Anticancer Treatments and Female Fertility: Clinical Concerns and Role of Oncologists in Oncofertility Practice

Abstract

Introduction:

Anticancer treatments such as aggressive chemotherapy and radiotherapy have deleterious gonadotoxic side effects and are considered the most common causes of pathological and iatrogenic fertility loss in women.

Areas Covered:

In order to preserve fertility of young women and girls with cancer, several established, experimental, and debatable options can be offered in the emerging field of oncofertility. This article reviews the effects of anticancer treatments on female fertility and discusses the current challenges and future directions of fertility preservation options that can be offered to the female patients with cancer.

Expert Commentary:

Although promising, several medical, economic, social and legal barriers face oncofertility practice around the globe especially in underserved areas. To overcome such barriers, more effective solutions should be provided to spread awareness and enhance communication between patients, oncologists and gynecologists. Early referral by oncologists before initiation of chemotherapy and radiotherapy is an important key factor for success in female fertility preservation strategies.

1. Introduction

Fertility loss is not rare in women. This condition results from complete depletion of ovarian follicles and oocytes that therefore leads to permanent inability of a woman to conceive. Female fertility loss can be either physiological due to menopause or pathological due to gonadotoxicity, premature ovarian failure (POF) before the age 40, bilateral oophorectomy, gonadal agenesis and other genetic disorders [1, 2, 3].

Anticancer treatments such as aggressive chemotherapy and radiotherapy have deleterious gonadotoxic side effects and are considered the most common causes of pathological and iatrogenic fertility loss in women [4, 5, 6, 7]. Each year worldwide, over 6.6 million women are diagnosed with cancer [8], and about 10% of them are diagnosed during their reproductive age (age < 40) [9, 10]; they usually receive aggressive chemotherapy and radiotherapy that may cause gonadotoxicity, POF and subsequent fertility loss in more than 80% of cases [11, 12].

2. Anticancer Treatments and Female Fertility

2.1. Anticancer treatments-induced gonadotoxicity

In young women (age < 40) and girls with cancer, gonadotoxicity usually occurs when ovaries are exposed to alkylating chemotherapy such as cyclophosphamide, ifosfamide, busulfan, or ionizing radiotherapy to pelvis and abdomen or cranial and total body irradiation (TBI). Nevertheless, the following anticancer treatments have lower risks for gonadotoxicity depending on the dose, dosage and the age of the patient: doxorubicin, epirubicin, cisplatin, carboplatin, methotrexate, fluorouracil, vincristine, bleomycin, dactinomycin and radiotherapy excluding pelvis, abdomen and head. As guidelines, some important reports published by American Society of Clinical Oncology (ASCO) classified anticancer treatments according to their risk of gonadotoxicity in women (Table 1) [13, 14].

Table 1:

Risk of female gonadotoxicity with modern anticancer treatments adapted from the American Society of Clinical Oncology (ASCO) guidelines on fertility preservation in female patients with cancer [13].

Modern anticancer treatments for female patients	Risk of female gonadotoxicity
▪Hematopoietic stem cell transplantation (HSCT) with cyclophosphamide/total body irradiation (TBI) or cyclophosphamide/busulfan. ▪External beam radiation to a field that includes the ovaries. ▪CMF, CEF, CAF X 6 cycles in women age 40 and older (adjuvant breast cancer therapy with combinations of cyclophosphamide, methotrexate, fluorouracil, doxorubicin, epirubicin).	High risk (> 80%)
▪CMF, CEF, CAF X 6 cycles in women age 30–39 (adjuvant breast cancer therapy with combinations of cyclophosphamide, methotrexate, fluorouracil, doxorubicin, epirubicin). ▪AC X 4 cycles in women age 40 and older (adjuvant breast cancer therapy with doxorubicin/cyclophosphamide).	Intermediate risk (20–80%)
▪ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine). ▪CHOP X 4–6 cycles (cyclophosphamide/doxorubicin/vincristine/prednisone). ▪CVP (cyclophosphamide/vincristine/prednisone). ▪Acute myeloid leukemia (AML) therapy (anthracycline/cytarabine). ▪Acute lymphoblastic leukemia (ALL) therapy (multi-agent). ▪CMF, CEF, CAF X 6 cycles in women less than 30 (adjuvant breast cancer therapy with combinations of cyclophosphamide, methotrexate, fluorouracil, doxorubicin, epirubicin). ▪AC X 4 cycles in women less than 40 (adjuvant breast cancer therapy with doxorubicin/cyclophosphamide).	Lower risk (< 20%)
▪Methotrexate, fluorouracil, vincristine, bleomycin, dactinomycin.	Very low or no risk
▪Taxanes, oxaliplatin, irinotecan, monoclonal antibodies, tyrosine kinase inhibitors.	Unknown risk (examples)

