Perioperative Hypogonadism in Men Undergoing Radical Cystoprostatectomy for Bladder Cancer
Conditions: Bladder Cancer, Low Testosterone Levels
Sponsor: University of Kansas Medical Center

 
 
 
Perioperative hypogonadism in men undergoing radical 
cystoprostatectomy for bladder cancer 
 
 
Document Date: January 2017 
 
NCT03063125 

Page 1 
STUDY PROTOCOL 
 
Study Title:   
 
      Perioperative hypogonadism in men undergoing radical  
 
 
 
 
      cystoprostatectomy for bladder cancer. 
 
Version Date:  
 
      January 2017 
 
Principal Investigator: 
Jeffrey Holzbeierlein, MD, FACS 
 
Chairman 
 
Dept. of Urologic Surgery 
 
ph: 913-599-7564 | e-mail: jholzbeierlein@kumc.edu 
 
Co-investigator: 
Woodson Smelser, MD 
 
Dept. of Urologic Surgery 
 
ph: 913-588-7571| e-mail: wsmelser@kumc.edu 
 
 
Jessie Gills, MD 
 
Dept. of Urologic Surgery 
 
Ph: 913-588-7571 
 
Collaborator: 
Eugene Lee, MD 
 
Dept. of Urologic Surgery 
 
ph: 913-588-7564 | e-mail: elee@kumc.edu 
 
Collaborator: 
Moben Mirza, MD 
 
Dept. of Urologic Surgery 
 
ph: 913-588-7564 | e-mail: mmirza@kumc.edu 
 
Collaborator: 
Ajay Nangia, MBBS 
 
Dept. of Urologic Surgery 
 
ph: 913-588-0799 | e-mail: anangia@kumc.edu 
 
Collaborator: 
Hadley Wyre, MD 
 
Dept. of Urologic Surgery 
 
ph: 913-588-6152 | e-mail: hwyre@kumc.edu 
 
Medical Monitor: 
Joshua Broghammer, MD 
 
Dept. of Urologic Surgery 
 
ph: 913-588-6982 | e-mail: jbroghammer@kumc.edu 
 
 
 
 
 
 

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PROTOCOL: 
 
BACKGROUND/LITERATURE REVIEW & SIGNIFICANCE 
 
Radical cystectomy is a morbid operation. Bladder cancer is the sixth-most prevalent 
malignancy in the United States.i The current standard treatment for invasive bladder 
cancer is neoadjuvant chemotherapy followed by radical cystectomy (RC), a complex 
operation that requires bladder excision and urinary tract reconstruction using a segment 
of the terminal ileum.ii,iii This surgery is associated with significant morbidity, with 90-
day readmission rates at approximately 26% and with infections accounting for 25% of 
complications at 30 and 90 days.iv Furthermore, the estimated mortality rate at 90 days 
has been reported at 7% in a previous series from a high volume center.4 
 
The stress response to surgery and its effect on testosterone.  Surgery evokes a 
cascade of hormonal and metabolic changes known as the stress response, and this can be 
seen with trauma, burns, severe infection, or strenuous exercise.v  This series of changes 
includes an increase in pituitary hormones and activation of the sympathetic nervous 
system.  These changes likely evolved to aid in survival in a more primitive environment 
by mobilizing substrates to provide energy, limit tissue damage, attack infectious 
organisms, and activate repair mechanisms.5  Furthermore, several studies have noted 
men develop temporary hypogonadism with decreased testosterone levels in response to 
surgery.vi,vii,viii This decrease in serum testosterone level does not appear to be due to 
reduced sex hormone-binding capacity, although the exact pathophysiology is not 
known.6  On a similar note, levels of luteinizing hormone (LH) will rise in response to 
surgery as levels of testosterone decrease, suggesting that suppression of testosterone 
results in compensatory elevation of LH.7  This suppression of testosterone levels can be 
found during and up to seven days following major surgery and general anesthesia.8 
 
Loss of lean body mass is a common side effect of Radical Cystectomy. Loss of body 
weight is a common postoperative observation, even in patients without nutritional 
deficiencies. A 5% loss of body weight and a 7% loss of body protein at postoperative 
day 14 was reported in a small observational study of 11 men undergoing RCix. Body fat 
remained unchanged; body protein did not fully recover at 6 months post-surgery9. This 
data suggests that even patients without nutritional deficiencies are at risk of weight and 
body protein losses after RC. 
 
