Systemic Inflammation and Symptomatology in Prostate Cancer Patients Treated with Androgen Deprivation Therapy: Preliminary Findings

Abstract

Background:

Increases in fatigue, depressive symptomatology, and cognitive impairment are common following initiation of androgen deprivation therapy (ADT) for prostate cancer. To date no studies have examined the potential role of inflammation in the development of these symptoms in ADT recipients. The goal of the current study was to examine circulating markers of inflammation as potential mediators of change in fatigue, depressive symptomatology, and cognitive impairment related to receipt of ADT.

Methods:

Prostate cancer patients (ADT+; n=47) were assessed around the time of initiation of ADT and 6 and 12 months later. An age- and education-matched group of men without cancer (CA-; n=82) was assessed at comparable time points. Fatigue, depressive symptomatology, and cognitive impairment were assessed with the Fatigue Symptom Inventory, Center for Epidemiological Studies – Depression Scale, and a battery of neuropsychological tests, respectively. Circulating markers of inflammation included IL-1RA, IL-6, sTNF-RII, and CRP.

Results:

Fatigue, depressive symptomatology, and serum IL-6, increased significantly over time in the ADT+ group compared to the CA- group; rates of cognitive impairment also changed significantly between the groups. No significant changes in IL-1RA, sTNF-RII, or CRP over time were detected. Treatment-related increases in IL-6 were associated with worsening fatigue but not depressive symptomatology or cognitive impairment.

Conclusions:

Results of this preliminary study suggest that increases in circulating IL-6, perhaps due to testosterone inhibition, may play a role in fatigue secondary to receipt of ADT. Additional research is needed to determine whether interventions to reduce circulating inflammation improve fatigue in this population.

Precis:

Androgen deprivation therapy is associated with increases over time in fatigue, depressive symptomatology, and circulating interleukin-6. Increases in interleukin-6 over time are associated with worsening treatment-related fatigue, but not depressive symptomatology or cognitive impairment.

It is estimated that more than 50,000 U.S. men with prostate cancer are candidates for androgen deprivation therapy (ADT) each year.¹ ADT, which acts against prostate cancer by blocking production of testosterone, is associated with symptoms such as fatigue,^2,3 depression,^4–6 and cognitive impairment.^7–15 Published reports indicate that these symptoms co-occur in patients receiving ADT such that higher levels of one symptom are associated with higher levels of one or more of the others.^9,16,17 Associations among these symptoms suggest they may have a common underlying mechanism which may result from the decline in testosterone induced by ADT.

Converging lines of evidence implicate inflammation in the development of fatigue, depression, and cognitive impairment in cancer patients. Cancer patients with these symptoms show higher circulating markers of inflammation, including interleukin-1 receptor antagonist (IL-1ra), interleukin-6 (IL-6), C-reactive protein (CRP), and soluble tumor necrosis factor receptor-II (sTNF-RII).^18–25 Moreover, fatigue, depression and cognitive impairment can be induced in humans and animals through therapeutic and experimental administration of cytokines linked to induction of inflammatory response.^26–28

To our knowledge, there have been no studies examining the association between inflammation and ADT symptomatology even though testosterone is known to modulate inflammation. Testosterone binds to androgen or testosterone receptors on several different types of immune cells, and attenuates production of pro-inflammatory cytokines such as IL-6 and TNF.^29–36 Testosterone also inhibits IL-6 gene expression.²⁹ Thus, blocking of testosterone production through ADT may result in increased inflammation which in turn may contribute to fatigue, depression, and cognitive impairment.

The goal of the current study was to examine relationships between changes in circulating markers of inflammation (i.e., IL-1ra, IL-6, CRP, sTNF-RII) and changes in symptoms (i.e., fatigue, depression, cognitive impairment) in men treated with ADT for prostate cancer (ADT+) compared to men without cancer (CA-). These inflammatory biomarkers were selected on the basis of previous studies demonstrating their association with symptomatology in cancer patients.^19,37,38 It was hypothesized that the ADT+ group would show greater increases in inflammatory markers relative to the CA- group. It was further hypothesized that increases in inflammatory markers would account for treatment-related increases in symptoms.

Methods

Participants

Study methodology has been described in detail elsewhere.^2,4,8 Briefly, participants were recruited as part of a larger, longitudinal study investigating side effects of ADT. Eligibility criteria for the larger study required that all participants: be at least 18 years of age, be able to speak and read English, have at least an eighth grade education, have no history of stroke, and be free of cognitive impairment (Short Portable Mental Status Exam score < 3).³⁹ Additional eligibility criteria for the ADT+ group were that they: be diagnosed with non-metastatic or asymptomatic metastatic prostate cancer, be scheduled to start or have started ADT in past month, be scheduled to received ADT for at least 6 months, have not received treatment for any other cancers in the 12 months prior to recruitment, have no history of brain cancer or previous treatment with cranial irradiation, and have not been treated with ADT in the 12 months prior to recruitment or an anti-androgen agent (e.g., bicalutamide) in the 6 months prior to recruitment. Additional eligibility criteria for CA- group were that they: have no history of any form of cancer except non-melanoma skin cancer, not be receiving testosterone supplementation, and have a working telephone number.

