ORIGINAL ARTICLE

PSA-nadir at 1 year as a sound contemporary prognostic factorfor low-dose-rate iodine-125 seeds brachytherapy

Leonardo Oliveira Reis • Brunno Cezar Framil Sanches •

Emerson Luis Zani • Lisias Nogueira Castilho •

Carlos Roberto Monti

Received: 29 April 2013 / Accepted: 6 August 2013

� Springer-Verlag Berlin Heidelberg 2013

Abstract

Objectives To identify predictors of outcomes in patients

with localized prostate cancer treated with iodine-125

brachytherapy in a longitudinal uncontrolled study.

Methods Between 2000 and 2011, 560 histologically

confirmed patients were treated with brachytherapy of

whom 305 with C24-month follow-up and localized tumor

were evaluated after exclusion of those locally advanced

and under androgen ablation.

Results Patients’ mean age was 63.93 years (44–88),

mean pretreatment prostate-specific antigen (PSA) was

6.34 ng/mL (0.67–33.09), overall median follow-up was

75.35 months (24–158.37), biochemical recurrence occur-

red in 17 patients (5.57 %), cancer-specific survival was

100 %, and overall survival was 98.03 %. At multivariate

analyses, only PSA-nadir at 1 year and age were related to

disease-free survival: To each unit of PSA-nadir, the risk

increases 87.3 %—OR 1.87 (p \ 0.001; 95 % CI

1.31–2.67), and risk was 4.7 times higher for those under

50 years (vs. [70)—OR 4.69 (p = 0.04; 95 % CI

1.39–18.47). Best cutoff for PSA-nadir at one year was

0.285 (AUC = 0.78; p \ 0.001; 95 % CI 0.68–0.89).

Kaplan–Meier analysis confirmed PSA-nadir (p \ 0.001)

as prognostic, while D’Amico’s classification failed

(p = 0.24). No grade 3 or 4 complication was reported, and

only 31.4 % of patients had grade 2 urinary or rectal tox-

icity. PSA bounce C0.4 ng/mL occurred in 18.4 % with no

impact on biochemical recurrence.

Conclusions Half (50.49 %) of patients in the scenario of

localized prostate cancer treated with iodine-125 brachy-

therapy reach PSA-nadir at 1 year\0.285, recognized as a

key independent prognostic factor.

Keywords Prognosis � Survival � Age �Radiotherapy � Prostate � Outcome �Marker � Gleason

score upgrading

Abbreviations

AA Androgen ablation

ABS American Brachytherapy Society

CSS Cancer-specific survival

DFS Disease-free survival

DT Doubling time

EBRT External beam radiotherapy

Gy Gray

PSA-nadir at 1 year Post-treatment PSA measurement at

12 months

OS Overall survival

PSA Prostate-specific antigen

Leonardo Oliveira Reis and Brunno Cezar Framil Sanches have

equally contributed to this work.

L. O. Reis � C. R. Monti

Faculty of Medicine (Urology), Center for Life Sciences,

Pontifical Catholic University of Campinas (PUC-Campinas),

Campinas, SP, Brazil

L. O. Reis (&) � B. C. F. Sanches � E. L. Zani

Urology Division, Department of Surgery, School of Medical

Sciences, University of Campinas (Unicamp), Rua: Tessalia

Vieira de Camargo, 126, Cidade Universitaria ‘‘Zeferino Vaz’’,

Campinas, SP CEP 13083-887, Brazil

e-mail: reisleo.l@gmail.com; reisleo@unicamp.br

L. O. Reis � L. N. Castilho � C. R. Monti

Radium Institute, Campinas, SP, Brazil

123

World J Urol

DOI 10.1007/s00345-013-1148-6

Introduction

Further identification and refinement of outcomes and

morbidity are fundamental in the optimal selection of

patients who can benefit from brachytherapy as a sole

modality of treatment [1–3].

The previously reported not significant difference in

outcomes between low and intermediate D’Amico’s risk

groups supports the need for better brachytherapy prog-

nosticators [2]. One strong argument is that it is better fitted

to discriminate patients under radical prostatectomy when

the entire prostate is examined avoiding sampling biopsy

limitations mainly related to staging and grading, under-

mining the value of biopsy Gleason score.

