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Random Serum Cortisol as a Predictor for Survival of Terminally Ill Patients With Cancer: A Preliminary Study
American Journal of Hospice & Palliative Medicine® 1-5 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1049909114563065 ajhpm.sagepub.com
Hyo Min Kim, MD1, Kyung Sang Ha, MD2, In Cheol Hwang, MD, PhD2, Hong Yup Ahn, PhD3, and Chang Ho Youn, MD, PhD4
Abstract Although previous research found that serum cortisol levels were associated with cancer prognosis, it is unclear whether this association remains robust even at the very end of life of patients with cancer. We conducted a retrospective chart review of 125 patients with terminal cancer to investigate the role of random serum cortisol levels in predicting the remaining life expectancy. The high random cortisol group had a significantly shorter survival time than the low random cortisol group (7.5 vs 26 days). After adjusting for potential confounders, key factors such as poor performance status, hypoalbuminemia, and high random cortisol level are associated with poor survival. Our results suggest that the random serum cortisol level is an independent predictor of survival time of patients with terminally ill cancer. Keywords end of life, hospice care, prognosis, random serum cortisol, survival, terminal cancer
Introduction Predicting remaining life expectancy is an important issue in patients with terminal cancer because it is significant for formulating a treatment plan. Accurate prediction of life expectancy has numerous advantages to all those involved: clinician, patient, and family of the patient.1 Numerous studies have revealed the factors related to the prognosis of terminal cancer2,3 and several factors have been clarified, that is, clinical estimate of survival by physicians,4 performance status,5 and specific laboratory markers such as albumin.6 However, it is still unclear which factor can predict the remaining life expectancy. Cortisol, an important stress hormone, is associated with the prognosis of cancer. A lack of diurnal variation in the salivary cortisol level is commonly related to early death in both patients with lung and breast cancer.7,8 In addition, patients with colorectal cancer who experience a marked circadian rhythm of serum cortisol had longer survival periods, and a flattened circadian rhythm was related to a high mean cortisol concentration.9 Although several studies have been conducted to determine the relationship between the variability of cortisol level and cancer prognosis, measuring the cortisol level sequentially may impose a strain on patients with terminal cancer in the clinical situation: a simple method to predict survival would be more beneficial to patients with terminally ill cancer. The goal of this
study was to clarify the relationship between random serum cortisol levels and the remaining life expectancy in patients with terminally ill cancer.
Methods Participants We used inpatient data of a palliative care unit with a chart audit. All participants were patients with terminal cancer who were likely to die within months. The audits were done in February 2014 to review the deaths from December 2012 to January 2014. We identified 178 consecutive patients with terminal cancer. Of those, the final analysis was limited to 125 patients who had available data for serum cortisol concentration. 1
Department of Family Medicine, Kyungpook National University Medical Center, Daegu, Republic of Korea 2 Department of Family Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea 3 Department of Statistics, Dongguk University, Seoul, Republic of Korea 4 Department of Family Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea Corresponding Author: In Cheol Hwang, MD, PhD, Department of Family Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea. Email: [email protected]
Downloaded from ajh.sagepub.com by guest on November 14, 2015
American Journal of Hospice & Palliative Medicine®
2 This study was approved by the institutional review board of Gachon University Gil Hospital.
Table 1. Characteristics of Patients According to the Random Serum Cortisol Levels.a Cortisol groupb
Data Collection
Low
The following data on demographics and clinical information were collected by an experienced palliative care team: age, cancer site, Eastern Cooperative Oncology Group (ECOG) performance status,10 evidence of infection, and daily amounts of opioids. Survival time was defined as the period from the day of evaluation to the day of death. Blood samples were obtained from an antecubital vein on admission. They were used to measure complete blood cell count, liver function, creatinine, lactate dehydrogenase (LDH), C-reactive protein (CRP), and serum cortisol concentration.
Statistical Analysis According to the level of cortisol, patients were divided into 2 groups (high and low); the median value (20 mg/dL) in the current sample was used as cutoff point because cortisol level varies throughout the day. We compared the differences between groups in the demographic, clinical, and laboratory characteristics using a Fisher exact test or an independent t test. To examine the association between the median survival time and associated variables, we used the log-rank test of the Kaplan-Meier method after dichotomizing all variables. In addition, we used a Cox proportional hazard model to assess the hazard ratio (HR) of the variables for survival. Each independent factor that was statistically significant at the P < .05 level in the univariate relationship was entered into the final model to calculate the adjusted HRs. Using a stepwise variable selection procedure, we obtained a best-fit multivariate Cox regression model.11 In all analyses, we considered P values of less than .05 generated in 2-sided tests to indicate statistical significance. All statistical tests were performed using SAS version 9.2 software (SAS Institute, Inc, Cary, North Carolina).
