng/ml) were 92.7% and 42.2%, respectively (p<0.0001). In univariate analysis, nPSA12, pre-radiotherapy PSA, Karnofsky performance status and the use of chemotherapy had a significant impact on BRFS, and in multivariate analysis, nPSA12 alone was an independent prognostic factor for BRFS. Conclusion: Postoperative radiotherapy results in an excellent local control rate for localized prostate cancer and nPSA12 is predictive of biochemical failure after postoperative radiotherapy.

Radical prostatectomy has been established as the primary curative procedure for the treatment of localized prostate cancer. However, despite a marked downward stage shift due to widespread serum prostate-specific antigen (PSA) screening and improvement in surgical techniques, approximately one-third of patients who undergo radical prostatectomy for their prostate cancer will experience biochemical recurrence after surgery (1-3). Many reports have indicated that the most significant risk factors for biochemical recurrence after prostatectomy are high Gleason score, extraprostatic extension, seminal vesicle invasion and a positive surgical margin (1, 4-8). Rising PSA levels following radical prostatectomy may be due to a local recurrence in the prostatic bed, occult distant metastases or a combination of both.

Although the optimal postoperative management of patients with localized prostate cancer has not yet been established, postoperative radiotherapy may be considered the treatment of choice to achieve both biochemical and local control (9-13). Recent randomized trials have demonstrated that in men who had undergone radical prostatectomy for pathologically advanced prostate cancer, adjuvant radiotherapy resulted in a significantly reduced risk of biochemical recurrence and disease recurrence compared with observation alone (11, 14). However, little information regarding clinically useful markers of recurrence risk exists for prostate cancer patients who undergo postoperative radiotherapy.

For patients with untreated prostate cancer, PSA has been utilized as an important marker for treatment response and disease recurrence for prostate cancer (15, 16). The nadir in PSA (nPSA) after radiotherapy has been shown to predict biochemical failure (17, 18), distant metastasis (19, 20), cause-specific mortality (21, 22) and overall mortality (22). However, the nPSA usually takes several years to occur, even as long as 8-10 years in some patients, and as a consequence, nPSA has little practical clinical value. It would be ideal to identify a surrogate nPSA that describes the lowest PSA achieved during a well-defined, relatively short time interval after completion of radiotherapy. Recently, time-limited survey of PSA, such as nPSA value within 12 months (nPSA12), has been reported to be an early predictor of biochemical failure, distant metastasis and mortality that is independent of radiotherapy dose and other determinants of outcome after radiotherapy for previously untreated localized prostate cancer (15, 16).

Because nPSA12 has been shown to be a useful predictor of treatment outcome for untreated localized prostate cancer treated with radical radiotherapy, we hypothesized that nPSA12 may also have potential applications in the monitoring of localized prostate cancer treated with postoperative radiotherapy. In the current study, we first analyzed the treatment results of postoperative radiotherapy for patients with localized prostate cancer. Next, we examined the nPSA12 level in patients with localized prostate cancer treated with postoperative radiotherapy and investigated whether nPSA12 could be a prognostic factor of clinical outcomes for these patients.

Patients and Methods

We used the detailed data from patients with localized prostate cancer who were included in the Japanese Patterns of Care Study (PCS). The PCS, which has been developed in the United States as a quality assurance program, was conducted in Japan in an attempt to obtain data on the national standards of radiotherapy for several diseases including prostate cancer (23). The Japanese PCS Working Subgroup of Prostate Cancer initiated a nationwide process survey for patients who underwent radiotherapy between 1996 and 1998. Subsequently, a second PCS of Japanese patients treated between 1999 and 2001 was conducted. We have previously reported the results of the first and second PCS surveys with respect to postoperative external beam radiotherapy for prostate cancer patients (24).