In this perspective, we aim to identify predictors of

outcomes of brachytherapy with permanent seed implan-

tation of iodine-125 in patients with localized prostate

cancer in a contemporary longitudinal uncontrolled study

based on a prospectively maintained database.

Materials and methods

From an institutional review board-approved registry of

560 prospectively collected histologically confirmed pros-

tate cancer patients treated with transperineal interstitial

implant under ultrasound guidance with low-dose-rate

permanent iodine-125 seeds to a dose of 145 Gy by a

unique radiotherapist, between February 2000 and Febru-

ary 2011, 305 patients with C24-month follow-up and

localized tumor were included in the study; 100 patients

receiving androgen ablation (AA), 148 presenting locally

advanced disease (CT3), and seven patients that were lost

to follow-up were excluded.

No associated therapy was offered, and all included

patients underwent C12-core biopsy with central uropa-

thology review and routine serial post-treatment PSA lev-

els utilizing previous validated Immulite � PSA kit, drawn

every 3 months during the first 2 years, every 6 months

during the third year, and annually thereafter.

Biochemical recurrence (BR) was defined as any PSA

increase to C2 ng/mL above the nadir value (‘‘nadir ? 2,’’

the Phoenix definition) [4], as well as the initiation of

secondary therapies, in particular initiation of AA.

Prostate-specific antigen bounce was defined as a post-

treatment PSA raise of ‡0.4 ng/mL, followed by a spon-

taneous return to the prebounce level or lower.

The independent variables analyzed were putative

prognostic factors as continuous and/or categorized vari-

ables properly classified according to cutoffs of literature

and/or median values:

• Continuous variables age, Gleason score, pretreatment

PSA, PSA-nadir at 12 months, prostate volume, num-

ber of positive cores biopsy, percentage of positive

cores biopsy, V100 gyp (the percentage volume of the

prostate receiving 100 % of the prescribed dose), V150

gyp (the percentage volume of the prostate receiving

150 % of the prescribed dose), and D90 prostate (dose

received by 90 % of the prostatic area).

• Categorical variables age ([70, 60–70, 50–60,

\50 years), Gleason score (\7 vs. C7), pretreatment

PSA (\10 vs. C10 ng/mL), D’Amico’s risk groups

(low, intermediate, or high) [5], prostate volume (\30,

30–40, [40 g), perineural invasion (no vs. yes), stage

(T1c, T2a or T2b ? T2c), and PSA bounce (no vs. yes).

Statistical analysis

The data were analyzed using the v2 test for comparison of

proportions or Fisher’s exact test (for expected values less

than 5), and the Mann–Whitney test for comparison of

numerical variables between two groups, due to lack of

normal distribution of variables. Uni- and multivariate

stepwise logistic regression models were used to identify

predictors of BR.

The analysis of receiver operating characteristic (ROC),

the area under the curve (AUC), 95 % confidence interval,

and the levels of sensitivity and specificity were calculated

for accurate cutoff discriminations for BR.

Kaplan–Meier product-limit analysis using the log-rank

test for comparison between the groups (PSA-nadir clas-

sifications and D’Amico’s risk classification) and Cox

(time to event) regression was utilized to define significant

predictors of shorter time to BR.

The software SAS System for Windows (statistical

analysis system) version 9.1.3 (SAS Institute Inc,

2002–2003, Cary, NC, USA) was utilized to analyze the

data. The two-sided level of significance for statistical tests

was 5 % (p \ 0.05).

Results

The clinical status at presentation is outlined in Table 1.

The mean age was 63.93 years (44–88), mean pretreatment

PSA was 6.34 ng/mL (0.67–33.09), and overall median

follow-up was 75.35 months (24–158.37).

Mean, median, standard deviation, and range of PSA-

nadir at 1 year post-treatment were 0.54, 0.28, 0.94, and

0–8.8, respectively.

Biochemical recurrence occurred in 17 patients

(5.57 %), and 288 patients (94.43 %) were disease free in

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the follow-up period. Cancer-specific survival (CSS) was

100 %, and overall survival (OS) was 98.03 %.

