Retrospective study of testosterone deficiency and symptom burden in patients with pancreatic cancer

Introduction

Pancreatic ductal adenocarcinoma (PDAC) is a leading cause of cancer-related death in the United States with increasing incidence. Unfortunately, this cancer has a poor 5-year survival rate of 12% (1). Treatment for PDAC involves an intensive combination of surgery, chemotherapy, and/or radiation.

Constitutional symptoms are common in patients with PDAC, with many people reporting fatigue, weakness, cognitive dysfunction, and weight loss (2,3). These symptoms likely contribute to patients with PDAC reporting worse quality of life compared to patients with other cancers (2). Furthermore, a significant proportion of PDAC patients note a lack of sexual interest or enjoyment (2-5). In clinical practice, constitutional symptoms are often assumed to be manifestations of disease or treatment. However, they are also consistent with testosterone deficiency in males, which is characterized by fatigue, weakness, cognitive dysfunction, decreased lean muscle mass, and sexual dysfunction (6).

Symptomatic testosterone deficiency, defined as low serum testosterone combined with associated symptoms, affects between 10% and 40% of adult males and increases in prevalence with age (7). Testosterone is not a current guideline recommended laboratory test in the diagnosis or management of PDAC (8). To our knowledge, no data are currently available on the clinical patterns for testosterone screening in this population and limited data exist regarding the prevalence of testosterone deficiency in male patients with PDAC. Therefore, we sought to investigate clinical practices regarding screening for testosterone deficiency, the prevalence of testosterone deficiency, and the relationship between testosterone status and oncologic outcomes in a cohort of male patients with PDAC. We present this article in accordance with the STROBE reporting checklist (available at https://tau.amegroups.com/article/view/10.21037/tau-22-684/rc).

Methods

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Two cohorts of patients were developed for this study. Cohort A was developed for the purpose of addressing our question about the frequency of testosterone screening in clinical practice for patients with pancreatic cancer under two retrospective records review approvals from the Institutional Review Board of the University of Iowa (protocols No. #201102712 and No. #201903702), and individual consent for this retrospective analysis was waived.

Cohort B was developed using patients who had consented to participation in an institutional tissue repository also approved by the Institutional Review Board of the University of Iowa (protocol No. #201202743) to investigate the frequency of testosterone deficiency in this patient population and to associate oncologic outcomes to testosterone levels. Most patients, but not all, were sampled shortly after diagnosis and prior to treatment initiation. Individual consent was obtained for future research at the time of donation to the tissue repository.

For cohort A, existing patterns of testosterone testing in patients with primary tumors of the pancreas were analyzed by querying the electronic medical record at the University of Iowa Hospitals and Clinics, a National Cancer Institute-designated comprehensive cancer center delivering high-volume pancreatic cancer care. This query sought to identify all male patients with billing codes for masses of the pancreas (C.25X) and then identify those who also had an available testosterone laboratory level between 2006 and 2020. Non-primary pancreatic masses were eliminated from analysis. Testosterone levels, as well as demographics and clinicopathologic variables, were abstracted and assessed. Available testosterone levels were analyzed for testosterone deficiency.

For cohort B, serum samples were obtained from male PDAC patients enrolled in an institutional prospective biospecimen repository at a National Cancer Institute-designated comprehensive cancer center from 2012–2020. Total testosterone (ng/dL) of each sample was measured using serum testosterone ELISA kits (11-TESHU-E01, Alpco, Salem, NH, USA). Demographic, clinicopathologic, treatment, and outcome data were abstracted from the electronic medical record. For both surgically- and medically-treated patients, clinical staging based on AJCC 7^th edition was used for consistency in analysis (9).

For both cohorts, low serum testosterone was defined as a level <300 ng/dL per the American Urological Association guideline (6) and obesity was defined as body mass index (BMI) >30 kg/m².

