August 12, 2009 — Surgery is a standard treatment for thyroid cancer. The recommended operation for differentiated thyroid cancer is a total thyroidectomy, and the standard follow-up treatment is radioiodine remnant ablation therapy (RRA), which acts as a "radioactive eraser," destroying any thyroid tissue that has been left. This is routine clinical practice in the United States, but should it be?
A prominent expert in the field argues that for the majority of patients who receive it, RRA represents overtreatment, with no documented benefit and a possibility for harm. Ian D. Hay, MD, PhD, professor of medicine at the Mayo Clinic in Rochester, Minnesota, mounted a detailed and passionate argument against the use of RRA in a keynote lecture here at the World Congress on Thyroid Cancer 2009.
The majority of patients (>80%) with thyroid cancer have papillary thyroid cancer (PTC), and the majority of PTC patients (about 80% to 85%) are considered low risk. "This is the most common thyroid cancer, and the best one to have," Dr. Hay said, adding that these patients, after surgery, have a less than 1% chance of dying from their disease.
There is no evidence that RRA is beneficial in this group, Dr. Hay told meeting attendees.
There are no clinical trials or prospective data, he noted. But large reviews of retrospective data have shown that RRA in low-risk PTC patients does not reduce the risk for relapse and does not affect recurrence rates, either at local or distant sites, which is the raison d'etre for using this treatment, he explained. So there is no benefit, but there is a potential for harm, including an increase in the risk for a second primary nonthyroid cancer.
RRA should be used selectively, Dr. Hay said, and it should only rarely be used in low-risk PTC patients.
This is a rather extreme view, and quite different from what is seen in clinical practice, said Bryan McIver, MD, PhD, also from the Mayo Clinic. Introducing the keynote lecture, Dr. McIver described himself as a friend and colleague, and said he considers Dr. Hay a mentor. In an interview with Medscape Oncology, Dr. McIver commented that he shares Dr. Hay's view about RRA, but he pointed out that it represents the polar opposite of what is seen in routine clinical practice throughout most of the United States.
Used in Vast Majority of Patients
Currently, RRA is used in the vast majority — probably in excess of 90% — of PTC patients, Dr. McIver explained. Clinical practice is even more aggressive than the guidelines recommend; the American Thyroid Association (ATA) advises that RRA be used selectively, he added.
RRA is widely used, despite the lack of evidence of benefit, because there is such great pressure to "do something," Dr. McIver said. "Cancer is very emotive, and many of these patients are young women. It is very difficult to tell these patients that a treatment is available but you won't give it to them," he said.
There is also a practical consideration, Dr. McIver added. "It is far more time-consuming to do nothing — an explanation of why I don't recommend RRA can take 45 minutes, whereas if I give RRA, the consultation can be over in 10 minutes."
The diagnosis of cancer is a great shock, and patients understandably have a strong fear of it returning — and about 20% of these patients do relapse, Dr. McIver said. Although he considers the practice of RRA to be "based on hope rather than supporting evidence," he also made the point that — if it is performed — the physician facing a patient whose cancer has returned can say: "Well, we tried everything."
Agreeing with this point was a vocal proponent of RRA, Kenneth Ain, MD, from the Thyroid Oncology Clinic at the University of Kentucky in Lexington. "None of my patients goes on the roulette wheel," he said. "The only cytotoxic tool that I have is radioactive iodine and, as an oncologist, I feel that I need to treat these patients."
Dr. Ain was debating Dr. Hay at a lively Meet the Professor session, which was moderated by Dr. McIver.
Dr. Hay argued that it might not be necessary to "blast every last cell," and Dr. Ain argued that leaving thyroid tissue behind leaves the patient open to the risk for the disease returning, perhaps in a "nasty way."
"There is a unique window of opportunity just after surgery to deliver RRA and remove this risk," Dr. Ain argued. "Tumor cells transform over time, and they inevitably become less responsive to treatment," he said.
Dr. Ain also said that the standard tests for detecting residual disease, including ultrasound and measuring serum thyroglobulin, could miss tiny pockets of tissue either because of where they are situated or because the tissue is malfunctioning. He has seen cases in which RRA was followed by a dramatic fall in serum thyroglobulin, which "suggests we are killing disease that is anatomically situated in a way that is not visible on ultrasound or whole-body scans."
He also suggested that endocrinologists, who are often the specialists treating thyroid cancer, have a softer approach to patients and a tendency to undertreat because of concern about doing harm, whereas "oncologists are assassins and are used to treatments that are harmful, such as cytotoxics that make hair fall out."
Potential for Harm With No Evidence of Benefit
In the case of RRA, there is a potential for harm without any evidence of benefit in the low-risk group of patients, Dr. Hay argued. He cited a review of 6841 patients who had undergone RRA at several European centers, which found that, compared with the general population, they were at a significantly increased risk (27%) for solid tumors and leukemia (Br J Cancer. 2003;89:1638-1644).
