Showing posts with label standard of care. Show all posts
Showing posts with label standard of care. Show all posts

Tuesday, August 30, 2016

Why we should care about standard of care

“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:
Low Dose Rate Brachytherapy for Prostate –(ABS) (ACR)
High Dose Rate Brachytherapy for Prostate (ABS)
High Dose Rate Brachytherapy (ASTRO)  (ACR)
Proton Beam Therapy  (ASTRO)
Adjuvant/Salvage IMRT after prostatectomy (AUA/ASTRO) (ACR)

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.