PCS methodology has been described previously (23, 25, 26). In brief, the PCS surveys were extramural audits that utilized a stratified two-stage cluster sampling design. The PCS surveyors consisted of 20 radiation oncologists from academic institutions, and each radiation oncologist collected data by reviewing patients' charts from their institution. Patients with a diagnosis of adenocarcinoma of the prostate were eligible for inclusion in the present study unless they had one or more of the following conditions: i) evidence of distant metastasis; ii) concurrent or prior diagnosis of any other malignancy; iii) prior radiotherapy. The PCS data used in the current study are from two Japanese national surveys conducted to evaluate prostate cancer patients treated with radiotherapy in the 1996-1998 and 1999-2001 PCS surveys. Of the 839 patients comprising the 1996-1998 and 1999-2001 PCS survey populations, a total of 169 patients who received postoperative radiotherapy after radical prostatectomy were identified. Of these, 93 patients with insufficient nPSA12 data and/or patients who received total doses of less than 50 Gy were excluded, and in total, 76 patients with measurable nPSA12 were subjected to this analysis. The disease characteristics of these 76 patients, such as the tumor stage and pre-treatment PSA levels, were not significantly different compared to those of 93 patients having insufficient data for nPSA12 and/or those who received total doses of less than 50 Gy. All 76 patients received surgical resection initially, followed by postoperative radiotherapy.

Table I shows the patient characteristics of all 76 patients. Postoperative radiotherapy was administered as an adjuvant therapy (undetectable PSA and postoperative radiotherapy in 3-12 months after surgery) to 42 patients and the remaining 34 patients received radiotherapy as salvage therapy (elevated PSA and/or delayed rise in PSA after surgery). PSA was defined as the PSA value before initial treatment and pre-radiotherapy PSA was defined as the PSA value just before radiotherapy.

The method of treatment is shown in Table II. Hormonal therapy was administered either alone or in combination with orchiectomy, estrogen agents, luteinizing hormone-releasing hormone (LH-RH) agonists or antiandrogens after radiotherapy. The median duration of hormonal therapy was 15.4 months (range, 0.1-77.6 months). Regarding chemotherapy, 11 patients (14%) were also treated with chemotherapy, such as estramustine and 5-fluorouracil.

Regarding radiotherapy, the majority of patients were treated with >10 MV linear accelerators and also treated with 4 or more portals. The median radiation dose delivered to the prostate bed was 60 Gy (range, 50-70 Gy), and the median dose per fraction was 2 Gy (range, 2-2.2 Gy). Thirty patients (39%) received treatment to the pelvic nodes in addition to prostate bed, and the remaining 46 patients (61%) received irradiation only to the prostate bed. Regarding lymph node status, 6 out of 7 patients (86%) with pathologically positive lymph nodes received treatment to the pelvic nodes in addition to prostate.

nPSA12 was defined as the lowest PSA level achieved during the first year after completion of radiotherapy. The median number of PSA evaluations within 12 months after radiotherapy was 4 times (range, 1-17) in all 76 patients. The median follow-up of all patients was 47.9 months (range, 12.4-101.3 months), and all patients without biochemical failure had at least 1 year's follow-up. Biochemical failure is defined according to the Phoenix consensus definitions: failure is considered when PSA levels reach 2 ng/ml or more above nadir (27). Concerning clinical failure, patients were categorized as having progression after radiotherapy if they developed local, pelvic nodal, or distant failure. Alone or combination of chest radiography, liver ultrasound, computed tomography scans and magnetic resonance imaging scans were used for confirmation of suspected progression.

Statistical analyses were performed using the Statistical Analysis System at the PCS statistical center (28). Overall survival, progression-free survival (PFS), biochemical relapse-free survival (BRFS) and local control rates were calculated actuarially according to the Kaplan-Meier method (29) and were measured from the start of radiotherapy. Differences between groups were estimated using the chi-square test, Student's t-test, Mann-Whitney U-test and the log-rank test (30). Multivariate analysis was performed using the Cox regression model (31). A probability level of 0.05 was chosen for statistical significance. The Radiotherapy Oncology Group (RTOG) late toxicity scales were used to assess the late morbidity (32).

View this table:
Table I.

Patient characteristics.

View this table:
Table II.

Treatment characteristics.

