Int. J. Radiation Oncology Biol. Phys., Vol. 61, No. 5, pp. 1299 –1305, 2005
IMPACT OF SHORT COURSE HORMONAL THERAPY ON OVERALL AND
CANCER SPECIFIC SURVIVAL AFTER PERMANENT PROSTATE
DAVID C. BEYER, M.D.,*† TIMOTHY MCKEOUGH,* AND THERESA THOMAS, M.S.†
*Arizona Oncology Services and †Foundation for Cancer Research and Education, Scottsdale, AZ
Purpose: To review the impact of prior hormonal therapy on 10-year overall and prostate cancer specific survival
after primary brachytherapy.
Methods and Materials: A retrospective review was performed on the Arizona Oncology Services tumor registry
for 2,378 consecutive permanent prostate brachytherapy cases from 1988 through 2001. Hormonal therapy was
administered before the implant in 464 patients for downsizing of the prostate or at the discretion of the referring
physician. All deceased patients with known clinical recurrence were considered to have died of prostate cancer,
irrespective of the immediate cause of death. Risk groups were defined, with 1,135 favorable (prostate-specific
antigen [PSA] < 10, Gleason < 7, Stage T1-T2a), 787 intermediate (single adverse feature), and 456 unfavorable
(two or more adverse features) patients. Kaplan-Meier actuarial survival curves were generated for both overall
and cause-specific survival from the time of treatment. Multivariate analysis was performed to assess the impact
of hormonal intervention in comparison with known risk factors of grade, PSA, and age.
Results: With follow-up ranging up to 12.6 years and a median of 4.1 year, a total of 474 patients died, with 67
recorded as due to prostate cancer. Overall and cause-specific 10-year survival rates are 43% and 88%,
respectively. Overall survival is 44% for the hormone naive patients, compared with 20% for the hormone-
treated cohort (p
؍ 0.02). The cancer-specific survival is 89% vs. 81% for the same groups (p
Multivariate analysis confirms the significance of age > 70 years (p
؍ 0.0013), Gleason score
> 7 (p
and prior hormone use (p
؍ 0.0065) on overall survival.
Conclusions: At 10 years, in prostate cancer patients receiving brachytherapy, overall survival is worse in men
receiving neoadjuvant hormonal therapy, compared with hormone naive patients. This does not appear to be due
to other known risk factors for survival (i.e., stage, grade, PSA, age) on multivariate analysis. The leading causes
of death were cardiovascular, prostate cancer, and other cancers with no obvious discrepancy between the two
groups. This finding is unexpected and requires confirmation from other centers.
2004 Elsevier Inc.
Hormone therapy, Prostate cancer, Survival, Brachytherapy.
increase in the frequency of brachytherapy administration asprimary treatment between 1992 and 2001. In low-risk
Men receiving external beam radiation therapy for prostate
patients, they report that in 2001 fully 22% were treated
cancer are now commonly treated with neoadjuvant andadjuvant hormonal therapy. There have been numerous ret-
with brachytherapy, rising to 31% in patients over 75 years
rospective single institution reports suggesting benefit to the
of age. High response rates have been reported based on
combination of androgen ablation and radiation therapy
careful prostate-specific antigen (PSA) follow-up of brachy-
A number of well-designed prospective multicenter
therapy series, and many such patients are considered cured
trials have underscored the value of adding hormonal ma-
of their disease, with long-term survival data comparable
nipulation to standard radiation therapy and have shown
improved cancer control rates and a survival benefit
Since the introduction of transperineal techniques, andro-
gen ablation has been used in selected cases to shrink the
Ultrasound-guided brachytherapy for early-stage prostate
gland and avoid interference from the pubic arch. More
cancer is now a standard treatment option for many patients.
recently neoadjuvant hormonal therapy has been integrated
In one survey, Cooperberg et al.
report a sevenfold
into brachytherapy treatment plans in the hopes that some of
Reprint requests to: David C. Beyer, M.D., Arizona Oncology
Services, 8994 East Desert Cove, Suite 100, Scottsdale, AZ 85260.
—The authors thank the members of the Arizona
Tel: (602) 274-4484; Fax: (480) 314-3343; E-mail: dbeyer@
State Tumor Registry for their contribution and assistance.
Received Jan 12, 2004, and in revised form Jul 26, 2004.
