AUA 2020: Panel Discussion: Multidisciplinary Discussion on Fertility, Hypogonadism, and Sexual Function for Testis Cancer Patients

• AFP: 112 IU/mL
• HCG: 92 IU/mL
• LH: 16 IU/L
• FSH: 13 IU/L
• Testosterone: 267 ng/dL

The patient attempted to bank sperm prior to orchiectomy, but unfortunately, he was azoospermic. He ultimately underwent a right radical orchiectomy with pathology showing a mixed germ cell tumor, confined to the testis, positive for lymphovascular invasion, histology showing embryonal carcinoma and teratoma. Following his right orchiectomy, his AFP and HCG normalized. His staging CT scan showed a 2.0 cm interaortocaval node, making him a clinical-stage IIA non-seminomatous germ cell tumor. 

Andrew Stephenson, MD, then provided a discussion of fertility and gonadal function among patients with germ cell testicular cancer. Dr. Stephenson notes that according to the AUA low-stage testis cancer guidelines,¹ cure rates approach 100% for clinical stage I-IIB germ cell tumors with appropriate integration of surveillance, surgery, and chemotherapy. Management should endeavor to limit the burden of therapy and treatment-related toxicity without compromising survival. He notes that all treatments have side effects: retroperitoneal lymph node dissection can lead to ejaculatory dysfunction, small bowel obstruction, and/or lymphocele, whereas chemotherapy can lead to infertility, hypogonadism, neurotoxicity, ototoxicity, nephrotoxicity, cardiovascular disease, and secondary malignancies. Prior to definitive management, patients should be counseled about the risks of hypogonadism and infertility (Moderate Recommendation, Grade C), and patients should be offered sperm banking, when appropriate. In patients without a normal contralateral testis or with known subfertility, this should be considered prior to orchiectomy (Clinical Principle). 

Up to 50% of germ cell tumor patients have impaired spermatogenesis and abnormal semen parameters (10% are azoospermic). With regards to chemotherapy, 50% of patients with azoospermia recovery within two years and 80% within five years. For those undergoing a retroperitoneal lymph node dissection, ejaculatory dysfunction occurs in 5-15% for those undergoing nerve-sparing and up to 30-50% for those undergoing modified templates. Dr. Stephenson highlighted that the AUA guideline suggests that patients with germ cell tumors should be monitored for signs and symptoms of hypogonadism, and if present serum morning testosterone and luteinizing hormone levels should be measured (Clinical Principle). Hypogonadism occurs in 10% of patients undergoing orchiectomy alone compared to 34% after receiving chemotherapy. 

Patients with testicular lesions suspicious for malignant neoplasm and a normal contralateral testis should undergo a radical inguinal orchiectomy and testis-sparing surgery is not recommended (Strong Recommendation, Evidence Level B). Testis-sparing surgery may be offered to highly selected patients wishing to preserve gonadal function with masses <2 cm and congenital, acquired or functionally solitary testis (Conditional Recommendation, Evidence Level C). In patients with germ cell neoplasia in situ after testis-sparing surgery, clinicians may offer surveillance, radiation, or orchiectomy (Moderate Recommendation, Evidence Level C). Between 20-80% of these patients may require testosterone replacement therapy after low dose (20 Gy) radiation, but there is little data regarding the preservation of fertility after testis-sparing alone. 

For patients with stage IIA-IIB non-seminomatous germ cell tumors, clinicians should recommend retroperitoneal lymph node dissection or chemotherapy for patients with stage II A disease with normal post-orchiectomy serum (S0) AFP and beta-HCG (Moderate Recommendation, Evidence Level B). In patients with clinical stage IIB disease and normal post-orchiectomy serum AFP and HCG, clinicians should recommend risk-appropriate multi-agent chemotherapy (Moderate Recommendations, Evidence Level B). Clinicians may offer retroperitoneal lymph node dissection as an alternative to chemotherapy in select patients with clinical stage IIB disease with normal post-orchiectomy serum AFP and HCG (Conditional Recommendation, Evidence Level C). 

For patients undergoing a retroperitoneal lymph node dissection, a full bilateral template dissection should be performed in patients with suspicious lymph nodes, whereas a modified template may be considered in patients with negative lymph nodes. Nerve-sparing should be offered in select patients desiring preservation of ejaculatory function. Retroperitoneal lymph node dissection should be performed by an experienced surgeon at a high-volume center (Moderate Recommendation, Evidence Level C). The rationale for modified templates is based on ejaculation rates as follows:

Robert Brannigan, MD, then discussed fertility implications among testis cancer patients. Dr. Brannigan notes that there is a multifaceted impact of cancer on reproductive health based on the disruption of the hypothalamic-pituitary-gonadal axis. Furthermore, immunological and cytological responses to cancer can lead to injury to the germinal epithelium, as well as systemic processes (ie. malnutrition, weight loss, fever) also adversely affecting sperm production. There are three cancer treatments, specific to testis cancer patients, that can impact male reproductive health, including the effect of radiation therapy, chemotherapy, and oncologic surgery. The effect of testicular radiation therapy has an additive effect with increasing dose, as highlighted in the following table:

