D'Amico AV, Manola J, Loffredo M, Renshaw AA, DellaCroce A, Kantoff PW. 6-Month Androgen Suppression Plus Radiation Therapy vs Radiation Therapy Alone for Patients With Clinically Localized Prostate CancerA Randomized Controlled Trial. JAMA. 2004;292(7):821–827. doi:10.1001/jama.292.7.821
Context Survival benefit in the management of high-grade clinically localized
prostate cancer has been shown for 70 Gy radiation therapy combined with 3
years of androgen suppression therapy (AST), but long-term AST is associated
with many adverse events.
Objective To assess the survival benefit of 3-dimensional conformal radiation
therapy (3D-CRT) alone or in combination with 6 months of AST in patients
with clinically localized prostate cancer.
Design, Setting, and Patients A prospective randomized controlled trial of 206 patients with clinically
localized prostate cancer who were randomized to receive 70 Gy 3D-CRT alone
(n = 104) or in combination with 6 months of AST (n = 102) from December 1,
1995, to April 15, 2001. Eligible patients included those with a prostate-specific
antigen (PSA) of at least 10 ng/mL, a Gleason score of at least 7, or radiographic
evidence of extraprostatic disease.
Main Outcome Measures Time to PSA failure (PSA >1.0 ng/mL and increasing >0.2 ng/mL on 2 consecutive
visits) and overall survival.
Results After a median follow-up of 4.52 years, patients randomized to receive
3D-CRT plus AST had a significantly higher survival (P =
.04), lower prostate cancer–specific mortality (P = .02), and higher survival free of salvage AST (P = .002). Kaplan-Meier estimates of 5-year survival rates were 88%
(95% confidence interval [CI], 80%-95%) in the 3D-CRT plus AST group vs 78%
(95% CI, 68%-88%) in the 3D-CRT group. Rates of survival free of salvage AST
at 5 years were 82% (95% CI, 73%-90%) in the 3D-CRT plus AST group vs 57%
(95% CI, 46%-69%) in the 3D-CRT group.
Conclusion The addition of 6 months of AST to 70 Gy 3D-CRT confers an overall survival
benefit for patients with clinically localized prostate cancer.
Prostate cancer–specific mortality (PCSM) following external beam
radiation therapy (RT) for patients with clinically localized prostate cancer
has been shown to be associated with the Gleason score, serum prostate-specific
antigen (PSA) level, and 1992 American Joint Commission on Cancer clinical
tumor category at diagnosis.1,2 Low-risk
patients who have a PSA of 10 ng/mL or less, a Gleason score of 6 or less,
and clinical category T1c or T2a disease have been reported to have PCSM estimates
of less than 2% a decade following RT, whereas these estimates range from
12% to 30% for patients with higher PSA levels or Gleason scores at diagnosis.
Attempts at decreasing PCSM have included RT dose escalation3 or the addition of androgen suppression therapy (AST)
to 70 Gy RT. Although a single randomized trial3 has
shown a decrease in PSA progression for patients receiving RT dose escalation,
survival data are not yet available. Given that PSA progression does not translate
into PCSM for the vast majority of patients,4 70
Gy RT remains the standard of practice. Combining 3 years of AST with 70 Gy
RT has been shown to improve survival for patients with locally advanced prostate
cancer.5 However, the toxicity of long-term
AST can be significant, particularly in elderly patients.6
This prospective randomized controlled trial was performed to determine
whether a survival benefit exists when adding 6 months of AST to 70 Gy 3-dimensional
conformal RT (3D-CRT) in patients with clinically localized prostate cancer.
Between December 1, 1995, and April 15, 2001, 206 patients from the
Harvard outreach (Saint Anne's Hospital, Fall River, Mass; Metro West Medical
Center, Framingham, Mass; Suburban Oncology Center, Quincy, Mass) and central
hospitals (Dana-Farber Cancer Institute, Brigham and Women's Hospital, and
Beth Israel Deaconess Medical Center) with 1992 American Joint Commission
on Cancer7 category T1b to T2b, NX, M0 centrally
reviewed adenocarcinoma of the prostate8 were
randomized to receive 70 Gy 3D-CRT alone or in combination with 2 months each
of neoadjuvant, concurrent, and adjuvant AST. Eligible patients included those
patients with a PSA of at least 10 ng/mL (maximum, 40 ng/mL) or a Gleason
score of at least 7 (range, 5-10). Low-risk patients were ineligible unless
they had radiographic evidence using endorectal coil magnetic resonance imaging
(MRI) of extracapsular extension or seminal vesicle invasion. Patients were
also considered ineligible if they had a prior history of malignancy except
for nonmelanoma skin cancer or any history of hormone therapy use.
