Comparative analysis of the effectiveness of assisted reproductive technology in oncology patients

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BACKGROUND

Improving the quality of life in patients with cancer is one of the most pressing challenges which the society faces today. The number of cancer cases is increasing every year, with approximately 5% of all cases reported in women of childbearing age. According to the Global Cancer Observatory: Cancer Today (GLOBOCAN) statistics [1], 940,667 women under the age of 40 years have cancer. Modern diagnostic and treatment options are improving survival in this patient population. However, treatment is often associated with adverse effects that affect the quality of life, including the development of premature ovarian failure and infertility [2].

Fertility preservation in patients with cancer is an important medical and social need. In recent years, research has focused on developing management strategies for this population in order to benefit from the reproductive potential of these women in the future. A new area of research, oncofertility, has been developed to address this problem by sharing information about the potential of assisted reproductive technology (ART) in women with cancer [3, 4]. Various options for reproductive function preservation are now available, including suppression of ovarian function with gonadotropin-releasing hormone (GnRH) agonists, oocyte and embryo vitrification, ovarian tissue transplantation, and ovarian transposition. Each of these options has its own characteristics and effectiveness, and their use requires a personalized approach [5].

Global clinical protocols recommend oocyte and embryo vitrification as the first-line option for fertility preservation. However, it is important to remember that the effectiveness of ART decreases with age. For example, the pregnancy rate after embryo transfer is 44% at the age of 31–35 years, 23% at the age of 41–42 years, and only 4% at the age of over 43 years [6–8]. Ovarian stimulation and retrieval of immature oocytes for subsequent in vitro maturation (IVM) may be used. Ovarian stimulation is not currently contraindicated in patients with cancer. The clinical protocol for the treatment of female infertility (2024) recommends the use of letrozole at 5 mg/day from menstrual days 2–3 for the entire period until the final trigger of oocyte maturation, with possible prolongation in case of high estradiol levels [9]. Any of the ovarian stimulation protocols can be used for this technique. However, Rodgers et al. demonstrated higher efficacy with GnRH antagonists and recombinant human chorionic gonadotropin as the final trigger. The 2020 European Society of Human Reproduction and Embryology (ESHRE) guidelines for fertility preservation in patients with cancer [10, 11] also provide these data.

IVM collects oocyte-cumulus complexes by transvaginal puncture of all visible follicles. However, this technique does not require hormonal stimulation or ovulation trigger [12]. The procedure takes only 48 hours and does not cause ovarian hyperstimulation syndrome, which may affect the course of cancer [13, 14]. Immature oocytes can be retrieved from ovarian tissue samples. However, insufficient data on the use of IVM in women with cancer and the lack of consistent management algorithms for these women require further research into the efficacy and safety of IVM.

Aim

The study aimed to evaluate the efficacy of different ARTs in preserving reproductive material in patients with cancer.

METHODS

This prospective, randomized trial enrolled 48 women of childbearing age with newly diagnosed cancer. The study also included three patients who underwent oophorectomy with immature oocytes retrieved from ovarian tissue.

The study was approved by the Local Ethics Committee (Protocol No. 213, dated 13 December 2021).

In the first phase, after diagnosis, a tumor conference was held to determine further treatment strategies and the need to preserve the patient’s reproductive function. Certain techniques were chosen based on the conclusion of a fertility specialist. A key criterion for group assignment was the possibility to perform ovarian stimulation. In case of contraindications or insufficient time for ovarian stimulation, patients were immediately assigned to the second group. The other women were randomized. Figure 1 shows the study design.

 

Fig. 1. Study design

 

Inclusion criteria: age 18–42 years, adequate ovarian reserve (anti-Müllerian hormone >1.2 ng/mL, total antral follicle count >5), and patient desire to preserve reproductive material.

Exclusion criteria: a serious somatic disorder, stage IV cancer, or ovarian cancer.

In the second phase, after further screening and randomization, group 1 patients received stimulation protocols. In most cases, a GnRH antagonist protocol was used. In addition, letrozole was used. A transvaginal puncture was then performed to obtain mature oocytes. Group 2 patients did not receive any additional medication, but immediately underwent transvaginal puncture of all visible follicles. All obtained oocyte-cumulus complexes were transferred to an embryologist to mature.

The third phase was an embryological one. An embryologist evaluated the retrieved oocytes. All immature oocytes were placed in an IVM maturation medium. If a patient had a sexual partner, IVF/ICSI was offered to fertilize the retrieved material. The retrieved material (oocytes and embryos) was then vitrified.

StatSoft STATISTICA 10 was used for statistical analysis of the obtained data.

RESULTS

The study included 48 women of childbearing age with cancer of different sites. Table 1 demonstrates that patients in both groups are comparable in age and ovarian reserve. No statistically significant differences were found (p > 0.05). Previous pregnancies were observed in <12% of cases, and only 4% of pregnancies resulted in delivery. This confirms the relevance of this area of research.

