Improvements in Clinical Trials Information Will Improve the Reproductive Health and Fertility of Cancer Patients

Abstract

There are a number of barriers that result in cancer patients not being referred for oncofertility care, which include knowledge about reproductive risks of antineoplastic agents. Without this information, clinicians do not always make recommendations for oncofertility care. The objective of this study was to describe the level of reproductive information and recommendations that clinicians have available in clinical trial protocols regarding oncofertility management and follow-up, and the information that patients may receive in clinical trials patient information sheets or consent forms. A literature review of the 71 antineoplastic drugs included in the 68 clinical trial protocols showed that 68% of the antineoplastic drugs had gonadotoxic animal data, 32% had gonadotoxic human data, 83% had teratogenic animal data, and 32% had teratogenic human data. When the clinical trial protocols were reviewed, only 22% of the protocols reported the teratogenic risks and 32% of the protocols reported the gonadotoxic risk. Only 56% of phase 3 protocols had gonadotoxic information and 13% of phase 3 protocols had teratogenic information. Nine percent of the protocols provided fertility preservation recommendations and 4% provided reproductive information in the follow-up and survivorship period. Twenty-six percent had a section in the clinical trials protocol, which identified oncofertility information easily. When gonadotoxic and teratogenic effects of treatment were known, they were not consistently included in the clinical trial protocols and the lack of data for new drugs was not reported. Very few protocols gave recommendations for oncofertility management and follow-up following the completion of cancer treatment. The research team proposes a number of recommendations that should be required for clinicians and pharmaceutical companies developing new trials.

Background

Improvements in cancer diagnosis and treatment of pediatric cancer patients (0–14 years of age) and adolescent, young adult, and adult patients of a reproductive age (15–45 years of age) have led to significant improvements in the survival rates around the world.^1–3 Unfortunately, a patient's fertility can be affected temporarily or permanently by their cancer treatment. Gonadotoxicity is the temporary or permanent damage to the ovaries or the testes, or damage to pituitary hormone secretion in the neuroendocrine axis after exposure to chemotherapy, radiotherapy, bone marrow transplantation, and surgery. Chemotherapy drugs given during pregnancy can also have an effect on the development of an embryo and fetus leading to congenital malformations or fetal death.⁴ These effects are called teratogenic effects of treatment and, if known, mean that clinicians should give cancer patients recommendations to avoid pregnancy during cancer treatment or avoid treatment if patients are pregnant.

In male cancer patients, chemotherapy may cause a reduction in sperm count or azoospermia depending on the dose of individual and combined drugs.⁵ The effects of chemotherapy on the spermatogonial stem cells may compromise survival of the stem cells and their ability to differentiate, and this may result in permanent infertility.⁵ If treatment is limited to the chemotherapy agents that do not kill stem spermatogonia, then normal sperm production can be restored months after the completion of treatment.^5,6

In female cancer patients, chemotherapy may cause a reduction in the primordial follicles in the ovary and result in an increase in the decline of oocytes leading to primary or second ovarian failure and premature menopause.⁷

Gonadotoxicity is multifactorial, but an important factor is the nature of individual chemotherapy drug and the dose, which may be different in male and female patients. The gonadal toxicity of many of the alkylating chemotherapeutic agents, platinum agents, and anthracyclines are well documented, but other drugs have a similar effect either individually or when combined in multimodality treatment and limited animal or human data are available.⁵

Clinical trial protocols should document what the known risks on reproductive health are, for patients receiving chemotherapy treatment, but it is also important to document when data are not available or when potential risk exists based on the class of drug or mechanism of action of a drug.

In the United Kingdom, Australia, and United States, each country has their own requirements for how they report reproductive information in their respective product information (PI) documents; however, none of these countries has an absolute requirement to report effects on fertility, but guidance is given.

In Australia, the information required in the PI document is detailed in subsection 7D(1) of the Therapeutic Goods Act, 1989, which provides guidance for sponsors to document the effects of fertility in the precaution section of the PI form. The use in pregnancy should also be included in the PI using the categories in the Australian Pregnancy Categorisation (genotoxicity, carcinogenicity, use in lactation, and pediatric use). The interpretation of exactly what to include in each section is up to the sponsor.⁸

In Europe, the Summary of Product Characteristics⁹ fertility reporting suggests that possible effects of medicinal male and female fertility should be included if clinical data are available, and recommendations for the use of the medicinal product when pregnancy is planned should be included. If there are no fertility data at all, then this should be reported.

In the United States, the FDA replaced the five-letter system (A, B, C, D, X) on prescription and biological drug labeling in 2015 by the pregnancy and lactation labeling final rule (see Appendix 2),¹⁰ which now includes narrative sections on the risks during pregnancy and lactation, as well as the risk to male and female reproductive potential.

