Original research

CAPRA-S predicts outcome for adjuvant and salvage external beam

radiotherapy after radical prostatectomy

1,2

Michel Zimmermann, MD; Guila Delouya, MD, MSc; Abdullah M. Alenizi, MD; Emad Rajih, MD;

1, 2

Kevin C. Zorn, MD; Daniel Taussky, MD

Department of Radiation Oncology, Centre hospitalier de l’Université de Montréal, Hôpital Notre-Dame, Montreal, QC, Canada; CRCHUM-Centre de recherche du Centre Hospitalier de l’Université de Montréal,

Montreal, QC, Canada ; Section of Urology, Department of Surgery, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada

logical exam to predict cancer recurrence and mortality.¹

Developed by Cooperberg et al, this tool generates a score

of 0‒12. In general, each two-point increase indicates at

least a doubling of recurrence risk. The CAPRA-S offers good

discriminatory accuracy, calibration, and ease of calculation

for clinical and research settings, and has been validated

Cite as: Can Urol Assoc J 2016;10(3-4):132-6. http://dx.doi.org/10.5489/cuaj.3365

Abstract

Introduction: We aimed to evaluate the predictive value of

the Cancer of the Prostate Risk Assessment Postsurgical Score

-4

(CAPRA-S) for patients treated with radical prostatectomy followed

externally following radical prostatectomy (RP).

by subsequent external beam radiotherapy (EBRT).

Assuming that biochemical recurrence (BCR) after RP will

mostly be related to local disease recurrence, external beam

radiotherapy (EBRT) after RP would be expected to improve

outcome. Our objective is to evaluate if the CAPRA-S score

further predicts outcome for patients treated both with RP

and EBRT, and whether other factors might be identiﬁed in

this setting. To the best of our knowledge, this has not yet

been reported in the literature.

Methods: A total of 373 patients treated with EBRT between

January 2000 and June 2015 were identiﬁed in the institutional

database. Followup and complete CAPRA-S score were available

for 334 (89.5%) patients. CAPRA-S scores were sorted into previ-

ously deﬁned categories of low- (score 0‒2), intermediate- (3‒5),

and high-risk (6‒12). Time to biochemical recurrence (BCR) was

deﬁned as prostate-speciﬁc antigen (PSA) >0.20 ng/mL after EBRT.

Survival analyses were performed using the Kaplan-Meier method

and comparisons were made using the log-rank test.

Results: Overall median time from surgery to EBRT was 18 months

Methods

(

was 48 months (IQR 28‒78). CAPRA-S predicted time to BCR

interquartile range [IQR] 8‒36) and median followup since EBRT

Following ethical review board approval, we retrospective-

ly reviewed all men included in our institutional database

who received EBRT either in the adjuvant or salvage set-

ting, between January 2000 and June 2015. Among the 373

patients identiﬁed, followup was available for 347 patients.

Moreover, incomplete data prevented us from calculating

CAPRA-S in another 13 patients, thus leaving 334 men avail-

able for ﬁnal analysis (89.5%). Of those, 136 (40.7%) were

included in prospective trials (RTOG 9601, RTOG 0534, and

NCIC-RADICALS). A total of 56 patients received androgen-

deprivation therapy (ADT) for more than six months.

(<0.001), time to palliative androgen-deprivation therapy (ADT)

(p=0.017), and a trend for signiﬁcantly predicting overall survival

(OS, p=0.058). On multivariate analysis, the CAPRA-S was predic-

tive of time to BCR only (low-risk vs. intermediate-risk; hazard ratio

[

HR] 0.14, 95% conﬁdence interval [CI] 0.043‒0.48, p=0.001). The

last PSA measurement before EBRT as a continuous and grouped

variable proved highly signiﬁcant in predicting all outcomes tested,

including OS (p≤0.002).

Conclusions: CAPRA-S predicts time to BCR and freedom from

palliative ADT, and is borderline signiﬁcant for OS. Together with

the PSA before EBRT, CAPRA-S is a useful, predictive tool. The

main limitation of this study is its retrospective design.