Fifty-six out of 305 patients (18.4 %) experienced a

bounce PSA during follow-up, median 1.18 ng/mL (range

0.62–4.02) with a median time of 20.1 months (range

13–38). Only one BR was observed in the bounce group.

Implant dosimetric quality indicators (brachytherapy

doses) are showed in Table 2.

Table 3 shows the most relevant uni- and multivariate

analyses. Multivariate analyses showed that only the vari-

ables PSA-nadir at 1 year and age were significantly rela-

ted to BR: The risk increases 87.3 % to each unit of PSA-

nadir—OR 1.87 (p \ 0.001; 95 % CI 1.31–2.67), and risk

was 4.7 times for those under 50 years (vs.[70)—OR 4.69

(p = 0.04; 95 % CI 1.39–18.47).

The PSA-nadir at 1 year cutoff that maximizes sensi-

tivity and specificity significantly discriminating between

patients with and without BR was 0.285, AUC = 0.78

(p \ 0.001; 95 % CI 0.68–0.89) (Table 1).

Figures 1 and 2 illustrate the Kaplan–Meier disease-free

survival curves for patients classified according to PSA-

nadir at 1 year (\ vs. C0.285) and D’Amico’s risk groups

(low vs. intermediate ? high), p \ 0.001 and p = 0.24,

respectively.

Even not our primary focus, complications were

weightless and uncommon; no grade 3 or 4 complication

was reported, and only 31.4 % of patients had grade 2

urinary or rectal toxicity.

Discussion

The American Brachytherapy Society (ABS) recom-

mended brachytherapy as monotherapy in patients with

clinical stages T1–T2a, PSA levels of 10 ng/mL or less,

and a Gleason score of 6 or less (patients categorized as

low-risk tumors by D’Amico’s classification), without BR

in 87–96 % at 5–10 years [5].

Our results suggest that even those patients classified as

intermediate- and high-risk tumors by D’Amico’s catego-

rization can take advantage of brachytherapy if they reach

PSA-nadir at 1 year \0.285, as a key independent prog-

nostic factor for BR, with the potential to supersede

D’Amico’s classification.

Several series of brachytherapy reported factors pre-

dicting outcomes: Gleason score [6], initial PSA [2], final

PSA [7, 8], PSA-nadir [9], risk group [10], percentage of

positive biopsies [11], dose of radiotherapy [12], and

quality of implants [13].

Recently, Bowes et al. [14] showed that brachytherapy

is a highly effective treatment option despite less favorable

clinical and pathologic factors, supporting our findings. At

the same time, final PSA or more applicably PSA-nadir

will emphatically reflect the balance among dose of

radiotherapy, quality of implants, as well as tumor real

aggressiveness and its responsiveness to radiation as

delivered.

We observed in our study that patients with high risk of

BR were those with higher PSA-nadir at 1 year and those

with lower age (\50 vs. [70 years) in multivariate

analysis.

Table 1 Clinical status at presentation (n = 305)

Variable Mean (range)

Age (years) 63.93 (44–88)

Preimplant PSA (ng/mL) 6.34 (0.67–33.09)

PSA N (%)

\10 269 (88.20 %)

10–20 33 (10.82 %)

C20 3 (0.98 %)

Gleason score N (%)

2–6 254 (83.28 %)

7 46 (15.08 %)

8–10 5 (1.64 %)

D’Amico’s risk groups N (%)

Low 212 (69.51 %)

Intermediate 85 (27.87 %)

High 8 (2.62 %)

TNM stage N (%)

T1c 195 (63.94 %)

T2a 73 (23.93 %)

T2b 20 (6.56 %)

T2c 17 (5.57 %)

Receiver operating characteristic curve analysis for PSA-nadir at

1 year

Table 2 Implant dosimetric quality indicators (brachytherapy doses)

(n = 305)

Variable Mean SD Min. Max.

