GyE indicates gray equivalents (see “Methods”); 3-D, 3-dimensional.*Patient underwent radical prostatectomy rather than radiation therapy because
the bowel was too close to the prostate for safe administration of radiation.†No follow-up data available for analysis.
A, Analysis of outcome using American Society for Therapeutic Radiology
and Oncology criteria, in which biochemical failure occurs on the third increase
but is backdated to a point midway between the last nonincreasing value and
the first increase. B, Same analysis as in A, but without backdating. GyE
indicates gray equivalents (see “Methods” section); PSA, prostate-specific
antigen. Error bars indicate 95% confidence intervals.
Analysis of these early cases is by risk subgroup. Low-risk patients
have prostate-specific antigen level <10 ng/mL, stage ≤T2a tumors, and
Gleason scores ≤6. ASTRO indicates American Society for Therapeutic Radiology
and Oncology; GyE, gray equivalents (see “Methods” section).
Zietman AL, DeSilvio ML, Slater JD, Rossi CJ, Miller DW, Adams JA, Shipley WU. Comparison of Conventional-Dose vs High-Dose Conformal Radiation Therapy
in Clinically Localized Adenocarcinoma of the ProstateA Randomized Controlled Trial. JAMA. 2005;294(10):1233-1239. doi:10.1001/jama.294.10.1233
Author Affiliations: Department of Radiation
Oncology, Massachusetts General Hospital, Harvard Medical School, Boston (Drs
Zietman and Shipley and Ms Adams); Loma Linda University Medical Center, Loma
Linda, Calif (Drs Slater, Rossi, and Miller); and American College of Radiology
and Radiation Therapy Oncology Group, Philadelphia, Pa (Dr DeSilvio).
Context Clinically localized prostate cancer is very prevalent among US men,
but recurrence after treatment with conventional radiation therapy is common.
Objective To evaluate the hypothesis that increasing the radiation dose delivered
to men with clinically localized prostate cancer improves disease outcome.
Design, Setting, and Patients Randomized controlled trial of 393 patients with stage T1b through T2b
prostate cancer and prostate-specific antigen (PSA) levels less than 15 ng/mL
randomized between January 1996 and December 1999 and treated at 2 US academic
institutions. Median age was 67 years and median PSA level was 6.3 ng/mL.
Median follow-up was 5.5 (range, 1.2-8.2) years.
Intervention Patients were randomized to receive external beam radiation to a total
dose of either 70.2 Gy (conventional dose) or 79.2 Gy (high dose). This was
delivered using a combination of conformal photon and proton beams.
Main Outcome Measure Increasing PSA level (ie, biochemical failure) 5 years after treatment.
Results The proportions of men free from biochemical failure at 5 years were
61.4% (95% confidence interval, 54.6%-68.3%) for conventional-dose and 80.4%
(95% confidence interval, 74.7%-86.1%) for high-dose therapy (P<.001), a 49% reduction in the risk of failure. The advantage to
high-dose therapy was observed in both the low-risk and the higher-risk subgroups
(risk reduction, 51% [P<.001] and 44% [P = .03], respectively). There has been no significant difference
in overall survival rates between the treatment groups. Only 1% of patients
receiving conventional-dose and 2% receiving high-dose radiation experienced
acute urinary or rectal morbidity of Radiation Therapy Oncology Group (RTOG)
grade 3 or greater. So far, only 2% and 1%, respectively, have experienced
late morbidity of RTOG grade 3 or greater.
Conclusions Men with clinically localized prostate cancer have a lower risk of biochemical
failure if they receive high-dose rather than conventional-dose conformal
radiation. This advantage was achieved without any associated increase in
RTOG grade 3 acute or late urinary or rectal morbidity.
