Some of the leading lights in radiation oncology have
collaborated on a study by
Evans et al. of patient-reported quality of life (QOL) following various primary radiation
treatments for prostate cancer. They analyzed three monotherapies (all without
hormone therapy): low dose rate brachytherapy (LDRBT), intensity-modulated
radiation therapy (IMRT), and stereotactic body radiation therapy (SBRT). It
did not include high dose rate brachytherapy or proton therapy.
Because this study was so far-reaching in its scope and its
findings, it is worth taking a close, detailed look at it. I will break it into
three parts. In the first part, we’ll look at the basis of the study – how the
study was designed and carried out, and what does it purport to tell us. In
Part 2, we will look at some of the more important findings of the study. And
in Part 3, we will discuss the implications and caveats of its findings, and
draw conclusions.
PART 1. THE BASIS OF THE
STUDY
The purpose of the study was to evaluate three primary
radiation therapies – LDRBT, IMRT and SBRT – with respect to the
patient-perceived side effects of those treatments, and to do so in a
standardized and consistent manner. While this was a prospective study, it was
not a randomized comparison, which is the gold standard for doing that.
However, it does provide the doctor and patient with more information on what
they can reasonably expect, across those treatments, than we’ve ever had
before.
Data was provided by several of the top institutions in the
US:
LDR or IMRT
Michigan (2 sites)
Mass General
Beth Israel Deaconess
MD Anderson
Cleveland Clinic
Washington University (St Louis)
SBRT
Georgetown
21st Century (2 sites)
The number of patients in the two-year follow up:
- ·
LDRBT:
243 patients
- ·
IMRT:
140 patients
- ·
SBRT:
272 patients
I don’t know how they selected which doctors and medical
centers to include. In addition, the study was done with the assistance of the
PROSTQA Study Consortium, a blue-ribbon panel of top researchers. They
previously published much of this data on IMRT and LDRBT in 2008 (
see this link).
The SBRT data are new. Their results are a good indicator of outcomes from top
practitioners at major treatment centers, and are not a good indicator of
expected outcomes in community practice. I’m sure that many patients have
favorite doctors whose work was not represented in this study, and they will
argue that these results are not representative.
Because this was not
set up as a randomized comparison of treatments, differences in patient
selection may skew the results. Importantly, the LDRBT cohort is 5 years
younger (65 years, median) than the other two groups (69 years, median). In all
quality-of-life studies, younger patients do better. They are less likely to
suffer deleterious effects of radiation, and they are more resilient in their
recovery. Paralleling the difference in age at baseline, the baseline sexual
QOL was best for LDRBT, and the baseline prostate symptom scores were best for
LDRBT, followed by IMRT and SBRT.
The instruments they used to evaluate quality of life were
EPIC-26
and
SF-12.
Patient-reported assessments have an advantage over physician-reported toxicity
reports. The physician data depends on the patient to voluntarily tell the
doctor about all adverse events, which is useful for highest grade events (3 or
4), but is less reliable for low grade events (1 or 2) that the patient might never
bring to the doctor’s attention. Some men “tough it out,” some see their PCP
instead (who may be more accessible), and some worry about even the most minor
events. The survey instruments used here are standardized and validated, and
guide the patient through a detailed assessment of the QOL issues that have
been found to matter most. Patients filled them out at baseline, at 1-2 months,
6, 12, and 24 months. EPIC scores are based on scale of 0 (worst) to 100
(best). Although they also measured such qualities as general physical and
mental status, and vitality/well-being, none of these were impacted by
treatments.
IMRT and LDRBT patients were treated from 2003 to 2006; SBRT
patients from 2007 to 2011. Contemporary best practice was observed as follows:
·
LDRBT: 144
Gy prescribed dose for I-125, US-guided, transperineal placement, I-125 or
Pd-103 used, and 3-5 mm margins (more details here)
·
IMRT:76-79 Gy in 1.8-2.0 Gy
increments, and 0.5-1.5 cm margins.
·
SBRT: 35-40
Gy in 5 fractions, fiducials or Calypso image guidance, and 3-5 mm margins.