V100 gyp 91.00 9.43 79.62 100.00

V150 gyp 67.51 19.32 38.03 96.92

D90 at treatment 143.75 22.77 103.51 172.79

D90 1 month 143.58 22.74 102.87 172.59

D90 6 months 149.10 23.76 106.66 192.10

D90 mean 146.35 21.40 102.09 175.15

V100 and V150 the percentage volume of the prostate receiving 100

and 150 % of the prescribed dose, respectively, D90 the minimal dose

in Gy covering 90 % of the prostate volume, SD standard deviation,

Min. minimum, Max. maximum

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Stock et al. [7] in a multivariate analysis revealed that

PSA status after treatment had the most significant effect

on CSS. Another study utilizing the Phoenix definition

among 119 patients showed that 30 % had at least one

positive post-treatment biopsy and in multivariate analysis,

PSA DT and time to PSA failure were the most significant

predictors of developing distant metastases [8].

While PSA DT has been largely investigated, the opti-

mal PSA-nadir in terms of cutoff value and best moment to

be addressed is to be better defined, mainly if an absolute

value as proposed or a percentile of the initial PSA and

prostate volume, as well as if related to the Gleason score.

In particular, the same PSA DT can occur in a wide range

of PSA-nadir limiting patient distinction, and the same

PSA DT for a higher PSA-nadir might represent worse

disease. Furthermore, PSA-nadir criterion [7] precedes the

PSA DT that is an indication of progression in most of the

patients [8], foreseeing a late salvage treatment, culmi-

nating in a delayed and limited utility of PSA DT consid-

ering the natural history of prostate cancer.

Although other authors have utilized arbitrary time to

PSA-nadir and cutoff levels of 0.5 ng/mL to predict worse

outcomes [9, 13, 15], Guarneri et al. [16] utilized cluster

analysis to identify the cutoff point of 0.35 ng/mL among

Table 3 Univariate and multivariate logistic regressions for biochemical recurrence (n = 305)

Variable Category p OR 95 % CI OR

Pretreatment PSA (ng/mL) \10 (ref.) – 1 –

C10 0.447 1.66 0.45–6.07

Prostate volume (g) \30 (ref.) – 1 –

30–40 0.697 1.24 0.42–3.64

[40 0.451 1.71 0.42–6.97

Gleason \7 (ref.) – 1 –

C7 0.916 1.07 0.30–3.87

Perineural invasion No (ref.) – 1 –

Yes 0.604 0.58 0.07–4.54

Positive core (n) CV 0.214 0.79 0.55–1.14

PSA-nadir at 1 year (ng/mL) CV <0.001 1.87 1.31–2.67

D‘Amico risk Low (ref.) – 1 –

Intermediate 0.093 2.33 0.87–6.26

High 0.552 1.25 0.07–23.38

Age (years) [70 (ref.) – 1 –

60–70 0.247 0.42 0.10–1.82

50–60 0.396 0.53 0.12–2.29

\50 0.014 5.07 1.39–18.47

Stage T1c (ref.) – 1 –

T2a 0.097 0.18 0.02–1.37

T2b ? T2c 0.681 0.73 0.16–3.34

V150 gyp (%) CV 0.232 1.07 0.96–1.20

V100 gyp (%) CV 0.172 0.97 0.93–1.01

D90 (Gy) CV 0.161 0.99 0.97–1.01

PSA bounce No (ref.) – 1 –

Yes 0.18 0.36 0.08–1.61

Variable Category p OR 95 % CI

PSA-nadir at 1 year (ng/mL) CV <0.001 1.87 1.31–2.68

Age (years) [70 (ref.) – 1 –

60–70 0.23 0.37 0.08–1.86

50–60 0.371 0.5 0.11–2.30

\50 0.04 4.69 1.07–20.50

ref., reference level; 95 % CI OR, 95 % confidence interval for risk ratio; positive core, number of biopsy cores with cancer; D90, the minimal

dose covering 90 % of the prostate volume; V100 and V150, the percentage volume of the prostate receiving 100 and 150 % of the prescribed

dose, respectively; CV, continuous variable

Bold values indicate the statistically significant p values

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105 patients, with no impact on BR in the bounce group; in

our study, utilizing the ROC curve, it appears that the value

of PSA-nadir at 1-year C0.285 significantly discriminated

between patients with and without BR, with no impact of

bounce.