Results

Seven out of 76 patients (9%) died during the period of this analysis. Of these patients, 6 patients died of prostate cancer and the remaining 1 patient died without any sign of clinical recurrence (intercurrent diseases). The 5-year actuarial overall survival, PFS, BRFS and local control rates in all 76 patients after radiotherapy were 86.1%, 77.8%, 80.0% and 92.2%, respectively (Figures 1 and 2). With regard to the site of recurrence, 15 patients had clinical failure (local only in 3, local with distant metastases in 2, regional in 1, distant metastasis in 7, regional and distant metastasis in 1 and unknown site in 1 patient). Distant metastases and/or regional lymph node metastases developed in 11 patients (11%) after radiotherapy, while local progression was observed in only 5 patients (7%). Regarding the total radiation dose (Table III), 51 out of 56 patients (91%) treated with less than 66 Gy achieved local control, while 20 out of 20 patients (100%) treated with 66 Gy or more achieved local control (p=0.17). Regarding the radiation field used, 28 out of 30 patients (93%) treated for the whole pelvis with boost and 43 out of 46 patients (93%) treated with a local field achieved local control; this difference was not statistically significant (p=0.98).

Figure 1.
Figure 1.

Actuarial overall and progression-free survival curves for 76 patients with prostate cancer treated with postoperative radiotherapy.

View this table:
Table III.

Local control according to the radiation dose and field.

Of all 76 patients, the median nPSA12 in patients with biochemical failure and that in patients without biochemical failure were 1.16 ng/ml and 0.05 ng/ml, respectively. Patients treated with adjuvant therapy had significantly lower nPSA12 (median: 0.07 ng/ml) than those treated with salvage therapy (median: 0.23 ng/ml, p=0.018). On the other hand, patients treated with hormonal therapy had almost similar nPSA12 (median: 0.10 ng/ml) compared to those without hormonal therapy (median: 0.09 ng/ml, p=0.45). Figure 3 shows the distribution of nPSA12 according to the achievement of biochemical control. Over 80% of patients with biochemical control (52 out of 62 patients, 84%) had a nPSA12 of <0.5 ng/ml, while only 4 patient out of 14 patients (29%) with biochemical failure had a nPSA of <0.5 ng/ml (p<0.0001). For the 52 patients who achieved a nPSA12 level <0.5 ng/ml and who did not experience biochemical failure, the median time from the completion of radiotherapy to achievement of a nPSA12 level <0.5 ng/ml was 2.0 months (range, 0.2-11.5 months).

Figure 2.
Figure 2.

Actuarial biochemical-free survival and local control curves for 76 patients with prostate cancer treated with radiotherapy.

Figure 3.
Figure 3.

Distribution of nPSA12 values according to biochemical control (yes: controlled, no: not controlled). Over 80% of patients with biochemical control had a nPSA12 <0.5 ng/ml, while only 29% of patients who experienced biochemical failure had a nPSA12 <0.5 ng/ml.

When dividing patients into low (<0.5 ng/ml) and high (>0.5 ng/ml) nPSA12 groups, the 5-year BRFS rates in patients with low nPSA12 and those with high nPSA12 were 92.7% and 42.2%, respectively (p<0.0001) (Figure 4). In univariate analysis, nPSA12, pre-radiotherapy PSA, Karnofsky performance status (KPS) and the use of chemotherapy had a significant impact on BRFS, and other factors, such as type of therapy (adjuvant vs. salvage), the total radiation dose and the use of hormonal therapy, did not influence BRFS (Table IV). In multivariate analysis, nPSA12 alone was an independent prognostic factor for BRFS after radiotherapy (Table V).

View this table:
Table IV.

Univariate analysis of various potential prognostic factors for biochemical-free survival in patients with prostate cancer treated with postoperative radiotherapy.

View this table:
Table V.

Multivariate analysis of various potential prognostic factors for biochemical-free survival in patients with prostate cancer treated with postoperative radiotherapy.

Regarding clinical control, the median nPSA12s in patients without clinical failure after radiotherapy and those with clinical failure were 0.04 ng/ml (range, 0.00-5.90 ng/ml) and 0.90 ng/ml (range, 0.00-5.00 ng/ml), respectively. The 5-year actuarial PFS rates in patients with high nPSA12 levels and patients with low nPSA12 levels were 92.7% and 35.9%, respectively (Figure 5). The difference between these two groups was statistically significant (p<0.0001). In a univariate analysis, nPSA12, surgical margin status, KPS, pre-radiotherapy PSA and the use of chemotherapy had a statistically significant impact on PFS (Figure 5; Table VI). However, in a multivariate analysis, no factors were independent prognostic factors for PFS (Table VII).

