Abstract
INTRODUCTION
Distinct PSA kinetics have been reported across the breadth of radiation modalities used to definitively treat prostate cancer. This study uses a patient-specific model to characterize and compare ideal PSA kinetics for low- and intermediate-risk prostate cancer following definitive treatment with conventionally fractionated (CFRT), hypofractionated (HFRT), ultra-hypofractionated or stereotactic body radiation therapy (SbRT), or brachytherapy, both high-dose-rate (HDR) and low-dose-rate (LDR).
METHODS
This retrospective analysis includes patients with low- or intermediate-risk prostate cancer treated with definitive radiation between 1998 and 2018 at a single, NCI-designated Comprehensive Cancer Center. Patient demographics, treatment characteristics, and follow-up information were prospectively collected in an institutional database. Eligible patients had at least two PSA measurements within 24-months of treatment and were free from biochemical recurrence and receipt of androgen deprivation therapy. The incidence of, time to, and risk factors for PSA nadir (nPSA) and bounce (bPSA) were analyzed by radiation modality. Ideal PSA kinetics were characterized for each modality and compared.
RESULTS
Of 1,047 patients included, 45% had low-risk prostate cancer, 37% had favorable intermediate-risk, and 19% had unfavorable intermediate-risk. The majority of patients were treated with CFRT or LDR; the smallest subset was 52 patients (5%) who received SbRT. nPSA measurements within the two-year follow-up period were significantly higher for those treated with ablative modalities, both as absolute nPSA values and relative to initial PSA (iPSA). Median time to nPSA ranged from 14.8 to 17.1 months. Over 50% of those treated with non-ablative therapy (CFRT, HFRT, and LDR) reached a critical nPSA threshold of ≤0.5 ng/mL, while only 23% of SbRT and 33% of HDR cohorts achieved the same threshold. The overall incidence of bPSA was 13.3% and was not affected by treatment modality, Gleason Score, or prostate volume. A piecewise linear regression showed no statistically significant difference in the PSA decay rates between radiation modalities over time, though there was a trend toward faster PSA decay in ablative therapies between the 6–24-month period.
CONCLUSION
Ablative therapies, such as HDR and SbRT, are associated with a latent PSA response and higher nPSA when compared to non-ablative therapies. Multivariate logistics modeling revealed younger age, iPSA above the mean, presence of bPSA, and receipt of ablative therapy as significant predictors for not achieving an nPSA ≤0.5 ng/mL. Understanding the different PSA kinetic profiles for the various radiation modalities is critical to assess treatment response and survey for disease recurrence.
Keywords: prostate cancer, PSA, kinetics, low-risk, intermediate-risk
INTRODUCTION
Patients with low- and intermediate-risk prostate cancer have an excellent prognosis with a long-expected lifespan following definitive therapy. Therefore, there is a need to improve surveillance for disease recurrence. In the absence of symptoms, serum prostate-specific antigen (PSA) is the best clinical screening tool. However, PSA kinetics are less predictable following definitive radiation therapy, with a non-trivial proportion of patients experiencing a PSA bounce and evidence suggesting unique trends in PSA decay kinetics across radiation modalities.1–11 Although PSA kinetics following conventionally-fractionated prostate irradiation (CFRT) are well-documented, PSA response is less understood for other radiation approaches.4,8–10 A well-accepted dogma purports that ablative radiation (i.e. radiotherapy with a higher dose per fraction) provokes brisker PSA decay kinetics, which results in a persistent decline that drives PSA levels below those seen with non-ablative therapies.1,3,11
With the increasing utilization of abbreviated radiation courses (i.e. hypofractionation (HFRT), ultra-hypofractionation or stereotactic body radiation therapy (SbRT), and brachytherapy, both high- (HDR) and low-dose rate (LDR)), characterization of the distinct PSA kinetics associated with each radiation modality and a comparison between them are needed. This analysis uses a patient-specific PSA decay rate model with longitudinal regression analysis to examine the early PSA kinetics for low- and intermediate-risk prostate cancer patients with favorable treatment response following CFRT, HFRT, SbRT, HDR and LDR brachytherapy treatment.