Procedures

Data were collected between September 2008 and October 2013. ADT+ participants were recruited from Moffitt Cancer Center and the James A. Haley Veterans’ Affairs Medical Center. CA- participants were identified through use of information obtained from Marketing Systems Group, Inc. (Fort Washington, PA). Eligible CA- participants were matched to ADT+ participants on age and education. Baseline assessments were completed by ADT+ participants before or within 21 days of starting ADT, with follow-up assessments 6 and 12 months later; CA- participants were assessed at similar time intervals. Self-reported symptoms and cognitive performance were assessed at each time point. Blood collection was added partway through the study which is why there is a smaller number of ADT+ participants than CA- participants in the current report. For inclusion in the current report, participants were required to have blood samples available at all three time points. Written informed consent was obtained prior to initiation of study procedures. Participants were paid $80 at each evaluation. This study was approved by the Institutional Review Board at the University of South Florida.

Measures

Demographic and Clinical Characteristics.

Demographic information was collected at baseline via self-report. Medical comorbidities were assessed at baseline using a self-report version of the Charlson Comorbidity Index.⁴⁰ Clinical information for the ADT+ participants was collected via medical record review.

Fatigue.

The Fatigue Symptom Inventory (FSI).⁴¹ was used to measure fatigue severity, which represented the average of 3 items assessing the most, least, and average level of fatigue experienced over the previous week. Scores range from 0 to 10 with higher scores indicating greater fatigue. The FSI has established reliability and validity in cancer patients.⁴²

Depressive Symptomatology.

Depressive symptomatology was assessed using the Center for Epidemiological Studies Depression Scale (CES-D),⁴³ a 20-item measure that asks participants to rate the frequency of symptoms of depression in the past week. Scores range from 0 to 60 with higher scores indicating greater depressive symptomatology. Validity of the CES-D has been demonstrated with cancer patients.⁴⁴

Cognitive Impairment.

Cognitive performance was assessed in accordance with recommendations from the International Cancer and Cognition Task Force (ICCTF)⁴⁵ using eleven neuropsychological tests as previously described.⁸ Impaired cognitive performance was defined as a score ≥2.0 standard deviations below published norms on at least one test⁸ and the percentage of participants with impaired performance within each group at each time point was calculated.

Circulating Markers of Inflammation.

Blood samples were obtained prior to noon to minimize diurnal variation effects. Blood samples were obtained, processed to serum, and stored at −80 degrees C until shipped frozen to the UCLA Cousins Center laboratory for immunoassays. High sensitivity (IL-6) and regular sensitivity (IL1RA, sTNF-RII) enzyme-linked immunosorbent assays (R&D Systems Human Quantikine ELISA; Minneapolis, MN), were performed according to the manufacturer’s instructions. The lower limit of detection of the assays, taking sample dilution into account, were 0.2, 31.2, and 234 pg/mL, respectively. High sensitivity CRP ELISAs (Immundiagnostik, ALPCO Immunoassays, Salem, NH) were performed according to the manufacturer’s instructions, with a routine sample dilution of 1:200 and an extended standard curve, to yield a lower limit of detection of 0.2 mg/L. Samples were blinded for participant status and assayed in duplicate. All three samples from a given participant were tested on the same immunoassay plate and an internal control sample was included on every immunoassay plate to monitor inter-assay variability. Intra- and inter-assay precision of all tests was less than or equal to 10%.

Statistical Analyses

Raw inflammatory biomarker values were natural log-transformed to normalize their distributions and the natural log values were used in all analyses. For ease of interpretation, non-transformed data are presented in selected tables. Of the 140 participants available for analyses, 11 (6 ADT+, 5 CA-) were removed due to biomarker values over three standard deviations above their group’s mean for more than one assessment, use of opioids or steroids, and/or presence of autoimmune disease (e.g., rheumatoid arthritis). Thus, data from 129 participants were analyzed. Age, body mass index, and years of education were included as covariates in all multivariate analyses. Mixed model analyses were conducted to examine group differences in change over time in inflammatory biomarkers and symptoms.⁴⁶ To reduce the number of statistical analyses performed, indirect mediation analyses were conducted only for inflammatory biomarkers with significant group by time interactions. Indirect mediation analyses examined whether the relationship between receipt of ADT and residualized changes in fatigue, depression, or cognitive function were mediated by change in the biomarker.⁴⁷ These mediation analyses yielded bias-corrected bootstrap 95% confidence intervals using 10,000 bootstrap samples. Those 95% confidence intervals that do not include zero are indicative of an indirect effect that is statistically significant with an alpha of 0.05. Mixed model and mediation analyses were conducted in Mplus 7.4 (Los Angeles, CA).⁴⁸

