A new study by Ohri et al. (with additional information in the ASCO Post) found that for
certain cancers, there was a 22% non-compliance rate at the Montefiore/Albert
Einstein Cancer Center in NY. Non-compliant patients extended their total
treatment time by about a week. The recurrence rate was 7% among compliant patients,
but was significantly higher, 16%, among non-compliant patients. Now, the
authors only looked at compliance with radiation schedules for head and neck,
breast, lung, cervix, uterus and rectal cancers. Should prostate cancer radiation
oncologists and their patients be concerned?
All cancers are different. It is impossible to generalize
from one cancer to another. This is as true for radiation treatments as it is
for medical treatments. Prostate cancer has some very unique characteristics
that affect radiation treatments:
(1) Prostate
cancer is very slow growing. For
certain cancers like some head and neck cancers, the tumor growth is so fast
that multiple radiations sessions must be scheduled each day (called hyperfractionation) in order to keep
ahead of the high cancer cell repopulation rate. In fact, the repopulation rate
increases as radiation progresses for such cancers. In contrast, even high-risk
prostate cancers repopulate so slowly that delays of a few days to a week are
insignificant. In fact, some treatment schedules for SBRT and HDR brachytherapy
are a week apart with no apparent loss of efficacy.
(2) Prostate
cancer responds to fewer, higher doses of radiation – hypofractionation. Prostate cancer has a peculiarly low
radiobiological characteristic, called an alpha/beta ratio, which means it is
killed more effectively by hypofractionated radiation. Two major randomized
clinical trials have proved that shortened radiation schedules (20 fractions or 28 fractions) have equivalent effectiveness and no worse toxicity than the traditional fractionation of 40-44 treatments. The
most extreme kinds of hypofractionation, SBRT and HDR brachytherapy, typically
only need 4 or 5 treatments. Recent HDR brachytherapy protocols are using as
few as 2 treatments. Therefore, patient compliance isn’t much of an issue. For
cancers with a high alpha/beta ratio, more fractions with lower dose per
fraction are needed to kill the cancer. Showing up every day for many weeks can
be burdensome to the patient.
(3) Fatigue
increases with the number of fractions, so reducing the number of prostate
cancer treatments helps maintain vigor. With normally fractionated prostate radiation,
fatigue peaks at 4-6 weeks after the start of therapy (See this link.). While fatigue scores increased a month after SBRT, it was not a
clinically meaningful change (See this link.).
Fatigue reported from prostate cancer radiation is less than from radiation to
head and neck, alimentary and lung cancers (See this link.); therefore,
non-compliance due to fatigue from radiation is probably less important for
prostate cancer, particularly with hypofractionation. Other issues sometimes
associated with extended fractionation include anxiety, nausea, lost days of
work and financial burden. Ohri et al. found that compliance was worse among
those of lower socio-economic class.
(4) Prostate
cancer’s alpha/beta ratio is much lower than the ratio attributable to healthy
surrounding tissues – a therapeutic advantage. This means that prostate cancer
cells are more efficiently killed by the hypofractionated regimen, but the
healthy tissues of the bladder and rectum that respond quickly to radiation are
not killed at all efficiently. So a total SBRT dose of, say, 40 Gy in 5 fractions,
has much more cancer killing power than an IMRT dose of, say 80 Gy in 40
fractions, but less acute toxicity to healthy tissues. This contrasts with other cancers
where the alpha/beta ratio of the cancer is similar to that of nearby healthy
tissues. In that case, the only way to mitigate damage to healthy tissues is to
deliver the radiation in much smaller fractions, and allow time in between for
sub-lethally damaged healthy tissues to self-repair. It doesn’t take long, only
a few hours, but for practical purposes, treatments are a day apart.
(5) Prostate
cancer is multi-focal in at least 80% of men. Tumors are almost always
distributed throughout the entire prostate, so the entire organ is irradiated.
This contrasts with many other cancers where there is a single large tumor
growing in the organ, at least for a long time. For non-prostate cancers, it is
rare for the entire organ to be treated.
(6) There
are many important organs (including the bladder, rectum, penile bulb and femur)
that fall, at least in part, within the radiation field. Prostate radiation
requires sophisticated image-guidance and intensity modulation to treat the
prostate and nothing else. Unlike radiation for other cancers where there are
toxic effects due to treating the organ itself, there is almost no toxicity due
to irradiation of the prostate itself (other than loss of seminal fluid).
Discomfort from bladder and rectal toxicity arrives only towards the end or
after the end of treatments, so there is little reason to discontinue or miss
treatments.
(7) Unlike
the other organ cancers that were treated in the study, the prostate is deep
within the body. Higher energy X-rays are needed for that depth, and that
spares closer-to-surface organs. Consequently, radiation burns of the skin
rarely occur, and there is no discomfort associated with each treatment. There
are exceptions in men who are hypersensitive to radiation, but burns, necrosis,
and fistulas have rarely been reported.
There are some radiobiological
considerations that are similar to other cancers that respond to radiation (not
all of them do). Some cancer cells may self-repair sub-lethal damage to the
DNA, and poor tumor-tissue oxygenation (hypoxia) may protect the tumor from
radiation damage. For these reasons, it is important to deliver enough
radiation to overcome the hypoxia and kill all the cancer cells. Dose
escalation has improved the curative potential of radiation for prostate cancer.
An argument in favor of longer treatment regimens is that
cancer cells are more vulnerable during certain phases of their cell cycle; therefore,
there will be more opportunities to kill them over a longer treatment schedule.
Another argument for longer schedules is that hypoxic protection of the tumor
is worn away by the treatments, and subsequent growth of blood vessels around
the tumor will re-oxygenate it, thus radio-sensitizing it. The greater local control we’ve seen with extreme hypofractionation suggests that it
may elicit unique radiobiological mechanisms that might overcome hypoxia and
cell cycle phase issues.
Because of prostate cancer’s low repopulation rate, higher
quality of life during treatment, and with increasing use of hypofractionation
(both moderate and extreme) there is no reason why patient compliance with
prostate cancer treatment schedules should be a problem as it is for other
cancers.
(Update 12/6/20) In the National Cancer Database, patient non-completion of SBRT for prostate cancer was 1.9% vs 12.5% for conventionally fractionated treatment.