There were two kinds of urinary problems that were measured:
urinary incontinence (leakage, dribbling, control & pad use) and urinary
irritation/obstruction (frequency, pain/burning, weak/incomplete). Bowel issues
comprised urgency, frequency, leakage, bleeding and pain. The sexual domain
comprised ability to have erections, their firmness, and frequency when needed;
also, quality of orgasms and overall sexual function.
All of the study’s findings relate to how much patient
evaluations changed compared to their baseline evaluations in the urinary,
rectal and sexual quality of life domains. We expect that the radiation
therapies that do the least damage will show the least deterioration in the
patient perceptions in each domain.
Because the study was not randomized, and it did not attempt
to match triplets of patients on their demographics and co-morbidities, we have
the difficulty of comparing results in different kinds of patients. The
analysis of patient characteristics across treatments revealed only one real
glaring discrepancy – LDRBT patients were 5 years younger than the rest. The
authors made some attempt to restore comparability by only looking at sexual
scores among patients who were 60 years of age or older, but such analyses were
limited in their published results. In my opinion, they ought to have computed
age-adjusted scores in all domains. The failure to do so will compound the
difficulties in interpreting results as they carry their tracking into the
future when the aging of the study population has greater effects.
PART 2. DETAILED FINDINGS
In this part we’ll look at the results of their analysis.
The authors did a great job of compiling a vast amount of information. Even so,
in some cases, I wish more of the information had been presented (I was able to
see the full text). Perhaps they will reveal more of the details in future
analyses of this rich database.
Change from Baseline
The following table shows the EPIC score change from
baseline after two years among patients having each kind of therapy. The last
column shows, for reference, the minimum amount of change that has been found
to be clinically important for that set of symptoms.
|
|
LDRBT
|
IMRT
|
SBRT
|
|
|
Urinary- irritative/obstructive
|
-6*
|
+2
|
0
|
5-7
|
|
Urinary - incontinence
|
-6*
|
-5*
|
-3
|
6-9
|
|
Bowel
|
-7*
|
-8*
|
-1
|
4-6
|
|
Sexual†
|
-24*
|
-21*
|
-14*
|
10-12
|
* Change is statistically significant
†Among those with scores over 60 at baseline (to help
compensate for age-related differences).
Sexual status was the domain that was most affected by all the
treatments. For LDRBT, it had the greatest deterioration. Deterioration in
urinary and bowel scores were statistically significant and clinically
meaningful in patients who had LDRBT. IMRT also had its greatest impact on
sexual status, and not much different from LDRBT. Other than sexual status, only
IMRT bowel scores deteriorated meaningfully; urinary status returned to near
baseline. SBRT had the smallest change in sexual status, albeit large enough to
be meaningful. Bowel and urinary status returned to baseline.
Minimal Clinically
Detectable Change
The authors also looked at what% of patients suffered a
minimal clinically detectable (MCD) change in each of those components of their
quality of life over time. The typical pattern was a sharp increase at 1 or 2
months (acute effects). In all but sexual scores, that was followed by
improvement. Predictably, urinary irritation/obstructive were most impacted,
reaching about 90% at two months for LDRBT, and significantly better at all
time points for IMRT and SBRT. The proportion who had MCD bowel symptoms and
sexual symptoms was consistently more favorable for SBRT than for LDRBT or
IMRT.
As a measure of the severity of symptoms, the authors looked
at the % of patients who suffered an MCD increase of twofold or more over
baseline after two years:
|
|
LDRBT
|
IMRT
|
SBRT
|
|
Urinary (all)
|
45%
|
25%
|
18%
|
|
Bowel
|
25%
|
30%
|
11%
|
|
Sexual†
|
35%
|
33%
|
20%
|
|
None of the above
|
34%
|
40%
|
65%
|
|
All of the above
|
8%
|
7%
|
2%
|
In general, large clinical deteriorations in QOL were about
twice as frequent for LDRBT compared to SBRT, with IMRT falling in the middle.
