Brachytherapy in men aged ≤ 54 years with clinically localized prostate cancer

Authors


Gregory S. Merrick, Schiffler Cancer Center, Wheeling Hospital, 1 Medical Park, Wheeling, WV 26003–6300, USA. e-mail: gmerrick@urologicresearchinstitute.org

Abstract

OBJECTIVE

To report the biochemical progression-free survival (BPFS) in hormone-naive men aged ≤ 54 years who underwent brachytherapy with or without supplemental external beam radiation therapy (EBRT), as despite favourable biochemical control rates with brachytherapy, there remains a reluctance to recommend non-extirpative approaches for young men with clinically localized prostate cancer.

PATIENTS AND METHODS

From April 1995 to October 2002, 108 hormone-naive patients aged ≤ 54 years (median 52 years, range 45–54) had permanent interstitial brachytherapy for clinical stage T1c-T2c NXM0 (2002 American Joint Committee on Cancer staging) prostate cancer. No patient had a seminal vesicle biopsy or pathological lymph node staging. The mean (sd, median) follow-up was 5.3 (1.8, 4.8) years. BPFS was defined by a prostate-specific antigen (PSA) level of ≤ 0.40 ng/mL after the nadir. Risk groups were assigned using the Memorial Sloan-Kettering Cancer Center criteria. Several clinical, treatment and dosimetric variables were evaluated for their effect on BPFS.

RESULTS

For the entire group, the actuarial 8-year BPFS was 96%; for low- (57 men), intermediate- (47) and high- (four) risk patients, the BPFS rates were 96%, 100% and three of four, respectively. For biochemically disease-free patients, the median PSA level after treatment was 0.05 ng/mL. In a multivariate analysis, only pretreatment PSA level predicted biochemical control, while dosimetry variables after treatment were almost statistically significant.

CONCLUSIONS

Hormone-naive patients aged ≤ 54 years have a high probability of a good 8-year BPFS after permanent interstitial brachytherapy with or without supplemental EBRT.

Abbreviations
RP

radical prostatectomy

BPFS

biochemical progression-free survival

EBRT

external beam radiation therapy

ASTRO

American Society of Therapeutic Radiology and Oncology

RR

relative risk

BMI

body mass index

mPD

minimum peripheral dose

NIST

National Institute of Standards and Technology

TG-43

Task Group no. 43.

INTRODUCTION

The implementation of routine PSA screening and a greater public awareness of prostate cancer has resulted in a stage migration and a substantial decrease in patient age at the time of diagnosis [1,2]. Although studies before the advent of PSA testing reported conflicting conclusions for the effect of patient age on prostate cancer outcome [3–6], most series of contemporary radical prostatectomy (RP), external beam radiation therapy (EBRT), and brachytherapy showed lower-risk pathological features and/or favourable biochemical outcomes in younger patients [7–16].

Despite long-term durable biochemical control rates and a favourable morbidity profile [17–19], there remains a reluctance to recommend non-extirpative approaches for young men with clinically organ-confined prostate cancer. In the present study we report the biochemical progression-free survival (BPFS) in hormone-naive men aged ≤ 54 years who had brachytherapy with or without supplemental EBRT.

PATIENTS AND METHODS

Between April 1995 and October 2002, 108 consecutive hormone-naive patients (67 treated by G.S.M. from April 1995 to October 2002, and 41 by K.E.W. from January 1999 to October 2002) had permanent interstitial brachytherapy for clinical stage T1c-T2c (2002 TNM) prostate cancer. All patients had brachytherapy >3 years before the present analysis. Before formulating a treatment plan, all biopsy slides were reviewed by in-house pathologists (E.A. and/or L.T.). The pre-planning technique, intraoperative approach and dosimetric evaluation were described in detail elsewhere [20–22]. Calculation algorithms and seed parameters used in pre-planning and postoperative dosimetry were those recommended by the American Association of Physicists in Medicine Task Group no. 43 (TG-43) [23]. Patients were clinically staged by a medical history, physical examination including a DRE, and serum PSA determinations. Bone scans, CT of the pelvis and prostatic acid phosphatase levels were obtained at the discretion of the referring physician or the brachytherapist. No patient had a seminal vesicle biopsy or pathological lymph node staging.

Of the 108 patients, 57 presented with low-risk disease (PSA level of ≤ 10 ng/mL, Gleason score ≤ 6 and clinical stage ≤ T2b), 47 with intermediate-risk disease (one adverse factor; PSA level of >10 ng/mL or Gleason score ≥ 7 or clinical stage ≥ T2c), and four with high-risk features (two or three adverse factors). In all, 47 patients (43%) received supplemental EBRT, i.e. 43 intermediate-risk and all four of the high-risk patients. In general, the supplemental EBRT target volume consisted of the prostate gland, seminal vesicles and first-echelon lymph nodes. EBRT was delivered via a conformal four-field technique with custom treatment devices, administered before brachytherapy. No patient received androgen-deprivation therapy.