Presented at the 45th Annual Meeting of the American Society
Accepted for publication Aug 9, 2004.
for Therapeutic Radiology and Oncology, Salt Lake City, UT,
I. J. Radiation Oncology ● Biology ● Physics
the improved results seen with external beam irradiation can
as recorded in the Arizona Department of Vital Records, was
also be achieved with brachytherapy. However, to date there
obtained from the Arizona State Cancer Registry and confirmed,
are no compelling studies supporting this combination ther-
when possible, through primary medical records.
apy, and its use remains an extrapolation from the external
Patients were stratified retrospectively in risk groups according
to commonly accepted criteria. Favorable patients had no adverse
beam data. This study was performed to assess the value of
risk factors of PSA Ͼ 10, Gleason Grade Ն 7, or Stage Ն T2b.
hormone use in this setting using overall survival and cause-
Intermediate risk patients exhibited one of these three risk factors.
Unfavorable patients had two or more of these adverse findings.
For the purposes of analysis, death was considered due to
prostate cancer in all patients who were reported to have died of
METHODS AND MATERIALS
prostate cancer, or those who died with any treated recurrence,
Between December 1988 and December 31, 2001, 2,378 con-
even if not recorded as due to the cancer. An untreated rising PSA
secutive patients were treated at Arizona Oncology Services with
at the time of death was not alone considered as evidence of cancer
brachytherapy for clinically localized prostate cancer. All were
death. Survival and cause-specific survival were calculated from
prospectively entered into an institutional tumor registry. This
database and the patients’ records were retrospectively reviewed
Stepwise multivariate models were developed using Cox pro-
under an Institutional Review Board–approved protocol in 2003.
portional hazards regression. Predictors of cause-specific and over-
All patients had biopsy-proven adenocarcinoma of the prostate,
all survival in both cases include Gleason Score, PSA value, stage
staged T1-T3, N0, M0. Central pathology review was not per-
value, and risk group levels. Graphical displays of the survival
formed. Treatment consisted of ultrasound-guided transperineal
curves for predictor levels were produced using the actuarial
permanent brachytherapy with 125I or 103Pd. Details of the tech-
method of Kaplan-Meier. Log–rank tests for the equality of sur-
nique changed significantly over the span of this review with the
vivor functions were made for each predictor with reference to
introduction of biplanar ultrasound, computed tomography (CT)
based dosimetry and other innovations. The basic approach haspreviously been reported but is briefly as follows. All
patients were preplanned with computerized dosimetry optimizedto deliver 160 Gy over the lifetime decay of 125I (145 Gy after the
The median patient age was 73 years. Follow-up ranged
introduction of TG-43) or 120 Gy over the lifetime of 103Pd (125
from 0 –12.6 years with a median of 4.1 years. At the time
Gy after incorporation of NIST-1999) to the prostate with a 3–10
of presentation, the median PSA was 7.3 ng/mL. Details of
mm margin. Patients also receiving 45 Gy external beam irradia-
the presenting characteristics of the study population are
tion were implanted with reduced doses of 120 Gy (110 Gy after
shown in for the entire population and stratified for
TG-43) or 90 Gy (100 Gy after NIST-1999) for the two isotopes,
the 464 men who used neoadjuvant hormones. At the time
respectively. Transperineal implantation was carried out as anoutpatient procedure under spinal or general anesthesia with intra-
of analysis, 1,297 patients are known to be alive and with no
operative ultrasound guidance utilizing afterloaded needles and theMick Applicator (Mick Radio-Nuclear Instruments, Inc., MountVernon, NY).
Neoadjuvant hormone therapy was given to 464 men. An anti-
androgen was added to the luteinizing hormone releasing hormone
(LHRH) agonist in 226 patients. This was generally given for 3– 6months to reduce the size of the prostate, to avoid pubic arch
interference, or at the discretion of the treating physicians. Fre-
quently, the reasons for hormonal intervention were not spelled out
in the record, particularly when treatment was instituted before the
initial referral. The duration of androgen deprivation was 6 months
or less in 80%, 6 –9 months in 15%, 9 –12 months in 2%, and more
than 12 months in 3%. Hormonal treatment was not continued
more than 3 months after implantation.