METHODS
PATIENT POPULATION
This retrospective analysis includes prostate cancer patients treated at a National Cancer Institute (NCI)-designated Comprehensive Cancer Center between 1998 and 2018. Patient demographics, staging information, radiotherapy details, and PSA levels were extracted from an institutional database after obtaining IRB approval. All patients had a pathologic diagnosis of localized prostate cancer classified as low- or intermediate-risk according to the NCCN prostate cancer risk stratification.12 Patients were treated with definitive radiotherapy using institutional regimens (see Table 1). Eligibility included freedom from biochemical failure defined by the ASTRO Phoenix criteria (nadir + 2 ng/ml) through last follow-up and two or more PSA measurements within the first 24 months of follow-up. Androgen deprivation therapy was not allowed.
TABLE 1:
Institutional dose and fractionation for Definitive Radiotherapy of Low- and Intermediate-risk Prostate Cancer
| Radiation Modality | Total Dose (Gy) | Fraction Size (Gy/fx) | Number of Fractions |
|---|---|---|---|
| CFRT | 78–80 | 2.0 | 39–40 |
| HFRT | 70.20 | 2.7 | 27 |
| SBRT | 37 | 7.4 | 5 |
| HDR | 27 | 13.5 | 2 |
| LDR (I125 seed implant) | 145 | 145 | 1 |
Abbreviations: CFRT – conventionally fractionated radiation therapy; CI – confidence interval; HDR – high-dose rate brachytherapy; iPSA – initial pre-treatment PSA; LDR – low-dose rate brachytherapy; nPSA – PSA nadir; SbRT – stereotactic body radiation therapy
PSA MEASUREMENT CRITERIA
PSA was measured four months after completion of definitive radiation therapy and again at six-month intervals.12 Pre-treatment PSA (iPSA) was obtained within 180 days of starting radiation therapy. The lowest PSA at any point in the follow-up period established the nadir (nPSA). The time to nPSA was measured from the completion of radiation therapy. PSA bounce (bPSA) was defined as a rise in PSA less than 2 ng/mL with a subsequent decrease towards the prior value or lower. The nPSA + 2 ng/mL cutoff was used to discriminate between bPSA and biochemical failure per the ASTRO Phoenix definition. An nPSA threshold of ≤0.5 ng/mL was used in the analysis as it is a well-established and clinically meaningful PSA threshold indicating an increased likelihood of disease-free survival.8,9,13,14 As an additional measure, nPSA ≤0.2 ng/mL was similarly analyzed.
STATISTICAL ANALYSIS
Descriptive statistics compared patient demographics by radiation modality, with differences assessed by ANOVA and Fisher’s exact tests (with simulated p-values using 2,000 replicates). Smoothing-spline mixed-effects models were used to account for the average PSA over time.23 These models allow for more flexibility in the relationship between PSA and time than standard regression models. The spline models assume that the PSA of each individual and the average PSA for the population will follow smooth curves but without a pre-defined shape. The models account for repeated measures within individuals by fitting spline curves for each patient (random effects) and for the population as a whole (fixed effects). Informed by the results of the spline models, radiation modalities were stratified into either ablative (e.g. HDR or SbRT) or non-ablative (e.g. CFRT, HFRT, or LDR) based on differences in PSA kinetics and crude analysis. This differentiation was utilized for subsequent portions of this analysis. Piecewise linear regression models tested for differences in the rate of change in PSA by treatment modality. Based on the shape of the population average spline curves, a single knot at 6 months was determined to be appropriate, allowing an estimate of the rate of change in PSA in the initial (0–6 months) time period followed by the 6–24-month time period. The longitudinal nature of the data (repeated measures across individuals) was controlled using Generalized Estimating Equations (GEE). Logistic regression models assessed the effect of treatment modality on the likelihood of low nPSA (threshold at ≤0.2 and ≤0.5) and bPSA. These regressions controlled for iPSA, Gleason score, age, and prostate volume.
