Three randomized
clinical trials (
Sathya et al. 2005,
Hoskin et al.2012, and
Guix et al.2013) established combination therapy of
external beam radiation (EBRT) with a high dose rate brachytherapy (HDRBT)
boost as a standard of care in the treatment of high-risk prostate cancer. In
all three of those trials, the outcomes exceeded those from EBRT alone, but at
a cost of higher toxicity.
In previous studies of this combination therapy for
high-risk patients, freedom from biochemical relapse have ranged from 67-97% at
5 years, and from 62 -74% at 10 years. Late term genitourinary (GU) grade 3
toxicity ranged from 0-14.4% (median 4.5%); gastrointestinal (GI) grade 3 toxicity
ranged from 0-4.1% (median .5%); chronic incontinence ranged from <1%-3.8%;
urethral strictures ranged from .9-7.4% (median 4.5%); and erectile dysfunction
ranged from 10-51% (median 31.5%).
It
may be helpful to understand how large the effective doses of radiation were
that were used in all of the aforementioned studies. The term “biologically
effective dose” (BED) enables us to compare the cancer-killing power of the
absorbed radiation across different radiation modalities. To provide a point of
comparison, I show the BED as a % of the BED of a typical modern IMRT schedule,
80 Gy in 40 fractions (fx), which has a BED of 187 Gy.
Table 1 – Improved recurrence-free
survival, but higher GU toxicity from boost therapy
Study
|
Modalities
|
Dose Schedule
|
BED
Compared to 80 Gy
IMRT
|
Freedom from
recurrence among high risk
|
Follow up
|
Late grade 3 GU
toxicity
|
Sathya et al. (2005)
|
HDRBT
+ EBRT
|
35 Gy over 48 hrs.
+40 Gy/20 fx
|
-6%
|
71%
|
8.2 yrs median
|
14%
|
EBRT only
|
66 Gy/33 fx
|
-17%
|
39%
|
8.2 yrs median
|
4%
|
Hoskin et al. (2012)
|
HDRBT
+ EBRT
|
17 Gy/2 fx + 35.75 Gy/13 fx
|
+15%
|
66%
|
7 yrs
|
11%
|
EBRT only
|
55 Gy/20 fx
|
-17%
|
48%
|
7 yrs
|
4%
|
Guix et al. (2013)
|
HDRBT + EBRT
|
16 Gy/2 fx + 46 Gy/23 fx
|
+12%
|
98%
|
8 yrs
|
NA
|
EBRT only
|
76 Gy/38 fx
|
-5%
|
91%
|
8 yrs
|
NA
|
Could equal oncological
outcomes be accomplished but with less toxicity by using high dose rate
brachytherapy as a monotherapy? The maturing of data from a clinical trial in
Japan suggests it can be.
Yoshioka et al. (2015) have used HDRBT monotherapy on 111
high-risk patients treated from 1995 to 2012. Almost all of them (94%) received
ADT as well. They evaluated 3 dosing schedules: 48 Gy/8
fractions, 54 Gy/9 fractions, or 45.5 Gy/7 fractions inserted over 4
to 5 days.
With a median of
8 years of follow up, the authors report:
- ·
Biochemical
no evidence of disease – 77%
- ·
Metastasis-free
survival – 73%
- ·
Overall
survival – 81%
- ·
Cause-specific
survival – 93%
- ·
Late
GU grade 3 toxicity – 1%
- ·
Late
GI grade 3 toxicity – 2%
Unfortunately,
they haven’t reported rates of erectile dysfunction. Other monotherapy series
report ED rates of about 25%, and there’s no reason to suppose it would be
particularly different for high-risk patients. They report no significant
differences in oncological control or toxicity according to total dose or dose
schedule used.
The biochemical
control rates are well within the range seen for combination therapy at 5 to 10
years after treatment. At the same time, the rates of serious late term GU and
GI side effects seem to be improved by the monotherapy.
Other recent studies
have reported excellent results for HDRBT monotherapy for high-risk patients. Zamboglou et al. (2012) reported the monotherapy outcomes of 146
high-risk patients treated between 2002 and 2009. 60% received ADT as well. They
evaluated 3 dosing schedules: 38 Gy in four fractions in one implant, 38 Gy in
four fractions in two implants, and 34.5 Gy in three fractions in three
implants. After 5 years,
biochemical control was 93%, late grade 3 GU toxicity was 3.5%, and late grade
3 GI toxicity was 1.6%. The differences in toxicity among the dosing schedules
were not statistically significant. Among previously potent men, only 11% lost
potency sufficient for intercourse. The highest dose schedule did not have
better oncological control or worse toxicity than the lower dose schedules.