The brachytherapy target volume consisted of the prostate gland with a periprostatic margin including the proximal 1.0 cm of the seminal vesicles [20,22]. The minimum peripheral dose (mPD) was prescribed to the target volume with margin. Of the 108 patients, 73 (68%) were implanted with 103Pd and 35 (32%) with 125I. For monotherapeutic approaches, the mPD was 125 Gy (National Institute of Standards and Technology, NIST-99) for 103Pd and 145 Gy (TG-43) for 125I. 103Pd was used for all brachytherapy boosts with doses of either 90 Gy or 115 Gy mPD (NIST-99). At implantation, the prostate gland, periprostatic region and base of the seminal vesicles were implanted [20,22].

Patients were monitored by a physical examination including a DRE and PSA level. The endpoint of the analysis was BPFS, defined as a PSA level of ≤ 0.40 ng/mL after the nadir [16,24]. No patient had a routine biopsy after implantation.

Clinical, treatment and dosimetric variables evaluated for comparison with BPFS included patient age, Gleason score, pretreatment PSA level, risk group, percentage of positive biopsies, perineural invasion, isotope, supplemental EBRT, prostate volume, brachytherapy planning volume, percentage of the target volume receiving 100%, 150% and 200% of the prescribed dose (V100/150/200), minimum percentage of the prescribed dose covering 90% of the target volume (D90) and body mass index (BMI).

Actuarial 8-year results were determined by calculated Kaplan–Meier cumulative hazard curves. Univariate Cox regression analysis was used to determine univariate predictors of failure. Variables with P ≤ 0.1 were then included in a multivariate model of Cox regression as a means of identifying multiple predictors. For all tests, P < 0.05 was deemed to indicate statistical significance.

RESULTS

Table 1 summarizes the clinical, treatment and dosimetric variables of the patients; of the 108 patients, 105 (97%) presented with Gleason score 6 or 7 histology (two were diagnosed with Gleason score 5 and one with Gleason score 9), 101 (94%) with a PSA level of ≤ 10 ng/mL, and 104 (96%) with either low-risk (57) or intermediate-risk (47) disease. Seventy-three patients (68%) were implanted with 103Pd and 35 (32%) with 125I; all those with Gleason scores of ≥ 7 were implanted with 103Pd, while those with Gleason score 5 and 6 were distributed between the isotopes.

Table 1. 
Clinical, treatment and dosimetric variables for the brachytherapy patients aged ≤ 54 years
VariableMedian, mean (sd) or n (%)
  • *

    Perineural invasion was available for only 67 patients.

Continuous:
Age, years 52, 52.2 (2.4)
Follow-up, years  4.8, 5.3 (1.8)
PSA level, ng/mL  5.7, 6.4 (2.8)
Gleason score  6.0, 6.4 (0.8)
% positive biopsies 33.3, 38.4 (24.8)
BMI, kg/m2 27.9, 28.6 (4.7)
Prostate volume, mL 30.3, 30.3 (8.5)
Planning volume, mL 53.6, 46.9 (23.1)
V100 96.2, 93.7 (7.1)
V150 69.9, 66.9 (15.9)
V200 39.8, 39.1 (14.8)
%D90 114.9, 113.7 (23.1)
Most recent PSA level, ng/mL  0.05, 0.10 (0.15)
Categorical, n (%)
Perineural invasion*
 no 45 (67)
 yes 22 (33)
EBRT
 no 61 (57)
 yes 47 (43)
Isotope
 125I 35 (32)
 103Pd 73 (67)
Risk
 Low 57 (53)
 Intermediate 47 (44)
 High  4 (3.7)

Figure 1a shows the Kaplan–Meier BPFS for all 108 patients with an 8-year biochemical control rate (PSA level of ≤ 0.40 ng/mL after nadir) of 96%. The median PSA level at the last follow-up for patients in whom the treatment did not fail was 0.05 ng/mL (Table 1).

Figure 1.

BPFS: a, for men with a PSA level of ≤ 0.40 ng/mL after nadir; b, stratified by risk group; c, stratified by Gleason score; d, stratified by pre-implant PSA level; e, stratified by isotope; f, stratified by V100; and g stratified by D90.

When stratified by risk group, biochemical control rates for low-, intermediate- and high-risk patients were 96%, 100% and three of four, respectively. Biochemical control rates of 96% and 98% were reported for Gleason score 5–6 and Gleason score 7, respectively (Fig. 1c, P = 0.690). Figure 1d shows the BPFS stratified by pretreatment PSA level; 97% and 86% of patients with a PSA level of ≤ 10 and >10 ng/mL, respectively, remained free of biochemical progression. There was a trend for a better biochemical outcome in patients implanted with 103Pd than with 125I (Fig. 1e, at 99% vs 91%, P = 0.059).

Figure 1f shows the importance of implant quality on biochemical outcome; a V100 of 90% and D90 of >100% at day 0 were statistically significant in predicting the biochemical outcome. These thresholds for V100 and D90 resulted in almost identical biochemical outcomes.