Results Patients Characteristics Among 125 participants, 50.4% (n ¼ 62) were male and 52.1% (n ¼ 63) were 65 years or older. The cancer site in descending order was lung, gastrointestinal tract, hepatobiliary system, pancreas, female genital organ, and breast. According to serum cortisol level with a cutoff of the median value (20 mg/dL), there was a significant difference in ECOG performance status (P ¼ .013), white blood cell count (P < .001), neutrophil fraction (P < .001), creatinine (P ¼ .027), prothrombin time international normalized ratio (INR; P ¼ .009), and CRP (P < .001; Table 1).
Univariate Analysis Related to Survival Time There were no significant differences in survival time according to sex, site of cancer, current infection, or opioid amount.
High
Sex, n (%) Female 28 (44.4) 34 Male 35 (55.6) 28 Age, n (%), years 60 27 (42.9) 28 Laboratory findings WBC counts, 8.7 + 3.5 13.5 103/mm3 Neutrophil fraction, % 74.8 + 9.7 83.4 Hemoglobin, g/dL 10.0 + 1.9 9.9 Platelet, 103/mm3 240.4 + 131.5 213.2 Creatinine, mg/dL 0.8 + 0.5 1.2 Albumin, g/dL 3.2 + 0.5 3.5 Total bilirubin, mg/dL 2.3 + 4.2 3.7 PT INR 1.1 + 0.2 1.3 C-reactive protein, 6.2 + 5.4 10.8 mg/dL LDH, IU/L 911.1 + 1556.9 1388.1
P valuec
(54.8) (45.2)
.245
(54.8) (45.2)
.180
(19.4) (24.2) (12.9) (12.9) (12.9) (6.5) (11.3)
.240d
(9.7) (38.7) (51.6)
.013
(75.8) (24.2)
.485
(27.4) (27.4) (45.2)
.941
+ 6.6
485 U/L) No 36 26 Yes 85 12 C-reactive protein level,a mg/dL Low (7) 62 21 High (>7) 63 14 Random cortisol level,a mg/dL Low (
Random Serum Cortisol as a Predictor for Survival of Terminally Ill Patients With Cancer: A Preliminary Study
American Journal of Hospice & Palliative Medicine® 1-5 ª The Author(s) 2014 Reprints and permission: sagepub.com/journalsPermissions.nav DOI: 10.1177/1049909114563065 ajhpm.sagepub.com
Hyo Min Kim, MD1, Kyung Sang Ha, MD2, In Cheol Hwang, MD, PhD2, Hong Yup Ahn, PhD3, and Chang Ho Youn, MD, PhD4
Abstract Although previous research found that serum cortisol levels were associated with cancer prognosis, it is unclear whether this association remains robust even at the very end of life of patients with cancer. We conducted a retrospective chart review of 125 patients with terminal cancer to investigate the role of random serum cortisol levels in predicting the remaining life expectancy. The high random cortisol group had a significantly shorter survival time than the low random cortisol group (7.5 vs 26 days). After adjusting for potential confounders, key factors such as poor performance status, hypoalbuminemia, and high random cortisol level are associated with poor survival. Our results suggest that the random serum cortisol level is an independent predictor of survival time of patients with terminally ill cancer. Keywords end of life, hospice care, prognosis, random serum cortisol, survival, terminal cancer
Introduction Predicting remaining life expectancy is an important issue in patients with terminal cancer because it is significant for formulating a treatment plan. Accurate prediction of life expectancy has numerous advantages to all those involved: clinician, patient, and family of the patient.1 Numerous studies have revealed the factors related to the prognosis of terminal cancer2,3 and several factors have been clarified, that is, clinical estimate of survival by physicians,4 performance status,5 and specific laboratory markers such as albumin.6 However, it is still unclear which factor can predict the remaining life expectancy. Cortisol, an important stress hormone, is associated with the prognosis of cancer. A lack of diurnal variation in the salivary cortisol level is commonly related to early death in both patients with lung and breast cancer.7,8 In addition, patients with colorectal cancer who experience a marked circadian rhythm of serum cortisol had longer survival periods, and a flattened circadian rhythm was related to a high mean cortisol concentration.9 Although several studies have been conducted to determine the relationship between the variability of cortisol level and cancer prognosis, measuring the cortisol level sequentially may impose a strain on patients with terminal cancer in the clinical situation: a simple method to predict survival would be more beneficial to patients with terminally ill cancer. The goal of this
study was to clarify the relationship between random serum cortisol levels and the remaining life expectancy in patients with terminally ill cancer.
