Long-term biochemical results after high-dose-rate intensity modulated brachytherapy with external beam radiotherapy for high risk prostate cancer.

Abstract

BACKGROUND: Biochemical control from series in which radical prostatectomy is performed for patients with unfavorable prostate cancer and/or low dose external beam radiation therapy are given remains suboptimal.The treatment regimen of HDR brachytherapy and external beam radiotherapy is a safe and very effective treatment for patients with high risk localized prostate cancer with excellent biochemical control and low toxicity.

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RESEARCHOpen Access
Long-term biochemical results after high-dose-
rate intensity modulated brachytherapy with
external beam radiotherapy for high risk prostate
cancer
Pedro J Prada1,3*, Lucia Mendez1, José Fernández2, Herminio González1, Isabel Jiménez1and Elisabeth Arrojo1
Abstract
Background: Biochemical control from series in which radical prostatectomy is performed for patients with
unfavorable prostate cancer and/or low dose external beam radiation therapy are given remains suboptimal.
The treatment regimen of HDR brachytherapy and external beam radiotherapy is a safe and very effective
treatment for patients with high risk localized prostate cancer with excellent biochemical control and low toxicity.
Introduction
Patients with clinical stage T1c, Gleason score sum 6
tumors, and prostate-specific antigen (PSA) values < 10
ng/ml have a high likelihood of disease-free survival,
regardless of the treatment option chosen.
Nevertheless, we are faced with a great dilemma when
we seen newly diagnosed patients with high-risk pros-
tate cancer. Unfortunately, results of conventionally
accepted therapies such as radical prostatectomy and/or
standard radiotherapy have not provided these patients
with good outcomes [1-3].
The need for increased dose in patients with prostate
cancer was suggested by dose response observations by
Pollack [4,5] and Hanks [6,7].
In an effort to improve outcomes several new radia-
tion therapy strategies have been developed over the last
decade. One approach was a combination of external
beam radiotherapy (EBRT) with an intensity modulated
with high dose rate (HDR) prostate brachytherapy boost.
It has been possible to increase dose, thanks to the
brachytherapy advances, which allows for an increase in
tumour dose (boost doses greater than 125 Gy can be
safely delivered) while reducing the volume of surround-
ing normal tissue that is irradiated.
From a biologic perspective, the low prostate cancer
a/b [8] favors a large dose per fraction in terms of can-
cer control. At the same time, the a/b of the rectum
and bladder favors larger doses per fraction to increase
the therapeutic window, thus improving control while
limiting toxicity.
This study reports the long-term outcome during the
PSA era for patients with high-risk prostate cancer who
were treated with intensity modulated HDR boost.
Material and methods
Selection of patients
From June 1998 to August 2006, 252 consecutive
patients were treated for high risk clinically localized
prostate cancer with external beam radiation and inten-
sity modulated HDR brachytherapy boost.
Staging
In all cases, staging evaluation included a history and
physical examination, digital rectal palpation, serum
PSA, chest X-ray, bone scan, abdominal CT and/or
MRI, transrectal ultrasound (TRUS), and TRUS-guided
biopsy with Gleason score histologic grading. All
patients were x’ according to the American Joint Com-
mittee on Cancer (AJCC) 4th edition [9]. Tumour char-
acteristics are shown in Table 1.
* Correspondence: pprada@telecable.es
1Department of Radiation Oncology, Hospital Universitario Central de
Asturias, Oviedo, Spain
Full list of author information is available at the end of the article
Prada et al. Radiation Oncology 2012, 7:31
http://www.ro-journal.com/content/7/1/31
© 2012 Prada et al; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons
Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in
any medium, provided the original work is properly cited.

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Excluded from the program were those patients who
had any of the following conditions:
- Previous radiotherapy to the pelvis
- Patients with another malignant process (except
skin tumour) 5 years before the diagnosis of the
prostate cancer
- Recurrence of prostate tumour
- Life expectancy < 5 years
Definition groups
Patients were considered high risk according to the
Memorial Sloan Kettering group definition (clinical
stage ≥ T2c or prostate-specific antigen, PSA > 20 ng/
ml or Gleason score > 7 or 2-3 intermediate-risk cri-
teria) [10].