Oncofertility is a subspeciality that focuses on the collaboration between cancer and fertility specialists to develop reproductive healthcare provisions for cancer patients, maximizing the reproductive health of cancer survivors by discussion, uptake of fertility preservation, and fertility-related psychosocial support, as well as developing new research to prevent infertility.^11–13 There are a number of fertility preservation techniques, which are standard practices and recommended by international guidance documents on fertility preservation.^14–18 These guidelines give clinicians recommendations about the oncofertility management of cancer patients receiving gonadotoxic risk treatment. Despite these guidelines, less than 50% of patients are currently informed of the reproductive risk of treatment.^19–25

There are a number of barriers to delivering oncofertility care,²⁶ but one barrier that has not been reported on before is the lack of available information that is documented in clinical trial protocols about the gonadotoxic and teratogenic risk of treatment and recommendations for oncofertility care in clinical trial protocols. Clinicians and healthcare professionals look to these clinical trial protocols to guide the work-up, treatment, and subsequent follow-up of patients, and our research group was interested in defining how much information clinicians are given. The documentation about reproductive risks is an important factor that allows the translation of knowledge about reproductive risk into adequate oncofertility care, and the lack of this information may limit improvements in the oncofertility care of cancer patients.

Hypothesis

The reproductive complications of cancer treatment are poorly documented in clinical trial protocols, and limited advice on oncofertility assessment, management, and follow-up is provided to clinicians who are using these protocols.

Purpose

The aim of this study was to describe the level of reproductive information available to clinicians in clinical trial protocols and for patients in the information sheets or consent forms. The secondary aim was to describe the recommendations for oncofertility investigation and management documented for clinicians in the clinical trial protocols and compare these data with the available published literature on reproductive risk of individual chemotherapy agents.

Methods

The authors identified and reviewed 78 Australian, American, and European clinical trial protocols opened between 1996 and 2016. Ten protocols were excluded as they either did not use chemotherapy agents or only included nonchemotherapy drugs such as androgen inhibitors. The protocols were chosen as they have been used to treat pediatric patients or patients of a reproductive age (15–45 years of age) with either a hematological or oncological cancer diagnosis common in this age group, who are at risk of treatment-related infertility. Only studies with complete protocols were included in the review.

The full protocol, information sheets, and consent forms were reviewed by four researchers and data were collected documenting a number of variables:

(1) Type of protocol (disease treated, type of trial, and age of patients treated)

(2) Recommendations on the gonadotoxic risk for each individual drug

(3) Recommendations on the gonadotoxic risk of completed protocols

(4) Recommendations about the teratogenic effect of chemotherapy and management

(5) Recommendations on fertility preservation before or after cancer treatment given in the protocol or available on patient information sheets

(6) Recommendation for reproductive follow-up following the completion of treatment

(7) The usability of the protocol for oncofertility information

Four researchers then performed a literature review on the gonadotoxic and teratogenic risk of the 71 antineoplastic agents identified from the 68 protocols to look at current evidence on the gonadotoxic and teratogenic risk of treatment and compare the evidence from animal and human trials to what was reported in the 68 clinical trial protocols reviewed. Unfortunately, as limited data were available in the literature, the researchers also looked at the PI sheets and pharmaceutical websites for gonadotoxicity information.

Statistics

Descriptive statistics (percentages) were used to describe information associated with the level of gonadotoxic and reproductive information as well as recommendations provided in clinical trial protocols, and compare data that were available and documented in the literature. Data analysis was performed using STATA software, version 14.0 (StataCorp LP, TX).

Results

There were 68 reviewed protocols for infant, pediatric, adolescent young adult (AYA), and adult aged cancer patients. One of 68 (1%) was an infant protocol, 26/68 (38%) were pediatric and AYA protocols, 26/68 (39%) were adult protocols, and 14/70 (21%) were protocols that covered all age groups.

The protocols covered 30 different cancer types. Twenty-four of 68 (35%) were protocols for leukemia and lymphomas, 5/68 (7.35%) for brain tumors, and 39/68 (57%) for solid tumors. The protocols covered all clinical trial stages: 11/68 (16%) were phase 1 protocols, 7/68 (10%) were phase 1/2 protocols, 9/68 (13%) were phase 2 protocols, 3/68 (4%) were phase 2/3 protocols, and 38/68 (56%) were phase 3 protocols.

A literature review on the teratogenic and gonadotoxic effects of individual drugs did not provide much original research data; so the PI and prescribing information sheets were also reviewed. Of the 71 antineoplastic drugs, included in the 68 clinical trial protocols reviewed, 68% of the antineoplastic drugs had gonadotoxic animal data, 32% had gonadotoxic human data, 83% had teratogenic animal data, and 32% had teratogenic human data (Table 1).

Table 1.

Information Available in the Literature About the Risk of Gonadotoxicity and Teratogenicity of Anticancer Drugs