RESULTS:
Patient characteristics
From 1998 to 2018, 1,042 patients met the inclusion criteria: 45% had low-risk prostate cancer, 37% favorable intermediate-risk and 19% unfavorable intermediate-risk. Among this cohort, 398 (38%) were treated with CFRT, 112 (11%) HFRT, 52 (5%) SbRT, 114 (11%) HDR, and 366 (35%) LDR. Median follow-up for the entire cohort was 3.8 years (IQR 2.3–6.5) and 3.6, 7.2, 1.8, 2.4, and 5.2 years for each of the modalities (CFRT, HFRT, SbRT, HDR, and LDR), respectively. Low-risk patients were more often treated with SbRT or brachytherapy while favorable intermediate-risk patients were evenly distributed among radiation options. Prostate volume and iPSA measurements were larger for patients treated with external beam radiation therapy. Baseline patient characteristics stratified by radiation modality are summarized in Table 2, and a summary of PSA characteristics is listed in Table 3.
TABLE 2:
PATIENT DEMOGRAPHICS BY RADIATION MODALITY
| Median (IQR) unless stated | Total n = 1,042 |
CFRT n = 398 |
HFRT n = 112 |
SbRT n = 52 |
HDR n = 114 |
LDR n = 366 |
p-value |
|---|---|---|---|---|---|---|---|
| Age, years: | 67 (61–72) |
70 (64–75) |
68 (62–73) |
66 (62–71) |
65 (62–70) |
65 (59–69) |
<0.001 |
| Treated from: | 1998–2018 | 2006–2018 | 2002–2018 | 2012–2018 | 2011–2018 | 1998–2015 | |
| Follow-up, years: | 3.8 (2.3–6.5) |
3.6 (2.5–5.7) |
7.2 (2.3–10.8) |
1.8 (1.4–2.5) |
2.4 (1.4–3.4) |
5.2 (2.8–7.6) |
<0.001 |
| Race, n (%): | 0.258 | ||||||
| White | 878 (84.3) |
324 (81.4) |
97 (86.6) |
43 (82.7) |
95 (83.3) |
319 (87.2) |
|
| Black | 143 (13.7) |
66 (16.6) |
12 (10.7) |
8 (15.4) |
16 (14.0) |
41 (11.2) |
|
| Hispanic | 12 (1.2) |
3 (0.8) |
3 (2.7) |
1 (1.9) |
3 (2.6) |
2 (0.5) |
|
| Asian | 8 (0.8) |
5 (1.3) |
- | - | - | 3 (0.8) |
|
| Other/Unknown | 1 (0.1) |
- | - | - | - | 1 (0.3) |
|
| NCCN Risk Group, n (%): | <0.001 | ||||||
| Low | 467 (44.8) |
43 (10.8) |
27 (24.1) |
16 (30.8) |
32 (28.1) |
349 (95.4) |
|
|
Favorable
Intermediate |
381 (36.6) |
221 (55.5) |
55 (49.1) |
30 (57.7) |
62 (54.5) |
13 (3.6) |
|
|
Unfavorable
Intermediate |
194 (18.6) |
134 (33.7) |
30 (26.8) |
6 (11.5) |
20 (17.5) |
4 (1.1) |
|
| Clinical Tumor Stage, n (%): | <0.001 | ||||||
| T1 | 835 (80.1) |
294 (73.9) |
74 (66.1) |
48 (92.3) |
104 (91.2) |
315 (92.3) |
|
| T2a | 156 (15.0) |
72 (18.1) |
23 (20.5) |
4 (7.7) |
9 (7.9) |
4 (7.7) |
|
| T2b | 39 (3.7) |
24 (6.0) |
12 (10.7) |
- | 1 (0.9) |
2 (0.5) |
|
| T2c | 12 (1.2) |
8 (2.0) |
3 (2.7) |
- | - | 1 (0.3) |
|
| Gleason Score, n (%): | <0.001 | ||||||
| 6 | 528 (50.7) |
64 (16.1) |
54 (48.2) |
20 (38.5) |
34 (29.8) |
356 (97.3) |
|
| 7 | 514 (49.3) |
