Author: Velez, Marissa

Platinum Study Newsletter

Summer 2021

Inside this issue:

Summary of / Publications: / Clinical and / Genome Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms / Relationship of Cisplatin-related Adverse Health Outcomes with Disability and Unemployment / Relationship of...Unemployment	2
American Society for Clinical Oncology 2021 Annual Meeting Abstracts	3
Wanted: Participant Spotlight	3
Coming Soon...	3
Clinician’s Corner	4

Stay connected with The Platinum Study Team! If you have moved, changed your email address, or have a new phone number, please notify your clinic or study team or you may share your contact information with the current study headquarters at Indiana University by:
Calling us toll-free at
833-770-8700
Emailing us at ptstudy@iu.edu

A Platinum Study Update

We continue to thank you, the research study participant! To refresh your memory, The Platinum Study started in 2013 and was open to accrual at five cancer centers in the United States, two cancer centers in Canada, and one cancer center in the United Kingdom. The purpose of the study is to examine how the chemotherapy you received to treat your cancer impacts you over a lifetime.
To begin looking at this, we asked you to complete a questionnaire, a hearing test and to provide us with a blood sample. The study has allowed us to answer many questions with regard to the effects of your chemotherapy that are described on The Platinum Study website. If you opted in to receive study newsletters, we trust they have been informative. All newsletters are also posted for your information on The Platinum Study website:
https://apps.cancer.iu.edu/platinum/.
Because of your participation, The Platinum Study has now received funding from the National Institutes of Health so we can continue to follow you for at least another 5 years. By now you may have received an introductory packet to this new phase of the study, including an informed consent document.
During this next phase of the study, we will ask you to complete another questionnaire. You may also be included in a group of approximately 200 people from Memorial Sloan Kettering Cancer Center and Indiana University Simon Comprehensive Cancer Center who will be invited to complete another hearing test, a test looking at the sensitivity and pain levels in your hands and feet through additional questions and a physical exam focused on these areas, and a short music questionnaire.
If you have already returned your consent form, we thank you for your prompt attention. If you have not had a chance to review the consent form regarding this new phase of our study, please take a few moments to do so and fill out and return. If you have any questions or concerns, please do contact us. Our information is in the far left column in red.

Featured Clinician: David J. Vaughn, MD

Dr. Vaughn is the Genitourinary Medical Oncology Professor at the Perelman School of Medicine at the University of Pennsylvania, and serves as Vice-Chief for Clinical Affairs in Penn’s Division of Hematology/Oncology. A medical oncologist, Dr. Vaughn focuses his clinical practice and research on genitourinary cancer. His passion is caring for men with testicular cancer, and he has the largest testicular cancer practice in the Philadelphia tri-state region.
Dr. Vaughn serves on the National Comprehensive Cancer Network Testicular Cancer Guideline Panel, as well as on the American Board of Internal Medicine Medical Oncology Examination Committee. He is a founding member of the Platinum Study Group. An author of over 140 peer-reviewed articles, his research focus is new drug development for genitourinary cancer and testicular cancer survivors.