Anticancer treatments with high risk (> 80%) of gonadotoxicity include: (1) Hematopoietic stem cell transplantation (HSCT) with cyclophosphamide/total body irradiation (TBI) or cyclophosphamide/busulfan, (2) External beam radiation to a field that includes the ovaries, (3) CMF, CEF, CAF X 6 cycles in women age 40 and older (adjuvant breast cancer therapy with combinations of cyclophosphamide, methotrexate, fluorouracil, doxorubicin, epirubicin) [13, 14].

Anticancer treatments with intermediate risk (20–80%) of gonadotoxicity include: (1) CMF, CEF, CAF X 6 cycles in women age 30–39 (adjuvant breast cancer therapy with combinations of cyclophosphamide, methotrexate, fluorouracil, doxorubicin, epirubicin), (2) AC X 4 cycles in women age 40 and older (adjuvant breast cancer therapy with doxorubicin/cyclophosphamide) [13, 14].

Anticancer treatments with lower risk (< 20%) of gonadotoxicity include: (1) ABVD (doxorubicin/bleomycin/vinblastine/dacarbazine), (2) CHOP X 4–6 cycles (cyclophosphamide/doxorubicin/vincristine/prednisone), (3) CVP (cyclophosphamide/vincristine/prednisone), (4) Acute myeloid leukemia (AML) therapy (anthracycline/cytarabine), (5) Acute lymphoblastic leukemia (ALL) therapy (multi-agent), (6) CMF, CEF, CAF X 6 cycles in women less than 30 (adjuvant breast cancer therapy with combinations of cyclophosphamide, methotrexate, fluorouracil, doxorubicin, epirubicin), (7) AC X 4 cycles in women less than 40 (adjuvant breast cancer therapy with doxorubicin/cyclophosphamide) [13, 14]

Anticancer treatments with very low or no risk of gonadotoxicity include methotrexate, fluorouracil, vincristine, bleomycin, and dactinomycin. Anticancer treatments with unknown risk of gonadotoxicity include taxanes, oxaliplatin, irinotecan, monoclonal antibodies, and tyrosine kinase inhibitors [13, 14]

According to recent statistics, the most common cancers in prepubertal girls (age 0–14) are leukemia (31%), central nervous system malignancies (21%), lymphoma (10%), neuroblastoma (7%), Wilms tumor (5%), bone tumors (4%), rhabdomyosarcoma (3%) and retinoblastoma (3%). The most common cancers in female adolescents (age 15–19) are lymphoma (23%), leukemia (12%), thyroid (11%), central nervous system malignancies (10%), bone tumors (7%), melanoma (6%) and ovarian germ cell tumors (2%). The most common cancers in young women (age < 40) are breast (29%), lung (13%), colorectal (8%), uterine and cervical (6%) cancer, thyroid carcinoma (6%), lymphoma (4%), melanoma (4%), leukemia (3%), kidney (3%) and pancreatic (3%) cancer [9, 10].