Statistical analysis

Chi-squared or Fisher’s exact tests were used to compare categorical variables, and Wilcoxon rank sum tests were used to compare continuous variables between low and normal testosterone groups. Survival probabilities were estimated and plotted using the Kaplan-Meier method. Cox regression models were used to assess the association of patient and disease characteristics on progression-free survival (PFS) and overall survival (OS). Survival time was calculated from date of diagnosis to progression or death due to any cause for PFS and to death due to any cause for OS. Patients (n=1) for whom the date of progression is unknown were excluded from the PFS analysis. All tests were two-sided and assessed for significance at the 5% level using SAS v9.4 (SAS Institute, Cary, NC, USA).

Results

In cohort A, 1,566 male patients were identified with a pancreatic mass billing code. Of these, 35 (2.2%) had both a primary pancreatic mass and a testosterone level in their electronic medical records. Table 1 contains demographic and clinical data of interest.

The most common documented reason prompting a provider to check a testosterone level in these 35 cancer patients were complaints of fatigue (n=14, 40%), followed by low libido and/or erectile dysfunction (n=8, 23%), or monitoring ongoing testosterone therapy (n=4, 11%).

In cohort A, 16 patients (46%) had a low testosterone level while an additional 4 (11%) patients had a normal testosterone level, but were on testosterone therapy at the time of the blood draw and therefore included within the low testosterone group. Therefore, 20/35 (57%) of cohort A were considered to have low testosterone. When limiting our analysis to patients for whom testosterone levels were measured within one year before or after cancer diagnosis, 4/12 (33%) had measured low testosterone. An additional 3 patients were already on testosterone therapy at time of the lab draw, which represents a low testosterone proportion of 7/12 (58%).

In cohort B, the majority of patients (62/89, 69.7%) had documented symptoms associated with testosterone deficiency in the medical record prior to sample collection. Fatigue was the most-commonly reported symptom consistent with testosterone deficiency.

Upon analysis, nearly half (44/89, 49.4%) were found to have a low serum testosterone level (median: 301 ng/dL; range, 123–2,378 ng/dL). Only 2/89 (2.2%) patients had a prior testosterone level measured; none had received testosterone therapy per review of electronic medical records.

Low and normal testosterone subgroups of cohort B are compared in Table 2. Patients with low serum testosterone were of similar age and were no more likely to be obese, have diabetes, or have heart disease. For the 49 patients with an Eastern Cooperative Oncology Group (ECOG) score, there was no difference between groups. Patients with low serum testosterone were not more likely to report any symptom of testosterone deficiency (low: 77.3%, normal: 62.2%, P=0.12) or more likely to have documented fatigue or weakness. There was no significant difference between groups in receipt of surgery, chemotherapy, or radiation. Furthermore, patients with low testosterone were not more likely to have more advanced disease.

Univariate and multivariable analysis of the serum sample cohort is presented in Tables 3,4, respectively. Stage III or IV disease and presence of metastatic disease at diagnosis were significantly associated with decreased PFS and OS in univariate analysis. Receiving surgery was significantly associated with increased PFS and OS, with receipt of radiation therapy also associated with increased OS on univariate analysis. A statistically significant difference in PFS and OS by testosterone level was not evidenced on univariate analysis (Figures 1,2). Only the presence of metastatic disease and receiving surgery remained associated with both PFS and OS on multivariable analysis. After adjusting for metastatic disease at the time of diagnosis and treatment, testosterone level had no statistically significant association with PFS (P=0.66) or OS (P=0.95).

Figure 1 Univariate analysis of PFS by low testosterone status for the serum sample cohort. PFS was not significantly different between patients with low or normal testosterone levels (P=0.56). PFS, progression-free survival.

Figure 2 Univariate analysis of OS by low testosterone status for the serum sample cohort. OS was not significantly different between patients with low or normal testosterone levels (P=0.81). OS, overall survival.

Discussion

Patients with PDAC are not only afflicted by a poor prognosis, but also experience a poor quality of life, particularly in comparison to patients with other cancers. We found that while pancreas cancer patients are rarely assessed for testosterone deficiency, nearly 70% of patients in our samples have symptoms consistent with low testosterone. Further, nearly 50% of our sampled cohort had low levels of testosterone in their serum.