Hypogonadism and Cancer.  Low testosterone levels are common in male patients with 
cancer, and up to two thirds of men with advanced or metastatic cancer have 
hypogonadism.x,xi,xii The cause of hypogonadism in cancer patients is multifactorial and 
includes inflammation, comorbidities, opioids, weight abnormalities, or chemotherapy.xiii  
Despite the high prevalence of the association between hypogonadism and cancer, there 
are no clear studies delineating how extensive the hypogonadism is and how long does it 
persist after surgery, especially in bladder cancer.  
 
Testosterone use Testosterone use has been studied extensively in hypogonadal men 
with other chronic medical conditions.  Specifically, several studies have shown 

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improvement in energy levels, body proportions, obesity parameters, and health related 
quality of life with respect to hypogonadism, diabetes, metabolic syndrome, and 
COPD.xiv,xv,xvi,xvii While these studies do not directly relate to bladder cancer or post-
operative outcomes, they suggest that testosterone therapy can improve fitness outcomes, 
energy levels, and a patient’s self-perception of their health status.  These improvements 
would be a welcome addition to the post-operative course after radical cystectomy, as it 
is typically associated with decreased quality of life and significant morbidity.  
Furthermore, testosterone analogs have been used in the burn population, a setting of 
intense surgical stress, to restore weight loss and muscle mass.xviii,xix  A randomized 
prospective study utilizing oxandrolone, a testosterone analog, found that testosterone 
replacement decreases weight loss and increases healing without side effects, compared 
to a control substance and human growth hormone.18 Knowing whether hypogonadism st 
persists status post RC may provide a rationale for treating these patients with 
testosterone.   
 
Significance.  Radical cystectomy (RC) is a major urologic surgery involving bladder 
excision and urinary tract reconstruction utilizing a portion of the terminal ileum. 
Surgical stress leads to a catabolic state and temporary hypogonadism with decreased 
testosterone levels, both of which contribute to morbidity and mortality. The results of 
this study will lead to a better understanding of the stress response to RC surgery with 
specific emphasis on the hypogonadal state and how long this state lasts.  If this 
hypogonadal persists or worsens at 90 days post RC then this may provide a rationale to 
provide testosterone supplementation to patients that are status post RC. 
 
PRELIMINARY DATA 
 
This project addresses an emerging need in a patient population at high risk for 
significant surgical morbidity and mortality. Hypogonadism is highly prevalent among 
patients with malignancy and is also surgically induced.  Furthermore, previous literature 
shows that hypogonadism is present in many other chronic medical conditions and 
replacement of testosterone may improve outcomes.  
 
Within our own 
institution, we have 
noted that 
hypogonadism is 
found within the 
radical cystectomy 
population to a high 
degree, even to 
castrate levels (<50 
ng/dl) in patients not 
undergoing any 
therapy for androgen 
deprivation.  To our 
knowledge, this has 

Page 4 
not yet been reported among this population.  Preliminary data highlight the clinical 
relevance of this project. We identified patients in the University of Kansas Hospital 
health system with urothelial bladder cancer that underwent RC over the last five months 
and had record of postoperative testosterone level. Seven patients met inclusion criteria, 
with a mean age of 76 years.  The mean postoperative testosterone level for these patients 
was 92ng/dl (normal 270-1070 ng/dl).  The mean time from RC until obtaining a 
postoperative testosterone level was 27 days (range 2 – 119 days).   
 
 
AIM: 
 
Aim 1: To perform a prospective observational study to determine the prevalence of 
hypogonadism in bladder cancer patients pre-operatively, immediately post- operatively, 
and at 30 and 90 days post-radical cystectomy. 
 
There is no hypothesis testing involved in this study as it is strictly observational to 
determine prevalence 
 
 
METHODS 
 
Study design. 
The study team will conduct a prospective, observational study in 25 male patients who 
are scheduled to undergo radical cystectomy for bladder cancer. Men who choose to 
participate will have a total and free testosterone level, as well as a serum luteinizing 
hormone level drawn at a preoperative visit.  
 