All patients were required to have a negative bone scan and pelvic lymph
node assessment using MRI or computed tomography (CT) within 6 months of randomization.
Eligible patients also needed to have an Eastern Cooperative Oncology Group
performance status of 0 or 1 (range, 0-4), white blood cell count of at least
3000/µL, hematocrit of more than 30%, platelet count of more than 100
× 103/µL, and a life expectancy of at least 10 years,
excluding death related to prostate cancer at study entry. All patients provided
written informed consent; the study was approved by the institutional review
boards at the Dana-Farber/Harvard Cancer Center, Saint Anne's Hospital, and
the Metro West Medical Center.
Randomization was centralized at the Quality Assurance Center of the
Dana-Farber/Harvard Cancer Center. A permuted blocks randomization algorithm
was used with a block size of 4. Patients were assigned to the treatment groups
with equal probability. Prior to randomization, patients were stratified based
on the baseline PSA level and centrally reviewed biopsy Gleason score8 as follows: group 1, PSA of 20 to 40 ng/mL; group
2, biopsy Gleason score of at least 7; group 3, PSA of 10 to 20 ng/mL and
a biopsy Gleason score of 6 or less; and group 4, low risk and extracapsular
extension or seminal vesicle invasion on endorectal coil MRI.
Radiation Therapy. Photons of 10 MV or more
were used. Patients were treated once daily and 5 days per week. The daily
dose was 1.8 Gy for the initial 25 treatments, totaling 45 Gy, and 2.0 Gy
for the final 11 treatments, totaling 22 Gy. Therefore, patients received
a total dose of 70.35 Gy (67 Gy normalized to 95%) to the prostate plus a
1.5-cm margin using a 4-field 3D-CRT technique, which involved CT-based treatment
planning and shaped conformal cerrobend blocks or a multileaf collimator.
The prostate and the seminal vesicles were included in the initial radiation
field using a 1.5-cm margin. Patients were simulated (radiation field mapped)
before the start of neoadjuvant hormone therapy.
Hormone Therapy. AST consisted of a combination
of a luteinizing hormone–releasing hormone (LHRH) agonist (leuprolide
acetate) or goserelin and a nonsteroidal anti-androgen (flutamide). Leuprolide
acetate (n = 88) was delivered intramuscularly each month at a dose of 7.5
mg or 22.5 mg every 3 months. Goserelin (n = 10) was administered subcutaneously
each month at a dose of 3.6 mg or 10.8 mg every 3 months. Both LHRH agonists
were permitted because they have been shown to have equivalent efficacy in
the treatment of prostate cancer.9 Flutamide
(n = 98) was taken orally at a dose of 250 mg every 8 hours and starting 1
to 3 days before the LHRH agonist to block the transient increase in testosterone
caused by the LHRH agonist. Treating physicians and patients were not blinded
to treatment groups because the institutional review boards did not believe
sham injections were justified.
At baseline and following the administration of the AST, a complete
blood cell count and liver function tests, including aspartate aminotransferase,
alanine aminotransferase, and total bilirubin, were obtained every 2 weeks
during the first month of AST and then monthly until the 6-month course of
AST was complete. Flutamide was discontinued if either aspartate aminotransferase
or alanine aminotransferase exceeded 2 times the upper limit of normal or
the patient developed drug-induced diarrhea or anemia causing clinical symptoms.
The treating physician assessed potency at randomization.
At each follow-up visit, a PSA level was obtained before performing
the digital rectal examination. Follow-up visits were performed at the end
of radiation treatment every 3 months for 2 years, every 6 months for an additional
3 years, and then annually thereafter. Genitourinary, gastrointestinal, dermatologic,
and endocrinologic toxicities were assessed at each follow-up visit using
common toxicity criteria.10
Patients were restaged with a bone scan and CT scan of the pelvis before
the initiation of salvage AST and after PSA failure, defined as a PSA of more
than 1.0 ng/mL and increasing by more than 0.2 ng/mL on 2 consecutive measurements.
Salvage AST was started in both treatment groups following PSA failure, at
a PSA level of approximately 10 ng/mL. Salvage therapy included an LHRH agonist
dosed identically to initial therapy or a bilateral orchiectomy, which have
been shown to be of equal efficacy.9
All patients were followed up directly by the site investigators (A.V.D.
and P.W.K.) until death or until January 15, 2004, whichever came first. Patients
who died with hormone refractory metastatic disease and an increasing PSA
at the time of death were considered to have died from prostate cancer.
Before the start of RT, the principal investigator (A.V.D.) reviewed
and modified as necessary the radiation prescription, simulation, and portal
films. Patients who were randomized to receive 3D-CRT plus AST were required
to keep a daily diary of flutamide usage, which was submitted monthly. The
delivery of the LHRH agonist was recorded in the medical record and checked
by the nurse protocol manager (M.L.).
