A new fertility risk rating system for surgical, radiotherapy, and chemotherapy interventions used in testicular cancer
Perspective

A new fertility risk rating system for surgical, radiotherapy, and chemotherapy interventions used in testicular cancer

Jessica R. Walter1, Mary E. Lohman2, Shilajit D. Kundu3, Shuai Xu4

1Department of Obstetrics and Gynecology, McGaw Medical Center of Northwestern University, Chicago, IL, USA; 2Northwestern University Feinberg School of Medicine, Chicago, USA; 3Department of Urology, Northwestern University Feinberg School of Medicine, Chicago, IL, USA; 4Department of Dermatology, McGaw Medical Center of Northwestern University, Chicago, IL, USA

Correspondence to: Shuai Xu, MD MSc (Lond.). Department of Dermatology, McGaw Medical Center of Northwestern University, 676 N. St. Clair St., Suite 1600, Chicago, IL 60611, USA. Email: stevexu@northwestern.edu.

Comment on: Rajpert-De Meyts E, McGlynn KA, Okamoto K, et al. Testicular germ cell tumours. Lancet 2016;387:1762-74.

Abstract: The vast majority of patients diagnosed with testicular germ cell tumors will survive their disease. This raises the importance of survivorship issues, particularly fertility preservation given that half of patients diagnosed with testicular cancer are under the age of 34. In this perspective, we offer a novel fertility rating system based on the FDA’s A/B/C/D/X/N pregnancy risk category system for first line therapies (surgical, chemotherapeutic, and radiation therapies) listed by the National Comprehensive Cancer Network (NCCN). All chemotherapies (bleomycin, carboplatin, cisplatin, etoposide and ifosfamide) have available human data demonstrating a negative impact on fertility yielding category D ratings. Radiation therapy and surgical interventions such as unilateral orchiectomy and retroperitoneal lymph node dissections (RLND) were also designated category D. Despite the clear risk to fertility, the majority of men do not undergo semen cryopreservation (SCP). Future efforts should be made to reduce the barriers to reproductive counseling and fertility preservation for testicular cancer survivors.

Keywords: Testicular cancer; fertility preservation; germ cell tumors; fertility risk; semen cryopreservation (SCP)

Submitted Sep 27, 2016. Accepted for publication Sep 29, 2016.

doi: 10.21037/tcr.2016.10.90

Introduction

The treatment of testicular germ cell tumors represents a success of modern medicine (1). In the 1970s, the cure rate for metastatic testicular cancer went from 10% to 60% with combination chemotherapy. In a recent article, Rajpert-De Meyts et al. provide an excellent overview of the current state of knowledge and treatment of testicular germ cell tumors. The authors note that with the surgical, radiotherapy, and chemotherapeutic treatment options available, 99% of patients will have a treatment cure (2).

The treatment success of testicular cancer raises the importance of survivorship issues for these patients. There is a need for continued surveillance for cancer recurrence (3), and monitoring for metabolic syndrome and cardiovascular disease thought to be secondary to low testosterone levels or the delayed effects of chemotherapy such as cisplatin, vincristine, etoposide or bleomycin (3,4). In this perspective, we will focus on how the treatment for germ cell tumors affects future reproductive health, specifically fertility preservation. A new interdisciplinary field, oncofertility, is dedicated to the reproductive needs of cancer patients facing potentially fertility-threatening treatments (5).

Recently, we have proposed a new rating system to grade the male and female fertility risk associated with novel melanoma therapies based on the Food and Drug Administration’s (FDA) previously used pregnancy risk stratification system (A/B/C/D/X/N) (6). Although the FDA mandated a labeling change to the pregnancy risk category system in 2014 (7), the new system will be phased in over time for drugs approved prior to June 2015 and the old system will continue to hold clinical relevance in the foreseeable future (6). Testicular cancer predominantly affects men under the age of 40 and more than 50% of testicular cancer is diagnosed in men 34 years or younger (8). Understanding the fertility risk associated with testicular cancer treatments will enable clinicians to better counsel patients about their future reproductive health.

Methods

The National Comprehensive Cancer Network (NCCN) clinical practice guidelines were used to identify first-line treatments for testicular cancer (9). The male fertility risk for each drug or treatment modality was evaluated based on information available from the FDA, European Medicines Agency, and Health Canada regulatory files, as well as previously published literature. Each treatment was graded based on a novel fertility risk category system based on the FDA’s A/B/C/D/X/N pregnancy risk categories (6). Category A is attributed to treatments that have not shown a risk to future fertility in human studies. Category B is assigned to treatments that have not shown evidence of gonadotoxicity in animal studies but do not have available human data. Category C is assigned to treatments in which there is evidence of gonadotoxicity in animal studies but there is no adequate human data. Category D ratings are assigned to treatments with evidence of fertility risk in human studies. Category X ratings are applied to treatments with irreversible fertility risk. Finally, an N designation indicates that there is no available data.

