Thanks to the continuously improving treatment options for cancer, the number of cancer survivors is increasing, and a large proportion of survivors is confronted with the long-term effects of cancer treatment. Especially for young patients, the question of the impact of therapy on fertility arises.
Dose adjustment or modification of the treatment regimen can achieve a lot. But experts at the congress of the European Society for Medical Oncology (ESMO) 2024 noted that knowledge about newer treatment options like immunotherapies is still insufficient.
Therapy Selection
The question of preserving fertility must be considered when deciding on the appropriate treatment, said Matteo Lambertini, MD, PhD, medical oncology consultant at the University of Genoa in Genoa, Italy. “Preserving fertility is also an aim of cancer therapy,” he said.
Lambertini, who is also a member of the ESMO Guideline Group on fertility preservation in cancer patients, referred to the 2020 ESMO guidelines, which list the gonadotoxicity of a substance depending on the treatment regimen and the patient’s age.
Isabelle Demeestere, MD, PhD, director of the research lab for human reproduction at the Erasmus Hospital of the Free University of Brussels in Brussels, Belgium, pointed out the limitations of general guidelines. “Therapies change over time, and a classification must be updated regularly.”
Knowledge gaps related to well-known therapies and many novel options persist. “For many FDA-approved medications, there are either no fertility data or only preclinical data available,” she added.
Chemotherapies and Immunotherapies
Chemotherapies with alkylating or platinum-containing substances are known for their effects on oocytes, follicle maturation, and spermatogenesis, said Demeestere.
Chemotherapy is gonadotoxic and leads to a temporary decrease in sperm quality or temporary azoospermia in men.
These effects, however, can lead to permanent azoospermia and endocrine disorders, depending on the dose, duration, or combination with radiation, said Demeestere.
Cryopreservation of sperm should always be performed before starting treatment. For high-risk patients who are prepubertal, samples of testicular tissue are taken.
In women, chemotherapy affects primordial follicles and follicle maturation through DNA damage. This process results in severe or temporary amenorrhea, a temporary or permanent decrease in egg reserve, and ultimately premature egg insufficiency.
Novel immunotherapies also influence fertility, presumably through interactions of the immune system with the reproductive organs. But insufficient data are available, according to Lambertini, who emphasized that “these data are urgently needed, especially for young patients with cancer.”
In a mouse model, immune checkpoint inhibitors affected ovarian function, and the inflammatory reaction in humans can affect fertility. No long-term data are available for women yet, however, explained Demeestere. The effects of other therapeutics such as PARP, CDK4/6, or tyrosine kinase inhibitors, as well as monoclonal antibodies like trastuzumab, are only seen sporadically.
In the PENELOPE-B phase 3 study, the CDK4/6 inhibitor palbociclib did not affect ovarian function, even though the cyclin-dependent kinases play an important role in mitotic arrest, said Demeestere.
Adjusting the Regimen
In a PET-guided approach, Demeestere’s research team investigated the effects of dose reduction or adjustment of the treatment regimen of procarbazine and cyclophosphamide on the fertility of patients younger than 45 years with advanced Hodgkin lymphoma.
By regularly controlling tumor growth with PET, the treatment could be adjusted so that the effect on egg reserve or spermatogenesis was significantly reduced and loss of fertility could be prevented.
During the 5-year follow-up period, the ovarian function of participating women was assessed by the serum concentration of follicle-stimulating hormone (FSH), estradiol, and anti-Müllerian hormone (AMH) to evaluate egg reserve. In men, testicular function was assessed at the beginning of the study. At the end of treatment, sperm analysis and FSH and testosterone levels were checked.
Demeestere and colleagues demonstrated that dose reduction or altering the treatment regimen for patients who responded early to treatment (determined by PET-guided monitoring) reduced the risk for gonadotoxicity from 46% to 14.5%. That is, the risk was reduced by more than half.
FSH and AMH correlated with the patient’s age and the dose of the alkylating agent. In men, sperm parameters recovered after dose or agent adjustment compared with the unchanged treatment regimen.
Newer results from the PHERGain study in women with early human epidermal growth factor receptor 2–positive breast cancer also provided hope, according to Demeestere. Under PET-guided control, chemotherapy could be reduced.
More Data Needed
The new treatment options pose a challenge to preserving fertility during cancer treatment, said Demeestere.
For new targeted therapies, uniform recommendations cannot be issued because of the lack of data and varying treatment durations. Still, the new therapies are safer than chemotherapy.
The need to collect data on fertility and long-term effects in cancer survivors in clinical studies is also reflected in the literature, according to Demeestere. “There are more review articles on this topic than clinical studies.”
This story was translated from the Medscape German edition using several editorial tools, including AI, as part of the process. Human editors reviewed this content before publication. A version of this article appeared on Medscape.com.