Original Article
Association Between Hypogonadism, Symptom Burden, and Survival in Male Patients With Advanced Cancer Rony Dev, DO1; David Hui, MD1; Egidio Del Fabbro, MD2; Marvin O. Delgado-Guay, MD1; Nikhil Sobti1; Shalini Dalal, MD1; and Eduardo Bruera, MD1
BACKGROUND: A high frequency of hypogonadism has been reported in male patients with advanced cancer. The current study was performed to evaluate the association between low testosterone levels, symptom burden, and survival in male patients with cancer. METHODS: Of 131 consecutive male patients with cancer, 119 (91%) had an endocrine evaluation of total (TT), free (FT), and bioavailable testosterone (BT); high-sensitivity C-reactive protein (CRP); vitamin B12; thyroid-stimulating hormone; 25-hydroxy vitamin D; and cortisol levels when presenting with symptoms of fatigue and/or anorexia-cachexia. Symptoms were evaluated by the Edmonton Symptom Assessment Scale. The authors examined the correlation using the Spearman test and survival with the log-rank test and Cox regression analysis. RESULTS: The median age of the patients was 64 years; the majority of patients were white (85 patients; 71%). The median TT level was 209 ng/dL (normal: 200 ng/dL), the median FT was 4.4 ng/dL (normal: 9 ng/dL), and the median BT was 22.0 ng/dL (normal: 61 ng/dL). Low TT, FT, and BT values were all associated with worse fatigue (P .04), poor Eastern Cooperative Oncology Group performance status (P .05), weight loss (P .01), and opioid use (P .005). Low TT and FT were associated with increased anxiety (P .04), a decreased feeling of well-being (P .04), and increased dyspnea (P .05), whereas low BT was only found to be associated with anorexia (P 5.05). Decreased TT, FT, and BT values were all found to be significantly associated with elevated CRP and low albumin and hemoglobin. On multivariate analysis, decreased survival was associated with low TT (hazards ratio [HR], 1.66; P 5.034), declining Eastern Cooperative Oncology Group performance status (HR, 1.55; P 5.004), high CRP (HR, 3.28; P 5% in last 6 mo Median 25OH vitamin D level, ng/mL (Q1-Q3) Median TSH, mg/mL (Q1-Q3) Median total testosterone, ng/dL (Q1-Q3) Median free testosterone, ng/dL (Q1-Q3)b Median bioavailable testosterone, ng/dL (Q1-Q3)c Median CRP, mg/L (Q1-Q3) Median WBC, K/UL (Q1-Q3) Median hemoglobin, g/dL (Q1-Q3) Median albumin, mg/dL (Q1-Q3) Median MEDD, mg/d (Q1-Q3) Median Edmonton Symptom Assessment Score, (Q1-Q3) Pain Fatigue Nausea Depression Anxiety Drowsiness Appetite Well being Dyspnea Sleep Median survival (95% CI), d
61 (31-91) 119 (100) 85 (71) 13 (11) 11 (9) 10 (8) 48 (40) 10 (8) 3 (3) 18 (15) 30 (25) 10 (8) 7.0 (3.2-12.9) 72 (62) 21 (13-31) 2 (1-3) 209 (98-378) 4.4 (1.9-7.5) 22.0 (8.1-41.5) 33.3 (9.5-91.0) 6.6 (4.6-10.0) 11.3 (10.2-12.6) 3.8 (3.3-4.1) 30 (0-100) 4 (2-6) 5 (3-7) 1 (0-2) 2 (0-3) 2 (0-4) 3 (1-5) 5 (2-7) 5 (3-6) 2 (0-5) 4 (2-7) 151 (116-186)
Abbreviations: 25OH, 25-hydroxy; 95% CI, 95% confidence interval; CRP, high-sensitivity C-reactive protein; MEDD, morphine equivalent daily dosing; Q, quintile; TSH, thyroid-stimulating hormone; WBC, white blood cell count. a Unless otherwise specified. b Total is 116. c Total is 118.