The majority of cases of prostate cancer now diagnosed in the United
States are detected while the disease is still clinically localized. External
beam radiation is one of the options used to treat more than 26 000 US
men annually.1 There is concern that conventional-dose
radiation therapy does not eradicate prostate cancer in a significant proportion
of cases, with a resultant increase in prostate-specific antigen (PSA) levels,
secondary treatment, and, ultimately, clinical recurrence.2,3
Increasing the delivered radiation dose may increase the probability
of local tumor control but carries a risk of greater adverse effects unless
the volume of normal tissue treated along with the tumor can be reduced. In
the 1990s a number of computed tomography–based techniques became available
to deliver radiation more accurately and thus allow the delivery of higher
doses. These techniques are together known as “3-dimensional conformal
therapy” and include the use of conformal photon beams, intensity-modulated
photon beams, and proton beams. Conformal photon-beam therapy has been the
standard external radiation therapy, although the more technically challenging
intensity-modulated radiation is becoming more widely used. Proton radiation
uses a beam with unique physical properties that allow its shape to be sculpted
in tissue to avoid normal structures. It is available in a small but increasing
number of US centers.
Several phase 2 studies have suggested an improvement in control of
prostate tumors using conformal approaches to escalate the delivered radiation
dose,4- 6 but all
are biased by the use of historical controls.7 Two
randomized trials of radiation dose have been reported, although both focused
on more advanced disease. In the first, a local control advantage was seen
for men with high-grade tumors.8 In the second,
a tumor control advantage was seen in men with intermediate-risk prostate
cancer.9 The latter trial contained only a
minority of patients with low-risk disease and was not powered to determine
the efficacy of dose escalation in this group, which now constitutes, by far,
the most common presentation in the United States.1
We hypothesized that tumor control could be improved in contemporary
patients with prostate cancer, including those with low-risk disease, by the
use of higher radiation doses and tested this in a randomized controlled trial.
In one group the prostate received a conventional dose of 70.2 Gy; in the
other, dose was increased to 79.2 Gy.
This randomized controlled trial was designed to compare 2 different
radiation doses delivered by conformal techniques. All patients received conformal
photon (x-ray) therapy to a fixed dose of 50.4 Gy. The difference between
groups was in the boost dose, which was delivered using proton-beam therapy
(Figure 1). The unique physical characteristics
of this beam allow the treatment of tumors with considerable sparing of normal
tissues.10 The boost dose was either 19.8 Gy
or 28.8 Gy, for total doses of either 70.2 Gy (conventional dose) or 79.2
Gy (high dose). All patients received their radiation without the administration
of any neoadjuvant, concurrent, or adjuvant hormonal therapy.
Patients were enrolled at 2 centers: Loma Linda University Medical Center,
Loma Linda, Calif, and the Massachusetts General Hospital, Boston. Eligible
patients with clinically localized adenocarcinoma of the prostate, as defined
by criteria available in 1995, were offered entry into this trial. These were
men with stage T1b through T2b tumors (using 1992 American Joint Committee
on Cancer criteria), serum PSA levels less than 15 ng/mL, and no evidence
of metastatic disease as assessed by both whole-body bone scan (with PSA level >10
ng/mL, tumor stage T2b, or Gleason score ≥7) and abdominopelvic computed
tomography scan. There was no exclusion from entry on the basis of tumor histology
(ie, Gleason score).
All participants provided written informed consent, and the institutional
review board at both participating institutions and at the American College
of Radiology approved the study protocol. Race/ethnicity data were obtained
using investigator-defined classifications, as is required for all studies
funded by the National Cancer Institute.
Three hundred ninety-three patients were randomized centrally by the
American College of Radiology statistical office on protocol 95-09 of the
Proton Radiation Oncology Group between January 1996 and December 1999. Stratification
was performed at randomization to ensure balanced groups. Patients were stratified
for serum PSA levels less than 4 ng/mL and from 4 to 15 ng/mL and for nodal
status NX or N0. In total, only 2 patients underwent a formal node sampling.
Conformal radiation therapy was given in 2 phases. Phase 1 used conformal
proton beams to treat the prostate alone. The applied proton-beam dose was
corrected to a photon equivalent using a radiobiological effectiveness ratio
of 1.1. Dose is thus expressed not as gray (Gy) but as gray equivalents (GyE).