However, the most common cancers during the female reproductive years that may require aggressive gonadotoxic chemotherapy and radiotherapy are breast, cervix, leukemia, lymphoma, central nervous system, renal and bone cancers [4–14]

2.2. Guidelines for preserving fertility of young women and girls with cancer

Due to recent advances in cancer diagnosis and treatment, the overall five-year survival rate in most cases of young women (age < 40) and girls with cancer has significantly increased up to ~90% [9, 10]. Accordingly, the topic how to prevent chemotherapy- and radiotherapy-induced gonadotoxicity and subsequent fertility loss has gained a growing attention.

Throughout the past 10 years, numerous international guidelines were published concerning anticancer treatments and female fertility. Such important guidelines were published by American Society of Clinical Oncology (ASCO) [13, 14], American Society for Reproductive Medicine (ASRM) [15, 16], European Society for Medical Oncology (ESMO) [17, 18], American Oncofertility Consortium (OC) [19, 20], International Society for Fertility Preservation (ISFP) [21, 22, 23, 24], Fertility Preservation Network FertiPROTEKT [25], American Academy of Pediatrics (AAP) [26], and Association of Pediatric Hematology/Oncology Nurses (APHON) [27].

In order to preserve fertility of young women (age < 40) and girls with cancer, several established, experimental, and debatable options can be offered in the emerging field of oncofertility. Established options include embryo or egg cryopreservation. Experimental options include ovarian tissue cryopreservation and further autotransplantation and/or in vitro maturation (IVM), while debatable options include surgical ovarian transposition (oophoropexy), gonadotropin-releasing hormone (GnRH) analogs and pelvic shielding [13–27].

3. Conclusion

We highlight that iatrogenic fertility loss in women is a serious complication of some anticancer treatments. Clinically, gonadotoxic agents such as aggressive chemotherapy and radiotherapy for treatment of cancer are the most common causes of pathological and iatrogenic fertility loss in women. In order to preserve fertility of young women (age < 40) and girls with cancer, several established, experimental, and debatable options can be offered in the emerging field of oncofertility. Early referral by oncologists before initiation of chemotherapy and radiotherapy is an important key factor for success in female fertility preservation strategies.

4. Expert Commentary

4.1. Clinical concerns in preserving fertility of young women and girls with cancer

According to the most recent guidelines, all fertility preservation options mentioned above except in vitro maturation of ovarian tissue and follicles are currently used in clinical practice and have resulted in healthy live births [13–27]. Recently, the following success rates of female fertility preservation options have been reported: embryo cryopreservation (live birth rate of ~ 30% per frozen embryo transfer), egg cryopreservation (live birth rate of > 6% per frozen oocyte), ovarian tissue cryopreservation and further autotransplantation (live birth rate of ~25% per transplant) [25], oocyte in vitro maturation (live birth rate half of that for traditional IVF), and ovarian protection techniques (success rates are debatable) [13–27].

In spite of promising success rates, each fertility preservation option has both advantages and disadvantages and may not be suitable for all patients. Furthermore due to wide variations in the dose and dosage of anticancer treatments as well as the age and health conditions of cancer patients, success rates of female fertility preservation options in each case should be extrapolated with caution. It is also important to emphasize that patient’s age plays a crucial role in estimating the success rate of any female infertility or oncofertility treatments. These concerns can be addressed by early counseling before initiation of chemotherapy and radiotherapy in order to tailor the most suitable fertility preservation strategy for each patient.

To provide fertility preservation services to young women (age < 40) and girls with cancer, the treating center should be properly equipped, and should have a highly skilled oncofertility team of oncologists, gynecologists, reproductive biologists, transplantation surgeons, and research scientists. Therefore, referring patients from oncology clinics, small medical centers or general hospitals to highly specialized oncofertility centers is strongly encouraged in order to guarantee a high standard of care [28, 29, 30].

