Hypomagnesemia and Survival in Patients with Cervical Cancer Treated with Definitive Chemoradiotherapy

Abstract

Hypomagnesemia is a common side effect of platinum-based chemotherapy regimens. Although there are data reporting that hypomagnesemia is associated with worse survival in patients receiving platinum-based chemotherapy or chemoradiotherapy (CRT), this has not been documented in patients with cervical cancer treated with definitive CRT. We hypothesized that in patients with cervical cancer undergoing definitive CRT, on-treatment hypomagnesemia would be associated with longer treatment duration and worse cancer-specific survival (CSS). Patients with cervical cancer treated with definitive CRT from 1999 to 2015 were identified from a single cancer center's clinicopathologic database. Lowest on-treatment magnesium value was recorded and categorized as per Common Terminology Criteria for Adverse Events (CTCAE) v5.0 grading (grade 1: <0.7 - 0.5 mmol/L, grade 2: <0.5 - 0.4 mmol/L, grade 3: <0.4-0.3 mmol/L, and grade 4 <0.3 mmol/L). Grade 0 was defined as ≥ 0.7 mmol/L. Treatment duration was defined as the number of days between the first day of radiotherapy until the last day of pelvic treatment (either brachytherapy or pelvic external beam radiotherapy boost). Prolonged treatment was considered as any treatment duration greater than 63 days. CSS for patients with either grade 0-1 or grade ≥ 2 CTCAE v5.0 magnesium toxicity was estimated using the Kaplan-Meier method, and the Peto & Peto modification to the generalized Gehan-Wilcoxon was used to determine statistical significance between groups. Associations with prolonged treatment duration was explored using logistic regression. P-values of <0.05 were considered statistically significant. A total of 186 patients were identified; median follow-up was 7 (IQR 2-11) years. 125 (67%) had stage I-II disease and 61 (33%) stage III-IV. Median treatment duration was 51 (IQR 48-57) days. All patients received concurrent weekly cisplatin-based chemotherapy with RT: the majority (n = 133; 72%) received 5 or 6 cycles. 147 (79%) patients received routine IV magnesium infusion with their chemotherapy and 173 (93%) received routine IV mannitol. During treatment the highest CTCAE v5.0 magnesium toxicity score was grade 0-1 in 158 (85%) and grade ≥ 2 in 28 (15%). Magnesium grade ≥ 2 was associated with worse 5-year CSS [grade 0-1: 5yr CSS 67.2%, (95% CI 60.1-75.1); grade ≥ 2: 5yr CSS 50%, (95% CI 34.5-72.4); p = 0.039]. Magnesium status was not associated with an increase in treatment duration [OR 1.465 (95% CI 0.3177 - 6.753); p = 0.625]. On-treatment hypomagnesemia ≥ grade 2 (CTCAE v5.0) was associated with worse CSS but did not predict longer treatment duration. This is the first study that shows a detrimental survival impact of on-treatment hypomagnesemia in this patient population. These findings highlight the need to ensure adequate monitoring, support and correction of magnesium during definitive CRT.