Late morbidity of RTOG grade 2-3 was observed in 8 patients (11%). A total of 4 patients experienced late rectal toxicity and the remaining 4 patients had late urinary toxicity. There were no cases of grade 4 toxicity (Table VIII). Regarding 4 patients who suffered grade 3 late complications, CT-based treatment planning was carried out in only 1 patient (25%), and conformal therapy was supplemented in 1 patient (25%).

Discussion

The current study indicated that postoperative radiotherapy gave an excellent local control rate for patients treated with radical prostatectomy. Several reports have also indicated that postoperative radiotherapy gave an excellent local control rate for these tumors (11, 33-35). The EORTC trial reported the cumulative incidence of locoregional failure at 5 years of follow-up, and a statistically lower incidence of failure was seen in the adjuvant radiotherapy arm (5.4%) than in the observation arm (15.4%) (11). Cozzarini et al. retrospectively analyzed 237 patients who underwent postoperative radiotherapy (within 6 months of surgery), and indicated that the actuarial 8-year local control rate was 93% (33). In the current study, only 5 out of 76 patients (7%) developed local failure after radiotherapy.

Figure 4.
Figure 4.

Actuarial biochemical-free survival curves according to the level of nPSA12. There were significant differences in PFS between patients with a low nPSA12 value (<0.5 ng/ml) and those with a high nPSA12 value (≥0.5 ng/ml).

Although the dose response in patients who undergo postoperative radiotherapy for localized prostate cancer has not yet been clearly established, higher doses with curative intent can result in favorable outcomes in some patients. In the current study, the 5-year local control in 76 patients treated with a median dose of 60 Gy was 92.2%, and 22 out of 22 patients (100%) treated with 66 Gy or more had achieved local control. Several reports have suggested that radiation doses of 65 Gy or more are associated with improved biochemical PFS (36, 37). Therefore, radiation doses of 65 Gy or more appear to be appropriate for prostate cancer patients when treated with postoperative radiotherapy. However, in the current study, it is important to note that the almost all patients who suffered grade 3 late complications were treated without CT-based treatment planning and/or conformal therapy. Therefore, CT-based treatment planning and/or conformal therapy should be required to reduce the late complications. Concerning the radiation field, we did not find significant differences in local control between patients treated for the whole pelvis with or without boost and those treated with a localized field only. Therefore, localized field irradiation may be sufficient in this patient population. Further studies are required to determine whether a localized field is sufficient for these patients.

The current study also indicated that patients with a high nPSA12 had a significantly lower BRFS rate than patients with a low nPSA12, and nPSA12 was an independent prognostic factor for BRFS in patients with localized prostate cancer treated with postoperative radiotherapy. Moreover, patients with low nPSA12 levels had significantly higher PFS than those with high nPSA12 level, although nPSA12 was not an independent prognostic factor for PFS in the multivariate analysis. To our knowledge, this is the first report to demonstrate the utility of nPSA12 in determining prognosis in patients with localized prostate cancer treated with postoperative radiotherapy. Concerning previously untreated prostate cancer, Alcantara et al. indicate that nPSA12 is independent of radiation dose, T stage, Gleason score, pretreatment initial PSA, age and PSA doubling time, and dichotomized nPSA12 (≤2 versus >2 ng/ml) was independently related to distant metastasis and cause-specific mortality (15). Ray et al. indicated that patients with nPSA12 ≤2.0 ng/ml had significantly higher 8-year PSA failure-free survival and overall survival than patients with nPSA12 >2.0 ng/ml, and nPSA12 was an independent prognostic factor for prostate cancer patients treated with radiotherapy alone (16). Furthermore, Ogawa et al. indicated that nPSA12 was an independent prognostic factor for hormone-refractory prostate cancer patients treated with radiotherapy (38). These results suggest that nPSA12 may be a useful marker for patients with localized prostate cancer treated with postoperative radiotherapy as well as patients with previously untreated prostate cancer treated with radiotherapy and clinically localized hormone-refractory prostate cancer.