Symptom Severity over
Time
As another measure of symptom severity, the table below
shows the% change versus baseline in the proportion who rated their symptoms as
moderate to severe, at 1-2 months and at 2 years:
|
|
LDRBT
|
IMRT
|
SBRT
|
|
|
2 mos.
|
24 mos.
|
2 mos.
|
24 mos.
|
1 mo.
|
24 mos.
|
|
Urinary (all)
|
+33%
|
+7%
|
+27%
|
+3%
|
+8%
|
-3%
|
|
Bowel
|
+14%
|
+6%
|
+16%
|
+6%
|
+7%
|
-2%
|
|
Erectile dysfunction†
|
+21%
|
+19%
|
+11%
|
+16%
|
+5%
|
+11%
|
† inability to have erections, among patients of all ages
Moderate to severe acute urinary and rectal side effects
increased markedly for LDRBT and IMRT. For SBRT, they increased much less and
returned to slightly better than baseline levels.
Keeping in mind that LDRBT patients were a median of 5 years
younger than the other two groups, the increase in erectile dysfunction among
LDRBT patients is troubling.
As we saw in a recent study, the deterioration occurs earlier than was
previously thought. For SBRT, in contrast, there was only a +5% increase in
erectile dysfunction severity at two months after treatment, but that increased
to +11% by two years. Nevertheless, that was still lower than the other two therapies.
PART 3. DISCUSSION
In this section, we will make an attempt to explain the
findings of the study and draw whatever conclusions we can from them.
We have seen a very consistent pattern across all the
measures of QOL and in all of the domains: LDRBT patients did worst, SBRT
patients did best, and IMRT patients were in between. Why should that be? Let’s
examine a few hypotheses:
Patient
selection/non-random
This was not a randomized comparative trial, so it is
possible that the LDRBT patients selected were, for some reason, more prone to
the damaging effects of radiation. This argument is weakened by the fact that
they were 5 years younger, and their urinal, rectal and erectile function at
baseline were better than in the other two groups.
Better practitioners
not represented
Some of the top LDRBT practitioners like Peter Grimm, Michael
Zelefsky, Brian Moran, and Gregory Merrick, to name a few, were not represented
here. One could also argue in the other direction that some of the most
experienced SBRT practitioners, like Christopher King, Alan Katz, and Debra
Freeman, were not represented here. Their results might have increased comparative
favorability of the SBRT results still further. However, the results do seem to
be comparable to those reported by
Katz and the
8-institution consortium.
Time of treatment
IMRT and LDRBT results were based on best practice in
2003-2006, while SBRT was based on patients treated in 2007-2011. There were
technological improvements in both modalities since then that might make their
outcomes more comparable to SBRT. As radiation technology continues to evolve,
it becomes problematic to choose among them based on past performance.
Hypofractionation
spares healthy tissue
Hypofractionation (SBRT or HDRBT) – radiation applied in
fewer treatments (or fractions) – has been found to kill cancer cells more
efficiently than normal fractionation (IMRT) or continuous fractionation
(LDRBT). Because prostate cancer is especially susceptible to hypofractionation
(technically, we say it has a low alpha/beta ratio of about 1.5), and because
healthy nearby early-responding tissues are less susceptible (they have a
higher alpha/beta ratio of about 10), healthy tissues are better spared by it.
A convenient measure for comparing the dose seen by nearby
healthy tissues is something called the biologically
effective dose (BED). We can compute for each modality the maximum BED
experienced by nearby early-responding tissues that are responsible for acute
side effects. With SBRT (7.5 Gy X 5 fractions), the BED to those tissues is 30%
less than the dose from IMRT (1.8 Gy X 44 fractions). For LDRBT (144 Gy
I-125 Rx dose), the maximum BED to those tissues is 56% greater than the dose
from IMRT. ). Making comparisons solely on BED is problematic because LDRBT radiation
is extremely short range, so a lower proportion of the bladder and rectum
surface may be exposed to that maximum dose.
Dose constraints
Radiation oncologists set strict dose constraints for the
bladder, urethra, rectum, and sometimes to the penile bulb, limiting the volume
of those organs that receive potentially toxic doses. However, there is only so
much that doses can be limited if they are to effectively kill the cancer in
the prostate. I don’t know what dose constraints were set for the three
modalities examined in this study. We can only assume that they used best
practices.
