Association between hypogonadism, symptom burden, and survival in male patients with advanced cancer
Rony Dev DO,
Department of Palliative Care and Rehabilitation Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas
Corresponding author: Rony Dev, DO, Department of Palliative Care and Rehabilitation Medicine, Unit 1414, The University of Texas MD Anderson Cancer Center, 1515 Holcombe Blvd, Houston, TX 77030; Fax: (713) 792-6092; email@example.com
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.
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.
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 = .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 = .034), declining Eastern Cooperative Oncology Group performance status (HR, 1.55; P = .004), high CRP (HR, 3.28; P < .001), and decreased albumin (HR, 2.52; P < .001).
In male patients with cancer, low testosterone levels were associated with systemic inflammation, weight loss, increased symptom burden, and decreased survival.
Low testosterone is reported in approximately two-thirds of male patients with advanced cancer.[1, 2] Even in patients with recently diagnosed metastatic cancer who had not received chemotherapy, low testosterone was noted in approximately 50% of the population tested. The etiology of hypogonadism is most likely multifactorial. Hypogonadism may result from the dysfunction of the hypothalamic-pituitary-gonadal axis due to the underlying cancer; chronic inflammation; or treatment with chemotherapy, corticosteroids, or appetite stimulants such as megestrol acetate. In addition, opioid therapy, which is often required to treat pain in patients with cancer, results in decreased testosterone levels.[6, 7]
A preliminary retrospective study conducted by our group found that hypogonadism was common in male patients with cancer and was associated with fatigue, anorexia, depression, and insomnia, as well as with elevated high-sensitivity C-reactive protein (CRP), with a poor prognosis for survival. Limitations of the study included the absence of serum testosterone measurements in nearly one-third of the patient population studied, the lack of testing for free testosterone (FT) or bioavailable testosterone (BT) levels, and a small sample size. To address these limitations, the current study examined the association between total testosterone (TT), FT, and BT with symptoms including fatigue and weight loss, laboratory indicators of systemic inflammation, and survival in male patients with advanced cancer.
MATERIALS AND METHODS
Approval by the Institutional Review Board at The University of Texas MD Anderson Cancer Center was obtained before data were collected, with waiver of informed consent.
We retrospectively identified male patients with cancer who were evaluated by a nurse and palliative medicine specialist and completed a laboratory workup for symptoms of cancer-related fatigue and/or cachexia in an outpatient supportive care clinic at The University of Texas MD Anderson Cancer Center before October 31, 2012. Male patients with prostate cancer or breast cancer or those who were being treated with testosterone supplementation, corticosteroids, or megestrol acetate were excluded. Demographic factors of the patient population including date of birth, age, sex, race, and the primary tumor diagnosis were recorded.
In addition, an electronic medical chart review that recorded clinical data including the symptom burden as measured by the Edmonton Symptom Assessment Scale (ESAS), laboratory tests, and history of weight loss over the past 3 months was obtained through documentation in the medical records or by patient history if no records were available.
The ESAS is a validated assessment tool that measures the response of patients with cancer to 10 common symptoms over a 24-hour period including pain, fatigue, nausea, depression, anxiety, drowsiness, shortness of breath, appetite, sleep, and feeling of well-being. Each of the 10 symptoms is rated by the patient on a scale of 0 (indicating best) to 10 (indicating worst).
Serum laboratory data values were recorded and included the following: TT, BT, and FT; CRP; thyroid-stimulating hormone; 25-hydroxy vitamin D; and albumin. All patients were instructed to obtain laboratory testing in the morning hours or, if they had altered sleep patterns, within 2 hours of awakening.
TT is measured by liquid chromatography-tandem mass spectrometry. Secondary to abnormalities of sex hormone-binding globulin (SHBG) noted in patients with cancer, FT and BT measurements were also obtained. FT is measured by equilibrium dialysis; FT results are expressed as a percentage of TT, which is multiplied by the value of TT to obtain an absolute FT value.[11, 12] BT values were obtained by differential precipitation of SHBG by ammonium sulfate. TT, FT, and BT were measured by Mayo Medical Laboratories of Rochester, Minnesota. CRP was measured by immunoturbidimetry, also at the Mayo Medical Laboratories.