334 (83.9) |
58 (51.8) |
32 (61.5) |
80 (70.2) |
10 (2.7) |
|
| iPSA, ng/ml: | 5.32 (4.0–7.5) |
5.40 (4.2–8.2) |
7.20 (5.2–10.7) |
6.35 (4.8–8.7) |
5.39 (4.3–7.7) |
4.80 (3.6–6.4) |
<0.001 |
| Prostate Volume, cc: | 41.71 (32–56) |
53.00 (39–70) |
52.42 (40–74) |
44.75 (37–58) |
34.00 (28–45) |
34.00 (28–42) |
<0.001 |
Abbreviations: CFRT – conventionally fractionated radiation therapy; HDR – high-dose rate brachytherapy; iPSA – initial pre-treatment PSA; IQR – interquartile range; LDR – low-dose rate brachytherapy; nPSA – PSA nadir; SbRT – stereotactic body radiation therapy
TABLE 3:
PSA CHARACTERISTICS BY RADIATION MODALITY
| Median (IQR) unless stated | Total n = 1,047 |
CFRT n = 399 |
HFRT n = 113 |
SbRT n = 52 |
HDR n = 115 |
LDR n = 368 |
p-value |
|---|---|---|---|---|---|---|---|
| iPSA, ng/mL (range): | 5.32 (0.20–19.40) |
5.40 (0.40–19.40) |
7.15 (0.30–19.20) |
6.35 (2.14–13.60) |
5.38 (0.80–17.50) |
4.80 (2.14–13.60) |
<0.001 |
| Below median, n (%): | 521 (50.0) |
192 (48.2) |
29 (25.9) |
20 (38.5) |
56 (49.1) |
224 (61.2) |
<0.001 |
| Above median, n (%): | 521 (50.0) |
206 (51.8) |
83 (74.1) |
32 (61.5) |
58 (50.9) |
142 (38.8) |
<0.001 |
| nPSA, ng/ml (range): | 0.52 (0.03–6.51) |
0.50 (0.03–5.45) |
0.50 (0.10–2.70) |
1.10 (0.10–3.61) |
0.89 (0.09–6.51) |
0.50 (0.04–4.70) |
<0.001 |
| ≤0.5 ng/mL, n (%): | 517 (50) | 213 (54) | 59 (53) | 12 (23) | 38 (33) | 195 (53) | <0.001 |
| ≤0.2 ng/mL, n (%): | 189 (18) | 79 (20) | 21 (19) | 4 (8) | 10 (9) | 75 (21) | <0.009 |
| Time to nPSA, months: | 15.63 (9.9–20.5) |
15.79 (10.8–21.1) |
17.07 (13.2–21.3) |
16.81 (13.3–20.7) |
15.63 (10.3–17.1) |
14.77 (9.2–18.1) |
<0.001 |
| nPSA/iPSA: | 0.11 (0.06–0.20) |
0.09 (0.05–0.16) |
0.09 (0.04–0.14) |
0.17 (0.09–0.27) |
0.15 (0.08–0.26) |
0.12 (0.07–0.21) |
<0.001 |
| PSA bounce, n (%): | 139 (13.3) | 43 (10.8) | 16 (14.0) | 9 (17.3) | 16 (14.0) | 55 (15.0) | 0.368 |
| Magnitude of PSA bounce, ng/mL (range): | 0.36 (0.01–1.90) |
0.22 (0.01–1.70) |
0.45 (0.20–1.60) |
0.27 (0.20–1.80) |
0.85 (0.01–1.81) |
0.35 (0.03–1.90) |
0.033 |
| Time to PSA bounce, months: | 10.30 (7.2–15.0) |
10.23 (7.5–15.3) |
10.72 (8.6–15.4) |
8.59 (3.8–9.7) |
9.75 (8.8–13.3) |
12.7 (7.7–15.1) |
0.342 |
Abbreviations: CFRT – conventionally fractionated radiation therapy; HDR – high-dose rate brachytherapy; iPSA – initial pre-treatment PSA; IQR – interquartile range; LDR – low-dose rate brachytherapy; nPSA – PSA nadir; SbRT – stereotactic body radiation therapy
nPSA