Hoskin et al. (2012) reported the monotherapy outcomes of 86
high-risk patients treated between 2003 and 2009. Almost all of them (92%)
received ADT as well. They evaluated 4 dosing schedules: 34
Gy in four fractions, 36 Gy in four fractions, 31.5 Gy in three fractions, and 26
Gy in two fractions. After 4 years, biochemical control was 87%,
late grade 3 GU toxicity was 12%, and late grade 3 GI toxicity was 1%. It is
not clear why GU toxicity was higher than in the other two studies. They did
not report erectile dysfunction. Although higher rates of strictures, ranging
from 3-7%, and urinary toxicity occurred on the most aggressive dosing
schedules, the differences were not statistically significant on this sample
size. Similarly, the difference in recurrence-free survival at the lowest dose
was not statistically significant.
Table 2. Clinical trials of HDRBT
monotherapy for high risk
Study
|
Dose Schedule
|
BED
Compared to 80 Gy
IMRT
|
Freedom from
recurrence among high risk
|
Follow up
|
Late grade 2+ GU
toxicity
|
Late grade 3+ GU
toxicity
|
Yoshioka et al. (2015)
|
48 Gy/8 fx
|
+29%
|
77%
|
8 yrs
|
NA
|
1%
|
54 Gy/9 fx
|
+45%
|
7%
|
45.5 Gy/7 fx
|
+30%
|
6%
|
Zamboglou et al. (2012)
|
38
Gy/4 fx/1 implant
|
+49%
|
97%*
|
5 yrs
|
9% retention
9%incontinence
|
3% retention
1% incontinence
|
38 Gy/4 fx/2 implants
|
+49%
|
94%*
|
5 yrs
|
7% retention
5% incontinence
|
2% retention
<1%incontinence
|
34.5 Gy/3 fx/3 implants
|
+60%
|
95%*
|
3 yrs
|
5% retention
8% incontinence
|
1% retention
1% incontinence
|
Hoskin et al. (2012)
|
34
Gy/4 fx
|
+21%
|
77%
|
5 yrs (median)
|
33%
|
3%
|
36 Gy/4 fx
|
+35%
|
91%
|
4.5 yrs (median)
|
40%
|
16%
|
31.5 Gy/3 fx
|
+35%
|
87%
|
2.8 yrs(median)
|
34%
|
14%
|
26 Gy/2 fx
|
+35%
|
NA
|
.5 yrs (median)
|
NA
|
NA
|
*across all risk groups, high risk only
was 93%
Within all three
published studies, there were no statistically significant dose-response
relationships in terms of either oncological control or toxicity. However,
looking across the three, it may be that the higher doses provided
better control at the cost of some higher toxicity. I hope someone will do a
meta-analysis on the full data sets to confirm that. Larger studies will be
needed to determine whether toxicity increases with the more aggressive dosing
schedules. All the control rates were within the range of the combination
therapies, and all of the toxicities were acceptable. Evidently, all of the
studies applied enough radiation to effectively kill the high-risk cancer. Nor
did the dosing schedule used have an impact on results. HDR brachy monotherapy as
currently practiced uses anywhere from a single fraction to nine fractions, and
anywhere from a single implant to three implants.
It is difficult
to draw conclusions about the use of ADT. All three studies utilized high rates
of adjuvant ADT – over 90% in two of the studies. The study with the lowest
rate of ADT utilization, Zamboglou et al., at 60%, also used the highest
radiation doses. Although Demanes et al. found that ADT had no incremental benefit
when used with combination therapy, that study was in the early years
(1991-1998) when relatively low radiation doses were used. Until there is a
randomized clinical trial of its use with HDRBT monotherapy, it will be hard to
walk away from using ADT.
Unlike low dose
rate brachytherapy (seeds), HDRBT can treat areas outside of the prostate,
including the prostate bed and the seminal vesicles. However, to my knowledge,
it has not been used to treat pelvic lymph nodes, which would be impossible to
find using current imaging technology. In all three studies, patients were
screened for evidence of lymph node involvement. Clearly, HDRBT monotherapy is
not a good choice if LN involvement is suspected. There are calculators for
predicting such risk based on Gleason score, PSA and cancer volume. High-risk
patients may have a statistically high risk for LN involvement without showing
evidence, but even the “high risk” levels are not very high, so treatment
remains controversial. One clinical trial (Lawton et al.) demonstrated a benefit to full-pelvic
IMRT coupled with neoadjuvant ADT, and there is a current clinical trial that
allows for a brachy boost (RTOG 0924) that may confirm that finding.
SBRT is
radiologically identical to HDRBT, and as discussed in a recent article, its use for high-risk patients is also
being explored. Both of these treatments have the potential to provide
excellent cancer control while minimizing the side effects of treatment, and
with a considerable time and cost advantage over IMRT-combo treatments. I
encourage high-risk patients to enroll in clinical trials for both alternatives.
HDRBT monotherapy for high risk is part of a clinical trial at Stanford (NCT02346253).