We used descriptive statistics to summarize data, including medians, means, standard deviations, ranges, and frequencies, together with a 95% confidence interval (95% CI). The Spearman correlation test was used to determine the associations between laboratory abnormalities and symptom burden. To determine whether there were significant differences between groups (those with normal vs those with low testosterone), we used a 2-sample Student t test when the data were approximately normally distributed, the Wilcoxon 2-sample test if the data were skewed, and chi-square tests for categorical variables. The Kaplan-Meier method was used to analyze survival with comparisons of curves performed using the log-rank test. Overall survival was calculated from the time of laboratory evaluation to death from any cause or the date at which the patient was last known to be alive.
For exploratory purposes, we divided TT, FT, and BT into low, middle, and high tertiles and examined the association with symptom burden and survival using the Kruskal-Wallis test. In addition, we evaluated the patient's age and race; TT, FT, and BT levels; Eastern Cooperative Oncology Group (ECOG) performance status; CRP; white blood cell count; and hemoglobin, albumin, and corrected serum calcium levels in a multivariate survival analysis as potential indicators of a poor prognosis using the Cox regression model with backward selection. The Statistical Package for the Social Sciences software package (SPSS version 21.0; IBM Corporation, Armonk, NY) was used for statistical analysis. A 2-sided P value of < .05 was considered to be statistically significant.
A total of 119 of 131 consecutive male patients with cancer (91%) were evaluable. Table 1 highlights the baseline characteristics of those patients being treated for symptoms of cancer-related fatigue and/or cachexia. The symptom burden of the patient population included pain, anorexia, fatigue, and poor overall well-being. The mean age for these male patients was 64 years (range, 31 years-91 years). The majority of patients who participated were white (85 patients; 71%) and were diagnosed with a gastrointestinal (40%) or lung (25%) cancer. Seventy-two patients (61%) had a history of weight loss of > 5% within the past 6 months, with a median of 7% loss of body weight (quintile [Q] 1-Q3: 3.2%-12.9%).
Table 1. Characteristics of Male Patients With Advanced Cancer
Associations Between Testosterone, CRP Level, Albumin, and Vitamin D
The median level of TT was 209 ng/dL (Q1-Q3: 98 ng/dL-378 ng/dL; normal: ≥ 200 ng/dL) (Table 1). The median FT value was 4.4 ng/dL (Q1-Q3: 1.9 ng/dL-7.5 ng/dL; normal: ≥ 9 ng/dL), and the median BT value was 22.0 ng/dL (Q1-Q3: 8.1 ng/dL-41.5 ng/dL; normal: ≥ 61 ng/dL), as specified by the normal reference range for each 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, −0.40 [P < .001], rho, −0.37 [P < .001], and rho, −0.27 [P < .001], respectively). TT was significantly associated with an increased white blood cell count (rho, −0.20; P = .03), which was not associated with either FT or BT values.
Table 2. Association Between Testosterone and Other Laboratory Values in Male Patients With Cancera
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.
Table 3. Association Between Testosterone, Symptom Burden, ECOG Performance Status, Weight Loss, and Opioid Use in Male Patients With Cancera
Both low TT and FT were correlated with worsening fatigue (rho, −0.21 [P ≤ .02] and rho, −0.24 [P = .01], respectively), increased anxiety (rho, −0.21 [P ≤ .02] and rho, −0.19 [P = .04], respectively), decreased feelings of well-being (rho, −0.24 [P ≤ .01] and rho, −0.20 [P = .04] respectively), and increased dyspnea (rho, −0.18 [P = .05] and rho, −0.21 [P = .02], respectively). BT was found to have a significant correlation with fatigue (rho, −0.19; P = .04), appetite (rho, −0.19; P = .045), weight loss history (rho, −0.23; P = .01), and ECOG performance status (rho, −0.19; P = .045) but was not found to be significantly associated with symptoms of anxiety, feelings of well-being, or dyspnea, unlike TT and FT values.