Before 1996, most patients received implant monotherapy. Sub-
sequently, combination therapy with the addition of external beam
was offered to 461 patients at the treating physician’s discretion
for high-risk features, such as PSA Ͼ 10, Gleason Ն 7 or stage Ն
Patients were asked to return 3 months after treatment for PSA
and DRE and were then typically seen every 3– 4 months for the
first year, every 6 months for the next 2 years, and annually
thereafter. In the case of either out-of-state patients or restrictive
insurance carriers, follow-up was achieved through referring phy-
sician notes or with the patients by phone or letter. Systematic
follow-up biopsies were not performed. The Social Security Death
Index, a national list of all Social Security recipients who havedied, was accessed to ascertain patient status. The cause of death,
PSA ϭ prostate-specific antigen.
Impact of hormonal therapy on survival after brachytherapy ● D. C. BEYER et al.
Fig. 1. Cause-specific survival is shown. At 10 years, cause-specific survival is 97% for the favorable risk group, 83%for the intermediate group, and 77% for unfavorable risk patients. Patients at risk are shown at the start, at 5 years, andat 10 years. All differences between curves are statistically significant (p
evidence of disease, with another 161 alive with recurrent
cancer, the comparable cause-specific survival is 88% at 10
disease. A total of 474 patients are known to have died.
years. The risk of prostate cancer death is highly correlated
Sixty-seven died of prostate cancer or after treatment for
with the initial risk group of the patient. As can be seen in
recurrent prostate cancer and 57 died with untreated recur-
patients in the low-risk group had a 10-year cause-
rent cancer, as evidenced by only a rising PSA. Addition-
specific survival of 97% contrasted with a cause-specific
ally, 333 died with no evidence of disease and 17 died of
survival of 77% for men with high-risk features (p
Overall actuarial survival at 10 years is 43%. As the vast
Cause-specific survival is shown in comparing the
majority of deaths were due to causes other than prostate
464 patients who received neoadjuvant hormonal therapy
Fig. 2. Cause-specific survival is shown comparing patients who did not receive hormones with patients who weretreated with neoadjuvant hormonal therapy. No significant difference is demonstrated for this endpoint (p
I. J. Radiation Oncology ● Biology ● Physics
Fig. 3. Overall survival is compared for the patients not receiving hormones and patients who were treated withhormonal manipulation. At 10 years, survival is significantly better (p
ϭ 0.02) for patients not receiving hormones(44%) vs. patients receiving neoadjuvant treatment (20%).
with the 1,884 men who received no hormone treatment. At
overall deaths and other cancers accounted for 10% and
10 years, there is no statistically significant difference in
16% of deaths in these two groups. Pulmonary deaths were
cause-specific survival, with 89% and 81% for the two
reported in 8% and 6%, respectively, while all other re-
groups, respectively (p
ϭ 0.13). This lack of benefit is seen
ported causes of death individually accounted for fewer than
in all three risk groups studied-favorable, intermediate, and
unfavorable as well (data not shown). However, the overallsurvival is noted to be different for these two patient groups.
The actuarial 10-year survival is 20% for the hormone-
treated cohort and 44% for the untreated group (p
ϭ 0.02)and is shown graphically in
Radical surgery, external beam irradiation, and brachy-
A stepwise multivariate analysis was performed for over-
therapy are all routinely offered to patients as definitive
all survival, looking at the independent risk factors thought
primary treatment for early-stage prostate cancer. Androgen
to most likely confound the outcomes, namely age, Gleason
deprivation hormone therapy has been extensively used in
score, baseline PSA, and hormone use. Not surprisingly, age
the palliative setting for advanced disease, and in selected
(Ͼ 70 years) and Gleason score (Ն 7) were most highly
early-stage patients who decline potentially curative treat-
correlated with survival. Hormone use was also found to be
ments. However, there has been growing interest in com-
independently significant. However, PSA was not found to
bining hormonal intervention along with definitive therapies
be an independent predictor of survival as shown in
It is not obvious why hormone-treated patients have this
Gleave et al.