Hormonal therapy
In our patient population, more than half of the
patients, 69% received hormonal ablative treatment
(LhRh agonists + antiandrogens) for one year. It was
initiated as neo-adyuvant treatment, three months
before the start of radiotherapy.
Treatment
For several years, patients diagnosed with prostate can-
cer have been treated at our Institution with EBRT
interdigitated with two intensity modulated brachyther-
apy (IMBT) HDR boosts (Table 2).
Total pelvic external beam radiation technique was 46
Gy delivered in 23 fractions of 2 Gy over 4.5 weeks. All
patients were treated using 18-MV photons. No external
radiation was delivered the same day of the HDR bra-
chytherapy procedure (day 5 and 15). Total treatment
time including the HDR boost was over a period of 5
weeks. All fields were treated daily. Isocentric technique
was used and all fields were equally weighted. The por-
tals used covered the prostate, seminal vesicles, and the
periprostatic tissues with a margin of at least 1 cm. The
tumour volume was encompassed in the fields by the
100% isodose line ± 5%.
Brachytherapy procedures were done under spinal
anesthesia. The dose administered in each application
was 11.5 Gy, except in the first group of patients treated
(17%) in whom the dose applied varied between 10.5
and 11. The target volume of the implant was the pros-
tate gland + 5 mm peri-prostatic area and medial
aspects of seminal vesicle. All patients were discharged
from the center the same day of the procedure between
6-8 hours of implantation.
The total combined BED dose ranged from 292 Gy to
366 Gy based upon a a/b ratio of 1.2 [8].
Toxicity
Patients were followed with symptom assessment and
PSA determinations every 3 months for the first year,
every 6 months for the second year and yearly
thereafter.
Toxicity was reported according to the Common
Toxicity Criteria for Adverse Event, Version 4.0 (CTAE
v4.02) by the National Cancer Institute. Chronic toxicity
was defined as those symptoms which persisted or pre-
sented beyond 6 months. Potency was defined as the
Table 1 Patient and tumor characteristic (n = 252)
CharacteristicsN° Patients (%)
Stage
≤ T2a
T2b
≥ T2c
36 (14%)
58 (23%)
158 (63%)
Geason score:
≤ 6
= 7
> 7
Pretreatment PSA (ng/ml)
≤ 10
10.1-20
> 20
Mean:20/Median 18 (2.05-59.60)
Adjuvant hormonal ablation
Yes
No
Age at diagnosis (yr)
≤ 60
61-70
> 70
Risk Level
High Risk by Gleason y/o PSA
High Risk by T
No. Prognostic factors
2 intermediate Risk Criteria
1 High Risk Criteria
2 High Risk Criteria
> 2 Risk Criteria
Gland Vol. Implant (cc): Mean:34/Median 31 (9-87)
109 (43%)
77 (31%)
66 (26%)
44 (17%)
101 (40%)
107 (43%)
173 (69%)
79 (31%)
32 (13%)
131 (52%)
89 (35%)
187 (74%)
65 (26%)
44 (17%)
100 (40%)
89 (35%)
19 (8%)
Table 2 Treatment scheme
WeeksExternal radiotherapyBrachytherapy
1st week
2nd week
3rd week
4th week
5th week
Total dose
2 Gy/day × 4 days
2 Gy/day × 5 days
2 Gy/day × 4 days
2 Gy/day × 5 days
2 Gy/day × 5 days
46 Gy/23 sessions
1st HDR; 5th day (11.5 Gy)
No
2nd HDR; 15th day (11.5 Gy)
No
No
23 Gy/2 sessions
HDR = high dose rate (brachytherapy)
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ability to achieve an erection that was sufficient for
intercourse.
Toxicity and sexual side-effects was scored by the
physician.