 
The patient’s will then undergo scheduled radical cystectomy. We will then repeat total 
and free testosterone as well as luteinizing hormone on post-operative days 2 and 3 to 
evaluate acute changes in serum testosterone and luteinizing hormone in the acute post-
surgical period in order to quantify the suspected further decrease in the levels of these 
hormones in patients undergoing RC. We will then repeat laboratory analysis of these 
hormones at the 30 and 90 day post-operative marks. If hypogonadism is confirmed, this 
will serve as a proof of concept study that not only are patients hypogonadal 
preoperatively, but that hypogonadism is maintained postoperatively. This will aid in 
hypothesis generation for future studies. All patients will continue to receive routine post-
cystectomy monitoring and guidance consistent with the current surgical standard of care.  
Daily weights, hospital length of stay, coronary events, deep venous thromboemboli, 
cardiovascular emboli (CVA), infections, and readmission rates will be measured as part 
of our normal radical cystectomy database collection methodology. 
 
 
Participants. 
The University of Kansas Hospital (KUH) performs an average of 80 RC procedures 
each year. Our recruitment goal is to recruit 25 patients in approximately 6 months, 

Page 5 
which should be readily feasible. Participants will be recruited from the KUH Urology 
Clinic, KUH Cancer Center, or during their KUH inpatient hospitalization. Eligible 
participants are adult men undergoing RC for primary bladder cancer. Patients with 
evidence of advanced metastatic disease, patients undergoing cystectomy for non-bladder 
primary malignancy or bladder cancer type other than urothelial cell, or patients with a 
history of breast or prostate cancer will be excluded.  Other contraindications include 
polycythemia, cardiovascular thromboembolism, untreated obstructive sleep apnea, 
uncontrolled heart failure, or acute coronary event in the past six months. 
 
Surgical procedure. 
Candidates for RC typically do not have evidence of metastatic disease and the majority 
will receive neoadjuvant chemotherapy.  The primary tumor will have been resected prior 
to RC and this will ensure pathologic confirmation of urothelial cell carcinoma. RC may 
be performed open through a low midline incision or with robotic-assisted laparoscopic 
assistance using the da Vinci Surgical System©. Ileal conduit using terminal ileum (10-15 
cm segment) or ileal neobladder (60 cm segment) will be performed for urinary 
diversion.  All patients will receive enoxaparin therapy for DVT prophylaxis 
postoperatively in accordance with the current surgical standard of care. 
 
 
 

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Study calendar. 
 
 
 
 
Outcomes. 
Postoperative Patient Outcomes. Complications will be recorded and defined as early 
(<30 days) versus late (31-90 days) and graded according to the Clavien-Dindo scheme 
per our current radical cystectomy database collection methodologyxx. Complications will 
be further categorized into infectious or non-infectious, and the specific location will be 
defined (urinary tract, wound, abdominal, etc.). Readmission, whether to KUMC or an 
outside facility, will be defined as admission to any hospital after discharge home up until 
90 days after surgery. The reason for readmission will be recorded. Hospital length of 
stay will be defined as day of admission through day of discharge. Age, gender, smoking 
history, comorbidities, and pathological information pertaining to participants’ 
perioperative and postoperative courses will be recorded. Severity of comorbid disease 
will be graded according to the Charlson Comorbidity Index, the most widely used index 
in oncologyxxi. Again, these data are currently collected on all radical cystectomy patient 
as part of our existing bladder cancer database and do not constitute additional measures 
or considerations beyond our current standard. 
 
 
Statistical analyses. 
 
This is a prospective, observational study with the goal of determining prevalence of 
hypogonadism in bladder cancer patient’s undergoing radical cystectomy. The prevalence 
rates will be calculated as the proportion of subjects with hypogonadism at different time 
points. The 95% confidence intervals will be provided. Determining prevalence will 
assist in hypothesis generation for future studies. 
 
We will consider performing post-study power analysis from the data accrued from this 
trial for the design of potential future trials. 
 
 
 
Study 
plan: 
Visit 1 
Date of 
Surgery 
Post-
Operative 
Inpatient 
Stay 
Visit 2 
Visit 3 
Timeline: 
Prior to Study 
Radical 
Cystectomy 
Post-Op Days 
2 & 3 
30 days post-op 
90 days post-op 
 
Data to 
collect 
Introduction 
 
N/A 
Testosterone 
measurement 
(total/free); 
LH level 
Testosterone 
measurement 
(total/free); LH 
level 
Testosterone 
measurement 
(total/free); LH 
level 
Consent 
Testosterone 
measurement 
(total/free); LH 
level 

Page 7 
 
Potential difficulties. 
 
Accrual. The study team does not anticipate any difficulty in recruiting for the proposed 
study from the patient pool at KUH. Even if accrual is slow, it should only take an 
additional 1-2 months to accrue the desired number of patients.  
 
