Diurnal cortisol and survival in epithelial ovarian cancer

Andrew Schrepf, Premal H Thaker, Michael J Goodheart, David Bender, George M Slavich, Laila Dahmoush, Frank Penedo, Koen DeGeest, Luis Mendez, David M Lubaroff, Steven W Cole, Anil K Sood, Susan K Lutgendorf, Andrew Schrepf, Premal H Thaker, Michael J Goodheart, David Bender, George M Slavich, Laila Dahmoush, Frank Penedo, Koen DeGeest, Luis Mendez, David M Lubaroff, Steven W Cole, Anil K Sood, Susan K Lutgendorf

Abstract

Introduction: Hypothalamic-pituitary-adrenal (HPA) deregulation is commonly observed in cancer patients, but its clinical significance is not well understood. We prospectively examined the association between HPA activity, tumor-associated inflammation, and survival in ovarian cancer patients prior to treatment.

Materials and methods: Participants were 113 women with ovarian cancer who provided salivary cortisol for three days prior to treatment for calculation of cortisol slope, variability, and night cortisol. Cox proportional hazard regression analyses were used to examine associations between cortisol and survival in models adjusting for disease stage, tumor grade, cytoreduction and age. On a subsample of 41 patients with advanced disease ascites fluid was assayed for levels of interleukin-6 (IL-6) and correlated with cortisol variables.

Results: Each cortisol measure was associated with decreased survival time, adjusting for covariates (all p<.041). A one standard deviation increase in night cortisol was associated with a 46% greater likelihood of death. Patients in the high night cortisol group survived an estimated average of 3.3 years compared to 7.3 years for those in the low night cortisol group. Elevated ascites IL-6 was associated with each cortisol measure (all r>36, all p<.017).

Discussion: Abnormal cortisol rhythms assessed prior to treatment are associated with decreased survival in ovarian cancer and increased inflammation in the vicinity of the tumor. HPA abnormalities may reflect poor endogenous control of inflammation, dysregulation caused by tumor-associated inflammation, broad circadian disruption, or some combination of these factors. Nocturnal cortisol may have utility as a non-invasive measure of HPA function and/or disease severity.

Keywords: Biological markers; Chronobiology disorders; Hydrocortisone; Inflammation; Ovarian neoplasms.

Copyright © 2015 Elsevier Ltd. All rights reserved.

Figures

Figure 1
Figure 1
Flow chart of patient recruitment.
Figure 2
Figure 2
Kaplan Meier survival curve for patients with high nocturnal cortisol (median 3.3 years, 95% CI=2.6, 3.8 years) vs. patients with low nocturnal cortisol (7.3 years, 95% CI =3.8, 10.8 years). Cox regression adjusted for covariates indicates that patients with lower nocturnal cortisol had longer survival times (p=.021).
Figure 3
Figure 3
Kaplan Meier survival curve for patients with flat diurnal cortisol slope (median 3.2 years, 95% CI=2.1, 4.3 years) vs. patients with steep diurnal cortisol slope (6.8 years, 95% CI =4.5, 9.0 years). Cox regression adjusted for covariates indicates that patients with steeper cortisol slopes had longer survival times (p=.040).
Figure 4
Figure 4
Scatterplot of Interleukin-6 assayed in ascites fluid and diurnal cortisol variability.

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