Reinforcing our data and the above-mentioned rational,

there are many contemporary studies suggesting that PSA-

nadir is much more than an outcome of treatment; it should

rather be considered an important post-treatment prognos-

tic factor [2]. Also, in a study with 142 patients, PSA-nadir

at 1 year correlated with recurrence: B1 (3 %), 1 to B4

(50 %), and C4 (100 %) [15].

Combining data of eleven institutions, the 8-year actu-

arial DFS was 92, 86, 79, and 67 %, respectively, for

patients with PSA-nadir values of 0–0.49, 0.5–0.99,

1.0–1.99, and[2.0 ng/mL (p \ 0.001) [13]. Another study

with 206 patients showed that PSA-nadir was the strongest

predictor of long-term biochemical disease-free survival

(p \ 0.001) with only two failures in 62 patients who

achieved a post-treatment PSA-nadir B0.5 ng/mL [17].

At present, an age-related bias exists within the urologic

community, with younger patients being referred more

often for radical prostatectomy than for either radiation or

no therapy [3].

While men younger than 60 years of age had identical

biochemical outcomes compared with older patients [18,

19], suggesting that age of this range should not bias

brachytherapy as an option, only a few examine men

younger than 50 years [9], once they represent a very

selected and small set of data on prostate cancer (usually

\10 %). Furthermore, the risk of second primary cancers

and the need for truly long-term follow-up are important

considerations to be discussed case by case when offering

brachytherapy to extremely young patients [20, 21].

While we are not able to identify any clear and

accountable evidenced biases, the results regarding the

group of youngest patients must be viewed with caution

once are surprising, and as observed in the literature, only

a few of studied patients (7.87 %, n = 24) were

\50 years and they tended to have slightly longer follow-

up: mean 80.85 and median 81.97 months (SD 29.54);

range 24.93–165.03. Even occurring barely to this subset

of data, these aspects are potential sources of biases, yet

unproven.

Fig. 1 Kaplan–Meier analysis

for PSA-nadir at 1 year and

time to biochemical recurrence

Fig. 2 Kaplan–Meier analysis

for D’Amico’s risk groups and

time to biochemical recurrence

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Interestingly, dose was not a significant predictor of

outcome. This may be the case because this series reflects

the conservative range of doses recommended by ABS [5].

Though the present study shows important strengths as a

representative well-balanced contemporary prospectively

collected data, diagnosed through at least 12-cores biopsy

with central uropathology review and produced by a single

radiotherapist working in a multidisciplinary team of

urologists and oncologists, and under the actual Phoenix

definition of biochemical recurrence with at least

24 months of follow-up, following the ABS guidelines, it is

not free of limitations related to its retrospective design.

PSA-nadir at 1-year \0.285 still represents the refine-

ment and evolution of a promising and sound prognostic

factor, being clinically important since occurring in a

considerable amount of patients with clinically localized

prostate cancer under low-dose-rate iodine-125 seeds

brachytherapy, independent of D’Amico’s risk categori-

zation. Furthermore, a 12-month prognostic marker may be

important compared with later outcomes, in order to pre-

dict the need for further therapy, which could be started

sooner after primary treatment.

Further guidelines should consider mentioning PSA-

nadir (mainly at 12 months), and future studies should be

controlled for patients’ testosterone once it impacts tumor

microenvironment and PSA-nadir. It would also be useful

to expand the investigation to look at PSA-nadir deriva-

tives, such as the percentile of the initial PSA, the PSA

density, and the relationship of PSA-nadir with the Gleason

score.

Conclusions

Half (50.49 %) of patients in the setting of localized

prostate cancer treated with iodine-125 brachytherapy

reach PSA-nadir at 1 year \0.285, recognized as a key

independent prognostic factor for disease-free survival,

independent of D’Amico’s risk categorization.

Acknowledgments The study was supported by Instituto do

Radium de Campinas (IRC), Campinas, SP, Brazil. Dr. John C.

Blasko has critically reviewed a preliminary draft of the manuscript.

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