		Gonadotoxic information		Teratogenic information
Name of chemotherapy agent	Class of chemotherapy drug	Gonadotoxic information in animals	Gonadotoxic information for males and females	Teratogenic information in animals	Teratogenic information in females: classified using the old FDA pregnancy categories (See Appendix 1)	Breastfeeding
Arsenic trioxide^27,28	Antineoplastic miscellaneous	No animal data are available.	No human data are available.	Rats: Embryo lethal and teratogenic. Increase in resorptions, neural tube defects, anophthalmia, and microphthalmia.	Category X: No human data are available.	No lactation data are available.
Asparaginase^29–37	Antitumor antibiotic	No animal data are available.	No human data are available.	Animal studies: Retards the weight gain of mothers and fetuses. Resorptions, gross abnormalities, and skeletal abnormalities.	Category C: No human data are available.	No lactation data are available.
Avastin (Bevacizumab)^38–48	Monoclonal antibody	Male cynomolgus monkeys: No adverse effects have been observed in repeat-dose toxicity. Female cynomolgus monkeys: Decreased ovarian and uterine weights, decreased endometrial proliferation, decreased menstrual cycles, and arrested follicular development. Multiple species: Decreases in ovarian and/or uterine weight and the number of corpora lutea, a reduction in endometrial proliferation, and an inhibition of follicular maturation. The changes in both monkeys and rabbits were reversible once cessation of treatment.	Females: New cases of ovarian failure were reported more frequently in patients receiving Avastin (39% in the Avastin group compared to 2.6% in the control). After discontinuation of Avastin, ovarian function recovered in a majority of women. Long-term effects of treatment are unknown, however, higher rates of amenorrhea are being observed in patients than control groups.	Rabbits: Embryotoxic and teratogenic when administered. Observed effects included decreases in fetal body weights, an increased number of fetal resorptions, and an increased incidence of specific gross and skeletal fetal alterations.	Category D: No human data are available. IgGs are known to cross the placental barrier, and AVASTIN may inhibit angiogenesis in the fetus. Angiogenesis has been shown to be critically important to fetal development. The inhibition of angiogenesis following administration of AVASTIN could result in an adverse outcome of pregnancy. Therefore, AVASTIN should not be used during pregnancy.	No lactation data are available.
Bendamustine⁴⁹	Alkylating agent	Rats and dogs: Testicular atrophy and reduced spermatogenesis.	Males: Impaired spermatogenesis, azoospermia, and total germinal aplasia in male patients treated, especially in combination with other drugs. Spermatogenesis may return in patients in remission.	Mice and rats: Embryo–fetal lethal and teratogenic, including decreased fetal body weights and an increase in fetal, skeletal, and visceral malformations (cleft palate, turricephaly, rib malformations and spinal deformities, and hepatic or intestinal ectopia).	Category D: No human data are available.	No lactation data are available.
Arsenic trioxide^50–53	Immune checkpoint inhibitor—PD1 inhibitor	No animal data are available.	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
BGB-283	BRAF inhibitor	No animal data are available.	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
BGB-290	PARP inhibitor	No animal data are available.	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
Bleomycin^54–59	Antitumor antibiotic	No animal data are available.	No human data are available.	It has been shown to be teratogenic in rats causing skeletal malformations and genitourinary abnormalities. Bleomycin is abortifacient, but not teratogenic in rabbits.	Category D: Bleomycin is suspected to have caused human fetal malformations.	No lactation data are available.
Blinatumomab^60–64	Monoclonal antibody	Mice: A murine surrogate molecule had no adverse effects on male and female reproductive organs in a 13-week repeat dose.	No human data are available.	Mice: Murine surrogate molecule had no embryo–fetal toxicity or teratogenicity in period of organogenesis. The expected depletions of B and T cells were observed in pregnant mice, but hematological effects were not assessed in fetuses.	Category C: There are no adequate and well-controlled studies in pregnant women. Based on its mechanism of action, it may cause fetal toxicity.	No lactation data are available.
Bortezomib^65–67	Proteasome inhibitor	Mice: Fertility studies have not been performed, but degenerative changes in the ovaries and testes in animal studies in rats suggest that this drug may affect male and female fertility.	No human data are available.	Rabbits: Fetal loss and decreased fetal weight were observed at doses less than the equivalent human dose. Rats: Not teratogenic during period of organogenesis in nonclinical developmental toxicity studies.	Category C: No human data are available.	No lactation data are available.
Brentuximab vedotin (Adcetris)^68–71	Monoclonal antibody	Male rats: Damage spermatozoa and testicular tissue, resulting in possible genetic abnormalities. Reduced spermatogenesis and aspermia. Testicular atrophy and degeneration have not fully reversed following a 16-week treatment-free time period. No female animal studies.	No human data are available.	Rats: Embryo–fetal toxicities, including congenital malformations when drug was administered during organogenesis.	Category D: No adequate and well-controlled studies, but based on mechanism of action, it can cause fetal harm.	No lactation data are available.
