The same
researchers (give or take a couple), in analyses of an Italian and US
databases, investigated whether it could diminish the side effects of radiation
by waiting longer after prostatectomy. The conventional wisdom is that waiting
longer allows the newly cut tissues more time to heal completely before the
onslaught of radiation.
Unfortunately,
the methodology they used for their analyses is problematic. I decided to write
about it because it illustrates some of the issues inherent in such database
analyses, and raises cautions in drawing conclusions from them.
Hegerty et al. used the US SEER/Medicare database to
find 3 groups of patients. All of them had adverse pathology (stage T3 and/or
positive margins) after prostatectomy in the period between 1995 and 2007. The
three groups were:
1. RP alone, didn’t have RT (RP only) – 4,509 patients
2. Adjuvant RT within 9 months of surgery (aRT) - 894 patients
3. Salvage RT, at least a year after surgery
(sRT) - 734 patients
Obviously, this
is a large database. The three groups differed somewhat with respect to age,
pathology, co-morbidities, history of ED, history of urinary and rectal
problems, and demographic characteristics.
·
The
RP-only group was most likely to be stage T2, lower Gleason score, older at
diagnosis, co-morbidities, no ADT, and a history of GI problems.
·
The
aRT group was most likely to be stage T3b, high Gleason score, and have had
laparoscopic/robotic surgery.
·
The sRT
group was most likely to be younger, have no co-morbidities, diagnosed more
years ago, have had open surgery, and ADT.
These
differences illustrate the first difficulty in this type of analysis: how do
the differences among the patient groups before
treatment affect how they will respond to treatment? Some researchers in other
studies get around this problem by finding matched pairs of patients selected
randomly within certain constraints. In this study, the researchers used two
different techniques: “propensity score matching” and a “Cox proportional
hazards model.” Propensity score matching attempts to compensate, after the
fact, for those factors that seem to be correlated with the treatment decision.
After “compensating,” the researchers took note of the Medicare claims for
procedures, and recorded diagnoses of side effects as some patients progressed
from “RP only” to “aRT” or “sRT.”
This raises
another problem with this kind of analysis: the diagnoses and side effects were
not necessarily related to the treatment the patient had. For example, a
patient who had a colonoscopy a year after his salvage radiation, and perhaps
had pre-cancerous polyps removed, is recorded as having a “gastrointestinal
diagnosis” and a “gastrointestinal procedure” even though they probably had
little relation to his treatment.
The other major
shortcoming is that there is also no possibility of investigating how serious
the side effects were. For example, urinary incontinence treated with an
artificial urinary sphincter carries the same diagnosis as incontinence that
only requires one pad a day. Erectile dysfunction managed with a Cialis pill is
recorded the same as ED that only
responds to tri-mix injections.
So, for what
it’s worth, the authors found the following:
Erectile
Dysfunction (ED)
The authors note
that rates of ED were high in all three groups, and most men who received post-surgery RT had erectile
dysfunction prior to RT. Because of the limitations of the database, we can’t
determine the seriousness or causes of the ED complications.
Gastrointestinal
(GI)
There were many
gastrointestinal procedures. There were more GI events among those who were
treated with radiation vs. those who were not. Inexplicably, aRT was associated
with lower rates of GI events than sRT. This, again, makes me suspicious that
what is observed is an artifact of the methodology rather than a real effect.
Genitourinary
(GU)
Men who had
radiation were more likely to be diagnosed with incontinence and other urinary
side effects than men who had no radiation. But earlier radiation treatment was
not associated with worse effects than later treatments. Was this because
patients were selected for earlier treatment had early signs of GU recovery
after surgery?
Showalter et al. also conducted a similar analysis of an
Italian database. They also found that radiation after prostatectomy was
associated with worse GI and GU outcomes, but found that outcomes did not
improve by waiting longer before radiation treatment.
Because of database
limitations, it is extremely difficult to draw meaningful conclusions from
these studies. There is no way to judge how serious any of the effects were, or
if they were even related to treatment.
“these
two studies provide further confidence that earlier treatment should not
increase the risk of treatment-related toxicities.”
While I agree that most of the healing of cut tissues from
the surgery that will take place has already occurred within a few months, I
don’t believe the data in these studies support their conclusions. Until we get
better data from randomized clinical trials, how soon to treat with radiation,
if at all, remains a difficult decision for both patient and doctor, with no
easy answers.