Patients were divided into tertiles based on the following TT values: low ≤ 127.2 ng/dL, 127.2 ng/dL < middle≤ 331.8 ng/dL, and high > 331.8 ng/dL; FT values: low ≤ 2.6 ng/dL, 2.6 ng/dL < middle ≤ 6.38 ng/dL, and high > 6.38 ng/dL; and BT values: low ≤ 12 ng/dL, 12 ng/dL < middle ≤ 33 ng/dL, and high > 33 ng/dL. Male patients with cancer with the lowest tertile for TT, FT, and BT values were all found to demonstrate a significant association with weight loss > 5% within the past 6 months (P ≤ .03). The lowest tertile of TT was significantly associated with increased anxiety (P = .047) and a poor sense of well-being (P = .045). Male patients with cancer with the lowest tertile of FT revealed a trend toward worse fatigue (P = .07). For patients with the lowest tertile of BT, a trend toward worse fatigue (P = .09) and poor appetite (P = .08) was also noted.
TT, FT, and BT levels were all found to be inversely associated with opioid use (morphine equivalent daily dosing) (rho, −0.36 [P = .004], rho, −0.33 [P = .005], and rho, −0.27 [P = .002], respectively).
Multivariate Survival Analysis
The median survival of the patient population in the current study was 151 days (95% CI, 116 days-186 days). The survival of male patients with cancer with testosterone levels < 200 mg/dL were significantly decreased compared with patients with levels ≥ 200 mg/dL (102 days vs 202 days; P = .007) (Fig. 1). For patients with the lowest tertile values for TT and BT, there was a significant association noted with worse survival, whereas only a trend was noted for FT values (Table 4). It is interesting to note that patients in the middle tertile of TT values had the best survival; however, for FT and BT levels, patient survival improved as values increased.
Table 4. Association Between Total, Free, and Bioavailable Testosterone and Survival in Male Patients With Advanced Cancer
Variables that were found to be significant with P values < .10 on univariate analysis included cancer diagnosis; ECOG performance status; TT, FT, and BT levels; CRP; white blood cell count; hemoglobin; albumin; and corrected calcium, whereas a patient's age and race were not found to be significant. On multivariate analysis, the groups were dichotomized as follows: TT level (≤ 200 ng/dL vs > 200 ng/dL), FT level (≤ 5 ng/dL vs > 5 ng/dL), BT level (≤ 40 ng/dL vs > 40 ng/dL), CRP (≤ 22.6 mg/L vs > 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 = .03), deteriorating ECOG performance status (HR, 1.55; P = .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 days-266 days) (P = .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 = .03). In 18 patients with head and neck malignancies, the median survival for hypogonadic males was 144 days (95% CI, 12 days to ∞) versus 240 days (95% CI, 86 days to ∞), which was not statistically significant (P = .27), most likely secondary to the small sample size.
Relationship Between FT and TT
Figure 2 shows the plot of FT versus TT in ng/mL; normal FT is ≥ 9 ng/mL and normal TT is ≥ 200 ng/dL. TT, when compared with FT, was noted to be 49% sensitive and 94% specific for determining hypogonadism in male patients with advanced cancer. A TT value of < 200 ng/dL was found to have a positive predictive value of 98%, a negative predictive value of 23%, and an accuracy of 55%. A receiver operating characteristic curve developed using the Gonen methodology resulted in an area under the curve of only 0.6, with no indication of the best cutoff value associated with increased symptoms or worse survival.
Various laboratory criteria have been used to define hypogonadism.[15-17] For young male patients, studies have used 2.5 standard deviations below the mean TT values of approximately 319 ng/dL as the cutoff point for the initiation of therapy. The American Association of Clinical Endocrinologists defines the cutoff value for low TT as between 200 ng/dL and 400 ng/dL, and although patients with symptoms are candidates for replacement therapy, to the best of our knowledge no specific recommendations have been established to date.
The results of the current study confirm the high frequency of hypogonadism in male patients with cancer who were seen in consultation for symptoms of cancer-related fatigue and/or anorexia-cachexia. Approximately one-half of male patients with cancer (44%) were hypogonadal based on a strict criteria for hypogonadism of a TT level of < 200 ng/dL, and a higher frequency of patients (86%) were noted to be hypogonadal when using a FT cutoff value of < 9 ng/dL; 89% of patients were considered hypogonadal when a BT level < 61 ng/dL was used.