Busulfan^72–79	Alkylating agents	Rats: Depleted oocytes and caused sterility in males. Busulfan disrupted spermatogenesis in rats, guinea-pigs, rabbits, and monkeys, depleted oocytes and impaired fertility in female mice, and induced sterility in male rats and male hamsters. The solvent dimethylacetamide (DMA) was found to impair fertility in studies with male and female rodents.	Females: Ovarian suppression, amenorrhea, and delayed puberty commonly occur in premenopausal women. Males: Sterility, azoospermia, and testicular atrophy have been reported in male patients.	Animal studies. Malformations and anomalies, including significant alterations in the musculoskeletal system, body weight gain, and size. Rats: Sterility in both male and female offspring due to the absence of germinal cells in the testes and ovaries.	Category D: No human data are available.	No lactation data are available.
Carbozantinib (Cometriq)^80–83	Tyrosine kinase inhibitor	Male rats: Carbozantinib at doses equal to human exposure had decreased sperm counts and reproductive organ weights. Female rats: Decrease in number of live embryos, significant increase in pre- and post-implantation loss in doses 50% of human exposure. Ovarian necrosis in rats treated equal to human dose for 14 days. Male and female dogs: Hypospermia and absence of corpora lutea.	No human data are available.	Multiple species: Cabozantinib was embryo lethal in rats at exposures below the recommended human dose, with increased incidences of skeletal variations in rats and visceral variations and malformations in rabbits. Rats: Increased loss of pregnancies.	Category D: No human data are available.	No lactation data are available.
Campath (Alemtuzumab)^84–86	Monoclonal antibody	In male transgenic mice, intravenous administration of alemtuzumab at doses of 3 and up to 10 mg/kg/day for 5 consecutive days had no effect on fertility or reproductive performance. Effects on sperm were observed, with a significant increase in abnormal (detached head/no head) sperm. The clinical significance of these effects is unknown. In female transgenic mice treated intravenously with alemtuzumab for 5 consecutive days, the numbers of corpora lutea and implantation sites were significantly reduced at 10 mg/kg/day. Other mating and fertility parameters were unaffected at these doses.	No human data are available.	Intravenous administration of alemtuzumab to pregnant mice during late organogenesis at a dose of 10 mg/kg/day for 5 consecutive days was associated with an increased number of dams with all conceptuses dead or resorbed, along with a concomitant reduction in the number of viable fetuses. There were no external, soft tissue, or skeletal malformations or variations.	Category C: No human data are available.	No lactation data are available.
Capecitabine⁸⁷	Antineoplastic	Female mice: Impairment of fertility in mice at 760 mg/kg/day, a reduction in litter size, decreased fetal weight and, fetal abnormality. No fetus survived pregnancy. The effect was reversible after a drug-free period. Male mice: Degenerative changes in the testis, including spermatocyte and spermatids.	No human data are available.	Mice: During organogenesis, caused malformations and embryo death. Monkeys: Fetal death during embryogenesis.	Category D: No human data are available.	No lactation data are available. In mice, oral dose of capecitabine excreted significant amounts of capecitabine metabolites in milk.
Carboplatin^88–91	Platinum-based antineoplastic agents	No animal data are available.	No human data are available.	Rats: Embryo toxic and teratogenic.	Category D: No human data are available.	No human data. Breast feeding contraindicated.
Carflizomib^92–97	Protease inhibitor	Rat and monkey: No effects on reproductive tissues in 28-day repeat dose or 6–9 month toxicity studies.	No human data are available.	Rabbits and rats: Not teratogenic. In rabbits, increase in pre-implantation loss and an increase in early resorption and post-implantation loss and a decrease in fetal weight.	Category D: No human data are available.	No lactation data are available.
Cisplatin⁹⁸	Platinum-based antineoplastic agents	Mice: Embryo toxic.	Males: Impairment of spermatogenesis and azoospermia have been reported.	Rabbits and rats: In rabbits increase in pre-implantation loss and an increase in early resorption and post-implantation loss and a decrease in fetal weight.	Category D: No human data are available.	No lactation data are available. Excreted in breast milk.
Cixutumumab^99–101	Monoclonal antibody	No animal data are available.	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
Crizotinib¹⁰²	Tyrosine kinase inhibitor	Male rat: Testicular pachytene spermatocyte degeneration. Female rat: Single-cell necrosis of ovarian follicles.	No human data are available.	Rat and rabbit: No teratogenic effect, but the maximum doses tested were lower than the clinical exposure dose. Reduced fetal body weights.	Category D: No human data are available.	No lactation data are available.
Cyclophosphamide^103–105	Alkylating agent	Female rats: Increased risk of failed pregnancy and malformations. Male rats: Alterations in male reproductive organs (e.g., decreased weights, atrophy, changes in spermatogenesis), and decreases in reproductive potential (e.g., decreased implantations and increased post-implantation loss) and increases in fetal malformations when mated with untreated females.	Males: May develop oligospermia or azoospermia, which are normally associated with increased gonadotropin, but normal testosterone secretion. May be irreversible in some patients. Sexual potency and libido are not impaired. Females: Amenorrhea, transient or permanent, associated with decreased estrogen and increased gonadotropin secretion develops in a proportion of women treated with cyclophosphamide. Affected patients generally resume regular menses within a few months after cessation of therapy. The risk of premature menopause with cyclophosphamide increases with age.	Multiple species: Various malformations, which included neural tube defects, limb and digit defects and other skeletal anomalies, cleft lip and palate, and reduced skeletal ossification.	Category D: Malformations of the skeleton, palate, limbs, and eyes, as well as miscarriage after exposure to cyclophosphamide in the first trimester. Fetal growth retardation and toxic effects manifesting in the newborn, including leukopenia, anemia, pancytopenia, severe bone marrow hypoplasia, and gastroenteritis.	Excreted in breast milk. Breastfeeding contraindicated. Neutropenia, thrombocytopenia, low hemoglobin, and diarrhea have been reported in infants breast fed by women treated with cyclophosphamide.