nPSA measurements were significantly higher with ablative modalities, both as an absolute value (ng/mL) and relative to iPSA (nPSA/iPSA). SbRT and HDR produced median nPSA values of 1.10 ng/mL and 0.89 ng/mL, respectively, while values of 0.5 ng/mL were seen among the other non-ablative modalities (p<0.001). Time to nPSA varied in a statistically significant manner, with a median time to nPSA of 15.6 months and ranges from 9.9–20.5 months across all modalities. More than 50% of patients treated with non-ablative modalities reached nPSA levels ≤0.5 ng/mL, with nearly 20% reaching nPSA levels ≤0.2 ng/mL. For ablative modalities, similar nPSA thresholds were reached by 23% and 8% for SbRT and 33% and 9% for HDR. Multivariate logistic regression revealed younger age (OR 1.06, CI 1.05–1.09, p<0.01), iPSA above the median (OR 0.40, CI 0.30–0.52, p<0.01), presence of bPSA (OR 0.41, CI 0.27–0.61, p<0.01), prostate volume (OR 0.99, CI 0.99–1.00, p=0.03) and treatment with HDR (OR 0.45, CI 0.28–0.73, p<0.01) or SbRT (OR 0.30, CI 0.15–0.62, p<0.01) to be significant predictors for not achieving an nPSA ≤0.5 ng/mL (see Table 4). Similar but less significant odds ratios were found when using an nPSA threshold of ≤0.2 ng/mL multivariate (see Table 4).
TABLE 4:
MULTIVARIABLE LOGISTIC REGRESSION FOR VARIOUS THRESHOLDS OF NPSA WITHIN 2 YEARS OF TREATMENT
| nPSA ≤0.5 ng/mL | nPSA ≤0.2 ng/mL | |||||
|---|---|---|---|---|---|---|
| Odds Ratio | 95% CI | p-value | Odds Ratio | 95% CI | p-value | |
| Age | 1.06 | 1.05–1.09 | <0.01 | 1.06 | 1.04–1.09 | <0.01 |
| Prostate volume | 0.99 | 0.99–1.00 | 0.03 | 1.00 | 0.99–1.00 | 0.30 |
| iPSA (median 5.32 ng/mL) | ||||||
| Below median | (reference) | (reference) | ||||
| Above median | 0.40 | 0.30–0.52 | <0.01 | 0.47 | 0.33–0.67 | <0.01 |
| PSA bounce | ||||||
| No PSA bounce | (reference) | (reference) | ||||
| PSA bounce | 0.41 | 0.27–0.61 | <0.01 | 0.45 | 0.25–0.83 | 0.01 |
| Gleason Score | ||||||
| GS 6 | (reference) | (reference) | ||||
| GS 7 | 1.03 | 0.70–1.52 | 0.87 | 0.85 | 0.52–1.40 | 0.52 |
| Treatment Technique | ||||||
| CFRT | (reference) | (reference) | ||||
| HFRT | 1.30 | 0.80–2.10 | 0.28 | 1.06 | 0.58–1.95 | 0.84 |
| SbRT | 0.30 | 0.15–0.62 | <0.01 | 0.41 | 0.14–1.19 | 0.10 |
| HDR | 0.45 | 0.28–0.73 | <0.01 | 0.42 | 0.20–0.88 | 0.02 |
| LDR | 1.11 | 0.69–1.78 | 0.66 | 1.04 | 0.57–1.88 | 0.90 |
Abbreviations: CFRT – conventionally fractionated radiation therapy; GS – gleason score; HDR – high-dose rate brachytherapy; iPSA – initial pre-treatment PSA; LDR – low-dose rate brachytherapy; nPSA – PSA nadir; SbRT – stereotactic body radiation therapy
bPSA
