Endocrine Ethics Blog

In progress

A “Special Article”, recently published in THYROID, tells the story of what happens when unsubstantiated clinical practice guidelines for thyroid cancer are promoted as optimal care. 

When the most recent revised thyroid nodule and thyroid cancer clinical practice guidelines were published by the ATA in 2015 (see: https://www.liebertpub.com/doi/pdf/10.1089/thy.2015.0020), the document remained at odds with the scientific consensus over the state of knowledge and previous standards of care. These guidelines made several sweeping recommendations without sufficient scientific or ethical justification (See: https://www.futuremedicine.com/doi/abs/10.2217/ije-2015-0010 and https://www.futuremedicine.com/doi/abs/10.2217/ije-2017-0008). The document also disclosed overt financial conflicts of interests by several of the authors, raising questions about whether some recommendations were influenced by authors’ industry ties. The fallout within the community of experts led to considerable moral distress amongst dissenting practitioners who felt they had beneficence-based duties to treat, but whose voices were marginalized. Indeed, thyroid cancer content presented at conferences in the post-2015 guideline years basically regurgitated the Haugen et al. (2015) recommendations as though they were partisan talking points. 

The most questionable departure from traditional thyroid oncology practice were recommendations against the diagnostic or therapeutic use of radioactive iodine, as well as recommendations against total thyroidectomy in patients whose tumors were as large as 4 cm – what some surgeons and thyroid oncologists would consider egregious. The guidelines also encouraged observation of “low risk” tumors (although I have argued elsewhere that such practice should be regarded as experimental, and violates the Belmont Report if it is not presented in a research context). No treatment, undertreatment and questionable disclosure to patients became the new paradigm in thyroid cancer care. Many of the recommendations were based on pet theories and biases of some of the authors, relying on highly flawed or ethically questionable studies to support them.  Of note, the nuclear medicine community refused to endorse the guidelines, which was unprecedented.

This month, in a stunning rebuke by Luster et al. entitled “European Perspective on 2015 ATA Management Guidelines for Adult patients with thyroid Nodules and DTC”, European experts called for revisions to approximately one-thirdof the ATA’s 101 recommendations in its 2015 document. (See: https://www.liebertpub.com/doi/abs/10.1089/thy.2017.0129.)

They stated the following in their abstract:

“Divergent viewpoints were the focus of an invited symposium organized by the European Association of Nuclear Medicine involving 17 European thyroidologists, four ATA Guidelines Taskforce members, and an audience of 200 international experts. The group discussed the preoperative assessment of thyroid nodules, surgery and the role of pathology, radioiodine (RAI) therapy (RAIT), the assessment of initial therapy and dynamic risk stratification, and the treatment of persistent disease, recurrences, and advanced thyroid cancer. The dialogue resulted in this position paper contrasting European and ATA 2015 perspectives on key issues. One difference pertains to the permissiveness of ATA 2015 regarding lobectomy for primary tumors ≤4 cm. European panelists cited preclusion of RAIT, potential need for completion thyroidectomy, frequent inability to avoid chronic thyroid hormone replacement, and limitations of supportive evidence as arguments against widely applying lobectomy. Significant divergence involved ATA 2015’s guidance regarding RAIT. European panelists favored wider use of postoperative RAIT than does ATA 2015. …European panelists suggested modifications to approximately one-third of ATA 2015 recommendations.” 

Facts can be a stubborn thing.  

There is a perfect “thyroid storm” brewing within the thyroid cancer community that will certainly result in preventable deaths. The storm has to do with dangerous misconceptions of appropriate management for so-called “low risk” thyroid cancer.

The problem involves confusing two separate issues: biopsy of nodules under 1 cm and treating biopsy-confirmed thyroid cancers over 1 cm.

A recent piece in the New England Journal of Medicine, has been misconstrued by the national press to mean  that for most cases of thyroid cancer, treatment is not necessary. Here’s the original piece: http://www.nejm.org/doi/pdf/10.1056/NEJMp1604412

There is nothing new reported in this epidemiology paper. It confirms the problem of mass screening of thyroid nodules, and confirms that, yes, many biopsy-confirmed thyroid cancers will likely remain indolent.

Misconceptions arise in how this translates from epidemiology to the bedside.

Here’s where everyone agrees: don’t biopsy thyroid nodules under 1 cm. Leave them alone unless there is some other alarming feature, such as invasion beyond the thyroid capsule or obviously enlarged local lymph nodes.

Here’s where it turns into a game of Russian Roulette with the practitioner holding the gun to the patient’s head: tell the patient you will “place bets” that a small biopsy-confirmed thyroid cancer will remain indolent – something no one can currently predict. Odds are it will. But some of the patients will be the unlucky losers of the Roulette game. In fact, all aggressive thyroid cancers, and all eventual lethal thyroid cancers, started as small tumors.