Either 19.8 GyE or 28.8 GyE was given, depending on randomization, in either
11 or 16 fractions (1.8-GyE fractions). The clinical target volume was the
prostate, with a 5-mm margin. An additional 7 to 10 mm was added for a planning
target volume, according to the technical requirements of the treating machines
at the 2 participating institutions. Thus, the planning target volume varies
in order to deliver identical treatment. Planning was performed using 3-dimensional
computed tomography–based techniques. Patient position and beam arrangement
differed according to the experience of the participating institutions. At
Loma Linda University Medical Center, patients were treated in the supine
position using opposed lateral 250-mV proton beams. At the Massachusetts General
Hospital, patients were treated in the lithotomy position using a single 160-mV
proton beam directed through the perineum.
In phase 2, all men, regardless of trial group, were planned to receive
50.4 Gy delivered with photons in 1.8-Gy fractions to the prostate and seminal
vesicles. Patients were treated in the supine position, and radiation was
delivered using high-energy (10-23 mV) beams. A combination of 4 beams (anterior,
posterior, and right and left lateral) was used. The clinical target volume
included the prostate and seminal vesicles, with a margin of 10 mm for potential
microscopic infiltration by tumor.
The total treatment time when both phases were combined was 8 weeks
in the conventional-dose group and 9 weeks in the high-dose group.
Patients were immobilized for daily treatment using casts of thermal-setting
plastic or body foam. During treatments, a balloon around a Lucite probe was
inserted 12 to 15 cm into the rectum and inflated with 25 to 50 mL of saline
along its length, as described previously.8,11 This
procedure immobilized the prostate and displaced the posterior rectal wall
out from the path of the beam. Setup error was minimized by obtaining daily
portal images throughout the first phase of treatment, imaging the bones and
also the metal markers within the Lucite probe that lay against the anterior
rectal wall. Portal images were obtained weekly during the second phase.
All patients were scheduled to be seen every 3 months for the first
year, every 6 months for the next 4 years, and annually after that. Median
follow-up for all patients was 5.5 years (range, 1.2-8.2 years). A median
of 9 PSA values were available per patient, and the median time between follow-up
visits was the same for each group (7 months).
Biochemical Failure. This was defined using
the American Society for Therapeutic Radiology and Oncology (ASTRO) criteria
of 3 successive increases in PSA level, with the failure backdated to a point
halfway between the first increase and the last nonincreasing value.12 Because of concerns that backdating may influence
the timing and degree of failure, a second analysis was performed in which
no backdating was used.13
Local Control. Ultrasound-guided sextant prostate
rebiopsy was recommended for men whose postradiation PSA level either did
not decrease to 1 ng/mL by 2 years or subsequently increased above that level.
A positive biopsy result was taken as evidence of locally persistent or recurrent
disease. It was, however, recognized that it is difficult to encourage elderly
men to undergo prostate rebiopsy and that a surrogate for local control would
be required. Evidence, reviewed by the ASTRO Consensus Committee on prostate
rebiopsy, showed that less than 6% of men with PSA levels less than 1 ng/mL
have a positive rebiopsy result.14,15 This
was therefore taken as surrogate evidence of local control in our trial. All
other PSA patterns, in the absence of demonstrable metastatic disease, were
judged to be consistent with local failure or persistence of disease unless
rebiopsy was performed and showed otherwise.
Morbidity. Acute and late genitourinary (GU)
and gastrointestinal (GI) morbidity were scored using the Radiation Therapy
Oncology Group (RTOG) criteria.16 This is a
0 to 5 scale in which lower scores equate with fewer symptoms.
The sample size estimate was calculated to have at least 80% statistical
power to detect a 40% to 20% reduction in the 5-year probability of local
failure. A 4.5% annual rate of dying without a local failure, 4 years of uniformed
accrual, and a 2-sided .05-level log-rank test were assumed and used in the
calculation. A sample size of 390 cases provides 80% statistical power to
detect a 50% to 30% reduction in the 5-year probability of failure. Actuarial
estimates for survival were calculated using Kaplan-Meier methods, and the
cumulative incidence method was used to estimate rates of local and biochemical
failure.17 The log-rank test was used to find
treatment differences in the overall survival distributions, and the Gray
test was used to find differences between the treatment groups for rates of
local and biochemical failure over time.18,19 Time-to-event
methods for right-censored data were used for the primary and secondary analyses.