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Summary of Publications:
Clinical and Genome-wide Analysis of Cisplatin-induced Tinnitus Implicates Novel Ototoxic Mechanisms
O. El Charif, B. Mapes, M.R. Trendowski, H.E. Wheeler, C. Wing, P.C. Dinh, R.D. Frisina, D.R. Feldman, R.J. Hamilton, D.J. Vaughn, C. Fung, C. Kollmannsberger, T. Mushiroda, M. Kubo, E.R. Gamazon, N.J. Cox, R. Huddart, S. Ardeshir-Rouhani-Fard, P. Monahan, S.D. Fossa, L.H. Einhorn, L.B. Travis, M.E. Dolan
Background: The success of cisplatin-based chemotherapy has been important in making testicular cancer highly survivable, but the use of these agents is not without cost to the health of the survivors. Among the various long-term effects of chemotherapy, it appears that as many as 40% of testicular cancer survivors experience ringing in the ears (known as tinnitus), which can lead to poorer quality of life. Yet, little is known about who is most likely to develop tinnitus or why it happens at all. This study was designed to uncover some of the factors that might make it more likely to develop tinnitus.
What we did: 762 testicular cancer survivors enrolled in the Platinum Study were evaluated with a hearing test (known as audiometry). Information was also collected about their physical and psychological health, lifestyle behaviors, and cancer treatment. Individuals also provided a blood sample to collect DNA for study. Based on the results of the questionnaire, the 762 survivors were divided into two groups. The “cases” were those with moderate-to-severe tinnitus and the “controls” were those without tinnitus. Tests were done to look for risk factors and some studies were done in a laboratory to test these theories.
What we found: Survivors who were older and/or received higher dosages of cisplatin were more likely to have tinnitus. Dosages higher than 400mg/m2 of body surface area seemed to produce the highest risk of tinnitus. Those with tinnitus had worse hearing, reported more vertigo (dizziness), had a harder time hearing in a crowd, had poorer self-reported health, and higher medication use for conditions like anxiety and depression. It was also found that higher expression levels of a gene called OTOS might protect against developing tinnitus.
What does the study mean: Testicular cancer survivors are likely to develop tinnitus, particularly those who are older and received high dosages of cisplatin. Tinnitus can lead to worse quality of life. Doctors and healthcare workers should be aware of these risks and actively look for changes in hearing or presence of tinnitus in order to properly assess health and manage symptoms. In particular, patients with tinnitus should monitor their blood pressure and avoid tobacco use and any additional damage to their hearing, including noise exposure.
Relationship of Cisplatin-Related Adverse Health Outcomes With Disability and Unemployment Among Testicular Cancer Survivors
S.L. Kerns, C. Fung, S.D. Fossa, P.C. Dinh, P. Monahan, H.D. Sesso, R.D. Frisina, D.R. Feldman, R.J. Hamilton, D. Vaughn, N. Martin, R. Huddart, C. Kollmannsberger, D. Sahasrabudhe, S. Ardeshir-Rouhani-Fard, L. Einhorn, L.B. Travis
Background: Testicular cancer is the most common cancer in men aged 18-39 years; an age when most are actively employed. Though survival rates are high, many cancer survivors suffer from impaired health and little is known about how that impacts job engagement or ability to hold employment.
What we did: 1,815 testicular cancer survivors who had undergone cisplatin-based chemotherapy were enrolled in the study and asked to complete a comprehensive questionnaire, report prescription medication, and participate in a physical exam and hearing test. Survivors provided information about employment status, health behaviors, and adverse health outcomes (e.g. peripheral neuropathy, hearing loss, tinnitus, and kidney disease) in answers to the questionnaire.
What we found: Survivors in this study were around 37 years of age, 64% of them were college educated, and 81% were employed full time at the time of the study. However, almost 1 in 10 were not working (out on disability or unemployed), a number higher than what would be expected in the typical population. Many of those not working reported neuropathy, hearing loss, and pain. Self-reported health was worse in survivors with more severe health outcomes.
What does the study mean: Survivors are young and their inability to be successfully employed can lead to loss of productivity and an impact on society. Providers should ask survivors about disability and employment status, and identify options to assist in returning survivors to the workforce.
The full published version of these articles can be accessed on our website at:
https://apps.cancer.iu.edu/platinum/published-research.php

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American Society of Clinical Oncology 2021 Annual Meeting
The Platinum Study Team presented the results of five scientific abstracts at the June meeting, with the content of each abstract now on the study website: http://cancer.iu.edu/platinum
M. Shuey, A. Faucon, M.R. Trendowski, M.J. Ratain, P.C. Dinh, D.R. Feldman, R.J. Hamilton, D.J. Vaughn, C. Fung, C.K. Kollmannsberger, R.A. Huddart, N.E. Martin, R. Hannigan, L.H. Einhorn, L.B. Travis, M.E. Dolan, N. Cox. Integration of a polygenic risk score of kidney function with cumulative cisplatin dose and time variables for the prediction of serum platinum levels.
X. Zhang, M.R. Trendowski, E. Wilkinson, D.R. Feldman, R.J. Hamilton, D.J. Vaughn, C. Fung, C.K. Kollmannsberger, R.A. Huddart, N.E. Martin, P.C. Dinh, R.D. Frisina, L.H. Einhorn, M.E. Dolan, L.B. Travis, Regeneron Genetics Center. Pharmacogenomics of cisplatin-induced neurotoxicities: hearing loss, tinnitus and peripheral sensory neuropathy.
S. Ardeshir-Rouhani-Fard, S. Fosså, R.A. Huddart, P.O. Monahan, C. Fung, Y. Song, M.E. Dolan, D.R. Feldman, R.J. Hamilton, D.J. Vaughn, N.E. Martin, C.K. Kollmannsberger, P.C. Dinh, L. Hou, Y. Zheng, L. Einhorn, R.D. Frisina, L.B. Travis. Hearing loss after cisplatin-based chemotherapy: patient-reported outcomes versus audiometric assessments.
S. Ardeshir-Rouhani-Fard, P.C. Dinh, P.O. Monahan, S. Fosså, R.A. Huddart, C. Fung, Y. Song, D.R. Feldman, R.J. Hamilton, D.J. Vaughn, N.E. Martin, C.K. Kollmannsberger, L. Hou, L. Einhorn, K. Kroenke, L.B. Travis. Factors associated with use of medications for anxiety and depression in testicular cancer survivors after cisplatin-based chemotherapy.
A.G. Wibmer, D.R. Feldman, C. Chen, M. Bromberg, P.C. Dinh, J. Zheng, M. Capanu, L.B. Travis, H.A. Vargas. Pre-treatment central adiposity increases the cardiometabolic risk of male germ cell tumor survivors after cisplatin-based chemotherapy.
A more in-depth description of selected results will be presented in future newsletters.