The primary therapy for testosterone deficiency is testosterone supplementation. Large trials suggest that testosterone therapy increases activity, sexual desire, erectile function, both perceived ability and objective distance of walking, vitality, mood, depressive symptoms, anemia, bone mineral density and bone strength (10). Additional reported benefits include stabilizing metabolic syndromes in hypogonadal patients (11). Testosterone therapy is generally considered safe, with the only significant adverse event associated with supplementation being erythrocytosis, which may become a potential benefit for those with chemotherapy-induced anemia (10). Although preclinical studies suggested that pancreatic cancer tissue may overexpress the androgen receptor (AR) (12,13), later studies have failed to replicate this finding or find an association between survival and AR expression (14,15). AR has been explored as a therapeutic target for PDAC but has not shown significant benefit (16-18). Low testosterone was not associated with a survival advantage in our data, consistent with a likely limited role for AR signaling in PDAC progression.

Androgen deficiency has previously been identified in patients with advanced cancer and is considered a potential contributor to systemic inflammation, fatigue, depression, decreased sexual desire, anorexia, and weight loss, consistent with the anorexia-cachexia syndrome (19-21). In our study, patients with low serum testosterone did not significantly differ from patients with normal serum testosterone in fatigue, weakness, obesity, diabetes, or heart disease, nor were they more likely to report symptoms of testosterone deficiency or have different ECOG scores. Our modest sample size may have contributed to this finding.

Decreased circulating testosterone has been associated with decreased OS in male cancer patients (19). In contrast to our study, an association between low testosterone and reduced survival has also been found in patients with pancreatic cancer (21). Although using a similar sample size, only advanced PDAC patients were included in this study, and more than 70% of patients were considered hypogonadal, which may account for the differences in our findings.

Higher circulating levels of testosterone have been associated with improved performance on a stair climb test in cancer patients (22), suggesting that testosterone likely impacts physical performance and that testosterone supplementation may benefit patients with cancer. Two small trials of testosterone supplementation have been conducted. In a double-blind, placebo-controlled trial of testosterone therapy for 10 weeks in patients with advanced cancer, treated patients demonstrated a decrease in fatigue, an increase in performance status, and an increase in sexual desire (23). A randomized trial of testosterone as an adjuvant supplement in patients with head and neck cancer undergoing therapy found that the testosterone cohort experienced improved lean body mass, quality of life, and physical activity compared to placebo (24). Additional larger trials are ongoing in cancer patients and cancer survivors, including NCT05367284, NCT04492553, NCT04301765, and NCT04049331, although patients with active PDAC are not eligible for any of these trials.

Our study has several limitations including a relatively small sample size and a single-institution setting. To diagnose testosterone deficiency, two morning testosterone measurements should be made at separate visits, and our study only was able to make one measurement. We were also unable to control for time of day that serum samples were drawn in our analysis cohort, and therefore our data may overestimate proportion of patients with testosterone deficiency due to late-day sampling. Circadian variation in serum testosterone becomes blunted in older men, however, and our study population median ages at diagnosis were in the 60’s, so morning samples are likely less important in our particular populations (25). Our study is also limited by its retrospective nature and a primarily Caucasian population, a byproduct of the patient population seen at our institution. Further, our method for developing cohort A was unable to limit this group to only patients with pancreatic adenocarcinoma. Therefore, patients with endocrine neoplasms are also included, limiting the precision of our estimation of testosterone assessment in this population. Finally, our sample is biased towards individuals who consented to participate in research and by a high percentage of surgery-eligible patients because of our status as a tertiary referral center.

Conclusions

Male patients with tumors of the pancreas commonly report symptoms associated with testosterone deficiency and meet guideline recommendations for screening for testosterone deficiency. However, at our center, these patients are rarely screened. One in two patients were found to have laboratory evidence of testosterone deficiency, and symptoms associated with testosterone deficiency were not statistically more common in patients with low testosterone. Further prospective studies are warranted to explore the role of testosterone supplementation in improving men’s health and overall well-being during PDAC treatment.

Acknowledgments

Portions of this work were presented at the Virtual Cancer Cachexia Conference in 2020, the 2020 Academic Surgical Conference, and the 2020 Sexual Medicine Society of North America Fall Scientific Meeting.