Dr. McIver said that the potential for harm should not be underestimated, and that some patients experience permanent damage to the salivary gland and tear ducts.
In a poster presented at the meeting, Carlos Duque, MD, from the Hospital Pablo Tobón Uribe in Medellín, Columbia, and colleagues reported that about 12% of patients have a long-term disruption of salivary gland function, with edema, swelling, dry mouth, and bad taste, and about 60% of patients experience nausea and vomiting.
"The way we present this information is really important," Dr. McIver said. "We think that we are objective and that we are presenting scientific evidence, but we inevitably influence the decisions our patients are making."
He admits that most of his patients decide not to undergo RRA, and said that this relates to data collected at the Mayo Clinic (a retrospective review of 1163 patients published in J Surg Oncol. 2006;94:692-700). But patients see "colleagues whom I really respect" often decide the other way, and opt for RRA, he said.
"This is why these discussions at these conferences are so important," Dr. McIver said. "These discussions are influencing the choices that our patients are making."
Decreasing Use of RRA at Some Centers
The Mayo Clinic has been progressively decreasing its use of RRA since 1983, and Dr. Hay has been speaking out against it since that time.
"Others have been coming to the same conclusion," he said, noting that the use of RRA has been decreasing at Princess Margaret and Mount Sinai Hospitals in Toronto, Ontario, and at the University of Southern California Hospital in Los Angeles.
A recent meta-analysis of 28 studies of observational data, which consisted of more than 5000 patients, found no evidence of benefit (Endocrinol Metab Clin North Am. 2008;37:457-480). The Canadian authors, headed by Anna Sawka, MD, PhD, from the University Health Network in Toronto, wrote: "Upon carefully examining the best existing long-term observational evidence, the authors could not confirm a significant, consistent benefit of RRA in decreasing cause-specific mortality or recurrence in early-stage well-differentiated thyroid cancer."
The authors call for a randomized controlled trial to examine this issue, but in the meantime, they emphasize that it is important for physicians treating well-differentiated thyroid cancer to evaluate each case carefully, and to "advise patients about the uncertainty of the existing evidence supporting RRA."
"The current reality is that decision-making about RRA in early-stage thyroid carcinoma is a complex, evolving issue, and long-term higher-quality evidence is needed to inform future clinical practice," Dr. Sawka and colleagues conclude.
Selecting Patients Who Can Avoid RRA
In his lecture, Dr. Hay made the distinction between low-risk PTC patients who can skip RRA, in his opinion, and the 20% of patients who have high-risk disease and should undergo RRA. There is no biomarker to identify the high-risk patients, he noted, but there are several classification systems, based on clinical and pathological measures, that are used, including MACIS (metastases, patients age, completeness of surgery, invasiveness, and size of the tumor), which he defined in 1993.
Patients with a MACIS score of 6 or less are considered to be low risk; those with a higher score are considered to be high risk. This can guide the decision of who should receive RRA or, as Dr. Hay put it: "This allows us to use appropriate punishment to fit the crime." In this picture, the low-risk PTC patients would be "petty thieves," he said.
Currently at the Mayo Clinic, 85% of PTC patients who are low risk (with MACIS scores less than 6) do not receive RRA, he said.
Another way of identifying patients who could skip RRA was described at the meeting in an oral presentation by Paul Walfish, MD, and colleagues from Mount Sinai Hospital. They use the stimulated serum thyroglobulin test after surgery to detect residual disease, and patients who are found to have undetectable levels of this marker are offered the option of deferring RRA and opting for long-term surveillance instead.
Dr. Walfish told Medscape Oncology that the use of this test in patients with well-differentiated thyroid cancer has reduced the proportion of patients who undergo RRA to 20%; if they followed ATA guidelines, that proportion would be 60% to 80%, he said.
However, Dr. Ain was rather dismissive of both approaches, and said; "I don't treat numbers, I treat individual patients." Both of these approaches rely on statistics and populations, and they give estimates of the likelihood of residual disease, he told Medscape Oncology. He said that he prefers to consider each case individually and to rely on his clinical experience, which stretches 25 years. He treats only thyroid cancer, and sees about 2000 cases each year.
"I treat every patient as if she were my wife," he said, adding that — incidentally — his wife had thyroid cancer, although she was not a patient of his (they met when she approached him to review a book she had written). His wife, Sara Rosenthal, PhD, has since trained as a bioethicist, and they have cowritten a book aimed at the general public, called The Complete Thyroid Book.World Congress of Thyroid Cancer (WCTC) 2009: Abstracts 039 and P33. Presented on August 7, 2009