Propensity Score Matching Reveals Non-Significance of Male Sex as a Prognostic Factor in Differentiated Thyroid Cancer Post Iodine Treatment

Differentiated thyroid cancer (DTC) is the most common type of endocrine malignancy and characterized by favorable prognosis and good treatment response. Despite the relatively high survival rates, the incidence of DTC has been steadily increasing worldwide specially in China where the annual growth rate of thyroid cancer cases has reached alarming levels which prompted significant interest to optimize treatment protocols and improve prognostic assessments for affected patients. The standard treatment for DTC is surgical resection of the thyroid gland, followed by adjuvant radioactive iodine (¹³¹I) therapy. ¹³¹I treatment is important for ablating residual thyroid tissue and targeting potential microscopic metastases, which reduce the risk of recurrence and enhance disease-specific survival rates. However, the effectiveness of ¹³¹I treatment can vary significantly among patients, influenced by various clinicopathological factors and role of patient sex in the prognosis of DTC is still not clear. Previous studies have yielded conflicting results with some believe that male sex is a risk factor for poorer outcomes following ¹³¹I treatment, while others have found no significant difference between male and female patients. This ambiguity is further complicated by the presence of confounding variables and potential selection biases in many retrospective analyses.  Several challenges impede a clear understanding of the impact of sex on DTC prognosis including selection bias of retrospective studies, confounding variables age, tumor stage, presence of metastases, and thyroglobulin (Tg) levels) can influence the prognosis of DTC, and heterogeneity of tumor characteristics

To this end, new study published in The Journal of Clinical Endocrinology & Metabolism and conducted by Yaqian Zhou, Yan Wang, Zhiting Zhang, Xue Yin, Jianjun Liu, and led by Dr. Wei Zheng from the Department of Nuclear Medicine at Tianjin Medical University General Hospital determined whether male sex is an independent risk factor for poor prognosis in DTC patients treated with ¹³¹I. They employed the propensity score matching (PSM) method to minimize the impact of selection bias and confounding variables and provided a more rigorous analysis of the relationship between sex and treatment outcomes. The study involved a retrospective analysis of 1,948 postoperative DTC patients treated with ¹³¹I at Tianjin Medical University General Hospital. The cohort included 645 male and 1,303 female patients, with a median age of 43 years. All patients had undergone total thyroidectomy and had a follow-up period exceeding six months. The researchers collected extensive clinicopathological data, including tumor stage (T), node stage (N), metastasis stage (M), TNM stage, thyroglobulin (Tg) levels, and ¹³¹I doses. Before applying any data balancing methods, they observed that male patients tended to present with more aggressive disease characteristics, such as higher TNM stages, more frequent distant metastases (M1 stage), and higher sTg levels. Additionally, male patients had a significantly higher proportion of poor prognosis outcomes compared to female patients (22.9% vs. 14.6%, P < .001). To address selection bias and confounding variables, the researchers employed the PSM method. This statistical technique creates a logistic regression model with sex as the dependent variable and various clinicopathological factors as independent variables. Patients were then matched on these propensity scores at a 1:1 ratio with a caliper value of 0.01, which resulted in 633 matched pairs of male and female patients. The team found that post-PSM there were no significant differences in most clinicopathological features between male and female patients, except for sTg levels and the balanced cohorts allowed for a more accurate comparison of treatment outcomes and revealed that the proportion of poor prognosis was no longer significantly different between the two groups and indicated that male sex was not an independent risk factor for poor prognosis after control of confounding variables. Moreover, the researchers conducted univariate and multivariate logistic regression analyses to identify risk factors for poor prognosis. Initially, the univariate analysis before PSM showed that male sex, age ≥55 years, high T stage, N1b stage, M1 stage, high TNM stage, high sTg levels, and high ¹³¹I dose were significant risk factors. Multivariate analysis confirmed these findings, maintained that male sex was a significant predictor of poor prognosis and after PSM, multivariate logistic regression analysis indicated that high T stage (T3 + T4), M1 stage, high sTg levels, and ¹³¹I dose ≥260 mCi remained significant risk factors. However, male sex was no longer a significant predictor which aligned with the post-PSM findings that male and female patients had similar prognoses when other variables were balanced. Before applying PSM, the analysis showed male sex, older age, advanced tumor stages, and high sTg levels associated with poorer outcomes, however, the propensity score matching was critical in isolating the effect of sex from these factors and the post-PSM analysis reiterated that advanced tumor stage (T3 + T4), distant metastasis (M1 stage), high sTg levels, and high ¹³¹I dose were consistent predictors of poor prognosis. The removal of male sex as a significant independent risk factor post-PSM was an important observation and suggested that previous associations of male sex with poor outcomes were likely confounded by other variables. Additionally, before PSM, the male group had a lower proportion of ER and a higher proportion of BIR and SIR compared to the female group. After matching, the distribution of response categories between male and female patients became more comparable, with no significant differences in treatment outcomes.

In conclusion, Dr. Wei Zheng and her colleagues effectively clarified that male sex is not an independent risk factor for poor prognosis in DTC patients treated with radioactive iodine. Moreover, the authors’ use of PSM to balance the clinicopathological characteristics between male and female patients ensured that the comparisons made in their studies are robust and less susceptible to selection bias which enhanced credibility and generalizability of the findings. Furthermore, they identified high T stage (T3 + T4), distant metastasis (M1 stage), elevated stimulated thyroglobulin (sTg) levels (≥10.15 ng/mL), and high ¹³¹I dose as significant independent risk factors for poor prognosis. These insights are critical for tailoring patient management strategies and improve prognostic assessments. According to the authors, patients with high-risk factors should receive more intensive monitoring and follow-up to detect and manage recurrences or metastases promptly and such proactive approach can improve long-term survival rates and quality of life for DTC patients. Additionally, the authors suggested that routine screening for thyroid diseases in males, such as with ultrasonography should be strengthened to eliminate the difference in time of diagnosis between men and women.  Overall, the study highlighted the need of personalized treatment plans based on comprehensive risk assessments rather than relying on sex-based assumptions and ultimately improve the management and prognosis of DTC patients.