Cytosine arabinoside (Cytarabine)^106–111	Antimetabolite	Male mice: Cytarabine lead to an increase in sperm-head abnormalities and chromosomal aberrations.	No human data are available.	Mice: Teratogenic, including cleft palate, phocomelia, deformed appendages, and skeletal abnormalities. Reduced brain size and permanent impairment of learning ability were noted. Embryotoxic with decreased litter size and increased early and late resorptions.	Category D: A review of the literature has shown 32 reported cases where cytarabine was given during pregnancy, either alone or in combination with other cytotoxic agents: Eighteen normal infants were delivered. Four of these had first-trimester exposure. Five infants were premature or of low birth weight. One apparently normal infant died of gastroenteritis at 90 days.	No lactation data are available.
Dacarbazine^31,112,113	Alkylating agent	Male rats and dogs: Testicular degeneration and/or depletion. Female rats: Reduction in the number of ovarian corpora lutea.	No human data are available.	Rats: Teratogenic and embryo toxic, including ventricular septal defects and variation in thymic shape. Delays in skeletal development and reduced fetal body weight were also noted.	Category D: No human data are available.	No lactation data are available.
Dactinomycin^{112,114–119}	Antitumor antibiotic	Rat, rabbit, and hamster: Embryo toxicity.	Increased incidence of infertility in conjunction with other antineoplastic agents.	Rats, rabbit, and hamster: Malformation in all species reported.	Category D: No human data are available.	No lactation data are available.
Dasatinib^120–128	Tyrosine kinase inhibitor	Male animals: Reduced size and secretion of seminal vesicles, and immature prostate, seminal vesicle, and testis. The effects on sperm have been evaluated in an oral study and Dasatinib was not a reproductive toxicant in male rats. Female monkeys: Uterine inflammation and mineralization. Rodents: Cystic ovaries and ovarian hypertrophy.	No human data are available.	Rats and rabbits: Embryo–fetal toxicity, including skeletal malformations, edema, and microhepatia.	Category D: There have been post-marketing reports of spontaneous abortion and fetal and infant anomalies from women taking Dasatinib in pregnancy.	No lactation data are available.
Daunorubicin^129–136	Anthracycline	Male dogs: Testicular atrophy, aspermatogenesis.	Can cause chromosomal damage in human spermatozoa.	Rats and rabbits: Fetal abnormalities. Mice: Decrease in fetal birth rate and post-delivery growth rate.	Category D: No human data are available.	No lactation data are available.
Decitabine^137–142	Antimetabolite	Male mice: Reduced testes size, decrease in sperm numbers. Female mice: Reduced pregnancy rates and increased pre-implantation loss.	No human data are available.	Mice: Reduced fetal survival, decreased fetal weights. Fetal abnormalities, including cleft palate and skeletal defects.	Category D: No human data are available.	No lactation data are available.
Docetaxel^143–147	Plant alkaloid	Male rats and dogs: Decreased testicular weight and testicular atrophy, degeneration of tubular germinal epithelium, Leydig cell hyperplasia, epididymal hypospermia. Female rats: Follicular atresia.	No human data are available.	Rats and rabbits: Embryo–fetal toxicities, including intrauterine mortality, increased resorption, reduced litter sizes, reduced fetal weight, and fetal ossification delay.	Category D: No human data are available.	No lactation data are available.
Doxorubicin^56,148–151	Anthracycline	Male rats: Decreased spermatogenesis and seminal vesicle/prostate gland secretion. Testicular atrophy, diffused degeneration of the seminiferous tubules, and hypospermia.	Doxorubicin may cause amenorrhea. Although ovulation and menstruation appear to return after termination of therapy, premature menopause can occur.	Mice and rabbits: Embryo–fetal toxicity, including reduced fetal weight and delayed ossification.	Category D: No human data are available.	No lactation data are available.
Epratuzumab^152–155	Monoclonal antibody	No animal data are available.	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
Epirubicin^{56,150,156–160}	Anthracycline	Male rats: Atrophy of testis and epididymis, reduced spermatogenesis. Male rabbits and dogs: Atrophy of male reproductive organs. Female rats: Uterine atrophy.	Epirubicin may cause amenorrhea. After termination of therapy, ovulation and menstruation may be expected to return in a few months, often accompanied by normal fertility. Premature menopause may occur. Oligospermia or azoospermia may be permanent, although fertility may return several years after ceasing therapy.	Rats: Embryo toxicity (increased resorptions and post-implantation loss) and caused fetal growth retardation (decreased body weight).	Category D: Two pregnancies have been reported. A 34-year-old woman, 28 weeks pregnant at her diagnosis of breast cancer, was treated with cyclophosphamide and epirubicin. She received the last dose at 34 weeks of pregnancy and delivered a healthy baby at 35 weeks. A second 34-year-old woman with breast cancer metastatic to the liver was randomized to FEC-50, but was removed from study because of pregnancy. She experienced a spontaneous abortion.	No lactation data are available.