During chart review, we recorded the constituting vari-

ables of CAPRA-S (i.e., pre-EBRT PSA and PSA before sur-

gery, pathological Gleason score, status of surgical margins,

as well as presence or absence of extracapsular extension,

seminal vesicle involvement [SVI] and lymph node involve-

ment). Table 1 demonstrates point distribution of CAPRA-S

among the cohort. Patients were categorized as low-risk

(CAPRA-S score 0‒2), intermediate-risk (score 3‒5), and

Introduction

The Cancer of the Prostate Risk Assessment Postsurgical

(

CAPRA-S) score is a post-surgical prediction tool that uses

preoperative prostate-speciﬁc antigen (PSA) and pathologic

parameters from radical prostatectomy specimen histopatho-

high-risk (score ≥6), as in the original publication. Further

CUAJ • March-April 2016 • Volume 10, Issues 3-4

2016 Canadian Urological Association

caPra-s ꢀꢁ pꢂꢃdꢄꢅtoꢂ of eBrT outꢅomꢃ

Table 1. Clinical and pathological characteristics (n=334)

collected data included the last PSA at the initiation of sal-

vage EBRT, age at time of EBRT, use of concomitant ADT,

date of BCR deﬁned as an increasing PSA of at least 0.2 ng/

mL, initiation of palliative ADT, and presence of radiological

metastatic disease.

Most patients received EBRT to the prostate bed up to a

total dose of 66 Gy in 2 Gy/fraction, ﬁve sessions a week;

alternatively, 64.8‒66.6 Gy in 1.8 Gy/fraction were adminis-

tered for patients enrolled in two out of three aforementioned

studies, as per that particular protocol. Standard conformal

three-dimensional or intensity-modulated radiotherapy

Number of

patients (%)

Points on

CAPRA-S

Characteristic

Age at EBRT median (IQR)

64 (range 59–68)

277 (82.9)

70 years

Preoperative PSA (ng/mL) median

IQR)

≥

57 (17.1)

7 (5–12)

(

–6

118 (35.3)

106 (31.7)

79 (23.7)

31 (9.3)

.01–10

0.01–20

(

IMRT) technique was used with a 4‒6 MV linear accelera-

Gleason score in surgical specimen

tor. If a macroscopic recurrence within the prostate bed

was evidenced by computed tomography (CT) scan or rectal

examination, EBRT was increased to a total dose of 70‒72

Gy in 2 Gy/fraction (in three patients). Whether pelvic lymph

nodes were included (and treated up to 44‒46 Gy) was left

to the discretion of the treating radiation oncologist, as was

the prescription of concomitant ADT, according to the ran-

domized arm of the treatment protocol. Survival analysis was

performed using the Kaplan-Meier method and comparisons

were made using the log rank test. Statistical signiﬁcance

was deﬁned for p values ≤0.05. Statistical analysis was done

using SPSS 17.0 for Windows (IBM SPSS, Chicago, IL).

-6

72 (21.6)

93 (27.8)

89 (26.6)

80 (24.0)

-10

Extracapsular extension

Yes

205 (61.4)

69 (20.7)

213 (63.8)

13 (3.9)

Seminal vesicle extension

Yes

Surgical margin status

Positive

Lymph node status

Positive

CAPRA-S

Results

≥

–2 (low risk)

52 (15.6)

149 (44.6)

132 (39.5)

–5 (intermediate risk)

6 (high risk)

Median age at time of EBRT was 64 years (interquartile

range [IQR] 59‒68). Median time from surgery to EBRT was

Concomitant ADT

8 months (IQR 8‒36). Median followup after EBRT was

8 months (IQR 28‒78) (Table 1). Concomitant ADT was

Yes

24 months

ADT: androgen-deprivation therapy; EBRT: external beam radiotherapy; IQR: interquartile

range; PSA: prostate-speciﬁc antigen.

121

8 (6.6)

57 (47.1)

56 (46.3)

months

administered in 36.2% of cases, for a median duration of

nine months (IQR 6‒24).

Forty patients (12.0%) received EBRT within four months

of surgery; among them, 10 patients had a PSA of 0.0 ng/

ml, four patients between 0.01 and 0.03 ng/ml, and six

patients between 0.04 and 0.10 ng/ml. The CAPRA-S in

these patients was >5 in 80% (16/20). Table 2 lists the PSA

values before EBRT. Median PSA value was 0.35 ng/mL

3, according to CAPRA-S score and other clinical factors.

