Diurnal Cortisol and Survival in Epithelial Ovarian Cancer

IntroductionHypothalamic-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 methodsParticipants 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.ResultsEach 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).DiscussionAbnormal 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

Cortisol and inflammatory processes in ovarian cancer patients following primary treatment: Relationships with depression, fatigue, and disability

a b s t r a c t Elevations in the pro-inflammatory cytokine interleukin-6 (IL-6) and alterations in the anti-inflammatory hormone cortisol have been reported in a variety of cancers. IL-6 has prognostic significance in ovarian cancer and cortisol has been associated with fatigue, disability, and vegetative depression in ovarian cancer patients prior to surgery. Ovarian cancer patients undergoing primary treatment completed psychological self-report measures and collected salivary cortisol and plasma IL-6 prior to surgery, at 6 months, and at 1 year. Patients included in this study had completed chemotherapy and had no evidence of disease recurrence. At 6 months, patients showed significant reductions in nocturnal cortisol secretion, plasma IL-6, and a more normalized diurnal cortisol rhythm, changes that were maintained at 1 year. The reductions in IL-6 and nocturnal cortisol were associated with declines in self-reported fatigue, vegetative depression, and disability. These findings suggest that primary treatment for ovarian cancer reduces the inflammatory response. Moreover, patients who have not developed recurrent disease by 1 year appear to maintain more normalized levels of cortisol and IL-6. Improvement in fatigue and vegetative depression is associated with the normalization of IL-6 and cortisol, a pattern which may be relevant for improvements in overall quality of life for ovarian cancer patients

The combination of a low-dose chemotherapeutic agent, 5-fluorouracil, and an adenoviral tumor vaccine has a synergistic benefit on survival in a tumor model system.

Standard cancer therapies, particularly those involving chemotherapy, are in need of modifications that both reduce short-term and long-term side effects as well as improve the overall survival of cancer patients. Here we show that combining low-dose chemotherapy with a therapeutic vaccination using an adenovirus encoding a model tumor-associated antigen, ovalbumin (Ad5-OVA), had a synergistic impact on survival in tumor-challenged mice. Mice that received the combinatorial treatment of Ad5-OVA plus low-dose 5-fluorouracil (5-FU) had a 95% survival rate compared to 7% and 30% survival rates for Ad5-OVA alone and 5-FU alone respectively. The presence of 5-FU enhanced the levels of OVA-specific CD8(+) T lymphocytes in the spleens and draining lymph nodes of Ad5-OVA-treated mice, a phenomenon that was dependent on the mice having been tumor-challenged. Thus 5-FU may have enhanced survival of Ad5-OVA-treated mice by enhancing the tumor-specific immune response combined with eliminating tumor bulk. We also investigated the possibility that the observed therapeutic benefit may have been derived from the capacity of 5-FU to deplete MDSC populations. The findings presented here promote the concept of combining adenoviral cancer vaccines with low-dose chemotherapy

Levels of gMDSCs and mMDSCs in the spleen and draining lymph node.

<p>C57BL/6 mice were challenged with E.G7 cells and then, 7 days post tumor challenge, were treated as indicated and then 5 days later, spleen and draining lymph nodes were harvested and stained using direct immunofluorescence for detection mMDSCs and gMDSCs and then analyzed using flow cytometry (see materials and methods for further details). <i>A</i>. Example of FloJo-generated dot-plots showing how mMDSCs and gMDSCs were delineated in samples obtained from the spleen. Total splenocytes were gated using a forward scatter (FSC) versus side scatter (SSC) dot-plot (<i>top row</i>). These cells were further gated to select for CD11b^+hi cells using a SSC versus CD11b dot-plot (<i>middle row</i>). Then these CD11b+hi cells were further defined using a Ly6G versus Ly6C dot-plot (<i>bottom row</i>). mMDSCs were defined as CD11b⁺Ly6G⁻Ly6C^+hi (<i>circled (left side)</i>) and gMDSCs were defined as CD11b⁺Ly6G⁺Ly6C^+low (<i>circled (right side)</i>). A similar method of analysis was used for cells obtained from the draining lymph node. <i>B–E</i>. On day 5 post treatment, the levels of mMDSCs (<i>B</i> and <i>D</i>) and gMDSCs (<i>C</i> and <i>E</i>), as a percentage of total cells, were determined, in both the spleen (<i>B</i> and <i>C</i>) and the draining lymph node (<i>D</i> and <i>E</i>). Mean percentage values (and range) for the naïve groups prior to normalization were as follows: mMDSCs in the lymph node = 0.24% (range: 0.02–0.84%); mMDSCs in the spleen = 0.26% (range: 0.02–0.63%); gMDSCs in the lymph node = 0.03% (range: 0.01–0.08%); gMDSCs in the spleen = 1.35% (0.87–4.1%). Results displayed are derived from pooled data from four separate experiments, where the number of mice/treatment group in each experiment was n = 1, n = 2, n = 2, n = 4 and therefore a total of n = 9 mice from each pooled treatment group were analyzed. Statistical significance was determined using an ANOVA one way analysis of variance (with Tukey post-test) (*<i>P</i><0.05, **<i>P</i><0.01, ***<i>P</i><0.001)). Error bars represent standard error of the mean.</p

Treg levels in spleen and draining lymph node.

<p>C57BL/6 mice were challenged with E.G7 and then, 7 days post tumor challenge, were treated as indicated. On day 5 post treatment the levels of Tregs (Foxp3⁺), as a percentage of total CD4⁺CD3⁺ cells, was determined using direct immunofluorescence (see materials and methods for further details) on the samples from the spleen (<i>A</i>) and the lymph node <i>(B</i>). Results displayed are from one representative experiment (n = 4 mice per group). These results were reproducible. Using an ANOVA one way analysis of variance (with Tukey post-test) no statistically significant differences were observed in independent experiments nor after pooling of the data. Error bars represent standard error of the mean.</p