We recommend that immediately after diagnosis of cancer, oncofertility counseling has to start. If the patient is below 40 and has a reasonable chance of survival, good health conditions and satisfactory reproductive functions, the plan of chemotherapy and radiotherapy should be checked and the risk of gonadotoxicity and subsequent fertility loss should be assessed. If the risk of gonadotoxicity and subsequent fertility loss is greater than 50% and the patient is willing to conceive in the future, a fertility preservation strategy should be performed before initiation of chemotherapy and radiotherapy.

From a clinical perspective, we suggest that the following three major strategies of female fertility preservation should be attempted respectively when not contraindicated: (i) Strategy one: Emergency or conventional hormonal ovarian stimulation followed by ovum pickup, egg cryopreservation, and/or in vitro fertilization (IVF) and embryo cryopreservation (established options), (ii) Strategy two: Partial or unilateral oophorectomy followed by ovarian tissue cryopreservation and further autotransplantation and/or in vitro maturation (experimental options), (iii) Strategy three: Ovarian protection techniques such as oophropexy, pelvic shielding, GnRH analogs, and/or fractionated doses of chemotherapy and radiotherapy (debatable options). In strategy one, conventional hormonal ovarian stimulation is contraindicated in prepubertal girls and in women with estrogen sensitive tumors such as breast and endometrial cancers. In strategy two, ovarian autotransplantation is contraindicated in ovarian carcinomas and malignancies that may metastasize to ovaries such as leukemia, lymphomas, breast and gastrointestinal cancers. In strategy three, oophropexy and pelvic shielding do not provide ovarian protection when chemotherapy is used, while GnRH analogs do not provide ovarian protection when radiotherapy is used [31, 32, 33, 34]. In order to avoid such different contraindications, new advances in research to restore fertility of female cancer patients have been recently attempted including artificial ovary [35, 36, 37, 38], and use of mesenchymal stem cells [39, 40, 41].

When a patient cannot benefit from fertility preservation options, adoption or third party reproduction including egg donation, sperm donation, embryo donation and surrogacy may be considered as an alternative.

4.2. Barriers to oncofertility practice

In fact, there are several medical, economic, social and legal barriers that face oncofertility practice around the globe. Medical barriers may include lack of awareness among oncologists and gynecologists, lack of advances in early diagnosis and treatment of cancer, lack of referrals from oncologists, lack of inter-institutional communications, and lack of oncofertility specialists. Economic barriers may include lack of adequate health insurance coverage for fertility services, lack of institution and research fund, and the fact that most of fertility services are provided in private centers and paid as out-of-pocket services. All of these factors create a financial burden to the patients. Social barriers may include conservative cultural and religious attitudes towards third party reproduction, surrogacy and adoption. Legal barriers may include prohibition of third party reproduction, surrogacy and adoption due to cultural or religious reasons.

In Germany and USA, we experience common barriers while delivering fertility preservation services to young women and girls with cancer. Such common barriers are lack of awareness among physicians and inadequate health insurance coverage that may create financial burden to the patients. Unfortunately due to lack of awareness among oncologists and gynecologists, many young women and girls with cancer are not informed about preserving their fertility prior to chemotherapy and radiotherapy [42, 43, 44, 45]. As a result, many patients lose their fertility and become sterile. These patients will have no other options left to get children except considering adoption or third party reproduction including egg donation, sperm donation, embryo donation and surrogacy. As fertility services have become more internationalized, some patients prefer to travel abroad and get third party reproduction as a cross border reproductive care (CBRC) in order to protect their privacy or even to circumvent law when third party reproduction is not legally allowed in their home countries [46, 47, 48, 49, 50, 51].

5. Five-year view

5.1. Overcoming barriers to oncofertility practice

To overcome the different barriers that arise in oncofertility practice especially in underserved areas, more effective solutions should be provided [52, 53, 54, 55]. For example, better awareness among oncologists, gynecologists and patients can be achieved via media, networks and sponsored scientific conferences and workshops. In Germany and USA particularly in the field of fertility preservation and oncofertility, two effective networks exist; FertiPROTEKT 56 and Oncofertility Consortium 57. FertiPROTEKT Network connects fertility preservation centers in all German-speaking countries (Germany, Austria and Switzerland), while Oncofertility Consortium Network located at Northwestern University, Chicago, USA connects fertility preservation centers in USA and worldwide as well. Such networks are the place where new ideas for oncofertility research projects develop, efforts of clinical care converge, and the interdisciplinary community of oncologists, gynecologists, reproductive endocrinologists, research scientists and patients participate in this cutting edge field.