Funding: This study was supported by the Biospecimen Procurement and Molecular Epidemiology Resource (BioMER) and the Biostatistics Core of the Holden Comprehensive Cancer Center through funds from the National Cancer Institute of the National Institutes of Health (No. P30CA086862). Additional University of Iowa funds were used to support research costs, and a portion of EET’s salary was supported by National Institutes of Health (No. R00AR071508). This study was also supported by the National Heart, Lung, and Blood Institute of the National Institutes of Health T35 (No. HL007485 to AGK).

Footnote

Reporting Checklist: The authors have completed the STROBE reporting checklist. Available at https://tau.amegroups.com/article/view/10.21037/tau-22-684/rc

Data Sharing Statement: Available at https://tau.amegroups.com/article/view/10.21037/tau-22-684/dss

Peer Review File: Available at https://tau.amegroups.com/article/view/10.21037/tau-22-684/prf

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://tau.amegroups.com/article/view/10.21037/tau-22-684/coif). AGK receives support from the National Heart, Lung, and Blood Institute of the National Institutes of Health T35 (No. HL007485). AMP receives grant funding from and is a consultant for Boston Scientific. She also is a consultant for Endo Pharmaceuticals and she is on the medical advisory board for FirmTech. After the conclusion of data collection but prior to publication, AMP co-founded the PRIME institute, a for-profit company. EET has received salary support provided by NIH (No. NIH R00AR071508) and Institutional NIH support for core resources (No. NIH P30CA086862). She has also received grants from NIH (No. NIH R21 CA257972), lecture honoraria from the University of Kentucky and West Virginia University, travel costs for AACR Annual Meeting 2023 (Invited Speaker) from the American Association for Cancer Research, travel costs for the seminar from West Virginia University, Travel costs for 18th International Biochemistry of Exercise Conference (Invited Speaker) from International Research Group on Biochemistry of Exercise, and travel costs for Journées de la Société Française de Myologie (Invited Speaker) from Société Française de Myologie. EET was also the Co-chair of the education committee of Cancer Cachexia Society. The other authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). Cohort A received approvals from the Institutional Review Board of the University of Iowa (protocols No. #201102712 and No. #201903702) and individual consent for this retrospective analysis was waived. Cohort B was approved by the Institutional Review Board of the University of Iowa (No. #201202743) and individual consent was obtained for future research at the time of donation to the tissue repository.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