The study was designed to detect a difference in freedom from biochemical
progression between the 2 treatment groups, and assumed a true median time
to failure of 2.7 years among patients treated with 3D-CRT and 4.8 years among
patients treated with 3D-CRT plus AST, using a 2-sided log rank test with
80% power and type I error of 5%. Full power was projected to occur after
2.7 years of accrual at 100 patients per year and an additional 2 years of
follow-up. An interim analysis for monitoring the primary end point was planned
for 3 years following the end of accrual, using standard O'Brien-Fleming group
sequential boundaries. Before the interim analysis, a publication5 showed a much higher than expected (ie, 2-fold) reduction
in death when AST was added to RT in patients with locally advanced prostate
cancer. Therefore, follow-up was extended to allow assessment of the survival
end point. Three months before the first planned analysis, the study statistician
(J.M.) recommended an early analysis based on the number of deaths.
Descriptive statistics were used to characterize patients at study entry.
The Wilcoxon rank sum test for ordered categorical data11 was
used to test for differences in toxicity rates of selected toxicities and
the overall worst degree toxicity between treatment groups. The methods of
Kaplan and Meier12 and cumulative incidence13 were used to estimate and characterize survival and
mortality respectively over time. Overall survival was measured from the date
of randomization to the date of death or the date of last follow-up. Progression
was defined on the date of institution of salvage AST. The log-rank test14 was used to test for differences in survival between
patients treated with 3D-CRT compared with 3D-CRT plus AST. Hazard ratios
(HRs) and associated 95% confidence intervals (CIs) for death, death without
progression, and PSA failure for patients receiving 3D-CRT compared with 3D-CRT
plus AST were calculated before and after adjusting for the clinical tumor
category, using a Cox proportional hazards regression model multivariable
analysis.15 Data were analyzed according to
the intention-to-treat principle. SAS version 8.2 (SAS Institute, Cary, NC)
was used for all statistical analyses. P<.05 was
considered statistically significant.
From December 1, 1995, to April 15, 2001, 206 patients were randomized
to the study (n = 104 in the 3D-CRT group and n = 102 in the 3D-CRT plus AST
group) (Figure 1). The median duration
of follow-up was 4.52 years. As of January 15, 2004, all but 5 patients had
been evaluated. For the survival analyses, these 5 patients were considered
eligible. Four patients (1 in the 3D-CRT group and 3 in the 3D-CRT plus AST
group) withdrew consent after randomization. After randomization, 1 patient
in the 3D-CRT plus AST group was found to have clinical category T2c disease,
which was considered locally advanced disease; therefore, that patient was
considered ineligible. However, all patients regardless of eligibility were
included in the survival analysis. Excluding these patients from the survival
analyses did not affect the results. The 2 groups of patients were well balanced
with regard to age, Eastern Cooperative Oncology Group performance status,
Gleason score, percentage of positive prostate biopsies, prostate gland volume,
and baseline PSA level, as shown in Table
Information on treatment was available in 201 patients (n = 103 in the
3D-CRT group and n = 98 in the 3D-CRT plus AST group). The patients in the
3D-CRT group received 3D-CRT delivered per protocol guidelines. All patients
in the 3D-CRT plus AST group completed 6 months of the LHRH agonist but 27
(28%) did not complete the 6-month course of flutamide because of adverse
events: 23 patients (85%) had a liver function test result that was more than
twice the upper limit of normal, 1 patient (4%) had diarrhea, 1 patient (4%)
had anemia, and 2 (7%) patients requested to stop the drug (Figure 1).
Table 2 enumerates the genitourinary,
gastrointestinal, dermatologic, and endocrinologic toxicity stratified by
grade and treatment group. Patients receiving 3D-CRT plus AST therapy had
a significant increase in grade 1 and 2 gynecomastia (18 vs 3, P = .002) and, among men potent at baseline, grade 3 impotence increased
significantly (26 vs 21, P = .02). No other significant
differences in late toxicity were noted and the results remained unchanged
when estimates were performed by using an actuarial method.12
Estimates of overall survival were significantly higher for patients
who were treated using 3D-CRT plus AST therapy compared with patients receiving
only 3D-CRT (P = .04), with Kaplan-Meier method estimates
of 5-year survival of 88% (95% CI, 80%-95%) vs 78% (95% CI, 68%-88%), respectively
(Figure 2). For patients receiving
3D-CRT (n = 103), 6 deaths were due to prostate cancer and 17 were from other
causes (5 from second cancers, 9 from cardiovascular disease, 1 from sepsis,
and 2 from Alzheimer or liver disease), whereas, for patients who received
3D-CRT plus AST therapy (n = 98), no deaths occurred due to prostate cancer
and 12 were from other causes (3 from second cancers, 8 from cardiovascular
disease, and 1 from sepsis).