Figure 5.
Figure 5.

Actuarial progression-free survival curves according to the level of nPSA12. There were significant differences in PFS between patients with a low nPSA12 value (<0.5 ng/ml) and those with a high nPSA12 value (≥0.5 ng/ml).

Several previous studies have suggested other potential factors associated with the risk of prostate cancer recurrence, such as pre-radiotherapy PSA, PSA velocity and PSA doubling time (PSADT) (9, 39-42). For patients treated with salvage radiotherapy, Gleason score, pre-radiotherapy PSA level, surgical margins, PSADT and seminal vesicle invasion are prognostic variables for a durable response to salvage radiotherapy (41). Sasaki et al. indicated that a low pre-radiotherapy PSA level is a significant predictor of biochemical control for postoperative radiotherapy in patients with prostate cancer (42). King et al. reported that postoperative PSA velocity independently predicts for the failure of salvage radiotherapy after radical prostatectomy (39). Numata et al. indicated that PSADT appears to be a good predictor of response to salvage radiotherapy in patients with biochemical recurrence after radical prostatectomy (9).

View this table:
Table VI.

Univariate analysis of various potential prognostic factors for progression-free survival in patients with prostate cancer treated with postoperative radiotherapy.

View this table:
Table VII.

Multivariate analysis of various potential prognostic factors for progression-free survival in patients with prostate cancer treated with postoperative radiotherapy.

View this table:
Table VIII.

Late complications in patients with prostate cancer treated with postoperative radiotherapy.

Concerning the timing of radiotherapy, adjuvant radiotherapy following radical prostatectomy has been compared to salvage therapy in numerous retrospective studies that have included patients with high-risk pathological features (10, 43-45). Overall, the results from those studies support the use of adjuvant radiotherapy, with demonstrated improvements in local and biochemical control. In the current study, there was no significant difference in biochemical control between the adjuvant radiotherapy group and the salvage radiotherapy group. One of the reasons may be the small number of patients in the current study. Our results also indicated that pre-radiotherapy PSA, KPS and the use of chemotherapy had a significant impact on BRFS, although multivariate analyses failed to confirm the significance. Further studies are required to evaluate the influence of additional factors, such as PSA velocity and PSADT, on clinical outcomes for localized hormone-refractory patients treated with radiotherapy.

In conclusion, our results indicated that postoperative radiotherapy gave an excellent local control rate for localized prostate cancer after radical prostatectomy, and should be considered the treatment of choice for these tumors. Our results also indicated that nPSA12 is an early predictor of biochemical failure that is independent of radiotherapy dose and other determinants of outcome after postoperative radiotherapy for prostate cancer patients treated with radical prostatectomy. Therefore, nPSA12 could potentially help identify patients at high risk who might benefit from the earlier application of systemic therapy. However, this study is a retrospective study with various treatment modalities, and further prospective studies are required to confirm our results.

Acknowledgements

Supported by Grants-in-Aid for Cancer Research (Grant Nos. 10-17 and 14-6) from the Ministry of Health, Labor and Welfare of Japan. We thank all radiation oncologists who participated in this study throughout Japan. Their efforts to provide information to us make these surveys possible. We are grateful for the continuous thoughtful support we have received from the U.S. PCS committee for over 10 years.

  • Received May 6, 2009.
  • Revision received July 22, 2009.
  • Accepted September 2, 2009.

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Postoperative Radiotherapy for Localized Prostate Cancer: Clinical Significance of Nadir Prostate-specific Antigen Value within 12 Months
KAZUHIKO OGAWA, KATSUMASA NAKAMURA, TOMONARI SASAKI, HIROSHI ONISHI, MASAHIKO KOIZUMI, MASAYUKI ARAYA, NOBUTAKA MUKUMOTO, MICHIHIDE MITSUMORI, TERUKI TESHIMA, the Japanese Patterns of Care Study Working Subgroup of Prostate Cancer
Anticancer Research Nov 2009, 29 (11) 4605-4613;
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