All available information was used in the analysis; analysis was on an intent-to-treat
basis. Statistical analyses were performed using SAS version 9.1 (SAS Institute
Inc, Cary, NC).
The subgroup analyses performed by risk group were not based on tests
of interaction but on published reports of important risk groups and were
post hoc analyses. The study was not specifically powered to find differences
in the subgroup or overall survival analyses.
Table 1 shows the distribution
of patients across the 2 study groups by pretreatment prognostic factors (Table 1). It is notable that although patients
were stratified by risk parameters available in 1995, they are also balanced
for a more contemporary risk stratification.20
Of 393 patients, 1 refused to participate after randomization and was
lost to follow-up, leaving 392 eligible and available for analysis (Figure 1). Of the 197 patients randomized to
receive 70.2 GyE, 181 (91.9%) received this dose; 7 (3.6%) received lower
and 8 (4.1%) received higher doses. One patient underwent radical prostatectomy
rather than radiation therapy because the bowel was too close to the prostate
for safe administration of radiation. Of the 195 assigned to receive 79.2
GyE, 172 (88.2%) received this dose; 5 (2.6%) received higher and 18 (9.2%)
received lower doses. Of these, only 2 received lower doses because of documented
toxicity. Four received lower doses because of the development of new medical
issues; others did so for a mixture of anxiety, refusal to accept randomization
to the higher dose, and convenience.
In the conventional-dose group, 81.0% had a PSA nadir below 1.0 ng/mL,
and 44.7% had a nadir below 0.5 ng/mL. In the high-dose group those proportions
were 86.6% and 59.8%, respectively. The difference between the proportions
with a PSA nadir below 0.5 ng/mL was significant (P = .003).
Median time to nadir was 28.0 months after conventional-dose and 39.6 months
after high-dose therapy.
The 5-year freedom from biochemical failure was 61.4% (95% confidence
interval [CI], 54.6%-68.3%) for conventional-dose and 80.4% (95% CI, 74.7%-86.1%)
for high-dose therapy (P<.001) (Figure 2). This represents a 49% reduction in the risk of failure
at 5 years. This advantage for high-dose therapy was seen when those with
low-risk disease (PSA level <10 ng/mL, stage ≤T2a tumors, or Gleason
score ≤6; n = 227 [58% of total]) were examined alone (60.1%
in the conventional-dose group and 80.5% in the high-dose group; 51% risk
reduction; P<.001) (Figure 3). It was also significant for the higher-risk patients
(63.4% vs 79.5%; 44% risk reduction; P = .03).
When the higher-risk patients were broken out into contemporary intermediate-
and high-risk subgroups,20 the significant
difference persisted for the intermediate-risk subgroup (62.7 vs 81%, P = .02) but was lost in the small number (n = 33)
of high-risk patients (P = .80).
The backdating used in the ASTRO definition of biochemical failure may
affect the timing and rate of failure,13 so
we performed an analysis without it. The differences between the groups persisted
and remained significant (Figure 2).
At 5 years it was 66.2% vs 86.4% for conventional-dose and high-dose therapy,
respectively (P<.001). Significant differences
also persisted when men were divided into low-risk (60.6% vs 85.3%, P<.001) and intermediate-risk (71.5% vs 89.4%, P = .008) subgroups, although again there was
no difference seen in the very small number of men with high-risk disease.
Because the 2 involved institutions used different techniques for delivering
the proton boost dose, a multivariate Cox model was used to look for any interaction
between assigned dose, biochemical outcome, and institution. There was no
interaction between these factors (P = .40).
In the conventional-dose group, 13 patients have so far received secondary
treatment with androgen deprivation therapy, compared with only 7 in the high-dose
group. Treatment was started at the discretion of the oncologist or urologist,
usually for an increasing PSA level.