Statistical considerations
Distant metastatic disease was defined by an imaging
study or physical examination that demonstrated can-
cer outside of the prostate and its regional nodes. Fail-
ure in cause-specific survival (CSS) analyses was
defined as death due to prostate cancer. Failure in
tumour-free survival (TFS) analyses was represented as
detection of local and/or systemic tumour relapse, and
bNED for no clinical and biochemical evidence of dis-
ease. Overall survival reflected all deaths, cancer-
related or otherwise. To assess the local relapse, sex-
tant prostate biopsies were taken in patients with no
metastatic disease if they did not refuse this procedure.
Biochemical failure was defined according to the
“Phoenix definition” [11] consensus panel statement.
Estimated likelihood of events was calculated by the
Kaplan-Meier method from the time of completion of
radiotherapy. The statistical significance of the differ-
ence between estimated event-free
Curves were calculated with the long-rank test. Multi-
variate analysis was performed using the Cox propor-
tional hazards model [12]. Statistical analyses were
performed with SPSS version 17.0 (SPSS Inc, Chicago,
IL).
Results
Clinical characteristics
All patients treated in the protocol were included for
analysis and completed the planned course of radiation.
All patients have been seen in follow up.
The high risk group, as defined in this study, repre-
sented 100% of the patient population (74% were high
risk by Gleason and/or PSA and 26% by T-stage) (Table
1).
The median V100, V90, V150 and V200 (% volume of
CTV receiving 100% of prescription dose) were respec-
tively 93.73% (96.82-85.81), 97.90% (99.80-91.79%),
21.02% (38.17-12.64) and 5.97% (9.41-3.30). The median
D90 (The dose that covers 90% volume of CTV) was
12.04 Gy (18.38-9.45). Maximum urethral point dose
was 12.66 Gy (16.36 Gy-9.25 Gy) and maximum rectal
point dose was 9.56 Gy (14.09 Gy-8.2 Gy).
Oncologic endpoints
Of all 252 patients, 51 had evidence of biochemical
relapse, 42 had clinical relapse and 12 died from pros-
tate cancer; 35 patients died of other illnesses. Mean
and median follow-up for all patients were 77 and 74
months respectively with a range of 12 to 142 months.
In the 51 patients with a biochemical failure, the med-
ian time to PSA failure was 38 (5-80) months, with 55%
failing within 3 years and 98% within 6 years. In patients
with no biochemical failure, the mean and median PSA
level after treatment was 0.10 and 0.03 (0.0-1.2) ng/ml,
the last follow-up PSA levels were ≤ 0.2 ng/ml in 90%, <
1 ng/ml in 99.6% and 1.2 ng/ml in a patient.
The 5 and 10 years for biochemical control were 84%
and 78% (SD ± 2%), whereas in tumor-free survival
(TFS) they were 86% and 82% (SD ± 2%) at 5 and 10
years respectively. The 10 year cause specific survival
was 93% (SD ± 2%) with 99% (SD ± 1%) of patients
being free of local recurrence. The overall survival
according to Kaplan-Meier estimates was 88% and 78%
(SD ± 4%) at 5 and 10 years respectively (Figure 1).
Characteristics used for multiple regression analyses to
correlate with biochemical failure were: clinical T-classi-
fication, Gleason score, pretreatment PSA, age, bra-
chytherapy dose level, prostate volume and hormonal
ablative treatment.
The multivariate Cox regression analyses identified,
Gleason score as independent prognostic factors for bio-
chemical failure.
The 10-year actuarial biochemical control stratified by
Gleason score was 85%, 72% and 74% for patients with
Gleason score of ≤ 6, 7 and > 7, respectively (P = 0.039)
(Figure 2).
The 10-year actuarial biochemical control was 89% for
patients with two intermediate risk criteria, 80% with
one high risk criteria and 72% for patients with 2-3 high
risk criteria (P = 0. 04) (Figure 3).
