Apparent Survival Benefit of Postoperative Radioactive Iodine in Lymph Node–Positive Papillary Thyroid Carcinoma: A Negative‐Control Analysis for Unmeasured Confounding
Tengfei Liu, Junli Qiao, Mengxuan Mao, Qiang Guo, Fei YangABSTRACT
Background
Observational studies report an overall‐survival advantage for postoperative radioactive iodine (RAI) in lymph node–positive papillary thyroid carcinoma (PTC), but such estimates are vulnerable to confounding by indication and to bias from immortal time and the healthy‐user effect. We assessed the credibility of this apparent benefit rather than RAI efficacy itself.
Methods
Using SEER (2010–2015), we assembled a cohort of N1b, M0, totally thyroidectomized PTC patients and applied a 3‐month landmark analysis (sensitivity analyses at 1 and 6 months) with stabilized inverse‐probability‐of‐treatment weighting. We estimated RAI effects on overall survival, cancer‐specific survival, and relative survival, and on a negative‐control outcome—non–thyroid‐cancer death—that RAI cannot plausibly affect. Residual confounding was quantified with E‐values.
Results
Among 4275 patients, RAI showed an apparent survival benefit in direction across all three endpoints. However, the negative‐control outcome likewise showed an apparent benefit (IPTW hazard ratio 0.713, 95% CI 0.562–0.906), indicating residual confounding not removed by weighting. The apparent survival benefits therefore could not be distinguished from unmeasured confounding.
Conclusions
In registry data lacking key confounders, a negative control identifies the apparent RAI survival benefit as a candidate artifact of unmeasured confounding. The findings neither support nor refute RAI efficacy.