Over the follow-up period, a bPSA was detected in 139 (13.3%) patients; in 11% (n=43) of those treated with CFRT, 14% (n=16) HFRT, 17% (n=8) SbRT, 14% (n=14) HDR and 15% (n=57) LDR. Treatment modality did not produce significantly different rates of bPSA (p=0.368). However, the magnitude of PSA bounce ranged from 0.01 ng/mL to 1.90 ng/mL. Patients treated with HDR had a significantly larger PSA bounce (median 0.85) when compared to all other modalities (median bPSA ranging from 0.22 to 0.45; p=0.033). Median time to bPSA was 10.3 months, and time to bPSA was not significantly different across radiation modalities (p=0.342). Multivariate logistic regression revealed older patients (OR 0.98, CI 0.95–1.00, p=0.06), iPSA above the median (OR 0.65, CI 0.44–0.95, p=0.03), and nPSA ≤0.5 ng/mL (OR 0.40, CI 0.27–0.60, p<0.01) as significant variables decreasing the likelihood of a bPSA (see Table 4). Prostate volume (p=0.56), Gleason score (p=0.87), and treatment modality were not associated with the incidence of a bPSA (see Table 5).
TABLE 5:
MULTIVARIABLE LOGISTIC REGRESSION FOR PSA BOUNCE WITHIN 2 YEARS OF TREATMENT
| Odds Ratio | 95% CI | p-value | |
|---|---|---|---|
| Age | 0.98 | 0.95–1.00 | 0.06 |
| Prostate volume | 1.00 | 0.99–1.01 | 0.56 |
| iPSA (median 5.32 ng/mL) | |||
| Below median | (reference) | ||
| Above median | 0.65 | 0.44–0.95 | 0.03 |
| nPSA | |||
| nPSA > 0.5 | (reference) | ||
| nPSA ≤ 0.5 | 0.40 | 0.27–0.60 | <0.01 |
| Gleason Score | |||
| 6 | (reference) | ||
| 7 | 1.04 | 0.62–1.76 | 0.87 |
| Treatment Technique | |||
| CFRT | (reference) | ||
| HFRT | 1.59 | 0.82–3.08 | 0.17 |
| SbRT | 1.40 | 0.62–3.19 | 0.42 |
| HDR | 1.13 | 0.57–2.21 | 0.73 |
| LDR | 1.38 | 0.71–2.66 | 0.34 |
Abbreviations: CFRT – conventionally fractionated radiation therapy; CI – confidence interval; HDR – high-dose rate brachytherapy; iPSA – initial pre-treatment PSA; LDR – low-dose rate brachytherapy; nPSA – PSA nadir; SbRT – stereotactic body radiation therapy
Early PSA kinetics
Review of fitted average spline curves (see Figure 1) informed subsequent analysis comparing radiation modalities. Figure 1A shows clear delineation between ablative (SbRT or HDR) and non-ablative (CFRT, HFRT, or LDR) techniques that persisted when controlling for the variation in iPSA values (Figure 1B). These figures qualitatively show a more latent and prolonged PSA response for ablative approaches, eventually either merging towards or driving lower than PSA values for non-ablative approaches. To evaluate these groups further, Figures 1C and 1D compare the ablative approach with non-ablative by either Gleason score or the presence of bPSA, respectively. The ablative techniques consistently depicted a unique PSA trend in each setting; Gleason score and the presence of a bPSA showed little effect on PSA changes over time.
