Devora Schapiro

Clinical question: 

a 30M presents with PMH of testicular cancer treated with chemotherapy and unilateral orchiectomy 10 years ago,  who wants to conceive naturally with his wife. He wants to know if his chemotherapy and orchiectomy in the past will impact their chances.

Question:  does chemotherapy/unilateral orchiectomy as treatment for testicular cancer lead to infertility later in life?

This is a prognosis study, best answered by: Cohort Studies and Case control study (and meta-analysis and systematic review if available)

PICO terms: 

P I C O 

Adult male	Testicular cancer	No testicular cancer	Fertility
Adult male	Chemotherapy	No chemotherapy	fertility
Adult male	orchiectomy	No orchiectomy	Fertility

Search Summary: 

• Databases
  • Google Scholar, PubMed 
• Articles found
  • Pubmed: 6518 after restriction had been placed
  • Google scholar: 3580 after restriction had been placed
• How I chose my articles to appraise
  • Restrictions: patient age, articles within 10 years

Article I: Subfertility and Risk of Testicular Cancer in the EPSAM case-control study 

Background: this study looked at whether there is a relation with subfertility and the development of testicular cancer since they share genetic and environmental risk factors. They looked at the C-KIT ligand gene which is important for both fertility (it involved in spermatogenesis) and testicular cancer susceptibility.

Methods: The study included 245 cases of testicular cancer (diagnosed between 1997-2008), and 436 controls from EPSAM who were 20+ at recruitment. The questionnaire included questions on: number children, age when they attempted to conceive, how long it took to conceive, any ART, diagnosis of infertility, siblings, and history of cryptorchidism

Results: The study found that there is an inverse association between number of children and risk of testicular cancer but did not find evidence of other indications of subfertility. Meaning the more children the lower the risk of testicular cancer, but no other indications that testicular cancer and subfertility are connected.

Reason for choosing (including limitations): I chose this article because it discusses fertility in relation to testicular cancer regardless of the treatment provided. In other words because it shed light on whether testicular cancer on its own is related to infertility (prior diagnosis and treatment). The answer to that question would help answer the patients question about fertility in relation to testicular cancer. It is also a good study, perhaps the sample size could have been larger but the controls and the cases were kept consistent with age, and were all asked the same questions on the questionnaire. I would conclude from this study that having fewer children is associated with testicular cancer but that is not necessary to conclude that patients are subfertile or infertile prior to the diagnosis of testicular cancer. 

Type of study: case control 

Citation: Grasso, C., Zugna, D., Fiano, V., Robles Rodriguez, N., Maule, M., Gillio-Tos, A., … Richiardi, L. (2016, December 30). Subfertility and Risk of Testicular Cancer in the EPSAM Case-Control Study. Retrieved May 1, 2020, from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC5201268/

Article II: Hypogonadism and Sexual Dysfunction in Testicular Tumor Survivors: A systematic review

Background: This Study is a systematic review of how testicular cancer treatment- including orchiectomy alone or orchiectomy and adjuvant chemo and radiotherapy affect testosterone deficiency and sexual dysfunction and the effect on general health.

Methods: The study included a comprehensive review of studies from PubMed, Medline, Cochrane, Google Scholar, and Scopus databases searching for testicular cancer, testicular tumor, testosterone, hypogonadism, sexual dysfunction (and many other terms not relevant to the clinical question at hand)

Results: for hypogonadism they found that chemotherapy had a worse effect on Leydig cell function and therefore testosterone production and sexual function than orchiectomy alone and orchiectomy radiotherapy, and that radiotherapy also caused hypogonadism. The best outcome in terms of Leydig cell function was orchiectomy alone. 

Reasons for choosing (including limits): this study was a systematic review of many studies, which covered a lot of ground in terms of information regarding testicular cancer and fertility. The authors of this article disclosed that they had no conflicts of interest. The results of the longitudinal studies they discussed included that chemotherapy with orchiectomy often results in hypogonadism and dysfunction of Leydig cells. Since the patient in my clinical scenario was treated with chemotherapy and Orchiectomy he may have hypogonadism from the treatment.  

Type of study: systematic review 

Citation: La Vignera, S., Cannarella, R., Duca, Y., Barbagallo, F., Burgio, G., Compagnone, M., … Condorelli, R. A. (2019, May 7). Hypogonadism and Sexual Dysfunction in Testicular Tumor Survivors: A Systematic Review. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6513875/

Article III: Romantic and Sexual Relationships, Body Image, and fertility in Adolescent and Young Adult Testicular Cancer Survivors: A Review of the Literature

Background: This study was a systematic review of studies that have been done on romantic and sexual relationships, body image and fertility after being treated for testicular cancer. 

Methods: The study took articles from PubMed, MEDLINE, and PsycINFO databases. The search terms were: “testicular cancer survivors” or “testis cancer survivors”. Although they intended to research adolescents and Young Adults in terms of fertility they found that most studies were done among older testicular cancer survivors, which matches the clinical situation I am researching. 