Etoposide^59,161–165	Topoisomerase inhibitor	Male rats: Irreversible testicular atrophy with accompanying spermatogenesis defects in the testes and epididymis and reduced seminal vesicle and prostrate secretions.	No human data are available.	Rats and mice: Increased the incidence of intrauterine death and fetal malformations (skeletal abnormalities, exencephaly, and anophthalmia), as well as significantly decreased the average fetal body weight.	Category D: No adequate and well-controlled studies in pregnant women.	No lactation data are available.
Everolimus¹⁶⁶	mTOR inhibitor	Male rats: Completely impaired fertility at the maximum human doses. Testicular atrophy was observed in mice, rats, and monkeys. Female rats: Increased incidence of pre-implantation loss.	No human data are available.	Rat: Increased pre- and post-implantation loss. Low incidence of fetal abnormalities, including fetal cleft sternum. Increases fetal resorption. Rabbits: Increased fetal resorption.	Category C: No human data are available.	No lactation data are available.
Fludarabine^167–173	Alkylating agent	Multiple species (male rat, dogs,and rabbits): Decrease in testicular weight and spermatogenic epithelium necrosis.	No human data are available.	Rats and rabbits: Embryo lethal and teratogenic. Increase in skeletal variations and decrease in mean fetal weights. Higher number of fetal resoprtions and decreased live births.	Category D: Cases of skeletal and cardiac malformation have been reported.	No lactation data are available.
Gemcitibine^174–178	Antimetabolite	Male mice: Schedule-dependent hypospermatogenesis. Female mice: No effect on females.	No human data are available.	Mice and rabbits: Embryo toxicity and teratogenic. Mice: Retarded physical development in peri- and post-natal.	Category D: No human data are available.	No lactation data are available.
Glembatumumab Vedotin¹⁷⁹	Monoclonal antibody	No animal data are available	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
Idarubicin^{150,168,180–183}	Anthracyline	Male dogs: Testicular atrophy with inhibition of spermatogenesis and sperm maturation. Reversible after 8-week recovery period.	No human data are available.	Rats: Embryo toxic and teratogenic.	Category D: No human data are available.	No lactation data are available.
Idelalisib^{168,184–186}	First inhibitor of PI3K delta	Male rats and dogs: Seminiferous tubular atrophy/degeneration and hypospermatogenesis. Female rats: no effect on fertility, but embryo lethality was observed.	No human data are available.	Rats: Embryo toxic (reduced fetal weight and incomplete ossification) and teratogenic (structural abnormalities).	Category D: No human data are available.	No lactation data are available.
Ifosfamide^187–193	Alkylating agent	Animal studies: Ifosfamide interferes with oogenesis and spermatogenesis. Amenorrhea, azoospermia, and sterility were reported.	Females: Amenorrhea. Risk of permanent chemotherapy-induced amenorrhea increases with age. Pediatric patients treated during pre-pubescence subsequently may not conceive and those who retain ovarian function after completing treatment are at increased risk of developing premature menopause. Males: Develop oligospermia or azoospermia. Pediatric patients treated during pre-pubescence might not develop secondary sexual characteristics normally, may have oligospermia or azoospermia. Azoospermia may be reversible in some patients several years after cessation of therapy. Sexual function and libido are generally unimpaired in these patients. Some degree of testicular atrophy may occur.	Multiple species (Mice, rat, and rabbits): Embryo toxic and teratogenic effects, includes increased resorption and anomalies.	Category D: Fetal growth retardation and neonatal anemia have been reported following exposure to ifosfamide containing chemotherapy regimens during pregnancy. Ifosfamide is genotoxic and mutagenic in male and female germ cells.	Ifosfamide is excreted in breast milk. Breast feeding is contraindicated.
Imatinib (Glivec)^194–204	Tyrosine kinase inhibitor	Male rats: Testicular and epididymal weights and percent motile sperm were decreased. No effect on the number of pregnant females. At 60 mg/kg, female rats had significant post-implantation fetal loss and a reduced number of live fetuses.	No human data are available.	Female rats: Significant post-implantation fetal loss and a reduced number of live fetuses.	Category D: There have been post-marketing reports of congenital anomalies and spontaneous abortions for women who have taken Imatinib.	Both Imatinib and its active metabolite can be distributed into human milk. Administration of imatinib to rats resulted in delayed preputial separation and a decrease in pup viability (days 0–4 post-partum).
Irinotecan^{162,205–214}	Plant alkaloid	Male rodents: Atrophy of male reproductive organs. No significant adverse effects on fertility and general reproductive performance were observed after intravenous administration of irinotecan hydrochloride in doses of up to 6 mg/kg/day to rats. Atrophy of male reproductive organs was observed after multiple daily irinotecan hydrochloride doses both in rodents at 20 mg/kg (AUC approximately the same value as in patients administered 125 mg/m² weekly) and dogs at 0.4 mg/kg (AUC about 1/15th the value in patients administered 125 mg/m² weekly).	No human data are available.	Female rats: Embryo toxic and teratogenic. Resulted in decreased learning ability and female fetal body weight in surviving pups. Rats and rabbits: Increased post-implantation loss and decreased numbers of live fetuses.	Category D: No human data are available.	Radioactivity appeared in rat milk within 5 minutes of IV administration of radiolabeled irinotecan. Concentrated up to 65-fold at 4 hours after administration.