The 10-year actuarial biochemical control in patients
classified as high risk only by Gleason and/or PSA, no
by T-stage, was 86% for patients with two intermediate
risk criteria, 73% with one high risk criteria and 71% for
patients with 2 high risk criteria (P = 0. 45) (Figure 4).
Mean age was 67 years (range 49-78). The actuarial
analysis of biochemical control at ages less than 60, 60
to 69 and greater than 69 years demonstrated no signifi-
cant difference. As younger and older patients benefited
equally (P = 0.148).
The actuarial biochemical control was 80% and 74% (P
= 0.173), in patients who received hormones and in
those who did not.
All other variables (pretreatment PSA P = 0.898, T-
classification (p = 0.273), brachytherapy dose level P =
0.492, and volume P = 0.615) were statistical no signifi-
cant for biochemical failure.
Metastatic disease developed in 42 patients and the
distant metastatic rate at 10-years was 14%. Multivariate
analysis showed that Gleason score was the only factor
to significantly affect distant metastases, with 10-year
rates of 7%, 21% and 17% for scores of ≤ 6, 7 and > 7,
respectively (P = 0.014).
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The 10-year actuarial tumour-free survival (TFS) was
90%, 73% and 78% for patients with Gleason scores of ≤
6, 7 and > 7, respectively (P = 0.020).
Acute and chronic urinary toxicity
Moderate increase in urinary frequency and tract pain
(urethritis) occurred at the end of the treatment. At 6
month genitourinary grade I toxicity was 6% (increase in
urinary frequency and dysuria. Moderate symptoms).
Acute grade 1 urinary retention requiring a temporary
post-implant bladder catheter was seen in 4 (1.6%)
patients.
Grade 4 or 5 late toxicity was not detected in any
patients. Thirteen patients (5%) showed, increase in
urinary frequency and dysuria at 12 month.
A urethral stricture after treatment was observed in
seven patients (2.7%). Four patients required intermit-
tent bladder catheterization and endoscopic urethrot-
omy was required in three patients.
No patients reported incontinence after treatment.
Gastrointestinal toxicity
Acute gastrointestinal toxicity grade II was 3%, consist-
ing in increase of 4-6 stools per day over baseline and
mucus in stool, no patients developed grade 3 toxicity.
At six months gastrointestinal grade II toxicity was 1.6%.
At 12 months 99% of patients reported no change in
bowel function. Intermittent rectal bleeding without sys-
temic repercussions was reported in 5 patients (2%). No
patients with perineal pain were reported.
Figure 1 Actuarial analysis of all 252 patients for Cause specific survival, tumor-free survival, biochemical control and overall survival.
Figure 2 Actuarial analysis of biochemical control by Gleason score. P value generated from Log-Rank.
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Sexual function
Of the 131 (52%) patients who were potent preopera-
tively and hormonal manipulation was not used, 72%
were potent postoperatively but only 68% the patients
were potent when hormonal manipulation was used.
Potency was defined as the ability to achieve an erection
that was sufficient for intercourse.
Correlation between post implant dosimetry and toxicity
Characteristics used for multiple logistic-regression ana-
lyses which correlates probability of acute and chronic
urinary toxicity were: pre-treatment prostate volume,
year of implant, number of needles implanted,
brachytherapy dose, hormonal ablative treatment, maxi-
mum urethral dose.
The multivariate logistic-regression analyses showed
than patients with high urethral dose after established
brachytherapy technique are more likely to suffer acute
urethritis (P = 0.018).
Discussion
The importance of dose escalation, has been well docu-
mented, high radiation doses improve biochemical and
clinical results for prostate cancer patients [4-7]. Kuban
et al. reported an improvement in biochemical control of
78% for doses of 78 Gy, vs 59% for the 70 Gy arm [13].
Figure 3 Actuarial analysis of biochemical control by poor prognostic factors groups. P value generated from Log-Rank.
Figure 4 Actuarial analysis of biochemical control by poor prognostic factors groups in patients classified as high risk only by
Gleason and/or PSA, no by T-stage. P value generated from Log-Rank.
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