Stroke, myocardial infarction. In January of 2014 the FDA made a safety announcement 
regarding its investigation for the risk of stroke, heart attack and death in men taking 
testosterone products.  The FDA did not conclude that the risk of these events was any 
higher for men taking testosterone but noted that the risks should be weighed against the 
benefits by providers. No testosterone supplementation is planned in this pilot study. 
 
Venous blood clots.  In June of 2014 the FDA required manufacturers of testosterone to 
include a general warning on the drug label discussing the risk of venous blood clots, or 
venous thromboembolism (DVT). This new warning is not related to the FDA ongoing 
evaluation of stroke, heart attack, or death.  Furthermore, we do not definitively know if 
the risk of venous blood clots is increased for the RC population specifically. No 
testosterone supplementation is planned in this pilot trial. 
 
Evaluation of hypogonadism.  If patients are found to be hypogonadal postoperatively, 
then they will be referred for follow up with a fellowship trained urologist in Andrology.  
As part of the study they will not receive any testosterone replacement up to the 90 day 
post-operative mark. At this point, if they remain hypogonadal, they may receive 
testosterone supplementation outside of the confines of the study. This data would not be 
used for the current study, but may be used for any future studies. 
 
 
PROTECTION OF HUMAN SUBJECTS 
 
Informed consent process. Potential subjects will be approached by their urologic 
surgeon and informed about the possibility of research participation. Patients who are 
interested learning more about participation will be introduced to a member of the study 
team who will then explain the study in detail. The potential subjects will have the 
opportunity to read the consent form in the absence of the PI and study team. It will be 
explained to the subjects that the study is voluntary and that they may discontinue at any 
time without prejudice. Subjects will have the opportunity to ask questions before signing 
the consent form. Subjects who agree to participate will be consented according to HSC 
guidelines and in a private closed door setting. 
 
Risks of participation. Given that RC an abdominal incision and visceral manipulation, 
post-operative care can lead to abdominal cramps or distention, diarrhea, or vomiting. 
Participants will be provided intravenous or epidural analgesia for pain control as well as 
anti-emetics as needed. Blood will be drawn by a trained phlebotomist or nurse and could 
result in a small bruise, a minor risk. Furthermore, patients that undergo a major 
operation for underlying malignancy have an elevated risk for DVT.  Patients are 

Page 8 
routinely started on subcutaneous heparin or enoxaparin for anticoagulation prior to the 
operation, and this is continued until hospital discharge. 
 
Protection against risk. All questions that potentially eligible subjects have will be 
addressed. Participants will sign a consent form approved by the Human Subjects 
Committee (HSC). All RC participants will be followed and managed by their surgeon 
according to standard guidelines.  All personnel will complete training for ethical 
research and human subjects’ privacy and protection. Only persons directly involved with 
the study will have access to data identifying individuals. Records and forms will be kept 
in locked file cabinets when not in use. Names will not be stored on computer files for 
data analysis. No individual will be identified in the study’s results.  Participation in the 
study is voluntary and participants may withdraw at any time without a change in the 
normal flow of post-operative care. 
 
Potential benefits of the proposed research.  Participants may not have direct benefit 
from the study. The subjects and society in general will benefit from the knowledge 
gained about managing bladder cancer, with future benefits of improved patient 
outcomes. 
 
Safety Monitoring/Medical Monitor. Serious side effects or other problems during this 
study will be reported to PI, Dr. Jeffery Holzbeierlein MD and Medical Monitor, Dr. 
Joshua Broghammer MD. 
 
More specifically, the medical monitor will be responsible for reviewing: 
 
1. Monitoring for the impact of independent scientific investigations (other trials) on the 
trial being monitored, as well as recommending changes based on those external results. 
 
2. Requests for data from sponsoring organizations or any other party. This includes 
requests for preliminary data for planning ancillary studies. The research team may 
consult the medical monitor on other issues thereafter, such as appropriate action for late 
toxicities. 
 
3. The medical monitor will have face-to-face meetings with the research team twice per 
year. More frequent phone conferences will be held if deemed necessary, for an 
evaluation of adverse effects.  Any adverse effects will be reported to the medical 
monitor, although as an observational pilot study this is not anticipated. 
 
ClinicalTrials.gov Registration 
The proposed pilot trial will be registered on the ClinicalTrials.gov website. 
 
 
 

Page 9 
 
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