Figure 1:
Fitted average psa spline curves. A) Spline curve stratified by radiation modality. B) Spline curve of PSA/iPSA ratio to account for variation in iPSA values. C) Spline curve stratified by ablative versus non-ablative and GS6 versus GS7. D) Splive curve stratified by psa bounce versus absence of bounce and ablative versue non-ablative.
Informed by the spline curves, a piecewise linear regression with GEE methods compared the rate of change over time between the ablative and non-ablative groups. Dividing the follow-up period into early (0–6 months) and late (6–24 months) periods revealed an average monthly PSA decay of −0.78 ng/mL per month and +0.04 ng/mL per month for non-ablative techniques during the two periods, respectively. The PSA decay for ablative modalities yielded a similar difference in response to treatment (p=0.62 for early, p=0.06 for late), with rates of −0.81 ng/mL per month during the early period and +0.02 ng/mL per month during the late.
DISCUSSION:
This study accurately characterizes post-radiotherapy PSA trends by examining the PSA kinetics of all radiation modalities used to definitively treat prostate cancer. Though other studies have evaluated PSA kinetics following radiotherapy1–3,8,11,15,16, this is the first comprehensive analysis comparing all radiation modalities used to treat prostate cancer from a single NCI-designated Comprehensive Cancer Center.
Traditional dogma of PSA kinetics assert that, when compared to non-ablative techniques, ablative treatments are associated with a more rapid PSA response (18–29 months versus 32–62 months) and lower PSA nadirs (<0.1–0.3 ng/mL versus <0.1–1.4 ng/mL).1–3,11,17–20 Our results were not consistent with other published reports, a finding that is likely attributed to the 2-year follow-up period chosen for this analysis. Instead, this analysis revealed similar PSA decay rates across radiation techniques and lower nPSA levels in those treated with non-ablative treatment. Some of this difference may be attributed to the HFRT cohort from our institutional phase II randomized trial of CFRT versus HFRT for early-stage prostate cancer patients in the early 2000’s.21,22 Though PSA measurements within the 2-year follow-up revealed significantly lower nPSA values for non-ablative therapies, nPSA values for those treated with ablative therapies were still well-within the range associated with improved freedom from biochemical failure and survival endpoints, a range extending from ≤0.2 ng/mL to ≤1.5 ng/mL.1–3,11,14,15,23,24 Based on this analysis, an nPSA ≤0.5 ng/mL is most likely to occur in older patients with lower iPSA values in the absence of a bPSA. For non-ablative therapies in this analysis (CFRT, HFRT, and LDR), the proportion of patients reaching an nPSA ≤0.5 ranged from 53% to 54%, with median time to nPSA ranging from 14.8–17.1 months. Interestingly, patients treated with ablative techniques (SbRT and HDR) were significantly less likely to achieve an nPSA ≤0.5 ng/mL within the 2-year follow-up interval; only 23% and 33% reached this threshold, respectively. With prolonged follow-up, PSA measurements will likely continue to drive lower for these groups.
While we did not anticipate the latent PSA response to ablative therapies, these findings are not inconsistent with other studies. Kishan et al. compared SbRT, HDR, and CFRT and reported significantly longer times to nPSA using ablative techniques when compared to CFRT.3 The proportion of patients reaching nPSA ≤0.5 and the median time to nadir were 76% and 35 months for SbRT, 76% and 33 months for HDR, and 45% and 21 months for CFRT, respectively. Levin-Epstein et al. recently published a large multi-institutional analysis of PSA kinetics for patients treated with SbRT, HDR and LDR.25 Patients treated with LDR were reported to have significantly lower nPSA levels, with 72% of the cohort reaching an nPSA ≤0.2 and a median time to nPSA of 51 months. Although SbRT and HDR cohorts had median times to nPSA of 44- and 37- months, only 48% and 56%, respectively, reached the same threshold of nPSA ≤0.2.