The actuarial estimate of local control at 5 years was 47.6% (95% CI,
40.4%-54.8%) in the conventional-dose group compared with 67.2% (95% CI, 60.4%-74.0%)
in the high-dose group (P<.001). Of those recorded
as having local failure or persistence of disease, this was clinically evident
or biopsy-confirmed in 24%. In the remainder, the biochemical surrogate alone
At this time, there is no difference in the overall survival rates between
the treatment groups (97% vs 96%, P = .80).
There were 10 deaths in the conventional-dose group (2 related to prostate
cancer) and 8 in the high-dose group (none related to prostate cancer).
Table 2 shows morbidity associated
with treatment and randomization group. Only 1% of patients receiving conventional-dose
and 2% receiving high-dose radiation experienced acute GU or GI (rectal) morbidity
of RTOG grade 3 or greater. Forty-two percent and 49% of patients receiving
conventional-dose and high-dose therapy, respectively, experienced grade 2
acute GU morbidity (difference not significant by χ2 test).
The proportions for grade 2 acute GI (rectal) morbidity were 41% and 57%,
respectively (P = .004). Proportions for
grade 2 late GU morbidity were 18% and 20% (not significant); for grade 2
GI morbidity, they were 8% and 17% (P = .005).
Only 2% and 1% of patients receiving conventional-dose and high-dose therapy,
respectively, have so far experienced late GU or GI morbidity of RTOG grade
3 or greater. When analyzed as a function of time after treatment, most of
the late grade 2 or higher GI morbidity was seen by 3 years. However, GU morbidity
continued to accumulate. At 3 years, the actuarial risk of a GU event of grade
2 or greater was 15% and 13% in the conventional-dose and high-dose groups,
respectively, increasing to 19% and 18% by 5 years.
This randomized trial shows that when men with clinically localized
prostate cancer are treated with high-dose rather than conventional-dose external
radiation therapy, they are more likely to be free from an increasing PSA
level 5 years later and less likely to have locally persistent disease. The
data also show that when highly conformal radiation techniques are used, dose
escalation to 79.2 Gy can be safely achieved with only a small increase in
grade 2 rectal morbidity and no increase in GU morbidity. This study therefore
provides evidence to justify trends already emerging in the United States
toward conformal technology and higher radiation doses in early-stage disease.21
In 1995, when this trial was designed, early-stage disease was largely
defined by tumor stage and PSA level. Since then, more rigorous analysis has
developed risk groups, the lowest risk of which are believed to be those that
include patients with PSA values less than 10 ng/mL, stage T1-T2a tumors,
and Gleason scores of 6 or less.20 Such patients
comprised 227 of 393 (58%) of those entered into this trial. Men at intermediate
risk comprised the majority of the remainder. The advantage to higher radiation
dose was as clear and significant for those with low-risk disease as it was
for those with higher risk, and this represents the novel finding of the trial.
The advantage was slightly greater for the low-risk group (53% reduction in
risk of failure at 5 years, compared with 44%), perhaps reflecting the fact
that these men are more likely to have locally confined disease and thus are
more likely to benefit from an improved local therapy. Of note, the low- and
higher-risk groups appear to have very comparable 5-year freedom from biochemical
failure when adjusted for radiation dose. This unexpected finding may result
from an unseen bias in more recently recognized prognostic factors, such as
percentage of positive biopsy results, percentage of biopsy core involvement,
or perineural invasion that were not acknowledged and recorded at the time
of the trial design.
Median follow-up was 5.5 years, but this may be regarded as short for
a disease whose natural history can spread across decades. Given time, it
is therefore possible that the disease-free survival curves could come together.
If this proves to be the case, then it would seem that higher doses of radiation
delay, rather than prevent, recurrence. Roach et al22 have,
however, used a pooled analysis of prostate cancer randomized trials from
the RTOG to show that 5-year PSA data correlate strongly with clinical outcome
at 15 years. A lengthy delay in recurrence, though not a cure, may also be
of clinical benefit to patients, as it delays the use of secondary therapy.