References

1. Siegel RL, Miller KD, Wagle NS, et al. Cancer statistics, 2023. CA Cancer J Clin 2023;73:17-48. [Crossref] [PubMed]
2. Bauer MR, Bright EE, MacDonald JJ, et al. Quality of Life in Patients With Pancreatic Cancer and Their Caregivers: A Systematic Review. Pancreas 2018;47:368-75. [Crossref] [PubMed]
3. Frick MA, Vachani CC, Hampshire MK, et al. Survivorship after treatment of pancreatic cancer: insights via an Internet-based survivorship care plan tool. J Gastrointest Oncol 2017;8:890-6. [Crossref] [PubMed]
4. Moningi S, Walker AJ, Hsu CC, et al. Correlation of clinical stage and performance status with quality of life in patients seen in a pancreas multidisciplinary clinic. J Oncol Pract 2015;11:e216-21. [Crossref] [PubMed]
5. Beesley VL, Wockner LF, O'Rourke P, et al. Risk factors for current and future unmet supportive care needs of people with pancreatic cancer. A longitudinal study. Support Care Cancer 2016;24:3589-99. [Crossref] [PubMed]
6. Mulhall JP, Trost LW, Brannigan RE, et al. Evaluation and Management of Testosterone Deficiency: AUA Guideline. J Urol 2018;200:423-32. [Crossref] [PubMed]
7. Anaissie J, DeLay KJ, Wang W, et al. Testosterone deficiency in adults and corresponding treatment patterns across the globe. Transl Androl Urol 2017;6:183-91. [Crossref] [PubMed]
8. Pancreatic adenocarinoma (1.2022): National Comprehensive Cancer Network. Available online: https://www.nccn.org/professionals/physician_gls/pdf/pancreatic.pdf
9. Edge SB, Byrd DR, Compton CC, et al. editors. AJCC Cancer Staging Manual. 7th edition. New York, NY, USA: Springer; 2010.
10. Snyder PJ, Bhasin S, Cunningham GR, et al. Lessons From the Testosterone Trials. Endocr Rev 2018;39:369-86. [Crossref] [PubMed]
11. Salam R, Kshetrimayum AS, Keisam R. Testosterone and metabolic syndrome: The link. Indian J Endocrinol Metab 2012;16:S12-9. [Crossref] [PubMed]
12. Corbishley TP, Iqbal MJ, Wilkinson ML, et al. Androgen receptor in human normal and malignant pancreatic tissue and cell lines. Cancer 1986;57:1992-5. [Crossref] [PubMed]
13. Okitsu K, Kanda T, Imazeki F, et al. Involvement of interleukin-6 and androgen receptor signaling in pancreatic cancer. Genes Cancer 2010;1:859-67. [Crossref] [PubMed]
14. Georgiadou D, Sergentanis TN, Sakellariou S, et al. Prognostic role of sex steroid receptors in pancreatic adenocarcinoma. Pathol Res Pract 2016;212:38-43. [Crossref] [PubMed]
15. Targarona EM, Pons MD, Gonzalez G, et al. Is exocrine pancreatic cancer a hormone-dependent tumor? A study of the existence of sex hormone receptors in normal and neoplastic pancreas. Hepatogastroenterology 1991;38:165-9. [PubMed]
16. Keating JJ, Johnson PJ, Cochrane AM, et al. A prospective randomised controlled trial of tamoxifen and cyproterone acetate in pancreatic carcinoma. Br J Cancer 1989;60:789-92. [Crossref] [PubMed]
17. Negi SS, Agarwal A, Chaudhary A. Flutamide in unresectable pancreatic adenocarcinoma: a randomized, double-blind, placebo-controlled trial. Invest New Drugs 2006;24:189-94. [Crossref] [PubMed]
18. Konduri S, Schwarz MA, Cafasso D, et al. Androgen receptor blockade in experimental combination therapy of pancreatic cancer. J Surg Res 2007;142:378-86. [Crossref] [PubMed]
19. Dev R, Hui D, Del Fabbro E, et al. Association between hypogonadism, symptom burden, and survival in male patients with advanced cancer. Cancer 2014;120:1586-93. [Crossref] [PubMed]
20. Burney BO, Hayes TG, Smiechowska J, et al. Low testosterone levels and increased inflammatory markers in patients with cancer and relationship with cachexia. J Clin Endocrinol Metab 2012;97:E700-9. [Crossref] [PubMed]
21. Skipworth RJ, Moses AG, Sangster K, et al. Interaction of gonadal status with systemic inflammation and opioid use in determining nutritional status and prognosis in advanced pancreatic cancer. Support Care Cancer 2011;19:391-401. [Crossref] [PubMed]
22. Anderson LJ, Lee J, Mallen MC, et al. Evaluation of physical function and its association with body composition, quality of life and biomarkers in cancer cachexia patients. Clin Nutr 2021;40:978-86. [Crossref] [PubMed]
23. Del Fabbro E, Garcia JM, Dev R, et al. Testosterone replacement for fatigue in hypogonadal ambulatory males with advanced cancer: a preliminary double-blind placebo-controlled trial. Support Care Cancer 2013;21:2599-607. [Crossref] [PubMed]
24. Wright TJ, Dillon EL, Durham WJ, et al. A randomized trial of adjunct testosterone for cancer-related muscle loss in men and women. J Cachexia Sarcopenia Muscle 2018;9:482-96. [Crossref] [PubMed]
25. Plymate SR, Tenover JS, Bremner WJ. Circadian variation in testosterone, sex hormone-binding globulin, and calculated non-sex hormone-binding globulin bound testosterone in healthy young and elderly men. J Androl 1989;10:366-71. [Crossref] [PubMed]