appropriate assay conducted by the Mayo Clinic Laboratory. Fifty-two patients (44%) had TT levels < 200 ng/dL, 100 patients (86%) had FT levels < the cutoff value of 9 ng/dL, and 104 patients (89%) had BT levels < the lowest limit of 61 ng/dL. The median CRP level was 21 mg/dL (Q1-Q3: 9.5 mg/L-91.0 mg/L; reference range, < 13.00 mg/L) when used to assess for an inflammatory response as specified by the Cleveland Clinic laboratory. Table 2 summarizes the associations among testosterone and other laboratory values. We found a significant correlation between decreased levels of TT, FT, and BT and elevated levels of CRP (rho, 20.40 [P < .001], rho, 20.37 [P < .001], and rho, 20.27 [P < .001], respectively). TT was significantly associated with an increased white blood cell count (rho, 1588
20.20; P 5 .03), which was not associated with either FT or BT values. There was a direct correlation between levels of TT, FT, and BT with hemoglobin and albumin levels, which were significant, as summarized in Table 2. Fifty male patients with cancer had a vitamin D deficiency (43%) (25-hyrdroxy vitamin D level < 20 ng/dL). No significant associations were noted between testosterone values and vitamin D levels. Association Between Testosterone, Symptom Burden, Weight Loss, and Opioid Use
Table 3 summarizes the association between TT, FT, and BT levels; symptom burden as measured by the ESAS; ECOG performance status; history of > 5% weight loss; and opioid use in male patients with advanced cancer. Cancer
May 15, 2014
Hypogonadism in Male Patients With Cancer/Dev et al
TABLE 2. Association Between Testosterone and Other Laboratory Values in Male Patients With Cancera Laboratory Value CRP, mg/L WBC, K/UL Hemoglobin, g/dL Albumin, g/dL 25OH vitamin D level, ng/mL
Total Testosterone, ng/dL (n5119); rho, P
Free Testosterone, ng/dL (n5116); rho, P
Bioavailable Testosterone, ng/dL (n5118); rho, P
20.40, 22.6 mg/L), white blood cell count ( 6.1 K/UL vs > 6.1 K/UL), hemoglobin ( 11.3 g/dL vs > 11.3 g/dL), hypoalbuminemia ( 3.8 mg/dL vs > 3.8 mg/dL), and corrected calcium ( 10.2 mg/dL vs > 10.2 mg/dL). Decreased survival was associated only with low TT level (hazards ratio [HR], 1.66; P 5 .03), deteriorating ECOG performance status (HR, 1.55; P 5 .004), elevated CRP (HR, 3.28; P < .001), and decreased albumin (HR, 2.52; P < .001) (Table 5). Secondary to the heterogeneous patient population, patients with gastrointestinal, head and neck, and lung cancer were also analyzed separately. In 48 male patients with gastrointestinal cancer, patients with low TT levels ( 200 ng/dL) had a median survival of 80 days (95% CI, 31 days-105 days) versus 157 days (95% CI, 139 days266 days) (P 5 .004). In 30 patients with lung cancer, a median survival of 115 days (95% CI, 58 days-231 days) was noted for hypogonadic men versus 508 days (95% CI, 72 days-930 days) for patients with a TT level > 200 ng/dL (P 5 .03). In 18 patients with head and neck malignancies, the median survival for hypogonadic males was 144 days (95% CI, 12 days to 1) versus 240 days (95% CI, 86 days to 1), which was not statistically significant (P 5 .27), most likely secondary to the small sample size. TABLE 5. Multivariate Survival Analysis
Figure 1. Kaplan-Meier survival analyses are shown with comparisons of curves by the log-rank test. The survival of male patients with testosterone levels < 200 mg/dL (green line) was decreased compared with patients with testosterone levels 200 mg/dL (blue line). MS indicates median survival; 95% CI, 95% confidence interval.