The effects of chemotherapy on fertility are pertinent to testis cancer patients and are based on the regimen used. Cisplatin-based regimens (a cornerstone of BEP – bleomycin, etoposide, and cisplatin) are at medium risk for gonadal dysfunction. In a Norwegian study assessing 1,433 men with unilateral testis cancer for post-treatment paternity, 827 were fathers at the time of diagnosis.² There were 554 men that attempted post-treatment conception among whom the overall 15-year actuarial post-treatment paternity rate was 71% without the use of cryopreserved semen. This rate ranged from 48% in the high-dose chemotherapy group to 92% in the surveillance group. Furthermore, the median actuarial time from diagnosis to the birth of the first child after treatment was 6.6 years overall but varied according to treatment (range 3.6-19 years).

ASCO has guidelines for fertility preservation among young oncology patients,³ noting that it is important to discuss the risk of fertility impairment at the earliest possible time after a cancer diagnosis is made. Additionally, there should be a prompt referral to a qualified fertility preservation specialist if the patient is interested. There are several options for sperm procurement, including (i) masturbation, (ii) retrograde ejaculation (post-ejaculate urinalysis to collect sperm from urine), (iii) anejaculation (vibratory stimulation or electroejaculation), and (iv) for those who are azoospermic, oncologic testis sperm extraction can be used if other measures fail. Previous studies suggest that using intracytoplasmic sperm injection using cryopreserved sperm from men with malignant neoplasms yields high pregnancy rates. 

Dr. Brannigan concluded his portion of the panel discussion with the following take-home messages:

• Cancer and cancer therapies can disrupt sperm production and fertility in patients with testicular cancer
• Fertility preservation measures should be offered to patients at the time of cancer diagnosis
• Onco-TESE is an option for patients with azoospermia and others who are unable to provide ejaculated sperm for cryopreservation
• Reproductive outcomes are similar for sperm from patients with cancer versus sperm from unaffected men

John Mulhall, MD, then concluded this panel discussion by providing a talk highlighting testosterone deficiency and sexual dysfunction among men with testis cancer. Dr. Mulhall notes that there are challenges in the literature assessing these topics given that there is heterogeneity of therapies, few comparative studies, small patient numbers, testosterone measurement issues, and differences in defining testosterone deficiency. However, the literature suggests that rates of 12-40% of hypogonadism among testis cancer patients, which may be due to a number of factors including testis dysgenesis syndrome, orchiectomy, chemotherapy or radiation. Wiechno and colleagues⁴ assessed testosterone levels among 62 patients in the pre-orchiectomy setting, and 120 patients 1 month after orchiectomy, with testosterone deficiency defined as testosterone <231 ng/dL. They found that 5% of patients had testosterone deficiency pre-orchiectomy compared to 16% of patients a month after orchiectomy. 

Testis cancer chemotherapy is heterogeneous depending on the disease stage and may include EP, BEP, TICE, or VIP regimens. All of these regimens contain agents that are toxic to testicular structure and function with the lowest risk associated with bleomycin, medium risk associated with etoposide, cisplatin, and carboplatin, and highest risk associated with ifosfamide. Internal radiation scatter is also associated with hypogonadism and radiotherapy dose also depends on the stage of the disease. This may vary from 2-30cGy with or without gonadal shielding, however, Dr. Mulhall notes that these doses are below the dose generally associated with permanent germ cell damage. 

A previous systematic review assessed low testosterone in testis cancer patients, which used a total of 12 studies in the data synthesis.⁵ Eleven studies assessed the risk of testosterone deficiency in testis cancer patients treated with standard chemotherapy, with an odds ratio for low testosterone of 1.8 (95% CI 1.3-2.5). Seven studies assessed the risk of testosterone deficiency in testis cancer patients treated with non-conventional chemotherapy, with an odds ratio for low testosterone of 3.1 (95% CI 2.0-4.8). Finally, six studies assessed the risk of testosterone deficiency in testis cancer patients treated with radiotherapy, with an odds ratio for low testosterone of 1.6 (95% CI 1.0-2.4). There was no indication of heterogeneity between studies in the three treatment groups. This study concluded that strong evidence exists that chemotherapy and radiotherapy are associated with an increased risk of low testosterone in this population.