have shown, in animal models, that
increased risk. Cardiovascular disease was the single largest
hormonal treatment given before definitive cancer therapy,
cause of death in both groups, with and without hormones,
(neoadjuvant therapy), is superior to hormone treatment
representing 24% and 22%, respectively, of the overall
after treatment (adjuvant therapy). This finding has been
mortality. Prostate cancer caused 17% and 14% of the
further examined in cancer patients. In both retrospectiveand randomized trials, neoadjuvant therapy before radicalprostatectomy, caused significant downstaging and reduced
Table 2. Multivariate analysis for survival
the risk of positive surgical margins However,there was no long-term benefit in cancer control rates. It has
been suggested that a longer duration of therapy might be of
benefit however, it is presently generally accepted
that neoadjuvant treatment has only limited value before
A number of well-controlled randomized trials assessing
the value of hormonal therapy and external beam irradiation
Impact of hormonal therapy on survival after brachytherapy ● D. C. BEYER et al.
have been reported over the past 2 decades by the Radiation
of these patients have risk factors not commonly found in
Oncology Therapy Group (RTOG). Early reports consis-
brachytherapy patients. More than 90% of the men in the
tently showed improved freedom from recurrence as mea-
EORTC report and subsequent updates had palpably
sured clinically or by PSA endpoints across
bulky cancers (Ն T3) and higher grade cancers. Patients in
many subgroups. More recently, and with longer follow-up,
RTOG 86 –10 had T3 cancers or PSAs ranging up to 560
improved overall survival has been shown in RTOG 86-10
ng/mL. These are clearly not the subset of patients usually
referred for brachytherapy, and are distinctly more ad-
Similar results were shown by Bolla et al.
vanced than patients in the present study. However, Bolla
randomized study of 415 patients treated for locally ad-
reports benefit to hormone use, even in those 10% who
vanced prostate cancer, hormone therapy instituted at the
were reported as the “low-risk category.” It should be noted,
time of external beam radiotherapy and continued for 3
however, that this low-risk group is not defined the same as
years, improved overall survival from 62% to 79% at 5
years. In an update with median follow-up of 66
In a meta-analysis pooling four major RTOG studies
months, they document benefit in patients treated with hor-
assessing the value of hormones, Roach et al.
mones for all endpoints studied: local failure (16% vs. 2%),
four risk groups and presented recommendations for the
disease-free survival 40% vs. 74%), and cause-specific sur-
incorporation of hormones in the treatment schema for
external beam. All of our prostate brachytherapy population
Neoadjuvant hormonal therapy has been used along with
is contained within Groups 1 and 2 from that report, for
prostate brachytherapy in an effort to shrink the prostate and
which benefit from hormone therapy was least convincing.
avoid pubic arch interference. There are several published
In fact, even Group 2 may represent a higher risk group of
studies confirming the value of hormones in this setting
patients, as many T3 and node positive patients could still
Others have used hormones with brachytherapy
be within this group. Subsequent publication of RTOG
with the hope that they might improve outcomes in a man-
94-13 suggests that only patients who receive neoadjuvant
ner analogous to patients receiving external beam irradia-
hormones plus whole pelvic radiotherapy truly benefit from
tion. Looking at biochemical control, Sylvester et al.
the additional treatment Thus, it is not entirely sur-
suggested some benefit to the use of hormones in a small
prising that our study fails to show any benefit on overall
series. However, with longer follow-up this conclusion
survival and cause-specific survival from the addition of
could not be supported A prospective multicenter
randomized trial using neoadjuvant hormones for interme-
That the use of hormones cut the overall 10-year survival
diate and unfavorable brachytherapy patients was attempted
in half was unexpected in the present study. Similar results
in the 1990s, but was closed owing to poor accrual
have not been previously published with LHRH agonists
Potters et al.
in a retrospective matched pair analysis,
and antiandrogens. A review of Group 1 alone in the RTOG
compared 132 patients who received neoadjuvant hormones
meta-analysis did suggest an adverse effect of hor-
and brachytherapy to 131 having brachytherapy alone. No
mones, though data on this group alone have never been
difference in PSA relapse-free survival was seen with a
published It remains entirely possible that some sys-
median follow-up of 42 months. In a multivariate analysis,
temic effect of these drugs had a detrimental effect on
Merrick et al.
suggest slight improvement in the PSA
overall survival. Such was the case in early studies of DES
endpoint only for the high-risk subgroup. In contrast, Stone
in prostate caner where despite a therapeutic benefit, overall
have found benefit from the use of neoadjuvant
survival was diminished owing to excess cardiovascular
hormones with brachytherapy. Routine biopsies performed
deaths Reviewing the reported cause of death for our
2 years after brachytherapy showed cancer in 14% of 181
patients, however, no single likely explanation can be iden-
patients who had no hormones compared with 3.5% of 115
tified for the excess deaths. The relative proportions for the
men treated with neoadjuvant hormones. Five-year freedom
most common causes appear to be roughly maintained.