In a population of elderly men, a regrowth delay may actually be sufficient
to prevent recurrence within the natural lifespan of many patients.
It is most likely that the improvement in biochemical disease-free outcome
seen in this trial is due to improved local control. We did not routinely
rebiopsy the prostates of all treated patients for several reasons. First,
interpretation of prostate biopsy results in the early posttreatment years
is unreliable.14 Second, it is ethically difficult
to recommend routine prostate rebiopsy, an uncomfortable procedure, when the
results are unlikely to influence subsequent management. We therefore used
a very stringent surrogate end point for local control, which demanded a PSA
of less than 1 ng/mL 2 or more years after radiation. This correlates strongly
with the likelihood of a negative rebiopsy result in retrospective data,15,23 though it has not been prospectively
evaluated. This strict end point might represent an underestimate of local
control, as patients with PSA values above 1 ng/mL do not always have positive
results on rebiopsy. Two prospective Canadian studies that included systematic
and regular rebiopsy have, however, reported positive rebiopsy rates of 38%
to 53%,24,25 consistent with the
rates obtained using the biochemical surrogate in the conventional-dose group
of our study.
The randomized trial of radiation dose reported by Pollack et al9,26 showed higher levels of rectal morbidity,
particularly bleeding, in the 78-Gy high-dose group at 5 years. We have also
observed this difference at the grade 2 level but not at the more serious
grade 3 level. It remains possible that a more sensitive quality-of-life instrument
would detect more morbidity than the physician-reported morbidity scales used
or that the grade 2 rectal morbidity that we observed may be more bothersome
than its low score value would suggest. We are currently performing a cross-sectional
study on long-term trial survivors using validated instruments to test these
possibilities. Questions regarding sexual function were asked, but these are
now recognized to be so prone to bias that the available data have not been
Although this trial validates the use of proton-beam therapy, it did
not test whether this modality is more or less efficacious than other less
expensive and more commonly available conformal techniques or, for that matter,
than brachytherapy or surgery.15,26,27 Nor
do the results justify using doses above 79 Gy outside the context of a clinical
In summary, this randomized controlled trial shows an advantage to high-dose
over conventional-dose conformal radiation in terms of freedom from biochemical
failure for men with low- and intermediate-risk prostate cancer. This advantage
was safely achieved with only a small increase in grade 2 rectal morbidity
and no increase in GU morbidity by the use of highly conformal radiation techniques
that included 3-dimensional photon and proton beams.
Corresponding Author: Anthony L. Zietman,
MD, Department of Radiation Oncology, Massachusetts General Hospital, Boston,
MA 02114 (firstname.lastname@example.org).
Author Contributions: Dr Zietman had full access
to all of the data in the study and takes responsibility for the integrity
of the data and the accuracy of the data analysis.
Study concept and design: Zietman, Slater,
Rossi, Miller, Shipley.
Acquisition of data: Zietman, Slater, Rossi,
Analysis and interpretation of data: Zietman,
DeSilvio, Rossi, Shipley.
Drafting of the manuscript: Zietman, Slater,
Critical revision of the manuscript for important
intellectual content: DeSilvio, Rossi, Miller, Adams, Shipley.
Statistical analysis: Zietman, DeSilvio.
Obtained funding: Shipley.
Administrative, technical, or material support:
Slater, Rossi, Miller.
Study supervision: Zietman, Slater, Rossi,
Financial Disclosures: None reported.
Funding/Support: This trial was supported by
National Cancer Institute grant P01 CA21239.
Role of the Sponsor: The National Cancer Institute
had no role in the design and conduct of the study; in the collection, analysis,
and interpretation of tha data; or the preparation, review, or approval of
Acknowledgment: We thank Susan Dean, BS, for
her fine data support. We also thank Herman Suit, MD, PhD, Michael Goitein,
PhD, and James Slater, MD, for their efforts and inspiration in building the
proton beam programs at the 2 sites.