Dr. Mulhall’s testosterone deficiency management strategies in testis cancer are as follows:

• Pre-orchiectomy appropriate testosterone labs (with LH)
• Pre-chemotherapy/radiotherapy testosterone labs (if pre-orchiectomy not done)
• Comprehensive patient counseling
• Define interest in future reproduction
• Review sperm bank records before prescribing testosterone replacement therapy
• Review (ex vivo) Onco-TESE results before prescribing testosterone replacement therapy
• Avoid exogenous testosterone replacement therapy
• Consider hCG combined with intramuscular testosterone replacement therapy
• Alternative testosterone therapies are optimal (CC, hCG, artificial insemination) – fertility-sparing
• Patients with normal E2 level not good candidates for artificial insemination
• Patients with elevated LH level not good candidates for CC/hCG
• If you’re faced with the need to use exogenous testosterone therapy: ensure sperm is banked; if the patient is azoospermic give serious consideration to TESE prior to exogenous testosterone replacement therapy

Sexual dysfunction in testis cancer has been summarized in a systematic review by Nazareth et al.⁶ This study included a detailed review of 79 studies: six controlled studies examined sexual function in 709 patients after they had received treatment. Seven uncontrolled studies examined sexual function in 337 subjects before and after treatment for testicular cancer. Unfortunately, few assessed psychological function, and none examined its possible interaction with sexual dysfunction. A meta-analysis of the controlled studies indicated significantly reduced or absent orgasm (OR 4.62, 95% CI 2.47-8.63) together with erectile dysfunction (OR 2.47, 95% CI 1.54-3.96) and ejaculatory dysfunction (OR 28.57, 95% CI 1.75-464.78) up to two years after treatment. 

According to Dr. Mulhall, the pathophysiology of erectile dysfunction in testis cancer is secondary to (i) very low testosterone, (ii) radiation scatter, and (iii) adrenaline-mediated (psychogenic). Psychogenic erectile dysfunction is characterized by intermittency of function, excellent nocturnal/masturbatory erections, but the loss of sustaining ability. This may also be secondary to fear of cancer its recurrence, body image concerns, emasculation, and erosion of erectile confidence. Dr. Mulhall summarized his talk with the following take-home messages, including (i) sexual and endocrine changes after testis cancer therapy, are not uncommon, (ii) pre-orchiectomy testosterone levels are ideal, (iii) follow testosterone levels post-treatment, (iv) enquire about testosterone deficiency symptoms and sexual function after treatment, and (v) where possible, avoid exogenous testosterone replacement therapy if fertility is of interest.

Dr. Khera provided a comprehensive summary of this excellent testis panel discussion:

• Prior to definitive testis cancer management, patients should be counseled about the risks of hypogonadism and infertility 
• Patients should be offered sperm banking, when appropriate, prior to orchiectomy
• Onco-TESE is an option for patients with azoospermia and others who are unable to provide ejaculated sperm for cryopreservation
• Reproductive outcomes are similar for sperm from patients with cancer versus sperm from unaffected men
• Serum testosterone values should be ideally be checked prior to orchiectomy and should be followed after orchiectomy
• Men with a history of orchiectomy should be assessed for testosterone deficiency symptoms and sexual dysfunction
• Clinicians should avoid exogenous testosterone therapy in men who desire future paternity

Moderated by: Mohit Khera, MD, MBA, MPH, Baylor College of Medicine, Houston, TX 

Panelist: Andrew Stephenson, MD, Rush University, Chicago, IL

Panelist: Robert Brannigan, MD, Northwestern University, Chicago, IL

Panelist: John Mulhall, MD, Memorial Sloan Kettering, New York, NY 

Written By: Zachary Klaassen, MD, MSc, Assistant Professor of Urology, Georgia Cancer Center, Augusta University/Medical College of Georgia, Agusuta, GA, USA, Twitter: @zklaassen_md at the 2020 American Urological Association (AUA) Annual Meeting, Virtual Experience #AUA20, June 27- 28, 2020. 

References:

1. Stephenson A, Eggener SE, Bass EB, et al. Diagnosis and Treatment of Early Stage Testicular Cancer: AUA Guideline. J Urol 2019 Aug;202(2):272-281.
2. Brydoy M, Fossa SD, Klepp O, et al. Paternity Following Treatment of Testicular Cancer. J Natl Cancer Inst. 2005 Nov 2;97(21):1580-1588.
3. Oktay K, Harvey BE, Partridge AH, et al. Fertility Preservation in Patients with Cancer: ASCO Clinical Practice Guideline Update. J Clin Oncol 2018 Jul 1;36(19):1994-2001.
4. Wiechno PJ, Kowalska M, Kucharz J, et al. Dynamics of hormonal disorders following unilateral orchiectomy for a testicular tumor. Med Oncol 2017 May;34(5):84.
5. Eberhard J, Stahl O, Cwikiel M, et al. Risk Factors for Post-Treatment Hypogonadism in Testicular Cancer Patients. Eur J Endocrinol 2008 Apr;158(4):561-570. 
6. Nazareth I, Lewin J, King M. Sexual Dysfunction After Treatment for Testicular Cancer: A Systematic Review. J Psychosom Res. 2001 Dec;51(6):735-743.