Results: They found that there was decreased fertility in as many as half of testicular cancer survivors. Reasons for this include: azoospermia, erectile dysfunction, and permanent dry ejaculation. They found that many survivors had subfertility, not infertility, meaning they were able to father children however it was much more difficult as compared to the general population, and often took ART. Furthermore they found that patients treated with chemotherapy reported an inability to conceive versus patients with orchiectomy and surveillance. 

Reasons for choosing (including limitations): This article while at the tail end of “recent” (since it is from 2010) answered many questions for this clinical situation. It compared fertility in men who had chemotherapy, orchiectomy alone, with the general population who did not have testicular cancer at all. It covered all my search terms. The results of this article suggest that the patient in this clinical scenario will likely have trouble conceiving, he may not be infertile, but subfertile (a delay in conceiving) due to his treatment. 

Type of study: systematic review 

Citation: Carpentier, M. Y., & Fortenberry, J. D. (2010, August). Romantic and sexual relationships, body image, and fertility in adolescent and young adult testicular cancer survivors: a review of the literature. Retrieved from https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2907366/

Article IV: Fertility among testicular cancer survivors: a case-control study in the U.S. 

Background: This study looked into whether testicular germ cell tumors affect fertility, because these cancers typically occur in men of reproductive age (15-49), and treatment is directed at gonadal tissue and they wanted to elucidate whether it permanently affected fertility.

Methods: They obtained a case group of 246 testicular cancer patients and 236 controls. The men chosen had been part of an earlier US Servicemen’s Testicular Tumor Environmental and Endocrine Determinants (STEED) study. In the current study all the participants answered a questionnaire about their ability to father children. 

Results: they found that patients with testicular cancer experienced more fertility distress as well as difficulty fathering children. However there was no difference among cases and controls in the end result of actually fathering children. This was primarily seen in patients who were treated with orchiectomy only or orchiectomy and chemotherapy.

Reasons for choosing (including limitations): this answered my patients question directly, that while he may experience more difficulty in fathering children, might need the help of a fertility specialist, he is not less likely to father children than a man who has not had testicular cancer. This study did have some limitations, it is from 2010 and they needed to expand their research. They suggested at the end that one of the possible reasons there is no difference in ability to father children is that testicular cancer survivors attempt to conceive at younger ages than others, but they did not discuss the ages of their case-control studies or discuss any studies that looked at ability to father children in older men. However this is also a good study, it had reliable authors, was published in a reliable journal and had a decent sample size, and it directly answered the clinical question. 

Type of Study: case control 

Citation: McGlynn, et al. “Fertility among Testicular Cancer Survivors: a Case-Control Study in the U.S.” Journal of Cancer Survivorship, Springer US, 1 Jan. 1970, link.springer.com/article/10.1007/s11764-010-0134-x.

Article V: Toxicities Associated with Cisplatin-Based Chemotherapy and Radiotherapy in Long-Term Testicular Cancer Survivors

Background: This study looked at long-term toxicities in patients who survive testicular cancer. Cisplatin-based chemotherapy in the 1970s made testicular cancer curable but often led to complications later in life, these include cardiovascular disease, secondary malignant neoplasms, pulmonary disease, kidney disease, hypogonadism and infertility. 

Methods: in terms of reviewing hypogonadism and testicular they reviewed several studies discussing both and synthesized the results. 

Results: they found for hypogonadism, the level of decreased hormones was directly related to how intense the testicular cancer treatment was. They found that chemotherapy and radiotherapy increased the risk for hypogonadism rather than orchiectomy alone. In terms of infertility the first study they discussed found that as many as half of men diagnosed with testicular cancer had decreased sperm counts and low motility prior to any treatment. They found that in the contralateral testes these patients also had low spermatogenesis, despite it being “healthy” and non cancerous. However they also found that in a retrospective study done with 178 testicular cancer patients who were treated with chemotherapy, who had normal sperm prior to the treatment regained their normal spermatogenesis a year after completing chemotherapy.

Reasons for choosing(including limitations): this study had a few limitations, they did not discuss why they chose which studies to include in their results, this may indicate bias that they chose studies which had results that they wanted. I chose this study because it reviewed several important studies that answer the clinical question. Many men who are diagnosed with testicular cancer are already infertile or subfertile, and the greatest predictor for whether there will be normal spermatogenesis after treatment is if there was normal spermatogenesis before. It is likely that this patient will experience some level of infertility/subfertility if he had low sperm counts and motility prior to treatment. Type of study: systematic review 

Citation: Fung, Chunkit, et al. “Toxicities Associated with Cisplatin-Based Chemotherapy and Radiotherapy in Long-Term Testicular Cancer Survivors.” Advances in Urology, Hindawi, 18 Feb. 2018, www.ncbi.nlm.nih.gov/pmc/articles/PMC5835297/.

Clinical bottom line: 

My research suggests that this patient will likely have trouble conceiving, it is impossible to say without testing whether he is infertile or subfertile, but it is commonly seen in men who survive testicular cancer. The data suggests that he will likely eventually be able to father children but I would recommend this patient to see a fertility specialist who can do exact measurements of sperm count and motility due to his history and the increased chance of infertility.