In a previous study by our group, we reported a high frequency of hypogonadism (74%) based on TT levels in male patients with cancer with cachexia, and a slightly lower frequency (64%) based on measurements of FT, compared with the current study. Other groups have recently reported hypogonadism, based on calculated BT level of < 70 ng/dl, to be more common in cancer patients with cachexia (73%), compared with patients with cancer without weight loss (53%) and a noncancer control group (45%). The variation in the frequency of hypogonadism may be due to differences in the patient populations being studied; the assay used to measure TT, FT, or BT (or the use of calculated BT); and the variability in the lower limit of testosterone that is used by researchers to define hypogonadism.
Testosterone is present in 2 forms in the blood: a “free” (1%-4%) unbound state or a bound state, with the majority (approximately 98%) either tightly bound (60%) to SHBG or loosely bound to albumin (38%). BT is the sum of FT plus testosterone loosely bound to albumin, which is able to readily enter cells and is considered to be biologically active. Testosterone bound to SHBG is considered inactive. SHBG is often altered during illness and, in patients with cancer, is increased, resulting in falsely elevated levels of TT.[2, 6] Unlike our previous studies, we measured not only serum TT, but also FT and BT levels. Compared with FT, TT had high specificity but moderate sensitivity and may not be adequate by itself to screen for hypogonadism in male patients with cancer. For those patients with a TT level < 200 ng/dL, the positive predictive value was high, confirming hypogonadism; however, for patients with a TT level ≥ 200 ng/dL, the negative predictive value was not adequate to rule out gonadal dysfunction. In addition, future studies with a larger sample size are needed to determine a receiver operating characteristic curve for testosterone values to determine the appropriate threshold for increased symptom burden and survival outcomes.
Both serum TT and FT were associated with clinical symptoms including fatigue, anxiety, a decreased sense of well-being, and dyspnea. BT was also significantly associated with symptoms of fatigue and uniquely with poor appetite but not anxiety, sense of well-being, or dyspnea. Previous studies by our group have reported a significant association among male patients with cancer with low testosterone with symptoms such as increased fatigue, poor libido, depression, and insomnia.[1, 8] In a recent study, TT was found to be significantly associated with clinical symptoms of poor libido whereas the calculated BT did not demonstrate a similar association, and the authors argue to test for both TT and calculated BT. In the current study, both TT and FT were found to have similar correlations with clinical symptom burden whereas the association among BT and clinical symptoms of anxiety, sense of well-being, and dyspnea were less significant. More research is needed to determine the best clinically significant test to determine gonadal dysfunction in male patients with cancer.
Similar to previous studies, the use of opioids had a direct correlation with the frequency of hypogonadism in the current study patient population. In addition, we have previously reported that in 61 male patients with advanced cancer who had been tested for 25 hydroxy vitamin D and BT, there was a trend toward a positive association between vitamin D and testosterone. In the current study with a larger sample size, no significant association among TT, FT, or BT with vitamin D was noted.
TT, FT, and BT values were all found to be inversely correlated with serum CRP and weight loss, and directly correlated with ECOG performance status. In addition, on an exploratory multivariate analysis, only TT, and not FT or BT, was found to be associated independently with poor prognosis, along with elevated CRP, poor ECOG performance status, and decreased albumin. Other groups have also shown low testosterone to be associated with signs of chronic inflammation, weight loss, and poor ECOG performance status. Low testosterone has been reported to be associated with all-cause mortality in men with type 2 diabetes, increased cardiovascular mortality, and poor survival in elderly males. To our knowledge, the current study is the first to confirm that low testosterone in male patients with advanced cancer is associated with poor survival. When patients were divided into tertiles based on TT, FT, and BT values, a significant association with poor survival was noted with TT and BT values, whereas among patients with FT only a trend toward poor prognosis was noted. On the multivariate analysis, only TT was found to be significant for worse survival in male patients with cancer. It is plausible that TT is a better marker for overall gonadal function and is more sensitive to suppression by chronic inflammation or cytokine-mediated immune response. Because these findings are preliminary, future studies with a larger sample size are needed.