Table 2 summarizes the results of the regression analysis as P values and relative risk (RR). In a univariate Cox regression analysis, pretreatment PSA level and V100 predicted the biochemical control, while the D90 was almost statistically significant. However, on multivariate analysis only pretreatment PSA level (P = 0.012) remained statistically significant and both dosimetric variables (V100 and D90) were almost statistically significant. To date, no patient has died from metastatic prostate cancer; four died from cardiovascular disease and two from second malignancies (lung cancer and an unknown primary).

Table 2. 
Univariate and multivariate analysis
VariableUnivariate PRRMultivariate* PRR
  • *

    Only those variables with P ≤ 0.1 were included in the multivariate analysis;

  • †categorical variable.

Age0.965   
PSA before implant0.0121.2640.0121.264
Prostate volume0.728   
V1000.0400.9140.051
D900.0750.063
EBRT0.444   
Isotope0.102   

DISCUSSION

Since the routine implementation of PSA screening in clinical practice the public awareness of prostate cancer has dramatically increased, resulting in a downward stage migration and a substantial decrease in patient age at diagnosis [1,2]. Most contemporary RP, EBRT and brachytherapy studies show a greater incidence of organ-confined disease [7,9–13] and/or favourable biochemical control rates in younger patients [7–16]. By contrast, older patients might be at a greater risk of extracapsular extension, higher Gleason scores and a greater incidence of distant metastases [7,25]. However, not all studies support patient age as a risk factor for biochemical recurrence [26].

Although permanent prostate brachytherapy has emerged as a mainstream treatment for clinically localized prostate cancer, there remains a reluctance to recommend non-operative approaches for younger patients. Previous studies documented favourable biochemical and morbidity outcomes in young patients [16,19]. Urinary and bowel function are not affected by patient age [19] but, consistent with other local treatments, the preservation of potency is inversely related to patient age [27]. Although radiation-induced second malignancies remain a theoretical concern, there are no data to link brachytherapy with such adverse events [28].

The present study shows that brachytherapy-related biochemical control rates in younger patients are at least as favourable as the results of RP and EBRT in comparable age groups (Table 3) [8,10,12,14–16,29]. However, any comparison between treatments is limited by different definitions of biochemical success [16]. We chose a PSA level of ≤ 0.40 ng/mL after the nadir as the definition of success, because of its close correlation with the American Society for Therapeutic Radiology and Oncology (ASTRO) consensus definition and its similarities to the Mayo Clinic definition for biochemical success after RP [16]. In addition, the median follow-up in the present study (4.8 years) compares favourably with those in previous RP and EBRT studies evaluating young patients (median follow-up 1.3–5.7 years; Table 3) .

Table 3.  Biochemical control rates in hormone-naive younger men with clinically localized prostate cancer treated with RP, EBRT or brachytherapy
StudyAge criterion, yearsLocal methodNo. of patientsFollow-up, yearsDefinition of biochemical success% with no evidence of biochemical disease at (years)
MedianMaximum
[14]<65EBRT 302.9 5.0ASTRO89 (5)
[8]≤50RP 792.8 9.5PSA ≤ 0.292 (5)
[29]≤60EBRT 984.0 7.0ASTRO47 (7)
[10]<50RP3415.7 (mean)18.0PSA ≤ 0.281 (10) 69 (15)
[15]≤60EBRT 964.5 11.0ASTRO79 (15)
[16]≤62Brachytherapy 1195.4 8.9PSA ≤ 0.496 (7)
[12]≤50RP 881.6 6.0PSA ≤ 0.280 (5)
Current≤54Brachytherapy1084.810.7PSA ≤ 0.496 (8)

For EBRT and brachytherapy alike (Fig. 1f) an adequate radiation dose is essential to secure durable biochemical control [30–33]. Indeed, the one study of EBRT reporting poorer biochemical outcomes in patients aged ≤ 60 years used suboptimal doses of EBRT [29]. In a subsequent report from the Memorial Sloan-Kettering Cancer Center evaluating patients aged <60 years and receiving optimal EBRT doses (≥75.6 Gy), Zelefsky et al.[15] showed that a lower patient age did not adversely affect the biochemical outcome. Because of the dose intensification effect of brachytherapy (Table 1), including irradiation of the prostate gland, periprostatic region and proximal seminal vesicles, the median PSA level after treatment in biochemically controlled patients in the present series was 0.05 ng/mL. After brachytherapy, a PSA nadir of ≤ 0.2 ng/mL was associated with a 99% chance of remaining free of biochemical progression [34]. Consistent with most contemporary RP, EBRT and brachytherapy series, the present study confirms that younger patients have a high probability of BPFS after high-quality local treatment.

In conclusion, hormone-naive patients aged ≤ 54 years have a high probability of a 9-year BPFS after permanent interstitial brachytherapy with or without supplemental EBRT.

CONFLICT OF INTEREST

None declared.

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