Prognostic Factors Analysis of Metastatic Recurrence in Cervical Carcinoma Patients Treated with Definitive Radiotherapy: A Retrospective Study Using Mixture Cure Model

Abstract

Objectives: This study aims to identify prognostic factors associated with metastatic recurrence-free survival of cervical carcinoma (CC) patients treated with radical radiotherapy and assess the cure probability of radical radiotherapy from metastatic recurrence.

Methods: Data were from 446 cervical carcinoma patients with radical radiotherapy for an average follow up of 3.96 years. We applied a mixture cure model to investigate the association between metastatic recurrence and prognostic factors and the association between noncure probability and factors, respectively. A nonparametric test of cure probability under the framework of a mixture cure model was used to examine the significance of cure probability of the definitive radiotherapy treatment. Propensity-score-matched (PSM) pairs were generated to reduce bias in subgroup analysis.

Results: Patients in advanced stages (p = 0.005) and those with worse treatment responses in the 3rd month (p = 0.004) had higher metastatic recurrence rates. Nonparametric tests of the cure probability showed that 3-year cure probability from metastatic recurrence was significantly larger than 0, and 5-year cure probability was significantly larger than 0.7 but no larger than 0.8. The empirical cure probability by mixture cure model was 79.2% (95% CI: 78.6-79.9%) for the entire study population, and the overall median metastatic recurrence time for uncured patients (patients susceptible to metastatic recurrence) was 1.60 (95% CI: 1.51-1.69) years. Locally advanced/advanced stage was a risk factor but non-significant against the cure probability (OR = 1.078, p = 0.088). The interaction of age and activity of radioactive source were statistically significant in the incidence model (OR = 0.839, p = 0.025). In subgroup analysis, compared with high activity of radioactive source (HARS), low activity of radioactive source (LARS) significantly contributed to a 16.1% higher cure probability for patients greater than 53 years old, while cure probability was 12.2% lower for the younger patients.

Conclusions: There was statistically significant evidence in the data showing the existence of a large amount of patients cured by the definitive radiotherapy treatment. HARS is a protective factor against metastatic recurrence for uncured patients, and young patients tend to benefit more than the elderly from the HARS treatment.

Keywords: activity of radioactive source; brachytherapy; cervical carcinoma; metastatic recurrence; mixture cure model.

Figure 1

Sample selection profile.

Figure 2

(A) Metastatic recurrence-free survival curves for the all patients; (B) p-value for the test of cure probability in different follow-up time; (C) Barplot of the metastatic recurrence frequency.

Figure 3

The K–M curves of metastatic recurrence in different subgroups: stage (A); treatment response in the 3rd month (B); local recurrence of cervical cancer (C); HARS and LARS for the patients with age no more than 53 (D); and for the group with age greater than 53 (E). The percentage of metastatic recurrence in different age groups (F).

Figure 4

Estimated MRFS survival curves for each patient, where the blue lines were by regular Cox model, and the red lines were by mixture cure model. The solid black line and the dash black line indicate the empirical mean of all individualized MRFS survival curves by mixture cure model and regular Cox model, respectively.