Several recent
studies shed light on the optimal use of androgen deprivation therapy (ADT)
used in conjunction with radiation therapy (RT), including new learning about
timing of ADT, RT dose, and their use in various risk categories.
When external
beam radiation doses of around 70 Gy were used in the 1990s, it was shown that
androgen deprivation therapy (ADT) used with it could improve oncological
outcomes. However, it was not at all clear that ADT provided any additional
benefit when higher doses radiation of about 80 Gy were used. DART 01/05 (Zapatero et al.) was a randomized clinical trial to
determine the optimal duration of ADT supplementation.
DART 01/05 was a
multi-institutional Spanish trial among intermediate and high risk men
receiving primary treatment with 3D conformal radiation therapy (3DCRT) between
2005 and 2010. The patients were randomized to receive either 4 months (short
term) or 28 months (long term) of ADT.
- Everyone received 2 months of ADT before and 2 months during their 3DCRT
- Everyone received goserelin, an LHRH agonist, throughout, and also received 2 months of anti-androgen therapy (bicalutamide or flutamide) at the beginning.
- 173 patients received short-term ADT, 171 patients received long-term ADT
o 90 were high risk on long-term ADT
o 91 were high risk on short-term ADT
o 83 were intermediate risk on long-term
ADT
o 78 were intermediate risk on short-term
ADT
- Everyone received a median radiation dose of 78 Gy.
The 5-year
outcomes were as follows:
- Biochemical disease-free survival was significantly better with long-term compared to short-term ADT: 90% vs. 81%
o The difference was only significant among
high risk patients: 88% vs. 76%.
- Metastasis-free survival was significantly better with long-term compared to short-term ADT: 94% vs. 83%.
o The difference was only significant among
high risk patients: 94% vs. 79%.
- Overall survival was significantly better with long-term compared to short-term ADT: 95% vs. 86%.
o The difference was only significant among
high risk patients: 96% vs. 82%.
o There were 5 deaths due to prostate
cancer, all among men on short-term ADT.
- There were no significant differences in acute or late term rectal or urinary toxicities.
The authors
conclude:
“Compared with short-term androgen deprivation, 2 years of adjuvant
androgen deprivation combined with high-dose radiotherapy improved biochemical
control and overall survival in patients with prostate cancer, particularly
those with high-risk disease, with no increase in late radiation toxicity.
Longer follow-up is needed to determine whether men with intermediate-risk
disease benefit from more than 4 months of androgen deprivation.”
For high risk
patients, at least, this establishes that dose-escalated RT with long-term ADT
is preferable to short term. It leaves several open questions about optimum
radiation treatment for this group:
- What is the optimal duration of ADT? We know from an earlier randomized clinical trial (Nabid et al.) that 18 months of adjuvant ADT is as good as 36 months, even with lower dose RT. So the optimal duration is somewhere between 6 months and 18 months.
- Is IMRT with a brachytherapy boost preferable, and is that enhanced by ADT? (See this link)
- Is SBRT monotherapy preferable, with or without adjuvant ADT? (This was discussed in a recent article.)
- What is the effect on erectile function?
- Should the pelvic lymph nodes be treated as well? This is the subject of an ongoing clinical trial.
Another randomized
clinical trial presented at the Genitourinary (GU) Conference found more
support for the addition of ADT to RT for intermediate risk patients. While
DART 01/05 looked at long-term vs, short-term ADT with RT and found no
difference for the intermediate risk subset, Nabid et al. looked at short-term vs. no
additional ADT with RT for intermediate risk patients. They also examined the
effect of radiation dose.
Their study
consisted of 600 intermediate risk men treated with external beam radiation at
several hospitals in Quebec between 2000 and 2010. The 3 arms of their study
were treated under the following protocols:
- Arm 1: 6 months of ADT + 70 Gy of RT
- Arm 2: 6 months of ADT + 76 Gy of RT
- Arm 3: 76 Gy of RT
Those who
received ADT were treated with 6 months of both goserelin and Casodex (bicalutamide)
beginning 4 months before their RT began. After a median follow up of 76
months, the researchers found that:
- Biochemical failure was significantly higher in Arm 3, but not statistically different between arms 1 and 2.
o Arm 1: 12.5%
o Arm 2: 8.0%
o Arm 3: 21.5%
- 10-year disease-free survival was significantly lower in arm3, but not statistically different between arms 1 and 2.
o Arm 1: 77%
o Arm 2: 90%
o Arm 3: 64.5%
- 10-year overall survival was not statistically different between any of the arms.
o Arm 1: 64%
o Arm 2: 70%
o Arm 3: 78%
- There were only 6 deaths (1%) attributable to prostate cancer, not enough to discern a difference among treatment arms.
The authors
conclude:
“In patients with intermediate risk prostate
cancer, the use of short term ADT in association with RT, even at lower doses,
leads to a superior biochemical control and DFS as compared to dose-escalated
RT alone. These outcomes did not translate into an improved overall survival.”
I
hope the authors will attempt a sub-group analysis to determine if there were
significant differences when favorable vs. unfavorable intermediate risk (see
below) is taken into account. It will also be interesting to look at the side
effect profile in the 3 arms.