As the field of fertility preservation expands, more attention towards the topic in the study programs of medical schools should be given in order to spread knowledge among medical students who will soon become future physicians. In addition, financial support for patients, technology, training and research can be achieved via grants and fundraising campaigns.

5.2. Enhancing oncologists’ role in oncofertility practice

Undoubtedly, we consider oncologists as the most important players in oncofertility practice as they see cancer patients first and therefore they can initiate the process and inform patients about the available fertility preservation options and their advantages, limitations and success rates 58. Oncologists are also encouraged to communicate with gynecologists and refer their patients as early as possible for oncofertility counselling before initiation of chemotherapy and radiotherapy in order to tailor the most suitable fertility preservation strategy for each patient. In order to fill gaps in oncofertility practice and enable oncologists and gynecologists to communicate and take action, Oncofertility Consortium designed a specialized decision tools platform online 59. Such decision tools web portal provides information to help oncologists and gynecologists guide patients through their fertility preservation options and help them make the best decision based on their cancer treatment, lifestyle, values, and future fertility goals. The decision tools web portal also answers questions that are frequently asked by oncologists and gynecologists and related to the interest of cancer patients in oncofertility services, time needed to apply fertility preservation options before initiation of anticancer treatments, effect of fertility medications on cancer prognosis, costs and insurance coverage as well as issues related to contraception, hormonal replacement therapy, sex and sexuality during the course of cancer treatment 59.

6. Key issues

• ▪Anticancer treatments such as aggressive chemotherapy and radiotherapy have deleterious gonadotoxic side effects.
• ▪Anticancer treatments are considered the most common causes of pathological and iatrogenic fertility loss in women.
• ▪In order to preserve fertility of young women (age < 40) and girls with cancer, several established, experimental, and debatable options can be offered in the emerging field of oncofertility.
• ▪There are several medical, economic, social and legal barriers that face oncofertility practice around the globe.
• ▪To overcome such barriers that arise in oncofertility practice especially in underserved areas, more effective solutions should be provided to spread awareness and enhance communication between patients, oncologists and gynecologists.
• ▪Early referral by oncologists before initiation of chemotherapy and radiotherapy is an important key factor for success in female fertility preservation strategies.

Abbreviations

AAP

American Academy of Pediatrics

ABVD

Doxorubicin (Adriamycin), Bleomycin, Vinblastine, Dacarbazine

AC

Doxorubicin (Adriamycin), Cyclophosphamide

ALL

Acute Lymphoblastic Leukemia

AML

Acute Myeloid Leukemia

APHON

Association of Pediatric Hematology/Oncology Nurses

ASCO

American Society of Clinical Oncology

ASRM

American Society for Reproductive Medicine

CAF

Cyclophosphamide, Doxorubicin (Adriamycin), Fluorouracil

CBRC

Cross Border Reproductive Care

CEF

Cyclophosphamide, Epirubicin, Fluorouracil

CMF

Cyclophosphamide, Methotrexate, Fluorouracil

CVP

Cyclophosphamide, Vincristine, Prednisone

EMSO

European Society for Medical Oncology

FertiPROTEKT

Fertility Preservation Network

GnRH

Gonadotropin-Releasing Hormone

HSCT

Hematopoietic Stem Cell Transplantation

ISFP

International Society for Fertility Preservation

IVF

In Vitro Fertilization

IVM

In Vitro Maturation

OC

Oncofertility Consortium

POF

Premature Ovarian Failure

TBI

Total Body Irradiation