from biochemical failure was 54% compared with 79% for
Accelerated deaths were also reported in patients receiv-
the two groups On multivariate analysis, they found
ing 150 mg bicalutamide compared with placebo in the
hormone treatment to be the single most important predic-
Early Prostate Cancer (EPC) trial program and on that
tor, when compared with dose, risk group, PSA, Gleason
basis this treatment is no longer recommended for low-risk
localized prostate cancer patients. This adverse effect was
The exact mechanism of action whereby hormones en-
not seen in patients with more advanced local disease. These
hance the effect of radiation is not entirely clear. Conse-
reports further support the hypothesis that patients suitable
quently, it is difficult to predict whether the same survival
for permanent brachytherapy do not have sufficiently ad-
benefit seen with external beam might be expected with
vanced disease to warrant the use of neoadjuvant hormones.
brachytherapy. And with only single-institution studies and
We conclude from these published studies that hormonal
no prospective research, it is not unexpected that the brachy-
therapy improves survival in patients who are most at risk of
dying of prostate cancer: men with undifferentiated tumors
In conjunction with external beam, survival benefits have
(i.e., Gleason 8 –10) or large volume disease (i.e., T3, N
been primarily seen in men with higher risk features. Many
or high PSA). In the majority of patients with early prostate
I. J. Radiation Oncology ● Biology ● Physics
cancer, the natural history of the disease suggests a rela-
formed to properly evaluate the value or risk of neoadjuvant
tively lower risk of dying. For these patients, the risks of
hormonal intervention in the brachytherapy population. In
hormonal intervention may be greater than the small benefit
the absence of specific data supporting the addition of
hormones to brachytherapy, we urge caution in applying
By the very study design, the present data are subject to
these combination therapies to patient populations for
the limitations inherent with all single-institution retrospec-
whom no benefit has been documented. Other than for
tive studies. Hormones were administered over a 13-year
reduction of the prostate size, there is still no clearly defined
period for a variety of uncontrolled reasons. Patients were
advantage to combining hormones with any brachytherapy
treated for gland size reduction, for downstaging, and in
some cases to allow patients to delay definitive treatment.
Additionally, it is clear from the data that hormones were
more commonly administered to unfavorable patients who
Long-term cause-specific and overall survival rates for
were also more likely to receive combination therapy with
prostate brachytherapy are 88% and 43%, respectively, at
external beam irradiation. This suggests a physician bias to
10 years. Cause-specific survival can be estimated from the
offer hormonal intervention with the hope that the benefits
risk group, using the stage grade and PSA. Favorable,
seen in the external beam literature would also accrue to
intermediate, and unfavorable patients have cause-specific
these brachytherapy patients. We are unable to control for
survivals of 97%, 83%, and 77%, respectively. The use of
these and other factors, and that may affect our endpoints. It
neoadjuvant hormonal therapy for up to 6 months provides
is entirely possible that significant selection bias existed in
no benefit in cause-specific survival and adversely affected
other undefined ways as well. As a result, all such retro-
the overall survival, with a reduction from 44% to 20%.
spective studies require confirmation from other centers
This finding remains strongly significant on multivariate
with access to similar long-term survival data before any
analysis. Confirmation is required from other series, and a
changes can be recommended in the routine management of
prospective evaluation of hormones in the brachytherapy
this patient population. Prospective studies should be per-
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e-mémoires de l'Académie Nationale de Chirurgie, 2010, 9 (2) : 110-112 Troubles sexuels et urinaires : plus qu'une association d'idées Lower Urinary Tract Symptoms and sexual disorders R.O.Fourcade Service d'Urologie, Centre Hospitalier 89000 Auxerre Mots clés Résumé L'exploration et l'évaluation des troubles urinaires du bas appareil (TUBAs) sont l'une des tâches
Salman Elawad Biology Instructor CVCC Sickle Cell Anemia: A Neglected Disease Outlines Introduction Definition History Inheritance Symptoms Diagnosis and Treatment Prevention Self-care Coping Skills Conclusion Literature Cited Introduction Sickle cell anemia is an inherited blood disorder caused by a defect in the gene that codes for beta hemoglobin. The de