MED14736²¹⁵	Immune checkpoint inhibitor—anti-PD1 antibody	No animal data are available.	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
Melphalan^{166,189,216–218}	Alkylating agent	Multiple species: Adverse effects on spermatogenesis.	Females: Melphalan has caused suppression of ovarian function resulting in amenorrhea post-treatment in >80% of women. Males: Both reversible and irreversible testicular suppression have been reported depending on dose and prolonged azoospermia.	Multiple species studies show significant risk.²¹⁹ Congenital anomalies included those of the brain (underdevelopment, deformation, meningocele, and encephalocele), eye (anophthalmia and microphthalmos), reduction of the mandible and tail, and hepatocele.	Category D: There are no adequate and well-controlled studies in pregnant women.	No lactation data are available. The molecular weight (about 305) is low enough that excretion into breast milk should be expected.
Methotrexate^{165,220–239}	Antimetabolite	No animal data are available.	No human data are available.	This drug causes teratogenic effects, embryo toxicity, abortion, and fetal defects in animals.	Category D: This drug causes teratogenic effects, embryo toxicity, abortion, and fetal defects in humans.	No lactation data are available.
Mitoxantrone^{112,240–244}	Antitumor antibiotic	No animal data are available.	Temporary reduction in sperm count, but no appreciable effect on the stem cells.	Studies in animals were associated with fetal growth retardation, increased incidence of premature delivery, and teratogenic effects.	Category D: There are no controlled data in human pregnancy; however, it is considered a potential human teratogen because of its mechanism of action and the developmental effects demonstrated by related agents.	Excreted into human milk: This drug is excreted in human milk and significant concentrations have been reported for up to 28 days after the last administration. Breast feeding is contraindicated.
MPDL328A (Atezolizumab/Tecentriq)^245–247	Immune checkpoint inhibitor- anti-PD-L1 antibody	No animal data are available.	Based on animal studies, Tecentriq may impair fertility in females of reproductive potential, while receiving treatment. No data is available for male patients.	Animal studies have demonstrated that inhibition of the PD-L1/PD1 pathway can lead to increased risk of immune-related rejection of the developing fetus resulting in fetal death.	Not classified under old FDA category. No human data are available. Based on its mechanism of action, it may cause fetal harm when administered to a pregnant woman.	No lactation data are available.
Nelarabine^{62,82,248–254}	Antimetabolite	No animal data are available.	No human data are available.	The animal reproduction data suggest that there are significant embryo–fetal risks.	Category D: No human data are available. Based on its mechanism of action, it may cause fetal harm when administered to a pregnant woman.	No lactation data are available. The molecular weight suggests that nelarabine will be excreted into breast milk.
Olaparib (Lynparza)^255–261	PARP inhibitor	There were no adverse effects on female fertility rates at doses up to 15 mg/kg/day.	No human data are available.	Teratogenic and caused embryo–fetal toxicity in rats at exposures below those in patients receiving the recommended human dose of 400 mg twice daily.	Category D: No human data are available. Based on its mechanism of action, it may cause fetal harm when administered to a pregnant woman.	No lactation data are available.
Paclitaxel²⁶²	Plant alkaloid	Male rats and dogs: Testicular atrophy/degeneration and reduced fertility. Female rats: Ovarian toxicity of paclitaxel leading to reduced pregnancy rates and increased loss of females.	No human data are available.	Rats: Animal data, embryo and fetal toxicity. Fetal abnormalities included skeletal and soft tissue malformations, such as eye bulge, folded retina, and dilation of brain ventricles.	Category D: Limited human data, but suspected to cause serious birth defects.	No lactation data are available. The molecular weight suggests that paclitaxel will be in breast milk.
Pembrolizumab (Keytruda)²⁶³	Immune checkpoint inhibitor—anti-PD1 antibody	Cynomolgus monkeys: No effects on male or female reproductive organs, but no fertility tests conducted.	No human data are available	No animal data are available. Blockade of PD1 pathways has been shown in mouse models to cause fetal harm.	Category D: In addition, an assessment of the reproduction effects suggested the drug may increase rates of abortion or stillbirth through its blockade of PD-L1 signaling.	Use is contraindicated. Excreted into human milk.
Procarbazine²⁶⁴	Alkylating agent	Animal reproductive studies have shown reduced fertility, decreased corpora lutea, and increased incidence of ovarian cysts and atrophy in females. 5FU	Reductions in sperm production rates, sperm motility, epididymal and testicular sperm concentrations, atrophy, and degeneration of the testes have been observed in males.	No animal data are available.	Category D: There are no controlled data in human pregnancy.	No lactation data are available.
Pazopanib²⁶⁵	VEGF inhibitor	No animal data are available.	No human data are available.	Animal studies revealed evidence of teratogenicity, embryo toxicity, embryo lethality, and fetus toxicity.	Category D: There are no controlled data in human pregnancy. There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans.	No lactation data are available.
Ramucirumab^{63,263,266–271}	VEGF inhibitor	No animal data are available.	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