Characteristic
HR
95% CI
P
ECOG performance status Total testosterone 200, ng/dL CRP >22.6 mg/L Albumin, 3.8 mg/dL
1.55 1.66 3.28 2.52
1.15-2.10 1.04-2.64 1.87-5.74 1.54-4.11
.004 .034
Association Between Hypogonadism, Symptom Burden, and Survival in Male Patients With Advanced Cancer Rony Dev, DO1; David Hui, MD1; Egidio Del Fabbro, MD2; Marvin O. Delgado-Guay, MD1; Nikhil Sobti1; Shalini Dalal, MD1; and Eduardo Bruera, MD1
BACKGROUND: A high frequency of hypogonadism has been reported in male patients with advanced cancer. The current study was performed to evaluate the association between low testosterone levels, symptom burden, and survival in male patients with cancer. METHODS: Of 131 consecutive male patients with cancer, 119 (91%) had an endocrine evaluation of total (TT), free (FT), and bioavailable testosterone (BT); high-sensitivity C-reactive protein (CRP); vitamin B12; thyroid-stimulating hormone; 25-hydroxy vitamin D; and cortisol levels when presenting with symptoms of fatigue and/or anorexia-cachexia. Symptoms were evaluated by the Edmonton Symptom Assessment Scale. The authors examined the correlation using the Spearman test and survival with the log-rank test and Cox regression analysis. RESULTS: The median age of the patients was 64 years; the majority of patients were white (85 patients; 71%). The median TT level was 209 ng/dL (normal: 200 ng/dL), the median FT was 4.4 ng/dL (normal: 9 ng/dL), and the median BT was 22.0 ng/dL (normal: 61 ng/dL). Low TT, FT, and BT values were all associated with worse fatigue (P .04), poor Eastern Cooperative Oncology Group performance status (P .05), weight loss (P .01), and opioid use (P .005). Low TT and FT were associated with increased anxiety (P .04), a decreased feeling of well-being (P .04), and increased dyspnea (P .05), whereas low BT was only found to be associated with anorexia (P 5.05). Decreased TT, FT, and BT values were all found to be significantly associated with elevated CRP and low albumin and hemoglobin. On multivariate analysis, decreased survival was associated with low TT (hazards ratio [HR], 1.66; P 5.034), declining Eastern Cooperative Oncology Group performance status (HR, 1.55; P 5.004), high CRP (HR, 3.28; P 5% in last 6 mo Median 25OH vitamin D level, ng/mL (Q1-Q3) Median TSH, mg/mL (Q1-Q3) Median total testosterone, ng/dL (Q1-Q3) Median free testosterone, ng/dL (Q1-Q3)b Median bioavailable testosterone, ng/dL (Q1-Q3)c Median CRP, mg/L (Q1-Q3) Median WBC, K/UL (Q1-Q3) Median hemoglobin, g/dL (Q1-Q3) Median albumin, mg/dL (Q1-Q3) Median MEDD, mg/d (Q1-Q3) Median Edmonton Symptom Assessment Score, (Q1-Q3) Pain Fatigue Nausea Depression Anxiety Drowsiness Appetite Well being Dyspnea Sleep Median survival (95% CI), d
61 (31-91) 119 (100) 85 (71) 13 (11) 11 (9) 10 (8) 48 (40) 10 (8) 3 (3) 18 (15) 30 (25) 10 (8) 7.0 (3.2-12.9) 72 (62) 21 (13-31) 2 (1-3) 209 (98-378) 4.4 (1.9-7.5) 22.0 (8.1-41.5) 33.3 (9.5-91.0) 6.6 (4.6-10.0) 11.3 (10.2-12.6) 3.8 (3.3-4.1) 30 (0-100) 4 (2-6) 5 (3-7) 1 (0-2) 2 (0-3) 2 (0-4) 3 (1-5) 5 (2-7) 5 (3-6) 2 (0-5) 4 (2-7) 151 (116-186)
Abbreviations: 25OH, 25-hydroxy; 95% CI, 95% confidence interval; CRP, high-sensitivity C-reactive protein; MEDD, morphine equivalent daily dosing; Q, quintile; TSH, thyroid-stimulating hormone; WBC, white blood cell count. a Unless otherwise specified. b Total is 116. c Total is 118.
