Mortality Risk of Nonoperative Papillary Thyroid Carcinoma: A Corollary for Active Surveillance

Abstract

Background: Active surveillance is established as an alternative to surgery for papillary thyroid microcarcinomas, but inclusion criteria and mortality risk for pursuing a nonsurgical approach have not been clearly defined. To gauge the feasibility of expanding active surveillance thresholds, we investigated the effects of increasing size and age on disease-specific survival (DSS) in a large nonoperative thyroid cancer cohort, compared against a matched group of surgical patients. Methods: Papillary thyroid carcinoma patients staged T1-4N0M0 were identified in the Surveillance, Epidemiology, and End Results (SEER) database between 1975 and 2015, stratified by nonsurgical and surgical management. Propensity score matching was performed to adjust for imbalances in covariates. Multivariable models were constructed using restricted cubic splines to model nonlinear relationships of age and tumor size with DSS. Results: Overall, 1453 nonoperative patients and 54,718 surgical patients met the inclusion criteria. Collectively, increasing age and size after certain thresholds independently led to greater differences in DSS between nonsurgical and surgical patients. For younger ages (14-55 years), surgical approach compared with nonsurgical approach was not associated with any difference in the 10-year DSS among 0-4 cm cancers (99.8% vs. 100%, p = 0.470), 4.1-6 cm cancers (98.8% vs. 100%, p = 0.599), or >6 cm cancers (97.3% vs. 100%, p = 0.718). Older patients with larger tumors (>75 years, >6 cm) demonstrated the greatest difference in DSS (48.1% vs. 91.3%, p < 0.001). Similar results were found when applying propensity score matching. For age, restricted cubic spline plots showed minimal relative survival hazard in nonoperative cases beginning after age 60 years, with a change point illustrating acceleration in relative hazard beyond age 72 years. For size, relative survival hazard was observed after 2.0 cm and increased slowly with nodule growth up to an inflection point of 4.5 cm. Beyond this, mortality risk escalated with each additional year without plateau. Conclusions: Increasing age and size lead to progressively greater mortality risk without surgery, but only beyond certain thresholds. We define escalating gradients at which a nonsurgical approach may be deemed appropriate, and beyond which survival benefits from surgery become apparent. Such findings reconcile controversial observations regarding age and size in active surveillance and further reshape evolving treatment paradigms in thyroid cancer.

Keywords: active surveillance; low-risk cancer; nonsurgical treatment; papillary thyroid carcinoma; thyroid cancer.

FIG. 1.

Histogram of cohort distribution. (A) Nonsurgical cohort by age. (B) Nonsurgical cohort by size. (C) Surgical cohort by age. (D) Surgical cohort by size. Color images are available online.

FIG. 2.

Kaplan–Meier survival curves for nonsurgical versus surgical cohorts comparing (A) noncancer mortality and (B) disease-specific survival. Color images are available online.

FIG. 3.

Kaplan–Meier survival curve matrix of disease-specific survival comparing surgery with nonoperative cohorts, with increasing size and age. (A) Age 14–55 years, tumor size 0–4 cm. (B) Age 14–55 years, tumor size 4.1–6 cm. (C) Age 14–55 years, tumor size >6 cm. (D) Age 56–75 years, tumor size 0–4 cm. (E) Age 56–75 years, tumor size 4.1–6 cm. (F) Age 56–75 years, tumor size >6 cm. (G) Age >75 years, tumor size 0–4 cm. (H) Age >75 years, size 4.1–6 cm. (I) Age >75 years, tumor size >6 cm. Color images are available online.

FIG. 4.

Restricted cubic spline plot exhibiting relative hazard from disease-specific mortality risk in papillary thyroid carcinoma patients managed nonoperatively. (A) Escalating mortality risk with increasing age (three knots at 39, 62, and 81 years), controlled for sex, race/ethnicity, marriage, geographic region, size (three knots at 2, 11, and 35 mm), surgery, and RAI. Linear change points are identified at 50, 72, and 88 years of age. (B) Escalating mortality risk with increasing size (three knots at 2, 11, and 35 mm), controlled for sex, race/ethnicity, marriage, geographic region, surgery, age (three knots at 39, 62, and 81 years), and RAI. Linear change points are identified at 4.6, 6.9, and 8.7 cm. RAI, radioactive iodine. Color images are available online.