CAPRA-S as a categorical variable (low-, intermediate-, high-

risk group) was predictive of freedom from BCR and pallia-

tive ADT use, and borderline signiﬁcant (p=0.058) of OS.

When considering only the CAPRA-S high-risk group, OS at

ﬁve and 10 years were 90% and 83%, respectively. In this

high-risk group, 62% had not received ADT for recurrence

at ﬁve years and 47% at 10 years.

(

IQR 0.2‒0.7).

During followup, palliative ADT was initiated for BCR in

0.9% of cases; median time between EBRT and initiation

of palliative ADT was 38 months (IQR 20‒66). Metastatic

disease was found on imaging in 8.0% of cases; median time

from EBRT to distant metastatic spreading was 44 months

(

IQR 24‒75).

Table 2. PSA before EBRT (ng/ml)

Twenty-two patients (6.6%) died during follow-up, nine

Group

Last PSA before EBRT (ng/mL)

(%)

from metastatic prostate cancer, seven from other cancers,

and one patient from cardio-vascular disease; in 5 of them,

the primary cause of death could not be determined. Median

time from EBRT to death was 48 months (IQR 28-78).

Freedom from BCR, palliative ADT (Fig. 1), metastatic

spreading, and overall survival (OS) are reported in Table

0.00–0.20

0.21–0.50

0.51–0.99

1.00–2.00

>2.00

26.2

38.9

18.9

11.5

4.5

ERBT: external beam radiotherapy; PSA: prostate-speciﬁc antigen.

CUAJ • March-April 2016 • Volume 10, Issues 3-4

133

Zꢄmmꢃꢂmꢀꢆꢆ ꢃt ꢀꢇ.

tive ADT (p=0.28), metastasis-free survival (p=0.18), or OS

p=0.94). The pre-EBRT PSA was predictive of time to pal-

(

liative ADT (p=0.015), metastasis-free survival (p=0.014),

and OS (p=0.037). Age was not predictive of any endpoints.

Discussion

We found that the CAPRA-S score predicted the freedom

from BCR and palliative ADT, but not the time to metasta-

ses on univariate analysis. There was a trend towards sig-

niﬁcance for OS (p=0.058). On multivariate analysis, the

CAPRA-S was only predictive of time to BCR. The pre-EBRT

PSA was the most signiﬁcant prognostic factor predicting

for time to palliative ADT, metastasis-free survival, and OS.

The management of a detectable PSA after RP remains

a difﬁcult challenge, as not all patients may beneﬁt from

salvage EBRT. Furthermore, up to 40% of patients will expe-

rience BCR after RP and a rising PSA will precede clinical

progression in most cases. Still, a small subset of patients

with detectable PS3365A recurrence after RP will not exhibit

biochemical or clinical progression, even after 10 years of

Fig. 1. Freedom from androgen-deprivation therapy after external beam

radiotherapy in months according to CAPRA-S groups (p=0.017, log-rank test).

All of the CAPRA-S subcategories were signiﬁcant predic-

tors of several endpoints, whereas extracapsular extension

followup.

(

ECE) was only predictive of BCR.

Using predeﬁned PSA categories before EBRT (accord-

The CAPRA-S score has been developed to stratify patients

and help predict the risk of prostate cancer recurrence and

mortality following RP, based on pathological data from the

surgical specimen and preoperative PSA. Our aim was to

evaluate the CAPRA-S score in a population of patients with

mostly high-risk of BCR and to assess whether the CAPRA-S

score retains its predictive value after both RP and salvage

EBRT. To the best of our knowledge, we are unaware of

any similar study published before. Our study shows that

even in patients with CAPRA-S >5, and thus at high-risk for

recurrence and mortality, only 47% received ADT at 10-year

followup; even in high-risk patients, EBRT is efﬁcient in only

about half of cases. In patients with a CAPRA-S of ≥8 (n=58),

ing to Table 2), we found that each rise to a higher group

increases the hazard of BCR by 28.6% (hazard ratio [HR]

.286; 95% conﬁdence interval [CI] 1.009‒1.641). When

evaluating the PSA before EBRT as a continuous variable,

each increase of 1 ng/mL translated into a 20% increase in

the risk of BCR (HR 1.199; 95% CI 1.070‒1.343).