It is reasonable to question data maturity in this analysis as all PSA measurements were obtained within 24 months of treatment while the lowest nPSA values for HDR and SbRT may not be achieved for 3–5 years. However, early time points are thought to be critical landmark time points and indicators of prostate cancer-specific mortality.8 Zelefsky et al. reported a 2-year nPSA ≤1.5 ng/mL as a statistically significant threshold that predicts for improved cancer-specific survival as well as fewer distant metastases. Other studies similarly support using early time point PSA measurements as crucial prognostic markers.15,16,23,26
The incidence of bPSA in this analysis was 13%, slightly lower than reported ranges of 17% to 31%.3,11,27,28 Differing rates of bPSA are likely due to the varying definitions of bPSA over time and by institution, though some evidence suggest radiation technique and underlying GS may influence these rates.11 bPSA was defined in this study as a PSA rise with subsequent return to pre-rise levels, provided the rise did not exceed 2.0 ng/mL. Any rise above this level was assumed to be biochemical failure and therefore excluded from this analysis. The median bPSA magnitude of 0.36 ng/mL is in line with historic ranges. Ablative therapies were thought to incite higher rates of bPSA3,11, though this was not supported by the findings in this analysis. bPSA rates were instead similar across all radiation modalities and all GS subgroups in this study. The primary drivers for bPSA were young age and those without a brisk PSA response.3,11,27,29–31 Other historic predictors, such as the type of therapy (ablative versus non-ablative) and the prostate size, were not significant predictors for bPSA in this analysis.
The small size of SbRT and HDR cohorts limits the strength of this analysis. The 2-year PSA cut-point produced uncertainty for a small group of patients with rising PSA because some may develop biochemical failure. Similarly, a group of patients were excluded under the pretense of biochemical failure though they may have instead had a benign bounce in their PSA. As this is a PSA kinetics analysis, the oncologic outcomes of survival and biochemical failure were not evaluated. There are additional limitations implicit in the statistical modeling and extrapolation of patient-level PSA measurements.
CONCLUSION:
This is the first PSA kinetic analysis comparing all radiation modalities used to definitively treat prostate cancer at an NCI-designated Comprehensive Cancer Center. Ablative therapies are associated with a latent and prolonged PSA decay kinetics when compared to non-ablative therapies. Within the 24-month follow-up period, the majority of patients in the non-ablative cohort reached a critical nPSA threshold of ≤0.5 ng/mL while less than 33% of the ablative cohort did. On multivariate analysis, receipt of non-ablative therapy, low iPSA, and absence of bPSA were all predictors for achieving an nPSA ≤0.5 ng/mL. A piecewise linear regression model comparing PSA kinetics for ablative and non-ablative modalities showed no statistically significant difference in PSA decay kinetics over time, but a trend toward faster PSA decay during the 6 to 24-month period favored the ablative group. Understanding the different PSA kinetic profiles for the various radiation modalities is critical to assess treatment response and survey for disease recurrence.
HIGHLIGHTS:
Ablative forms of radiation therapy (SbRT or HDR) produce a latent PSA kinetics profile with higher PSA nadirs (nPSA) when compared to non-ablative modalities (CFRT, HFRT or LDR).
Over 50% of those treated with non-ablative therapy reached a critical nPSA threshold of ≤0.5 ng/mL within 2 years; only 23% of SbRT and 33% of HDR cohorts achieved the same threshold.
Multivariate logistics modeling revealed younger age, iPSA above the mean, presence of bPSA, and receipt of ablative therapy as significant predictors for not achieving an nPSA ≤0.5 ng/mL.
Grant support:
This research was funded in part through the NIH/NCI Cancer Center Support Grant P30 CA006927.
Footnotes
Prior presentations: Portions of this analysis were presented at the ASTRO Annual Meeting, September 2018 in San Antonio, TX
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