Ovarian toxicity of targeted and immunotherapy in pediatric female patients with oncological diseases

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Abstract

Long-term survival of children with oncology is steadily increasing and currently stands at >80 %. For patients achieving sustained remission from oncological diseases, the issue of delayed complications of antitumor therapy, particularly related to gonadotoxicity, is of great importance.

Targeted therapy and immunotherapy for pediatric oncological diseases have recently been actively introduced into clinical practice, including as first-line treatments. Modern targeted and immunotherapeutic approaches allow long-term disease control or a prolonged remission to be achieved in pediatric female patients. Hence, it is essential to investigate the impact of these therapies on acute and delayed ovarian toxicity to evaluate the potential infertility risk and to determine indications for the use of fertility preservation methods.

This review systematizes and describes current understanding of the mechanisms of gonadotoxicity of various groups of targeted and immunotherapeutic agents used in pediatric oncology. Thus, BRAF/MEK inhibitors can impact the fertility of girls and women, as inhibition of MAPK signaling pathway components prevents ovulation, oocyte maturation, and luteinization. They also disrupt metabolic processes in ovarian follicle cells and can lead to delayed puberty when administered before puberty, as demonstrated in preclinical studies. Imatinib therapy in mouse models resulted in a reduction in the number of primordial follicles and the induction of apoptotic processes in follicles. The use of vascular endothelial growth factor (VEGF) inhibitors can increase the risk of reversible ovulatory dysfunction. Data regarding the use of mammalian target of rapamycin (mTOR) inhibitors indicate both an increased risk of oligomenorrhea and ovarian cysts, as well as their protective effect against gonadotoxicity induced by alkylating agents and platinum-based therapies. Immune-mediated ovarian damage is most widely described for immune checkpoint inhibitors and involves the induction of systemic or organ-specific autoinflammation, which can involve the ovaries and pituitary gland and lead to decreased ovarian reserve, including when used before puberty, as well as disruption of oocyte maturation and ovulation. Preclinical data and isolated clinical observations have been reported demonstrating the gonadotoxic effects of inotuzumab ozogamicin and gemtuzumab ozogamicin, but these have not been characterized in detail.

There is a lack of reliable data on the impact of various targeted and immunotherapeutic agents on the fertility of girls with oncological diseases. This requires research to update data on the acute and delayed toxicity of antitumor therapy and to determine the need for fertility preservation methods in children with oncological diseases, taking into account the emergence of new therapeutic options.

 

 

About the authors

Maksim E. Melnikov

Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia; Pavlov University, Ministry of Health of Russia

Author for correspondence.
Email: melmakse@gmail.com
ORCID iD: 0000-0003-4744-0882

R.M. Gorbacheva Research Institute of Pediatric Oncology, Hematology and Transplantology

Russian Federation, 2 Litovskaya St., Saint Petersburg 194100; 6–8 L’va Tolstogo St., Saint Petersburg 197022

A. O. Drobintseva

Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia

Email: melmakse@gmail.com
ORCID iD: 0000-0002-6833-6243
Russian Federation, 2 Litovskaya St., Saint Petersburg 194100

O. E. Savelieva

Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia

Email: melmakse@gmail.com
ORCID iD: 0000-0002-0301-8455
Russian Federation, 2 Litovskaya St., Saint Petersburg 194100

L. S. Lyapunova

Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia

Email: melmakse@gmail.com
ORCID iD: 0000-0002-6045-9134
Russian Federation, 2 Litovskaya St., Saint Petersburg 194100

G. V. Kondratiev

Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia

Email: melmakse@gmail.com
ORCID iD: 0000-0002-1462-6907
Russian Federation, 2 Litovskaya St., Saint Petersburg 194100

S. A. Kuleva

Saint Petersburg State Pediatric Medical University, Ministry of Health of Russia; N.N. Petrov National Medical Research Center of Oncology, Ministry of Health of Russia

Email: melmakse@gmail.com
ORCID iD: 0000-0003-0390-8498
Russian Federation, 2 Litovskaya St., Saint Petersburg 194100; 68 Leningradskaya St., Pesochny Settlement, Saint Petersburg 197758

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