 

Table 1. Clinical and medical history characteristics of the studied groups

Criterion	Group 1	Group 2
Age, years	33.2±2.4	34.1±1.3
Anti-Müllerian hormone ng/mL	1.92 [1.32; 3.02]	1.64 [1.26; 2.89]
Total number of antral follicles in both ovaries, n	7.8±2.7	8.2±2.9
Menstrual cycle duration, days	28.3±2.1	29.4±1.9
Pregnancies in medical history	3 (12.5%)	2 (8.3%)
Deliveries in medical history	1 (4.2%)	0 (0.0%)

Note. No statistically significant differences were found (p > 0.05).

 

Breast cancer was the most common cancer (31 patients); 5 women had cervical cancer, 2 had endometrial cancer, and 10 had hematologic cancer (Fig. 2). Gynecological cancers were diagnosed at an early stage and organ-sparing treatment was given to preserve reproductive function for the future.

 

Fig. 2. Structure of oncological pathology

 

Ovarian reserve plays an important role in assessing the potential for fertility preservation. In our study, most patients had anti-Müllerian hormone levels <2.0 ng/mL and antral follicle counts <10 in both ovaries. This may be related to the age of the patients; the mean age was 33.2 ± 2.4 years in group 1 and 34.1 ± 1.3 years in group 2.

Ovarian stimulation was performed to retrieve oocytes in group 1. Initially, the procedure did not need to be linked to menstrual function because of the use of a random start protocol, i.e., ovarian stimulation was performed on any day of the cycle. A GnRH antagonist, recombinant follicle stimulating hormone, and human menopausal gonadotropin were used. The average duration of stimulation ranged from 10 to 12 days. GnRH or recombinant human chorionic gonadotropin was used to induce final oocyte maturation. Group 2 received no medication, but underwent an immediate transvaginal puncture (Fig. 3), so the average duration of this oncofertility program was 1–2 days.

 

Fig. 3. Ultrasound during transvaginal puncture (dashed line indicates ultrasound guidance)

 

The primary aim of our study was to evaluate the efficacy of these techniques for the collection of reproductive material. In group 1, 256 oocyte-cumulus complexes were obtained, with 73.0% of mature oocytes suitable for fertilization. Significantly less material was obtained in group 2: 149 oocyte-cumulus complexes, of which 38.9% were mature. In vitro matured oocytes were 5 times more likely to degenerate than oocytes after ovarian stimulation (Table 2). In addition, grading of the collected material showed that the oocytes derived by IVM had more structural abnormalities (Fig. 4).

 

Table 2. Amount of material obtained in oncofertility programs

Criterion	Group 1	Group 2
Oocyte-cumulus complexes (total number)	256	149*
Blastocele stage	26 (10.1%)	30 (20.1%)
Metaphase I stage	35 (13.6%)	38 (25.5%)
Metaphase II stage	187 (73.0%)	58 (38.9%)
Degenerated	8 (3.1%)	23 (15.4%)
Embryos	161 (62.9%)	78 (52.3%)*

* p < 0.05 compared to group 1.

 

Fig. 4. Oocyte dysmorphisms in the study groups

 

The oocytes were then fertilized using IVF/ICSI techniques to obtain embryos. Group 1 had the significantly higher percentage of fertilized oocytes (62.9% vs. 52.3%). However, both groups showed comparable grade of blastocysts. The obtained data may indicate a lower fertilization potential of in vitro matured oocytes.

DISCUSSION

Current options for cancer diagnosis and treatment provide at least a 75% survival rate. However, in the future, the treatment may negatively affect the patients’ quality of life [15]. The phenomenon of postponed maternity, which often leads to the development of cancer before reproduction, should also be considered [16].

A variety of techniques are available for use in fertility preservation programs, and the first-line technique should be oocyte and embryo vitrification. Ovarian stimulation and in vitro oocyte maturation can be used for this purpose [17].

Initial ovarian reserve is a key factor in choosing a fertility preservation technique. Our study showed low efficacy of IVM due to low anti-Müllerian hormone levels and antral follicle counts. Mostinckx et al., Seok et al. suggested that anti-Müllerian hormone levels >8.5 ng/mL is required for successful reproduction [18, 19]. Ovarian stimulation shows better results even with low levels of anti-Müllerian hormone, in our study it was <1.92 ng/mL.

The key point is to evaluate the amount of retrieved material. IVM is an innovative technique for patients with cancer. For example, Cohen et al. [20] obtained from 2 to 6 mature oocytes in this group of patients, and Krasnopolskaya et al. [6] obtained an average of 5.8 mature oocytes. In our study, the average number of oocytes in metaphase II was 4.00 ± 2.37. These differences may be due to the use of different maturation media, as well as the use of an ovulation trigger or minimal doses of hormonal stimulation before a transvaginal puncture. Ovarian stimulation is more effective. For example, we obtained an average of 6.71 ± 1.92 fertilizable oocytes. Virant-Klun et al. reported this parameter to be 11.0 ± 9.0 [21]. This may be due to our use of letrozole, which, according to some authors, may negatively affect oogenesis. However, there is insufficient data to support this finding.