Results

We identified five chemotherapeutic agents, three radiotherapy regimens, and three surgical interventions [unilateral orchiectomy, bilateral orchiectomy and retroperitoneal lymph node dissection (RLND)] in the primary treatment of testicular tumors (Table S1). All five chemotherapeutic agents demonstrated a fertility risk in either animal or human studies (category D). For bleomycin, the fertility risk was based on a study evaluating the impact of the bleomycin, etoposide, and cisplatin (BEP) regimen, which caused azoospermia in 20% of patients at 36 months follow-up (10). For cisplatin, the drug’s ability to cross the blood-testis barrier causes nearly all patients to become azoospermic during cisplatin therapy (11). While permanent infertility is possible, a study by Namekawa et al. showed that the majority (86%) of patients treated for testicular cancer undergoing orchiectomy and cisplatin-based chemotherapy had reappearance of sperm; 54% recovered normospermia with a median time to recovery of 40 months (12). Another study by Lampe et al. observed an 80% chance of spermatogenesis at 5 years in 170 patients treated with cisplatin or carboplatin based chemotherapy (13). Finally, the package inserts for both etoposide and ifosfamide report a risk of oligospermia or azoospermia in humans; previously published data has also demonstrated a negative impact on future male fertility after exposure to these agents (10,14).

Radiotherapy and two surgical interventions, unilateral orchiectomy and RLND, also received category D designations. Permanent azoospermia due to radiotherapy is possible in doses as low as 1.2 to 2 gray units (Gy) (15). Avoiding pelvic lymph node dissection has a slightly higher risk of cancer recurrence but tends to impact fertility less severely. For surgical interventions, unilateral orchiectomy leads to a decrease in semen quality and even azoospermia (16,17). Bilateral orchiectomy in the setting of synchronous or metachronous disease in both testicles will render a man infertile (category X). In patients who receive a RLND for germ cell tumors, damage to the sympathetic chain, postganglionic sympathetic fibers, or pelvic plexus damage can result in ejaculatory dysfunction leading to infertility. Current surgical techniques report high rates, upwards of 75% (18), of post-surgical anterograde ejaculation. In the setting of retrograde ejaculation caused by RLND, sympathomimetic or anticholinergic medications can be used to treat retrograde ejaculation. Men can still produce sperm and are candidates for in-vitro fertilization after sperm aspiration or testicular sperm extraction.

Discussion

Testicular cancer treatment can have an adverse effect on future fertility. Each of the chemotherapeutic, surgical, and radiation interventions were classified as category D with the exception of bilateral orchiectomy (category X). Although fertility depends on several factors (e.g., age, prior gonadal function), the paternity rate for testicular cancer survivors is 30% lower than expected for age-matched controls (19). It is likely that combination therapies with surgery, radiotherapy, and chemotherapy may further increase the risk of infertility (20). For example, in patients that received no radiation treatment for localized germ cell tumors, infertility was estimated to be less than 20%. However, patients that received localized radiotherapy, either pelvic or testicular, had a much higher risk (>80%) of subfertility after treatment (21). For testicular cancer survivors, azoospermia is more likely to occur than hypogonadism. Germ cells are more sensitive to toxicity from radiation compared to Leydig cells, which are responsible for testosterone production. The Leydig cells exhibit a lower mitotic rate compared to the germinal epithelium, making them more resistant to damage from cytotoxic therapies (22).

Fertility preservation is a key component of cancer survivorship. Both the American Society for Reproductive Medicine and the American Society of Clinical Oncology recommend counseling on cancer treatments’ impact on future fertility, preferably prior to therapy initiation (23,24). Up to 75% of childless cancer patients anticipate the desire for parenting children in the future (25). Simply counseling female cancer patients on fertility preservation and referring to reproductive specialists improves quality of life and reduces regret (26).

In the field of oncofertility, fertility preservation in testicular cancer patients represents a unique opportunity. Unlike female fertility preservation, there is no need for hormonal stimulation for follicle development. The storage of sperm is a fraction of the cost compared to ovarian tissue or egg retrieval. Despite the clear risks to gonadal function, only 25% of patients facing fertility-threatening treatment undergo semen cryopreservation (SCP)—although more than 90% of oncologists agree that SCP should be offered, a significantly smaller proportion explicitly recommend or mention it to eligible male cancer patients (25). Ideally, SCP should be performed prior to any therapy (surgical, radiation, or chemotherapy) to ensure the highest quality semen sample for future use (17,27,28).

Currently, there are several barriers to fertility preservation, including: a lack of physician awareness, a concern for delay in cancer therapy, and cost of sperm preservation. Coverage laws and legal definitions of infertility vary by state; often coverage is only provided for couples unable to conceive after 1 year of unprotected intercourse. Since most patients with testicular cancer need expedited treatment, this delay is untenable. Previous legislative initiatives mandating insurance coverage for fertility preservation in cancer patients have failed to pass (29), but there are ongoing bills attempting to broaden access to care (30). Formal oncofertility programs that encourage collaboration between urologists, oncologists, and reproductive endocrinologists have demonstrated an increase in the rate of SCP for cancer survivors (31). Given the efficacy of the available treatments for patients diagnosed with testicular cancer, a greater emphasis must be placed on survivorship issues with fertility preservation representing one key component for men who have not completed family building.

Table S.1
Table S1 NCCN recommended therapies for testicular cancer and corresponding fertility risk
Full table

Acknowledgments

Funding: None.

Footnote

Provenance and Peer Review: This article was commissioned and reviewed by the Section Editor Weijun Jiang (Department of Reproductive and Genetics, Institute of Laboratory Medicine, Jinling Hospital, Nanjing University School of Medicine, Nanjing, China).

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at http://dx.doi.org/10.21037/tcr.2016.10.90). The 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.

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/.

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Cite this article as: Walter JR, Lohman ME, Kundu SD, Xu S. A new fertility risk rating system for surgical, radiotherapy, and chemotherapy interventions used in testicular cancer. Transl Cancer Res 2016;5(Suppl 4):S778-S781. doi: 10.21037/tcr.2016.10.90

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