Inflammatory cytokines may lead to endocrine dysfunction, which can contribute to symptoms of fatigue, weight loss, and poor quality of life. The eugonadal sick syndrome hypothesizes that gonadal dysfunction is a normal response to illness. In the short term, gonadal dysfunction may provide a survival advantage by diverting energy to fight off infection or repair a wound. However, in chronic illnesses such as cancer, gonadal dysfunction resulting in low testosterone may result in a symptom burden that diminishes the quality of life of patients over a sustained period of time. To the best of our knowledge, the issue of whether gonadal dysfunction is an epiphenomenon associated with cancer patients being critically and chronically ill or if hypogonadism directly contributes to the symptom burden experienced by male patients with cancer is still unclear.
Clinical practice guidelines by the Endocrine Society address testosterone replacement therapy in patients with chronic illnesses such as the human immunodeficiency virus but not in patients with cancer. A preliminary study conducted by our group examining the benefits of testosterone replacement therapy with the primary outcome of fatigue in hypogonadic male patients with cancer remained inconclusive but did demonstrate a trend toward improved sexual desire and significant improvements in ECOG performance status and fatigue (Functional Assessment of Chronic Illness Therapy [FACIT]-Fatigue subscale) with prolonged use (eg, ≥ 72 days). A limitation of the study included the small sample size and the modest increase in serum levels of testosterone after replacement. Other studies examining testosterone replacement in patients without cancer have reported improvements in fatigue and quality of life.
Further research is required to determine the effectiveness of testosterone replacement therapy in hypogonadal men with advanced cancer. In male patients with advanced cancer and a poor prognosis, clinical studies examining the symptomatic benefits of testosterone replacement on outcomes including libido, fatigue, and quality of life are needed. In patients with cancer with a survival prognosis of > 6 months, studies examining the benefits of testosterone replacement on lean body mass, bone health, need for blood transfusions, ECOG performance status, and overall survival are needed with close monitoring for potential complications.
A limitation of the current study is the lack of assessments for sexual concerns or decreased libido. Diminished libido has been previously observed in male patients with cancer with low testosterone and is noted to be a clinical symptom that is understudied and undertreated in patients with advanced cancer. Screening for sexual issues in patients with advanced cancer should be integrated into clinical practice. In addition, other symptoms unique to testosterone deficiency, including the loss of mental acuity and menopausal-type hot flushes, which often occur during the acute onset of hypogonadism, may have not be captured without routine screening.
In addition to limitations in comprehensive symptom assessment, diurnal fluctuations in testosterone posed a challenge for accurately determining hypogonadism, because levels peak at 8 am and reach a nadir 12 hours later. Patients were instructed to obtain laboratory values between 7 am and 11 am. Patients with altered sleep patterns were instructed to obtain a laboratory workup within 2 hours of awakening. Noncompliance with instructions in chronically ill patients may be a factor resulting in testosterone values that are falsely low. In addition, before testosterone replacement, it is advised to repeat testing to confirm hypogonadism in clinical practice.
The frequency of hypogonadism in male patients with advanced cancer was found to be high and associated with symptoms of fatigue and anxiety and a worse sense of well-being. Systemic inflammation as measured by CRP, history of weight loss, and the use of strong opioids was found to be significantly associated with decreased testosterone levels in male patients with cancer. Low testosterone is associated with decreased survival independent of CRP level, albumin level, and ECOG performance status. Whether inadequate gonadal function is an epiphenomenon associated with critical illness or a potentially treatable complication of cancer or its treatment is unclear and more research is needed.
No specific funding was disclosed.
CONFLICT OF INTEREST DISCLOSURES
Dr. Bruera is supported in part by National Institutes of Health grants RO1NR010162-01A1, RO1CA122292-01, and RO1CA124481-01 and The University of Texas MD Anderson Cancer Center support grant CA016672. Dr. Del Fabbro is supported in part by American Cancer Society grant PEP-08-299-01-PC1.