Imaging
The imaging of the pelvic organs both in planning and in the
application of radiation makes a large difference in toxicity. This is where
SBRT shines. SBRT commonly uses a fused image of a CT and MRI with fiducials or
transponders in place for planning. This helps to precisely predetermine, down
to less than a millimeter, where all the beams will be directed. These
practices can be used with IMRT as well. However, with IMRT, the images are
aligned only once per session, whereas with SBRT, the images are aligned
continually throughout the session.
We recently saw how disastrous SBRT could be without intra-fractional motion
tracking. LDRBT seed placement is commonly accomplished under ultrasound image
guidance, using computerized intra-operative planning. The ultrasound can help
the doctor see where the needles are going, but it can’t see the seeds well.
Even stranded seeds tend to move, the prostate is moved by each needle
insertion, and the prostate swells throughout the procedure, so that it is
impossible to know where their final position will be. An image is obtained
about a month later, after the swelling subsides, to check for major
discrepancies in seed positions and to give an after-the-fact reading of the
doses absorbed by organs at risk.
Late term effects
This study tracked patients for two years, which is long
enough for most of the late-term side effects to show up. However, some will inevitably
show up even later. Some tissues, particularly some in the bowel, are “late
responding” to radiation damage. Late responding tissues are relatively more
sensitive to the concentrated radiation of SBRT (they have an alpha/beta ratio
of 3-5), so it is possible that SBRT’s advantage will decrease with longer
follow up.
CONCLUSIONS
Although one can quibble over methodological issues in comparing the modalities, SBRT certainly
provides excellent quality of life to treated patients. SBRT also is the most
convenient of the treatments, requiring only five short visits, no intrusive
procedures (other than fiducial placement), and no anesthesia. LDRBT is the
winner on cost of treatment, with a $17,000 median Medicare reimbursement,
followed by SBRT ($22,000) and IMRT ($31,000). However, a full cost analysis should also include the costs of managing the
side effects of treatment, which seem to be much lower for SBRT and higher for
LDRBT. Based on the findings of this study, and approximately equivalent
oncological control for the 3 modalities in favorable risk patients, it is hard
to justify IMRT. Availability is an issue: IMRT is available everywhere, while
there is less access to excellent practitioners of SBRT (usually as CyberKnife®)
and LDRBT. Some insurance still will not cover SBRT, although that is less
often a barrier now.
An oft-heard argument against SBRT is that there’s not
enough long-term data. SBRT is the youngest of the three modalities, used
against prostate cancer since 2003.
The longest-running SBRT study, has 7 years of follow up on 515 patients. For comparison,
robotic prostatectomy has been used since 2000, and has never been proven
superior to open surgery in a randomized comparative trial. IMRT, likewise, has
never been evaluated in a comparative randomized trial, and in its current
form, using dose escalation and precision IGRT techniques, was only begun in
the mid-1990s.
The longest-running IMRT study, at Memorial Sloan Kettering, has 10 years of
follow up on 170 patients. LDRBT has been used, in some form, for over a
hundred years. However, in its modern form with dose escalation and
intra-operative planning methods, there are no studies older than 15 years that
have any decisional value. I have often bemoaned the problem of “irrelevance”
in long-term clinical studies: by the time we get the results, technology and
practice have changed so much that the results have become irrelevant in making
decisions among the best available therapies.
While this study raises the hypothesis that SBRT may be
superior to IMRT and LDRBT, it is prudent for the patient to keep them all in
his consideration set at least until the results of randomized comparative
trials become available. This study should influence patients and clinicians to
give serious consideration to SBRT.
Later this year, we will have the early results from Sweden of
a
randomized clinical trial of SBRT versus IMRT in intermediate-risk patients. There are several
more comparative trials that are scheduled for completion in the coming years.
If they confirm the results of this study, it will be difficult to justify IMRT
as first-line therapy. Unfortunately, as far as I know, there are none planned
comparing SBRT and LDRBT. There are few institutions that offer both modalities
(Memorial Sloan Kettering is an exception), so randomization would be
problematic.