What do the most recent American Thyroid Association (ATA) clinical practice guidelines say? (See: http://online.liebertpub.com/doi/abs/10.1089/thy.2015.0020).

Well, the guidelines do not recommend observation-only for biopsy-confirmed thyroid cancer and state that there is “not enough evidence” observation is more beneficial than treatment. But the authors do state that IRB-approved randomized controlled-trials regarding observation for papillary carcinomas under 1 cm, also known as papillary microcarcinomas, would help to generate data on this question. Clearly, there is a big difference between enrolling such patients in a clinical trial to investigate the validity of this approach, and having clinicians routinely do this in their clinical practice outside of a research setting and without any research subject protections in place.

What do guidelines say about radioactive iodine (RAI)? Nuclear medicine experts worldwide recommend RAI as beneficial in follow-up and treatment (See: http://erc.endocrinology-journals.org/content/21/6/R473.full). Of note, the ATA’s recent guidelines were not endorsed by the nuclear medicine community in either the United States or Europe. (See, for example: http://www.ncbi.nlm.nih.gov/pubmed/26883666).

As a result, the best consensus guidelines to follow regarding radioactive iodine therapy would be the 2009 ATA guidelines, which were endorsed by the entire nuclear medicine community.

What do bioethicists think? Bioethicists who appreciate the nuances of thyroid cancer treatment believe patients must be told about the full treatment options available, including potential benefits of radioactive iodine, as well as the risks associated with observation. Routine observation should not be done outside of the research setting. We say so here: http://www.futuremedicine.com/doi/abs/10.2217/ije-2015-0010?journalCode=ije

What will patients say should they become aware that they were not fully informed of their risks and treatment options? Some will say they were unwitting players in a game of Russian Roulette, which can have serious medico-legal consequences for practitioners who are playing this game.

In the spirit of last week’s April Fool’s Day, I’d like to point out a paper recently published in THYROID from a Japanese group by Oda et al that’s been getting a lot of buzz: http://www.ncbi.nlm.nih.gov/pubmed/26426735

This paper’s premise is to track the surgical side effects and complications (including scarring) of thyroid cancer patients with papillary microcarcinoma (PMC) who have surgery and then compare that to the treatment side effects in thyroid cancer patients with PMC offered “observation” instead. Guess what the results were? [Spoiler alert:] Yes, the PMC patients who have surgery have more surgical complications than patients who don’t.

It’s natural to ask whether there was any other point to this paper. For example, did the authors actually evaluate the long-term complications that can occur when a biopsy-proven thyroid cancer that is not surgically removed metastasizes? No. The patients were only followed for a median of 4 years in the context of a disease where recurrence may not be seen for decades. And they were only followed with ultrasound and thyroid function tests, which is not sufficient to conclude whether patients eventually developed distant metastases (radioactive iodine cannot be used as a therapy or diagnostic tool in patients who do not have surgery). Among the patients who did have surgery, many had merely a lobectomy, which also precludes any radioactive iodine follow-up. So in the end, the claims that the “oncological” outcomes were similar in the patients who had surgery and those who did not, cannot be known and cannot be stated. Since all aggressive, poorly differentiated thyroid cancers start out in each person as a “microcarcinoma” you can’t predict which PMCs will spread to distant sites.

See: http://www.ncbi.nlm.nih.gov/pubmed/26109472 and http://www.ncbi.nlm.nih.gov/pubmed/25602471

So it’s reasonable to conclude that a number of those unfortunate patients who had not received surgery could develop lung or bone metastasis that are not recognized and don’t receive any treatment or follow-up.

This begs the question as to whether this paper makes any contribution to science. The answer is No.

Studies with questionable heuristic value like this one are certainly in good company. The British Medical Journal, for example, published a study on sword swallowing, which found there were more side effects when the swallower is distracted or swallowing multiple or odd-shaped swords (See: http://www.ncbi.nlm.nih.gov/pmc/articles/PMC1761150/). It also published a study stating that people with acute appendicitis may feel pain when traveling over speed bumps (See: http://www.bmj.com/content/345/bmj.e8012).

The main problem with the Oda et al paper is that it’s not a joke. Not only did it make it through the peer review process into a good journal, but this paper could become an “Emperor has No Clothes” vehicle for proponents of observation.

So the ethical issue here is one of publication ethics and epistemic integrity. It’s not that a “Duh Study” was published. It’s the fact that it’s being misrepresented as having heuristic value when it’s really Fool’s Gold.

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Note: This blog was expanded from an initial Letter to the Editor I submitted to THYROID on 3/29/16 entitled “What Heuristic Value?” co-authored by Kenneth Ain, MD. Professor of Medicine and Director, University of Kentucky Thyroid Oncology Program, and Peter Angelos, MD, Ph.D., Professor of Surgery and Chief, Endocrine Surgery, and Associate Director, MacLean Center for Clinical Medical Ethics. The letter was not accepted for publication.