Results

Demographic and clinical characteristics of the sample are shown in Table 1. As expected due to matching and selection criteria, there were no significant differences between men with prostate cancer who were about to or had very recently initiated ADT (ADT+ group, n=47) and a control group of men without any history of cancer (CA- group, n=82) in age and education; the two groups also did not differ on race, ethnicity, or comorbidities (all p values>0.05).

Table 1.

Sociodemographic and Clinical Characteristics of the Sample.

	ADT+ (n=47)	CA− (n=82)	p
Age: mean (SD)	67.6 (9.2)	68.4 (8.4)	0.65
Race: n (%)			1.00
White	44 (94)	77 (94)
Non-White	3 (6)	5 (6)
Ethnicity			0.97
Hispanic	2 (4)	5 (6)
Non-Hispanic	45 (96)	77 (94)
Education: n (%) college graduate	18 (38)	31 (38)	1.00
Comorbidity index score: mean (SD)	2.7 (.9)	2.7 (1.0)	0.97
Time since diagnosis: mean (SD) years	2.9 (4.7)
Gleason score: n(%)
6	5 (11)
7	19 (40)
8	15 (32)
9	6 (13)
10	1 (2)
missing	1 (2)
Concurrent radiotherapy: n (%)	24 (51)
Concurrent brachytherapy: n (%)	5 (11)

The ADT+ group showed significantly higher levels of depressive symptoms at baseline compared to the CA- group (Table 2). The two groups did not differ significantly at baseline for fatigue, cognitive impairment, or any of the circulating levels of inflammatory markers (Table 2). Consistent with the larger sample that included patients who were not asked to provide blood samples,^2,4 in this subsample of participants, fatigue and depressive symptoms increased significantly over 12 months in the ADT+ group relative to the CA- group. Participants in the ADT+ group demonstrated fairly stable rates of cognitive impairment, while the CA- group showed decreases in cognitive impairment from baseline to 12 months, resulting in a significant difference between the groups over time.

Table 2.

Symptoms and Circulating Markers of Inflammation: Unadjusted Means and Standard Deviations

	Baseline	Baseline Group Comparison	6 Months	12 Months	Group*Time Comparison
	M (SD)	p	M (SD)	M (SD)	p
Fatigue		0.79			0.03
ADT+	2.2 (1.9)		3.0 (2.1)	3.2 (2.0)
CA−	2.4 (1.7)		2.6 (1.9)	2.5 (1.8)
Depressive symptomatology		0.003			0.048
ADT+	9.9 (9.4)		14.3 (11.2)	13.3 (11.1)
CA−	6.7 (6.7)		6.5 (5.8)	7.7 (8.0)
Cognitive impairment		0.43			0.02
ADT+	41%		39%	43%
CA−	44%		27%	23%
IL-1RA (pg/mL)		0.93			0.67
ADT+	421 (231)		526 (412)	493 (309)
CA−	431 (323)		511 (637)	463 (445)
sTNF-RII (pg/mL)		0.53			0.42
ADT+	3,011 (906)		3,204 (1090)	3,219 (963)
CA−	3,268 (1,358)		3,311 (1,394)	3,245 (1,261)
IL-6 (pg/mL)		0.62			0.03
ADT+	2.0 (1.0)		2.7 (1.7)	3.0 (2.5)
CA−	2.3 (1.5)		2.4 (1.9)	2.8 (3.5)
CRP (mg/L)		0.19			0.47
ADT+	4.72 (4.57)		5.01 (4.52)	6.43 (7.59)
CA−	5.46 (10.19)		3.32 (4.00)	4.70 (8.74)

Note: raw unadjusted means and SD are shown for ease of interpretation. CRP: C-reactive protein, IL-1RA: Interleukin-1 receptor antagonist, IL-6: interleukin-6, sTNF-RII: soluble tumor necrosis factor receptor 2.

As shown in Table 2, serum IL-6 levels increased significantly over time in the ADT+ group relative to the CA- group. Mean-level changes in fatigue and IL-6 by group are depicted in Figures 1 and 2. Group differences were not observed for change over time in IL-1RA, sTNF-RII, or CRP (p values≥0.47). Change in biomarkers among ADT recipients was not associated with Gleason score or receipt of radiation concurrent with ADT (p values≥0.33). Baseline levels of biomarkers within the ADT group did not differ based on when patients completed the first assessment (i.e., before initiation of ADT versus after) (p values≥0.17). Mediation analyses indicated that the effects of ADT on fatigue were attributable to increases in IL-6 (indirect effect=−0.10, 95% CI=−0.26,−0.02). The effects of ADT on depressive symptoms and cognitive impairment were not attributable to increases in IL-6 (p values>0.05).