A
randomized clinical trial (RTOG 0126) of low dose
(70 Gy) vs. high dose (79 Gy) radiation in intermediate risk patients, but
without ADT, found improvements in the risk of biochemical failure, distant
metastases, and time to local progression in those treated with the higher dose.
However, they found no improvement in overall survival with 10 years of
observation. Those treated with the higher dose did experience higher rates of
urinary and rectal toxicity, however.
One
must consider whether the higher rates of urinary and rectal toxicities are
still applicable with modern IGRT/IMRT techniques. The men in the above studies
were treated with 3DCRT – an older, less precise radiotherapy. As often occurs
with long-term clinical trials of radiation therapies, the results may become
irrelevant by the time they are reported because of technological advances.
I
think 10 years is too short a follow-up period to detect significant
differences in survival among intermediate risk men, and especially among
favorable intermediate risk men. It also begs the question of whether those men
require immediate treatment at all. Some of the sub-groups, including some who
are older with co-morbidities, some with favorable PSA kinetics, low volume of
cancer, and some with Gleason score≤ 3+4, may be better off with expectant
management.
In
contrast to the lack of survival benefit to the escalated dose found in RTOG
0126, a retrospective analysis reported at the GU Conference by Kalbasi et al. looked at
12,848 low risk patients, 14,966 intermediate risk patients, and 14,587 high
risk patients After a median 73 months of follow up, they found a significant
dose response for both the intermediate risk and the high risk patients, but
not the low risk patients. For every 2 Gy increase in dose, there was a
reduction in the hazard of death of 9% and 7% among the intermediate and high
risk patients, respectively.
Perhaps
sub-group analysis will explain the difference in the dose response between the
two studies. I will report on both further when more detailed findings become
available.
I don’t think it
will come as any surprise that radiation added to androgen deprivation has
better oncological outcomes than androgen deprivation alone. In a randomized
clinical trial among 1,205 locally advanced prostate cancer patients treated
between 1995 and 2005 with ADT and with or without low dose (64-69 Gy) RT, Mason et al., with median 8 years of follow-up, found
that the addition of RT reduced prostate cancer mortality by about half.
Favorable vs. Unfavorable Intermediate
Risk
In an earlier article, we noted that Dr. D’Amico raised a
caution that the results may look very different if the intermediate risk men
were divided into favorable and unfavorable groups. It may be that with further
follow-up time, significant differences will appear among the intermediate risk
men, and particularly among those with unfavorable features. In a retrospective
study by Castle et al. where intermediate risk men were divided
into favorable or unfavorable intermediate risk, favorable risk patients
had no
discernable benefit from the addition of ADT. Unfavorable intermediate risk
patients had significantly higher 5-yr freedom from failure if they also
received ADT, 74% vs. 94%, respectively. Similarly, Edelman et al. found that ADT combined beneficially
with RT only in intermediate risk patients with GS 4+3, more than 50%
positive cores, or multiple intermediate risk factors.
Another
retrospective study by Keane et al. confirming that finding was presented at
the recent Genitourinary Conference. They analyzed the oncological outcomes of
2,668 intermediate risk men (71% favorable, 29% unfavorable) treated between
1997 and 2013 with dose-escalated RT and with and without adjuvant ADT (median
4 months). After a median follow-up of 7.8 years, they found that there was a
significant amelioration of the risk of prostate cancer-specific mortality among
the unfavorable risk patients who also received ADT, but adding ADT did not
make a difference to prostate cancer-specific mortality in those men
categorized as favorable intermediate risk.
ADT Sequencing
The conventional
wisdom is that neo-adjuvant ADT (ADT started at least two months before the
start of radiation) and ADT given concurrently with RT have a
different functional benefit from adjuvant ADT (ADT given after the
completion of RT). Neoadjuvant and concurrent ADT is thought to radiosensitize
the cancer to the radiation treatment, while the adjuvant ADT is thought to
function as “clean-up,” killing off small amounts of hormone-sensitive stray
cancer cells that may already be systemic. A new study by Weller et al. is calling that model into question.
They analyzed the
records of intermediate and high risk patients treated from 1995 to 2002 who
had either
neoadjuvant and concurrent ADT with their dose-escalated RT (311 patients) or
only adjuvant ADT immediately after their dose-escalated RT (204 patients).
Ten-year biochemical recurrence-free survival was 61%, distant metastasis-free
survival was 80%, and overall survival was 66%. There were no significant
differences in any of those measures
based on the sequencing of ADT.
The authors
conclude:
“the synergy between RT and androgen
deprivation is independent of the sequencing of both modalities and the
initiation of RT does not need to be delayed for a course of neoadjuvant ADT.”
I think these findings have to be confirmed
by a randomized clinical trial. It raises interesting questions about the way
ADT and radiation interact to kill cancer cells, perhaps supporting the hypothesis
that ADT sustains the immune response to the radiation-induced increase in
cancer antigens. If the abscopal effect turns out to be of major importance in
the ADT/radiation killing of cancer cells, various immunotherapies, like
Provenge, Prostvac, Yervoy, and Keytruda, may improve the oncological benefits
still further.