In a multivariate analysis including age (<70 vs. ≥70

years) and both the pre-EBRT PSA level and the CAPRA-S

score as categorical variables, the CAPRA-S was predic-

tive of time to BCR (low-risk vs. intermediate-risk; HR 0.14,

5% CI 0.043‒0.48, p=0.001), but not of time to pallia-

Table 3. Inﬂuence of CAPRA-S and other clinical factors on OS, time to metastasis, and time to palliative ADT.

Time to metastasis

Time to ADT

Time to BCR

(p value)

CAPRA-S*

0.33

0.058

0.48

0.36

0.15

0.127

0.017

0.59

0.006

<0.001

0.53

CAPRA-S†

PSA (CAPRA-S categories)

0.56

Gleason (CAPRA-S categories)

0.10

0.001

0.58

<0.001

0.29

0.011

0.019

<0.001

0.46

ECE

0.37

SVI

0.16

0.003

<0.001

0.026

0.028

0.77

0.003

0.049

0.28

0.47

LNI

0.16

0.010

0.002

0.08

PSA pre-EBRT cont.

PSA pre-EBRT, cat.

Concurrent ADT to EBRT

Age (<70 vs. ≥70 years)

<0.001

0.23

<0.001

0.030

<0.001

0.72

0.82

0.21

0.16

*Continuous variable; †Categorical variable. Results reaching statistical signiﬁcance (p<0.05) are in bold. ADT: androgen-deprivation therapy; BCR: biochemical recurrence; EBRT: external beam

radiotherapy; ECE: extracapsular extension; LNI: lymph node invasion; OS: overall survival; PSA: prostate-speciﬁc antigen; SM: positive surgical margins; SVI: seminal vesicle invasion.

CUAJ • March-April 2016 • Volume 10, Issues 3-4

caPra-s ꢀꢁ pꢂꢃdꢄꢅtoꢂ of eBrT outꢅomꢃ

even though only 32% showed no BCR at ﬁve years, 44%

of patients were still without ADT.

This study is not without its limitations. This is a retro-

spective series, which may have introduced a selection bias.

PSA assays differed during the studied years; 46% of our

patients were treated with EBRT before 2010. Ultrasensitive

PSA assays now allow for earlier detection of biochemical

The fact that most factors, with the exception of the pre-

EBRT PSA, were not predictive of OS but of other endpoints

is not surprising. Palliative ADT occurs early in the course of

disease, delaying the occurrence of metastases and death by

years. The median followup of 48 months after EBRT might

have been too short to detect an inꢀuence of the CAPRA-S

on time to metastasis or OS. These patients continue to be

followed and we will later be able to update these endpoints.

In one of the series with the longest followup (median 126

months), only 56% experienced BCR after salvage EBRT;

relapse after RP. Furthermore, the ﬁrst postoperative ultra-

sensitive PSA ≥0.03 ng/ml has been demonstrated recently to

be an independent factor that identiﬁes biochemical relapse

more accurately, yielding a median lead time advantage of

18 months over the conventional deﬁnition of PSA ≥0.20

ng/ml.

Followup for patients enrolled in prospective studies

was more frequent and prolonged than for off-study-treated

patients. Furthermore, different PSA cutoff values were used

before starting palliative ADT. CT scan and bone scans were

not performed on a ﬁxed schedule, but left to the discre-

tion of the treating physician. Finally, we did not have any

control group (RP without EBRT), preventing us to evaluate

whether low-risk patients, according to CAPRA-S score, ben-

eﬁt from EBRT after RP. In a larger, retrospective analysis of

a cohort of 635 men who experienced biochemical and/or

local recurrence after RP, where 397 received no salvage

treatment, 160 were treated with EBRT alone, and 78 com-

bined with ADT, Trock et al demonstrated that salvage EBRT

alone was associated with a signiﬁcant three-fold increase in

prostate cancer-speciﬁc survival (HR 0.34, p=0.003), relative

OS averaged 13.6 years from the time of PSA failure.

Conversely, we might also interpret the present results as

showing the beneﬁt of EBRT in a majority of patients present-

ing with persistent or recurrent prostate cancer.