Wanted: “Participant Spotlight”

Do you have a unique story you would like to share in our next newsletter? The Platinum Study Team would love to hear your story for our next “Participant Spotlight”!
Please email ptstudy@iu.edu or call 833-770-8700 and tell us about your journey with testicular cancer survivorship.

Coming Soon...

In the next newsletter, we will start profiling some of the behind-the-scenes researchers who work on The Platinum Study. These include colleagues at the Harvard Medical
School (Dr. Howard Sesso), Vanderbilt University (Dr. Nancy Cox), the University of Chicago (Dr. Eileen Dolan), and the University of South Florida (Dr. Robert Frisina and Dr. Victoria Sanchez).

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Clinician’s Corner

In this issue of The Platinum Study newsletter, we begin a
new series spearheaded by our collaborating oncologists.
Dr. Lawrence Einhorn discusses the question most frequently asked by his patients at Indiana University: hypogonadism.
Hypogonadism
Testosterone
Testosterone is produced by the Leydig cells of the testis. It is a normal physiological process to have reducing levels of testosterone as men age. However, premature hypogonadism (low serum testosterone) can be seen in patients with testicular cancer. An orchiectomy alone usually does not cause hypogonadism as the remaining testis will usually compensate for the missing production of testosterone. However, occasionally the solitary testis can be deficient in production and also cause low serum testosterone. When patients have an orchiectomy and subsequently need chemotherapy, one of the side effects of cisplatin can be atrophy (reduction in size and function) of the remaining testis. Approximately 30% of patients undergoing chemotherapy may have hypogonadism, which when symptomatic, should be treated with replacement testosterone.
Symptoms of Hypogonadism
Most men recognize erectile dysfunction (difficulty having and maintaining an erection) or muscle weakness as primary symptoms of hypogonadism. Less well recognized are new symptoms that were not present prior to chemotherapy such as irritability, depression, insomnia, and increased sweating or night sweats. When women go through menopause, they have hot flashes, but men have increased sweating or night sweats. Many of these symptoms are seen in the U.S. population at large who have normal serum testosterone levels, but this refer to symptoms that developed after chemotherapy. It is best to measure serum testosterone levels in the morning. With normal Circadian rhythm, the male testosterone level is optimal in the morning and usually decreases by 25% in the afternoon. At Indiana University, serum testosterone levels above 300 ng/dL are considered to be normal. However, as men age, that normal value might be closer to 250 ng/dL. Chronic hypogonadism in testicular cancer survivors can lead to a constellation of signs and symptoms referred to as metabolic syndrome. This can cause obesity, hypertension, an abnormal lipid profile, and development of early cardiovascular disease. Further, patients with hypogonadism are more likely to be on medications for elevated cholesterol or triglyceride, hypertension, or diabetes.
Treatment for Hypogonadism
Men should be queried about symptoms of hypogonadism, especially when they have been through curative cisplatin combination chemotherapy. It is best, as mentioned above, to check a serum testosterone level in the morning. If it is low and the patient is symptomatic, they need to be on replacement testosterone. Patients should be aware that insurance companies do not always cover the cost of testosterone, especially some of the more expensive preparations. Testosterone can be given as a gel on a daily basis, as an underarm preparation (Axiron), as a testosterone injection every 2-4 weeks, a self-administered subcutaneous injection, or long-acting pellets that can be surgically implanted.
Side Effects of Testosterone
Testosterone replacement is very different than an athlete trying to build muscle mass to increase his performance in sports. The main concern about testosterone replacement is the presence of too high of a red blood count (erythrocytosis). This can lead to blood clots. Patients who are on replacement testosterone should periodically have a complete blood count including hemoglobin, hematocrit, and red blood count to check for this. Replacement testosterone does not cause prostate cancer, nor does it accelerate the progression of prostate cancer in men who are subsequently diagnosed with the malignancy.
Summary
Hypogonadism, especially in patients receiving cisplatin chemotherapy, can be a common occurrence. This is easily diagnosed by symptoms in an A.M. determination of serum testosterone and can be improved by replacement testosterone. Men who are in the process of family planning need to be aware that testosterone can theoretically lower the sperm count. A replacement during this time period can be medication such as Clomiphene, which then improves symptoms without affecting the sperm count.
Reference
N. Khanal, M.J. Brames, and L.H. Einhorn. The effects of hypogonadism on quality of life in survivors of germ cell tumors treated with surgery alone versus surgery + platinum-based chemotherapy. Supportive Care in
Cancer 28:3165-3170, 2020.