In an attempt to quantify the influence of RRA on outcome in low-risk PTC after adequate initial surgery, we performed in 2002 [25] and again in 2006 [50] analyses on 1163 MACIS low-risk PTC (scores <6) patients, who had undergone NT or TT during 1970–2000 for tumors confined to the neck that were completely excised at initial neck exploration. 498 (43%) of these patients had RRA within 6 months of the initial surgery. Those who received RRA were more likely to have had NNM at presentation (p < 0.001). Of 636 node-negative patients, 195 (31%) received RRA. However, of 527 node-positive patients, 303 (57%) were ablated.

At 20 postoperative years, the CSM rate for the surgery alone patients was 0.4%, and for the NT/TT and RRA group, it was insignificantly different at 0.6% (p = 0.64). At 20 years, the TR rate was actually significantly higher in the ablated group (14% vs. 9%; p = 0.008), likely reflecting the tendency to more readily ablate node-positive patients. When the patients were divided into node-negative and node-positive groups, there were no statistically significant differences in outcome (CSM and TR) between those having surgery alone and those who also received postoperative RRA. Interestingly, there were no deaths from PTC in the 636 node-negative cases and only two in the node-positive group.

For the node-negative patients, the 20-year TR rates were 3.4% after surgery alone and 4.3% after surgery and RRA (p = 0.80). For the node-positive group, who clearly had much higher TR rates, the CSM rates at 20 years were 1.2% after surgery alone and 0.9% after RRA (p = 0.99). The 20-year TR rates only differed by 0.4%, being 19.5% for surgery alone and 19.9% for surgery and RRA (p = 0.66). Clearly, it was our 2006 conclusion [50] that RRA did not significantly improve the outcome (either CSM or TR) in low-risk (MACIS scores <6) PTC patients previously treated with initial NT or TT with curative intent. This conclusion obviously became a pivotal part of our Mayo policy [51] for managing patients with low-risk PTC published in 2007.

As we prepared for this chapter and were working on updated outcome results from our eight-decade Mayo PTC cohort, we considered it relevant to extend the years of our MACIS <6 cohort a further 14 years to encompass those low-risk PTC patients who were surgically treated definitively, with or without RRA, in the years of 2001–2014. This added a further 911 patients to a new total cohort of 2074 adult MACIS <6 patients, of whom 760 (37%) underwent RRA within 6 months of NT or TT with curative intent. The principal details of the 20-year CSM and TR rates are included in the accompanying Table 17.1.

Figure 17.4 illustrates the differences in TR over 20 postoperative years between ablated and not ablated patients in the entire study cohort of 2074 low-risk PTC patients (left panel), the 1159 node-negative cases (middle panel) and the 915 node-positive patients (right panel). As expected, in the node-positive patients, most recurrences (83%) were situated in regional neck nodes. There were no significant differences between the ablated and the not ablated groups in terms of either local recurrences (p = 0.34) or distant metastases (p = 0.49), generally considered [3, 32] to be postoperative events associated with an increased risk of CSM. Interestingly, the recurrence rate in regional nodes was insignificantly higher (p = 0.05) in the 496 ablated patients, and this was felt to be attributable to significantly higher numbers of NNM found in those patients selected for RRA. The cumulative recurrence rates over 20 postoperative years in the 915 node-positive cases for all three anatomic locations (regional, local, and distant) are illustrated in Fig. 17.5.

The results of these two studies defining the lack of impact of RRA on outcome in MACIS <6 low-risk PTC have helped convince us that RRA can probably be avoided in, not just the 68% of PTC patients who have pT1 tumors but also the 84% who have MACIS scores <6 and have tumors localized to the neck and having complete primary tumor excision at initial definitive surgery.

That remarkable source of knowledge, Wikipedia, informs us that “conceptually, a meta-analysis uses a statistical approach to combine the results from multiple studies in an effort to increase power (over individual studies), improve estimates of the size of the effect and/or to resolve uncertainty when reports disagree.” Given the rancor expressed in the past 30 years over the vexed question of the efficacy of RRA in low-risk PTC, it is not perhaps surprising that multiple authors have jumped at the chance of “resolving uncertainty when reports disagree.”

Mayo-trained Anna Sawka started this type of study in 2002–2003, while she was working at McMaster University in Hamilton, Ontario. She began by screening 1543 unique references and ended up by studying in great detail those 23 references [27] that “met all inclusion criteria,” one of them from Mayo [25]. Her conclusion [27] from a systematic review of the 1966–2002 literature was that “the effectiveness of RAI ablation decreasing recurrence and possible mortality in low-risk patients with well differentiated thyroid carcinoma, although suspected, cannot be definitively verified by summarizing the current body of observational patient data.” She expressed the opinion [27] that “only a long-term randomized controlled trial may definitely resolve this issue” and concluded that “in the meantime, the decision for RAI ablation must be individualized, based on the risk profile of the patient, as well as patient and physician preference, while balancing the risk and benefit of such therapy.”

Four years later, Sawka published [26] an “updated systematic review” which included data from 20 studies from the original review [27], the original review itself, and seven newer studies from 2002 to 2007. Again, she was unable to identify any long-term randomized controlling trials examining outcomes after RRA; she therefore restricted her review to observational data. Her conclusion in 2007 was that “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 WDTC.” She observed [26] that “in an age of freely available information, patients themselves may have strong opinions about accepting or declining RRA and it is important for physicians to be sensitive to such concerns. 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.”

In a more recent systematic analysis of the 1966–2008 peer-reviewed literature, published in 2010, Sacks [52] from Cedars-Sinai reported “that the preponderance of evidence suggests that RAI treatment is not associated with improved survival in patients with low-stage or low-risk DTC. The data concerning recurrence rates following RAI treatment in this group of patients were less conclusive.” On the basis of her analysis, she recommended the adoption of a risk group categorization, based on AJCC TNM staging and the MACIS score, and proposed a management guideline based on a patient’s risk: very low, low, moderate, and high. Her final conclusion was that “a majority of very low-risk and low-risk patients, as well as select cases of patients with moderate risk, do not demonstrate survival or disease-free survival benefit from postoperative RAI treatment, and therefore we recommend against postoperative RAI in these cases.”

Finally, in 2015, an Italian systematic review [53] by a group of investigators from Rome and led by Cooper, the lead author of the 2006 [47] and 2009 [54] ATA Guidelines, concluded that, when compared to earlier meta-analyses [26, 52] of literature until 2007–2008, “our review of the more recent literature (2008–2014) clearly shows no advantage of RRA in low-risk patients, but it was unable to provide conclusive data for or against RRA in preventing disease recurrence in intermediate risk patients.” They recommended from their analysis that “a careful evaluation of tumor pathological features and patient characteristics and preferences should guide RRA decision making.” They expressed hope that the two presently ongoing European prospective randomized trials (the French Estimabl2 study and the British IoN study) will “provide valuable data to inform this issue.” They recommended that “an undetectable serum Tg, especially in a high-sensitivity Tg assay, and negative neck US 6–12 months after surgery should enable many low risk and intermediate risk patients to be categorized as being ‘free of disease’, despite not having undergone RRA,” thereby supporting a position remarkably close to that proposed in the 2007 description of the current Mayo management [51] of patients with low-risk PTC.