ATLANTAWith the use of highly conformal radiation
therapy (RT), men can safely receive a high dose of radiation for early-stage
prostate cancer, Anthony L. Zietman, MD, reported at the 46th Annual Meeting of
the American Society for Therapeutic Radiology and Oncology (ASTRO abstract 4).
Compared with a conventional radiation dose, the high dose was associated with
a lower rate of treatment failure.
"This trial was written in 1995, and the background at that
time was the mounting evidence that conventional-dose radiation was associated
with high rates of PSA failure and of locally persistent cancer, even in
those patients with early-stage disease," said Dr. Zietman, professor of
radiation oncology, Harvard Medical School, and a radiation oncologist at
Massachusetts General Hospital. "There was also mounting phase II evidence that
higher doses delivered by external beam could improve cancer outcome, but there
were valid concerns that higher doses could be associated with higher
Men were eligible for the randomized trial, PROG 95-09, if
they had prostate adenocarcinoma of any grade with a T stage of 1b to 2b, and a
PSA concentration of 15 ng/mL or lower. Men were ineligible if they had
received prior hormonal therapy, radiation therapy, or chemotherapy, and if
they had nodal involvement or distant metastases.
Patients in the conventional-dose arm received a proton
boost of 19.8 gray equivalent (GyE), whereas those in the high-dose arm
received a proton boost of 28.8 GyE. "The CTV [clinical target volume] was the
prostate and a 5-mm margin. It is prescribed as gray equivalent after
correction for an RBE [relative biological effectiveness] of 1.1, and patients
were treated at 1.8 GyE per fraction, prescribed to isodose," he said.
Patients were positioned in the lithotomy or supine
position, depending on the treatment center, and a rectal balloon was used
daily to stabilize the prostate and displace the posterior wall of the rectum.
After the boost, patients in both arms received the same 3D conformal photon
therapy (50.4 Gy at 1.8 Gy per fraction). "The CTV was the prostate, seminal
vesicles, and a 1-cm margin, again prescribed to isodose," Dr. Zietman said.
The total doses to the prostate were 70.2 and 79.2 GyE in the conventional- and
high-dose groups, respectively.
The 393 patients enrolled in the trial had a median age of
about 66 years. Most had a PSA level between 4 and 10 ng/mL (74%), a Gleason
score of 6 or lower (75%), and a T stage of 1c (61%). According to contemporary
risk categories, 58% had low-risk disease.
With a median follow-up of 5.5 years, the median time to PSA
nadir after radiation was longer in the high-dose arm than in the
conventional-dose arm (40 vs 28 months). "It is longer not because the PSA is
falling slower, but because the PSA is falling lower," Dr. Zietman noted. The
percentage of men with a PSA nadir of less than 0.5 ng/mL was significantly
greater in the high-dose group (60% vs 45%), he said.
The 5-year rate of freedom from biochemical failure
according to the ASTRO definition of biochemical failure (three consecutive
rises in PSA level) was significantly higher in the high-dose group (79% vs
"Many criticize the ASTRO definition of failure because it
incorporates backdating, which artificially flattens the curves and creates the
illusion that all the action is finished," Dr. Zietman said. "So we reanalyzed
using three PSA rises but without backdating, and this really just confirms the
When patients were grouped by their contemporary risk
category and the analysis was repeated with the ASTRO definition, high-dose
radiation remained associated with significantly higher rates of freedom from
biochemical failure, particularly among patients at low risk (79% vs 55%) but
also among those at intermediate or high risk (78% vs 61%). "And again, if we
reanalyze using ASTRO without backdating, it only emphasizes . . . that the
advantage appears even greater in the low-risk patients, those who have a lower
risk of distant metastases," Dr. Zietman said.
Local failure was assessed directly (from clinical
progression or a positive rebiopsy) or from a surrogate indicator (a PSA level
of greater than 1 ng/mL after more than 2 years): 57% of patients in the
conventional-dose group had a local failure vs 34% of those in the high-dose
The rate of salvage androgen-deprivation therapy in the
conventional-dose group was about double that in the high-dose group, but Dr.
Zietman cautioned that few patients have had this outcome to date. "At this
early stage, overall survival is, of course, absolutely identical," he
Morbidity was assessed with RTOG scales, which are not as
sensitive as current tests, Dr. Zietman noted. Rates of acute grade 3
genitourinary toxicity and gastrointestinal toxicity were low (1% or less for
each arm) and similar between the conventional- and high-dose groups. Likewise,
rates of late grade 3 genitourinary toxicity and gastrointestinal toxicity were
low (2% or less for each arm) and similar between groups.
"We conclude that dose escalation from 70 to 79 Gy can be
achieved without any increase in grade 3 acute or late morbidity using highly
conformal photon-proton techniques," Dr. Zietman said. "This escalation leads
to significantly lower nadir PSA values, is associated with an improvement in
5-year biochemical disease-free survival for all risk groups (but the low-risk
subgroup in particular), and is accompanied by an improvement in local control
as assessed by surrogate markers."
He added that longer follow-up will be needed to assess any
differences in rates of freedom from distant metastases and survival.