Methods Participants We used inpatient data of a palliative care unit with a chart audit. All participants were patients with terminal cancer who were likely to die within months. The audits were done in February 2014 to review the deaths from December 2012 to January 2014. We identified 178 consecutive patients with terminal cancer. Of those, the final analysis was limited to 125 patients who had available data for serum cortisol concentration. 1
Department of Family Medicine, Kyungpook National University Medical Center, Daegu, Republic of Korea 2 Department of Family Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea 3 Department of Statistics, Dongguk University, Seoul, Republic of Korea 4 Department of Family Medicine, Kyungpook National University School of Medicine, Daegu, Republic of Korea Corresponding Author: In Cheol Hwang, MD, PhD, Department of Family Medicine, Gachon University Gil Medical Center, Incheon, Republic of Korea. Email: [email protected]
Downloaded from ajh.sagepub.com by guest on November 14, 2015
American Journal of Hospice & Palliative Medicine®
2 This study was approved by the institutional review board of Gachon University Gil Hospital.
Table 1. Characteristics of Patients According to the Random Serum Cortisol Levels.a Cortisol groupb
Data Collection
Low
The following data on demographics and clinical information were collected by an experienced palliative care team: age, cancer site, Eastern Cooperative Oncology Group (ECOG) performance status,10 evidence of infection, and daily amounts of opioids. Survival time was defined as the period from the day of evaluation to the day of death. Blood samples were obtained from an antecubital vein on admission. They were used to measure complete blood cell count, liver function, creatinine, lactate dehydrogenase (LDH), C-reactive protein (CRP), and serum cortisol concentration.
Statistical Analysis According to the level of cortisol, patients were divided into 2 groups (high and low); the median value (20 mg/dL) in the current sample was used as cutoff point because cortisol level varies throughout the day. We compared the differences between groups in the demographic, clinical, and laboratory characteristics using a Fisher exact test or an independent t test. To examine the association between the median survival time and associated variables, we used the log-rank test of the Kaplan-Meier method after dichotomizing all variables. In addition, we used a Cox proportional hazard model to assess the hazard ratio (HR) of the variables for survival. Each independent factor that was statistically significant at the P < .05 level in the univariate relationship was entered into the final model to calculate the adjusted HRs. Using a stepwise variable selection procedure, we obtained a best-fit multivariate Cox regression model.11 In all analyses, we considered P values of less than .05 generated in 2-sided tests to indicate statistical significance. All statistical tests were performed using SAS version 9.2 software (SAS Institute, Inc, Cary, North Carolina).
Results Patients Characteristics Among 125 participants, 50.4% (n ¼ 62) were male and 52.1% (n ¼ 63) were 65 years or older. The cancer site in descending order was lung, gastrointestinal tract, hepatobiliary system, pancreas, female genital organ, and breast. According to serum cortisol level with a cutoff of the median value (20 mg/dL), there was a significant difference in ECOG performance status (P ¼ .013), white blood cell count (P < .001), neutrophil fraction (P < .001), creatinine (P ¼ .027), prothrombin time international normalized ratio (INR; P ¼ .009), and CRP (P < .001; Table 1).
Univariate Analysis Related to Survival Time There were no significant differences in survival time according to sex, site of cancer, current infection, or opioid amount.
High
Sex, n (%) Female 28 (44.4) 34 Male 35 (55.6) 28 Age, n (%), years 60 27 (42.9) 28 Laboratory findings WBC counts, 8.7 + 3.5 13.5 103/mm3 Neutrophil fraction, % 74.8 + 9.7 83.4 Hemoglobin, g/dL 10.0 + 1.9 9.9 Platelet, 103/mm3 240.4 + 131.5 213.2 Creatinine, mg/dL 0.8 + 0.5 1.2 Albumin, g/dL 3.2 + 0.5 3.5 Total bilirubin, mg/dL 2.3 + 4.2 3.7 PT INR 1.1 + 0.2 1.3 C-reactive protein, 6.2 + 5.4 10.8 mg/dL LDH, IU/L 911.1 + 1556.9 1388.1
P valuec
(54.8) (45.2)
.245
(54.8) (45.2)
.180
(19.4) (24.2) (12.9) (12.9) (12.9) (6.5) (11.3)
.240d
(9.7) (38.7) (51.6)
.013
(75.8) (24.2)
.485
(27.4) (27.4) (45.2)
.941
+ 6.6
485 U/L) No 36 26 Yes 85 12 C-reactive protein level,a mg/dL Low (7) 62 21 High (>7) 63 14 Random cortisol level,a mg/dL Low (