As shown in Figure 3, estimates
of the cumulative incidence of PCSM significantly favored the 3D-CRT plus
AST therapy (P = .02), whereas estimates of the cumulative
incidence of non-PCSM did not differ (P = .31). The
unadjusted and adjusted HRs for death were 2.07 (95% CI, 1.02-4.20; P = .04) and 2.04 (95% CI, 1.01-4.20; P = .05) for patients randomized to receive 3D-CRT compared with 3D-CRT
plus AST (Table 3).
Median (interquartile range) time to initiation of salvage therapy following
PSA failure was 8 months (3-13 months) in the 3D-CRT group vs 7 months (3-13
months) in the 3D-CRT plus AST group (P = .57). At
the initiation of salvage AST, patients randomized to receive 3D-CRT or 3D-CRT
plus AST therapy had a negative bone scan and a median PSA level of 9.6 ng/mL.
Survival without salvage AST was significantly higher for patients who were
randomized to the 3D-CRT plus AST group vs 3D-CRT group (P = .002). At 5 years, 82% of patients (95% CI, 73%-90%) in the 3D-CRT
plus AST group vs 57% of patients (95% CI, 46%-69%) in the 3D-CRT group had
not received salvage AST (Figure 4).
Forty-three patients had disease progression in the 3D-CRT group compared
with 21 patients in the 3D-CRT plus AST group. The unadjusted and adjusted
HRs for survival without salvage AST were 2.30 (95% CI, 1.36-3.89; P = .002) and 2.17 (95% CI, 1.28-3.69; P =
.004) for patients in the 3D-CRT group compared with the 3D-CRT plus AST group
An overall survival benefit has been observed following 70 Gy RT plus
3 years of AST when compared with 70 Gy RT for patients with locally advanced
and high-grade clinically localized prostate cancer.5 This
study found a similar 2-fold reduction in death before and after adjusting
for clinical tumor category for patients with clinically localized disease
and a PSA of at least 10 ng/mL or a Gleason score of at least 7 who were randomized
to 70 Gy 3D-CRT plus 6 months of AST compared with 70 Gy 3D-CRT.
Given that many men treated for prostate cancer are often older and
that AST use of more than 1 year has been shown to cause osteopenia,16 impairment of memory, attention and executive functions,17 and prolongation of the QT interval,18 in
addition to anemia,6 muscle loss in exchange
for body fat,19 hot flashes,6 and
impotence,6 minimizing these effects by decreasing
AST duration could profoundly impact a patient's quality of life. Therefore,
the clinically significant implication of our study is that a 6-month course
of AST in patients receiving RT who have clinically localized prostate cancer
may be sufficient to reduce the risk of death.
Several questions remain to be answered. First, the dose of radiation
used is the current standard (ie, 70 Gy) and the pelvic lymph nodes were not
treated. Whether a further increase in survival would have been observed if
the pelvic lymph nodes were treated20 remains
to be answered by further follow-up of a completed study. In addition, to
determine whether an RT dose of more than 70 Gy could improve survival over
that measured in our study using 70 Gy and 6 months of AST would require a
new randomized study. Second, patients received salvage AST when the bone
scan was negative. Whether delaying initiation of salvage AST until the bone
scan was positive would have further increased the survival benefit remains
unanswered. Third, the question of whether complete (LHRH agonist and nonsteroidal
anti-androgen) compared with partial androgen blockade (LHRH agonist) is necessary
to achieve the survival benefit noted in our study remains. Fourth, our study
did not have a control group of AST alone; however, the Canadian Urologic
Oncology Group has an ongoing study of AST with or without RT for patients
with locally advanced prostate cancer that will address whether RT adds to
overall survival when patients are androgen-suppressed.
Finally, whether long-term AST compared with short-term AST can provide
an additional survival benefit for patients with locally advanced or high-grade
clinically localized prostate cancer requires further study and is the subject
of a recently completed but not yet reported European randomized study in
which a 3-year and a 6-month duration of AST were compared. In addition, the
Radiation Therapy Oncology Group has completed and reported a randomized study21 of men with locally advanced prostate cancer in which
all patients received 70 Gy RT and were randomized to either 2 years and 4
months or 4 months of AST. Although a significant benefit of 3.4% in the 5-year
estimates of PCSM was observed for patients who received long-term AST and
RT, overall survival was not affected, likely the result of the competing
causes of mortality in their study population.
In conclusion, the addition of 6 months of AST to 70 Gy 3D-CRT confers
an overall survival benefit for patients with clinically localized prostate