 

Fig. 5. Evaluation of follicular fluid and presence of oocyte-cumulus complexes

 

Creux et al. compared ICSI outcomes by evaluating mature oocytes obtained in vitro and in vivo. On average, 5 stimulation embryos and 3 IVM embryos were cryopreserved [22]. We also observed a lower fertilization potential in oocytes obtained by maturation (52.3% vs. 62.9%). Therefore, the IVM technique showed lower efficacy compared with ovarian stimulation for fertility preservation in patients with cancer.

CONCLUSION

Fertility preservation in patients with cancer is an extremely urgent medical issue that requires a multidisciplinary approach involving oncologists and fertility specialists. When cancer treatment is needed, a timely and informed decision about preserving reproductive function is important. It can significantly expand a patient’s future options, including the potential for motherhood after treatment.

Ovarian stimulation is a well-established method of oocyte retrieval with high success rates. However, it should be noted that this procedure is time-consuming (at least 7 days) and may have contraindications that limit its use in some clinical situations. Therefore, in vitro oocyte maturation is a promising alternative for the preservation of reproductive material. However, the efficacy of IVM depends on adequate ovarian reserve, which should be considered when choosing a technique. For patients awaiting oophorectomy for any reason, IVM is the only way to preserve reproductive material.

It is possible to perform several cycles of ovarian stimulation or to combine techniques (e.g., IVM combined with ovarian stimulation) to increase the effectiveness of AST. This multidisciplinary approach not only optimizes outcomes, but also significantly increases the chances of successful fertility restoration after cancer treatment.

Therefore, a comprehensive approach to fertility preservation, including active collaboration between oncologists and fertility specialists, is essential for patients to realize their future reproductive potential, which is critical to their quality of life and psychological well-being.

ADDITIONAL INFORMATION

Authors’ contribution. Yu.E. Dobrokhotova: approval of the final version of the article; I.A. Lapina: design development of the study, approval of the final version; A.A. Malakhova: design development, preparation and editing of the text; T.G. Chirvon: text editing, literature search; V.M. Gomzikova: collection and analysis of patients with oncological pathology; Yu.A. Sorokin: collection and the analysis of patients with oncological pathology. All authors confirm that their authorship meets the international ICMJE criteria (all authors made a substantial contribution to the conception of the work, acquisition, analysis, interpretation of data for the work, drafting and revising the work, final approval of the version to be published and agree to be accountable for all aspects of the work).

Ethics approval. The study was performed within the framework of the dissertation of A.A. Malakhova and was approved by the local ethical committee of N.I. Pirogov Russian National Research Medical University (extract from protocol No. 213 dated 13 December 2021).

Consent for publication. The patients who participated in the study signed an informed consent to participate in the study and publish medical data.

Funding source. This study was not supported by any external sources of funding.

Disclosure of interest. The authors declares that there are no obvious and potential conflicts of interest associated with the publication of this article.

About the authors

Yulia E. Dobrokhotova

Russian National Research Medical University named after N.I. Pirogov

Email: pr.dobrohotova@mail.ru
ORCID iD: 0000-0002-7830-2290
SPIN-code: 2925-9948

MD, Dr. Sci. (Medicine), Professor

Russian Federation, 1 Ostrovityanova st, Moscow, 117997

Irina A. Lapina

Russian National Research Medical University named after N.I. Pirogov; Clinical and Diagnostic center MEDSI

Email: doclapina@mail.ru
ORCID iD: 0000-0002-2875-6307
SPIN-code: 1713-6127

MD, Dr. Sci. (Medicine), Professor

Russian Federation, 1 Ostrovityanova st, Moscow, 117997; Moscow

Anastasiya A. Malakhova

Russian National Research Medical University named after N.I. Pirogov; Clinical and Diagnostic center MEDSI

Author for correspondence.
Email: anastasimed@yandex.ru
ORCID iD: 0000-0002-2140-8000
SPIN-code: 2668-1696

Assistant

Russian Federation, 1 Ostrovityanova st, Moscow, 117997; Moscow

Tatiana G. Chirvon

Russian National Research Medical University named after N.I. Pirogov

Email: tkoltinova@gmail.com
ORCID iD: 0000-0002-8302-7510
SPIN-code: 9582-1650

MD, Cand. Sci. (Medicine)

Russian Federation, 1 Ostrovityanova st, Moscow, 117997

Valeriia M. Gomzikova

Russian National Research Medical University named after N.I. Pirogov

Email: gomzval1402@gmail.com
ORCID iD: 0000-0001-6297-8811

Postgraduate Student

Russian Federation, 1 Ostrovityanova st, Moscow, 117997

Yury A. Sorokin

Clinical and Diagnostic center MEDSI

Email: sorokin_y@mail.ru
ORCID iD: 0000-0001-9305-323X

Department Head

Russian Federation, Moscow

References

Supplementary files