“Standard of care (SOC),” is a legalistic term. As it
applies to medicine, it means that the doctor has proceeded with reasonable caution,
as any minimally competent doctor would exercise in such circumstances. It
clearly protects the doctor from malpractice lawsuits. But is it always in the
patient’s interest? Can following it too rigidly harm patients whose status
requires adjustment for natural variation? Conversely, what are the risks of
departing too far from the norms?
In radiation therapy, SOC can be determined by professional
organizations, consortiums of hospitals (like the National Comprehensive Cancer
Network - NCCN), NGOs (like the American Cancer Society), individual hospitals,
peer review, or by the customary practice of individual doctors. For clinical
trials of new therapies, an Internal Review Board (IRB) is responsible for
defining ethical constraints. In addition, the FDA, the Centers for Medicare and
Medicaid Services (CMS), and insurance companies may define SOC by dictating
which therapies are approved and reimbursable. The American College of
Radiology (ACR), the American Society for Therapeutic Radiation and Oncology
(ASTRO) and the American Brachytherapy Society (ABS) are the largest
professional organizations of radiation oncologists.
For interested readers, here is a list of some guidelines
and white papers on specific radiation therapies:
High Dose Rate Brachytherapy for Prostate (ABS)
SBRT (ASTRO)
Proton Beam Therapy (ASTRO)
Very few of the above are specific to radiation for prostate
cancer. In some cases, there is a paragraph or short chapter. In 2013, the
Radiosurgery Society (RSS) began writing guidelines for prostate SBRT, but has so far abandoned the effort. What’s the problem?
The problem is that developing guidelines is a lot of work,
and the work is usually unfunded and thankless. The top practitioners in each
field are often approached in order to enhance the credibility of the
guidelines. These are often the clinicians who are busiest and who have the
least to gain – they already know what works and what doesn’t through their own
research and experience. They must compile and sift through massive amounts of
data to summarize what’s known about the subject. Then they must issue draft
guidelines, send them to peers, wade through peer comments, send out second
draft guidelines, etc., until consensus is reached, or it becomes clear that no
consensus can be reached. The consensus opinion is then peer-reviewed and
published. By the time it is published, new information from studies and
clinical trials may render some of the conclusions outdated, so revisions must
be done continually.
While some patients (and clinicians) may worry that SOCs are
too restrictive, well-written ones acknowledge the variance in the data and
allow for adjustments depending on patient characteristics. Some doctors,
fearful of being sued, may follow them too slavishly, but I think most will
simply explain why adjustments must be made and are reasonable. This not only
protects the doctor, but the patient as well. A patients deserves to know what
adjustments to the SOC are planned for him, and why.
In some cases, the SOC fails to gain a consensus among
practitioners. The abovementioned AUA/ASTRO guidelines on adjuvant/salvage
radiation after prostatectomy are a case in point. Many doctors believe that
following those guidelines would result in overtreatment; consequently, they
are increasingly ignoring them. Unfortunately, they are not only delaying
radiation, which might be prudent, but seem to be forgoing it entirely. This
was discussed in a recent commentary (see this link).
SOCs also protect patients from being experimented on
without their consent. Although we may conceptually admire the maverick doctor
who thinks out of the box to come up with the next breakthrough, such
miraculous treatments seldom occur in practice. At the very least, even the
patient who is willing to be the test case of a new treatment, must sign a
waiver acknowledging that the treatment is experimental, has unknown and
possibly unsafe outcomes, and is outside the SOC.
This puts some clinical trials in a gray area. We have
reported on some radiation clinical trials that are so far outside the SOC,
that they are ethically questionable. SOC continually evolves along with medical evidence from new
clinical trials, so the two work hand-in-hand. Let’s look at a few that involve
SBRT. Unfortunately, there are no published SOC guidelines for prostate SBRT.
The lack of an official SOC has allowed some clinical trials to be implemented
that have put patients at risk.
• We looked at the Bauman et al. study that had to be terminated because of higher than expected
toxicity. SOC guidelines specific to prostate SBRT that included intra-fractional
motion tracking and tighter dose constraints might have spared those patients
injury.
• Kim et al. used a dose schedule as high as 50 Gy in 5 fractions, far above what
others use for SBRT. As a result, 6 of the 61 patients treated with this
extreme dose suffered Grade 3 and Grade 4 rectal toxicity. Four of them had to
have a colostomy, 2 suffered rectourethral fistulas, and one had grade 4
bleeding that was treated with cauterization. Toxicity like this has never been
reported in SBRT literature before or since. One might understand a study like this if they were trying to find an
optimally effective dose, but the stated purpose was only to find the
dose-limiting toxicity – they found it.
• As we commented earlier, the City of Hope is conducting a clinical trial of SBRT salvage radiation after prostatectomy (NCT01923506).
While SBRT for salvage is potentially a low cost and beneficial therapy worthy
of a clinical trial, their dosimetry is far outside of the SOC. They propose to
use a dose as high as 45 Gy in 5 fractions to the prostate bed. This is higher
than the dose typically delivered to the intact
prostate during primary SBRT radiotherapy. Doses for salvage radiotherapy are
usually reduced, not increased. They want to find the dose such that up to a
third of patients will experience dose-limiting toxicity. A third is a lot of toxicity.
• The Moffitt Center is conducting an SBRT clinical
trial (NCT02572284) that is
questionable for several reasons. First, they misinform with the statement,
“The standard dose is 10 Gy per day when SBRT is the only treatment to the
prostate and no surgery is planned.” That dose far exceeds customary practice,
and is quite toxic, as we saw in the Kim et al. study. Fortunately, they will
be using far lower doses of 25, 30, or 35 Gy across 5 fractions. Only the 35 Gy
dose is used in customary practice for prostate SBRT. All high-risk patients will also have a prostatectomy 2
weeks or 4 weeks after the radiation. Considering the known safety issues
involved in salvage surgery after radiation, even by very experienced surgeons,
I am perplexed that they would do this adjuvant surgery at all, let alone that
soon. I think there will be horrendous harm at all dose levels, and they will be unable to find an optimal dose
level. I also wonder if patients are being informed that either therapy alone
might be curative. Furthermore, I hope patients are told that there will be no
salvage therapies available to them if this combo treatment fails.
Dose escalation studies are usually done to find the optimal
dose. The “dose-response curve” is S-shaped. At the bottom, at very low doses,
there is little increase in cancer control. Then on the steep part of the
curve, cancer control increases rapidly with increasing dose. Finally the curve
flattens again as increasing dose adds little cancer control, but adds
significantly to toxicity. The goal is to locate the dose at the top of the
steep part, just before it flattens out. How are we to find that optimal dose –
the new SOC - without pushing the envelope of SOC so far that patient safety is
compromised?
Memorial Sloan Kettering Cancer Center is conducting an SBRT
dose escalation study (NCT00911118)
that illustrates how this can be done safely and ethically. The first group of
30 patients received 32.5 Gy in 5 fractions. If fewer than 10% suffered
dose-limiting toxicity, the next group of 30 patients received 35 Gy. The next
group received 37.5 Gy; and the next, 40 Gy. A patient told me that owing to
low toxicity rates, they added an additional cohort of 30 patients receiving
42.5 Gy. This is the way to find the SOC for SBRT – in incremental steps with
care taken to assure patient safety all along the way.
I hope ASTRO, ACR or the RSS will develop SOCs for prostate
SBRT and the other forms of prostate radiation for which SOCs are lacking. They
protect both the patient and clinician, and provide the ground above which
improvements can be made ethically and safely.
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