appropriate assay conducted by the Mayo Clinic Laboratory. Fifty-two patients (44%) had TT levels < 200 ng/dL, 100 patients (86%) had FT levels < the cutoff value of 9 ng/dL, and 104 patients (89%) had BT levels < the lowest limit of 61 ng/dL. The median CRP level was 21 mg/dL (Q1-Q3: 9.5 mg/L-91.0 mg/L; reference range, < 13.00 mg/L) when used to assess for an inflammatory response as specified by the Cleveland Clinic laboratory. Table 2 summarizes the associations among testosterone and other laboratory values. We found a significant correlation between decreased levels of TT, FT, and BT and elevated levels of CRP (rho, 20.40 [P < .001], rho, 20.37 [P < .001], and rho, 20.27 [P < .001], respectively). TT was significantly associated with an increased white blood cell count (rho, 1588
20.20; P 5 .03), which was not associated with either FT or BT values. There was a direct correlation between levels of TT, FT, and BT with hemoglobin and albumin levels, which were significant, as summarized in Table 2. Fifty male patients with cancer had a vitamin D deficiency (43%) (25-hyrdroxy vitamin D level < 20 ng/dL). No significant associations were noted between testosterone values and vitamin D levels. Association Between Testosterone, Symptom Burden, Weight Loss, and Opioid Use
Table 3 summarizes the association between TT, FT, and BT levels; symptom burden as measured by the ESAS; ECOG performance status; history of > 5% weight loss; and opioid use in male patients with advanced cancer. Cancer
May 15, 2014
Hypogonadism in Male Patients With Cancer/Dev et al
TABLE 2. Association Between Testosterone and Other Laboratory Values in Male Patients With Cancera Laboratory Value CRP, mg/L WBC, K/UL Hemoglobin, g/dL Albumin, g/dL 25OH vitamin D level, ng/mL
Total Testosterone, ng/dL (n5119); rho, P
Free Testosterone, ng/dL (n5116); rho, P
Bioavailable Testosterone, ng/dL (n5118); rho, P
20.40, 22.6 mg/L), white blood cell count ( 6.1 K/UL vs > 6.1 K/UL), hemoglobin ( 11.3 g/dL vs > 11.3 g/dL), hypoalbuminemia ( 3.8 mg/dL vs > 3.8 mg/dL), and corrected calcium ( 10.2 mg/dL vs > 10.2 mg/dL). Decreased survival was associated only with low TT level (hazards ratio [HR], 1.66; P 5 .03), deteriorating ECOG performance status (HR, 1.55; P 5 .004), elevated CRP (HR, 3.28; P < .001), and decreased albumin (HR, 2.52; P < .001) (Table 5). Secondary to the heterogeneous patient population, patients with gastrointestinal, head and neck, and lung cancer were also analyzed separately. In 48 male patients with gastrointestinal cancer, patients with low TT levels ( 200 ng/dL) had a median survival of 80 days (95% CI, 31 days-105 days) versus 157 days (95% CI, 139 days266 days) (P 5 .004). In 30 patients with lung cancer, a median survival of 115 days (95% CI, 58 days-231 days) was noted for hypogonadic men versus 508 days (95% CI, 72 days-930 days) for patients with a TT level > 200 ng/dL (P 5 .03). In 18 patients with head and neck malignancies, the median survival for hypogonadic males was 144 days (95% CI, 12 days to 1) versus 240 days (95% CI, 86 days to 1), which was not statistically significant (P 5 .27), most likely secondary to the small sample size. TABLE 5. Multivariate Survival Analysis
Figure 1. Kaplan-Meier survival analyses are shown with comparisons of curves by the log-rank test. The survival of male patients with testosterone levels < 200 mg/dL (green line) was decreased compared with patients with testosterone levels 200 mg/dL (blue line). MS indicates median survival; 95% CI, 95% confidence interval.
Characteristic
HR
95% CI
P
ECOG performance status Total testosterone 200, ng/dL CRP >22.6 mg/L Albumin, 3.8 mg/dL
1.55 1.66 3.28 2.52
1.15-2.10 1.04-2.64 1.87-5.74 1.54-4.11
.004 .034
