No Benefit From RAI After Second Thyroid Cancer Surgery

Liam Davenport

August 17, 2018

Adding a course of radioactive iodine (RAI) to a second surgery for recurrent or persistent papillary thyroid carcinoma (PTC) does not appear to offer a clinical benefit, and there is no reduction in the rate of subsequent recurrences, conclude US researchers.

Their conclusions come from a retrospective analysis of just over 100 patients who underwent reoperation for recurrent PTC.

The study showed that patients experienced reductions in levels of tumor markers whether or not they underwent RAI administration. There was no significant difference in recurrence rates between the two groups.

However, the study also found there were fewer recurrences among patients who underwent surgery alone compared to those who also received RAI therapy, and RAI recipients were less likely to have an excellent tumor marker response.

The study was published online August 15 in JAMA Surgery.

Study author Michael W. Yeh, MD, Section of Endocrine Surgery, David Geffen School of Medicine, University of California, Los Angeles (UCLA), said that "for many years, radioactive iodine was thought to be just a freebie, that you got it and there were almost no side effects."

Speaking to Medscape Medical News, he explained that, on the contrary, it has recently been understood that RAI is associated with an increase in the rate of blood-borne cancers, as well as with problems involving salivary glands and tear ducts and a reduction in live births among women who undergo RAI treatment after age 35 years.

"There are downsides to radioactive iodine, which we have probably underappreciated in the past and we're better understanding now," he added.

Yeh said that as a result of their findings, he and his colleagues are waiting a couple of months after reoperating for recurrent PTC to see whether thyroglobulin (Tg) levels decrease to "an acceptable range."

He continued: "So if we do a reoperation and the tumor marker level goes from 10 to 0, we feel more confident that that patient cannot need anything more other than close follow-up."

If, however, Tg levels do not decrease sufficiently, RAI treatment will be considered, with the aim of being "thoughtful about it"; they use postoperative tumor marker levels "as an indicator of the extent of surgical clearance during that second operation."

"What this whole paper is about is avoiding overtreatment," he said.

Approached for comment, R. Michael Tuttle, MD, Memorial Sloan Kettering Cancer Center, New York City, told Medscape Medical News that it is a "nice study."

He said that "there will be a lot of criticism because it's not randomized, but I think it's really going to help us reevaluate the discussion and ask questions about well-meaning additional therapy with radioactive iodine."

Tuttle, who was not involved in the study, added that the findings "should make you very cautious about the automatic use of another dose of radioactive iodine."

He pointed out that "if you look at the big picture," the vast majority of patients underwent RAI treatment with their initial operation, "which means, by definition, if they recurred, they failed radioactive iodine with that first treatment.

"So if they failed radioactive iodine with that first treatment, it's beyond me why we think that another dose of radioactive iodine would be helpful," he said.

"I think this study brings that kind of discussion to the front, which is really good," he continued. "While we can't rule out some small effect of radioactive iodine in this a minimum, it reminds us that a second dose of radioactive iodine is not the end of the story, and you can't guarantee the patients that they'll be fine after that.

"The old guys used to say to man with a hammer everything that looks like a nail," he commented. "We had one hammer, and it's radioactive iodine. If you failed, we just keep hammering away, but from an oncologic perspective, that doesn't make a lot of sense."

RAI After Thyroidectomy

Although RAI treatment is recommended after initial thyroidectomy for patients at high risk for recurrence and it decreases locoregional recurrence, its role after reoperation for persistent or recurrent PTC is less clear.

Yeh explained that, when he arrived at UCLA 12 years ago, every patient received RAI after initial surgery for thyroid cancer, "and now it's about 20% to 40%, and I think that's the appropriate number."

Following initial surgery, with or without RAI, up to 30% of patients will experience locoregional recurrence, necessitating a second operation.

Yeh said that these operations "are a little more challenging than initial operations because of the scar tissue after the first operation," and the patients ask: " 'You did my second operation because my cancer came back; do I need more RAI?' That was the question we set out to answer."

The researchers therefore examined electronic health record data from the University of California Integrated Clinical and Research Data Repository on 102 patients who underwent neck reoperation between 2006 and 2016.

The patients' median age was 44 years, and 66% were women. Fifty patients underwent reoperation followed by RAI treatment at a median dose of 155 mCi; 52 underwent reoperation without subsequently undergoing RAI treatment.

Although baseline clinicopathologic characteristics were similar between the two groups, T stage was higher among those who received RAI in comparison with those who did not; of patients with stage T3 or T4 disease, 28 (56%) who received RAI, vs 19 (37%) who did not.

During the reoperation, the total number of lymph nodes that were removed and the number of malignant lymph nodes that were removed were similar for those patients who did and for those who did not receive RAI. The extent of reoperation was similar for the two groups.

More patients who received RAI had microscopic extranodal extension than those who did not receive RAI, at 29 (58%) vs 17 (33%) (SD, 0.53).

Across both groups, Tg levels decreased from a median of 2.8 ng/mL just before reoperation (Tg0) to 0.2 ng/mL within 6 months after reoperation (Tg1). There was no significant difference in median Tg0 and Tg1 levels between the two groups.

However, the rate of excellent responses at Tg1 was lower in the RAI group than in the non-RAI group, at 12% vs 47% (P = .007).

Patients who received RAI were more likely to experience a pathologically confirmed recurrence after reoperation than those who did not, at 36% vs 19%. The median time to recurrence was 11 months and 12 months, respectively.

There was no significant difference in recurrence-free survival after reoperation between the two groups.

Multivariate analysis that took into account clinicopathologic characteristics such as T stage at initial operation, Tg0, reoperation extent, and extranodal extension demonstrated that RAI treatment after reoperation was not associated with the risk for a second recurrence (hazard ratio, 1.12; P = .81).

Even after limiting the analysis to patients with detectable Tg levels after reoperation or when treating Tg0 either as a continuous variable or a dichotomized cutoff, there was no association between RAI and the risk for a second recurrence.

Subanalysis of patients with T3 or T4 tumors at baseline still did not reveal a benefit of adding RAI treatment after reoperation.

Important Limitation

The study was retrospective, and the researchers acknowledge that the lack of randomization is the "most important" limitation.

This is because patients receiving RAI "were more likely to be selected on the basis of clinical features that were perceived to be associated with a higher risk of recurrence than were patients who underwent reoperation alone," the authors state.

Moreover, the study was conducted at a single referral center, "which limits our knowledge of clinical events before surgery" and means it may not be adequately powered, they write.

"With this caveat, after multivariable adjustment, we cautiously accept the null hypothesis that reoperation with receipt of RAI is not associated with a significant prolongation of recurrence-free survival," they state.

The research was supported by a grant from the National Institutes of Health, the National Center for Advancing Translational Science, and the University of California, Los Angeles. The Clinical and Translational Science Institute supported the analysis of the data. The authors have disclosed no relevant financial relationships.

JAMA Surg. Published online August 15, 2018. Abstract

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