Figure 1. Unadjusted Mean Changes in Fatigue Severity in ADT+ and CA- Participants Over 12 Months.

Unadjusted mean values are shown for fatigue for prostate cancer patients on ADT (ADT+; solid black line) and control participants with no history of cancer (CA-; dashed gray line).

Figure 2. Unadjusted Mean Changes in Circulating Interleukin-6 Levels in ADT+ and CA- Participants Over 12 Months.

Unadjusted mean values are shown for IL-6 for prostate cancer patients on ADT (ADT+; solid black line) and control participants with no history of cancer (CA-; dashed gray line).

Discussion

The current study is the first to our knowledge to examine the role of inflammation in ADT symptomatology. Results indicate that initiation of ADT administration was associated with increases over the following 12 months in depressive symptomatology, over and above the significantly higher level of depressive symptoms already present in the ADT+ group at baseline. Initiation of ADT administration was also associated with increases in fatigue and circulating IL-6 over the following 12 months, but not in circulating IL1-ra, CRP, or sTNF-RII. Improvement in cognitive performance (and therefore, decreased cognitive impairment) was observed over time in the CA- group, presumably as a result of practice or learning effects due to repeated administration of cognitive tests at baseline, 6 month, and 12 month assessments. In contrast, ADT+ participants did not demonstrate any improvement over repeated testing, which could be interpreted as a deficit in cognitive function relative to controls.⁸ Increases in IL-6 explained increases in fatigue related to receipt of ADT but not depressive symptoms or cognitive impairment.

ADT is a hormone inhibition therapy which acts by eliminating testosterone, in contrast to traditional chemotherapy which is designed to be directly toxic to tumor cells. Therefore, it is interesting that our results are consistent with previous findings supporting the role of inflammation in fatigue due to chemotherapy administration.^19,49–51 Unlike studies of chemotherapy, the current study found no evidence of a consistent relationship between ADT-related inflammation and cognitive impairment or depressive symptomatology. Because most chemotherapy studies have focused on breast cancer patients, it is unclear whether differences are due to gender, type of treatment, or both. Testosterone may affect cognition and mood directly^52,53 or through mechanisms yet to be determined.

Since testosterone has been demonstrated to have suppressive effects on circulating levels of IL-6 and IL-6 gene expression,^29,36,54 ADT may have some specificity for IL-6 but not IL-1β or TNF. CRP is widely utilized as a general marker of systemic inflammation and is produced by the liver in response to IL-6. CRP is sometimes viewed therefore as a surrogate marker of IL-6 activity. While the mean levels of CRP in the ADT+ group did rise over time, the lack of statistically-significant changes in ADT+ men in CRP is likely due to more variability in CRP values, and the relatively small absolute increases in IL-6 concentrations (1.1 pg/mL difference in mean IL-6 in ADT+ from baseline to 12 months) compared to absolute CRP concentrations (4.72–6.43 mg/L), which are 5,000-fold higher.

Strengths of the current study include a longitudinal design, well-validated measures of study outcomes, use of neuropsychological testing to assess cognitive impairment, and a matched control group. Study limitations should also be noted. The sample size was relatively small and homogenous in terms of race and ethnicity. Thus, additional research is needed to replicate these findings in larger and more diverse samples. Some men completed a baseline assessment within 21 days following initiation of ADT which may have resulted in higher baseline levels of inflammation and symptoms. However, there were no differences in symptoms or inflammation between patients who did and did not complete the baseline assessment before initiation of ADT. Further, because this exploratory study is the first to our knowledge to examine relationships between symptoms and inflammatory biomarkers in this population, we did not adjust for multiple statistical comparisons. Future research in this area would benefit from a larger sample size and greater statistical power.

In conclusion, fatigue in patients treated with ADT may be due in part to increases in systemic levels of the pro-inflammatory cytokine IL-6. Exercise has been shown to reduce fatigue in prostate cancer patients, perhaps due its effects on IL-6.^55–57 Research is needed to determine whether additional interventions to reduce overall inflammation (e.g., non-steroidal anti-inflammatory medication) or IL-6 specifically (e.g., tocilizumab) exert beneficial effects on fatigue among ADT-treated prostate cancer patients who are unable or unwilling to exercise. These efforts are important to improving quality of life in the large and growing population of prostate cancer patients receiving ADT.