Patients who received concomitant ADT and EBRT expe-

rienced a longer time to distant metastases (p=0.02), with-

out translating into improved OS (p=0.22). Regarding the

absence of beneﬁt for OS, we might hypothesize that the

expected positive effect from the concomitant ADT on OS

was countered by an excess of mortality from either the

cardiovascular causes or from a followup that was too short.

The CAPRA-S score showed a trend towards an inꢀuence

on OS (p=0.058); however, none of the single factors con-

tributing to the CAPRA-S total score were predictive of OS,

nor were age or concomitant ADT. The only factor predict-

ing for OS was the PSA before EBRT (p<0.001). A higher PSA

at the start of EBRT might reꢀect micro-metastatic disease.

The percentage of patients not on ADT for recurrence at

ﬁve years according to the groups described in Table 2 was

to those who received no salvage treatment. The beneﬁ-

cial effect of salvage EBRT appeared primarily conﬁned to

patients with a PSA doubling time <6 months, and treated

within two years following BCR.

Despite its merits, and being the first study reporting

CAPRA-S outcomes in this unique population of multimodal

therapy, this study has its limitations: single-institution study,

small cohort, and patients predominantly treated for PSA

recurrence or persistence and not in an adjuvant setting.

Prospective studies should investigate whether low-risk

patients, according to CAPRA-S, would actually beneﬁt from

EBRT after RP.

2%, 78%, 51%, 55%, and 36%, respectively.

In a retrospective survey of 151 patients (median followup

of 82 months), Lohm et al demonstrated a beneﬁt on BCR

from starting EBRT at lower PSA values; the best results were

actually achieved with a PSA in the lowest quartile (<0.147

ng/ml) before EBRT and this was highly predictive of BCR

(

p< 0.0005), however, the pre-EBRT PSA had no impact on

prostate cancer-speciﬁc survival (p=0.16) or OS (p=0.81).

We found that each 1 ng/ml increase of the last PSA

before EBRT translated into a shorter time of freedom from

BCR by 19.9% on average (HR 1.199; 95% CI 1.070‒1.343).

These results are in line with a systematic review and meta-

analysis suggesting, on a multivariate analysis, that biochem-

ical progression-free survival decreases with pre-EBRT PSA

Conclusion

For prostate cancer patients treated either with adjuvant or

salvage EBRT, CAPRA-S groups predicted freedom from BCR

and palliative ADT, and showed a trend towards signiﬁcance

for OS. The data also support a strong correlation between

the PSA before EBRT and all outcomes, including OS. This

seems to favour early salvage EBRT.

by 18.3% per 1 ng/mL (p < 0.001). Similar results were also

reported in another systematic review performed by King,

who found an average 2.6% loss of recurrence-free survival

for each incremental 0.1 ng/ml PSA at the time of RT. Our

paper contributes to the growing evidence that patients with

PSA recurrence after surgery should be referred and treated

at lower PSA levels to achieve better long-term outcomes.

Competing interests: Dr. Zimmermann has received grants/honoraria from Paladin; Dr. Zorn has

been an Advisory Board member for American Medical Systems. The remaining authors declare no

competing ꢀnancial or personal interests.

CUAJ • March-April 2016 • Volume 10, Issues 3-4

135

Zꢄmmꢃꢂmꢀꢆꢆ ꢃt ꢀꢇ.

Acknowledgement: The authors would like to thank Dr. Fred Saad for his continuous support in

maintaining the database.

7. Shinghal R, Yemoto C, McNeal JE, et al. Biochemical recurrence without PSA progression characterizes a

subset of patients after radical prostatectomy. Prostate-speciꢀc antigen. Urology 2003;61: 380-5.http://

dx.doi.org/10.1016/S0090-4295(02)02254-9

Ying J, Wang CJ, Yan J, et al. Long-term outcome of prostate cancer patients who exhibit biochemical

failure despite salvage radiation therapy after radical prostatectomy. Am J Clin Oncol 2015 Jul 9. [Epub

ahead of print] http://dx.doi.org/10.1097/COC.0000000000000207

This paper has been peer-reviewed.

Lohm G, Lütcke J, Jamil B, et al. Salvage radiotherapy in patients with prostate cancer and biochemical

relapse after radical prostatectomy: Long-term followup of a single-centre survey. Strahlenther Onkol

014;190:727-31. http://dx.doi.org/10.1007/s00066-014-0612-6

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