Regorafenib^{63,83,266,267,272–278}	Tyrosine kinase inhibitor	Animal studies have shown that Regorafenib can impair male fertility (tubular atrophy and degeneration in the testes and atrophy in the seminal vesicle and oligospermia in the epididymides). Animal studies have shown that Regorafenib can impair female fertility with a necrotic corpora lutea in the ovaries.	No human data are available, but based on animal data, potential for adverse effects in male and female patients.	Animal studies also reported delayed ossification in fetuses with dose-dependent increases in skeletal malformations, cardiovascular malformations, external abnormalities, diaphragmatic hernia, and dilation of the renal pelvis.	Category D: There is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience or studies in humans.	No lactation data are available.
Rituximab^45,279–303	Monoclonal antibody	No animal data are available.	No human data are available.	No animal data are available.	Category C: The use of rituximab in human pregnancy has been described in six cases, two of which involved the first trimester. All the infants were healthy with no anomalies.	No lactation data are available. The molecular weight is very high, but human IgG is excreted into milk, and therefore, rituximab also may be excreted.
Rucaparib³⁰⁴	PARP inhibitor	No animal data are available.	No human data are available.	No animal data are available.	Category D: No human data are available.	No lactation data are available.
Sunitinib^{82,166,305–324}	Tyrosine kinase inhibitor	Male rat: Adverse effects on the male reproductive system, including testicular tubular atrophy in doses that elicited major toxicity. Fertility was unaffected in male rats with recommended human doses. Female rats: Adverse effects on the female reproductive system, including corpora lutea degeneration and uterine atrophy in doses that elicited major toxicity. Fertility was unaffected in female rats with recommended human doses. Female cynomolgus monkeys: Impaired ovarian follicular development, uterine endometrial atrophy, and vaginal epithelial atrophy	No human data are available.	Embryo lethal and teratogenic (fetal resorption, decreased fetal weight and, skeletal malformation) in treated females at 5 mg/kg/day, but not at 1.5 mg/kg/day. In rabbits, cleft lip at doses of 1 and 5 mg/kg/day.	Category D: No human data are available.	Readily excreted in rat milk, but no human data.
Temozolomide^325–336	Alkylating agent	Male rats, mice, and dogs: Decreased, immature, and abnormal spermatozoa. Female rats: Decreased ovarian weight with no recovery.	Some small studies in males and females showing that Temozolamide is gonadotoxic.	Rats and rabbits: Teratogenic and fetal toxicity demonstrated in doses equivalent to human doses.	Category D: No human data are available.	No lactation data are available.
Temsirolimus^82,337–343	mTOR inhibitor	Male rats: Decreased sperm concentration and motility, decreased reproductive organ weights, and testicular tubular degeneration. Female rats: Increased pre- and post-implantation losses, reduced live births.	Decreases testosterone levels with elevated LH. FSH was generally elevated, indicated spermatogenic dysfunction.^344,345 No data in females are available.	Rats and rabbits: Increased embryo and fetal mortality and decreased growth in the maximum recommended human dose range.	Category D: No human data are available.	No lactation data are available. The molecular weight is low enough for excretion into breast milk.
Thioguanine^346–364	Antimetabolite	No animal data are available.	Males: Temporary reduction in sperm count. No data in female patients.	Reproduction studies in rats caused resorptions and malformed or stunted offspring. Malformations observed included generalized edema, cranial defects, general skeletal hypoplasia, hydrocephalus, ventral hernia, situs inversus, and limb defects.	Category D: Congenital abnormalities have been seen in all trimesters.	No lactation data are available.
Thiotepa^{56,74,359,365–373}	Alkylating agent	No animal data are available.	Genitourinary side effects, including amenorrhea, interference with spermatogenesis, and sterility have been reported.	Mice and rats: Teratogenic in both species. Rabbits: Embryo lethality was noted in rabbits.	Category D: No human data are available.	No lactation data are available.
Topotecan^{90,91,374–379}	Topoisomerase inhibitor	Rats: Topotecan given to female rats caused superovulation. Dogs: Studies in dogs suggest that treatment may cause an increase in the incidence of multinucleated spermatogonial giant cells in the testes.	Topotecan may impair fertility in men and women.	Animal data suggest high-risk embryo–fetal toxicity, pre-implantation loss, and congenital abnormalities at doses less than the clinical doses in humans.	Category D: Limited human data show risk.	No lactation data are available.
Vinblastine^380–389	Plant alkaloid	Mice: Administration in mice destroys testicular germinal epithelium by both cytotoxic effect and induction of apoptosis.	When administered as part of combination therapy, vinblastine can produce gonadal dysfunction in females and men.	Animal studies show teratogenic effects.	Category D: Limited human data, but available data in trimester 2 and 3 suggest teratogenic risk.	No lactation data are available.
Vincristine^{346,390–395}	Plant alkaloid	No animal data are available.	Temporary reduction in sperm count, but no appreciable effect on the stem cells when given alone. In combination, azoospermia can occur. Vincristine has not been studied alone in females, but it can cause permanent amenorrhea in post-pubertal patients.	Rats, mice, and hamsters: Fetal malformations. Monkeys: Gross evident malformations. Multiple species: Teratogenic as well as resulting in embryo death that are non-toxic to the pregnant animal.	Category D: Limited human data are available.	No lactation data are available.
Vinorelbine^{31,112,375,379,396}	Plant alkaloid	Rats: Vinorelbine did not affect female fertility to a statistically significant extent when administered to rats, but dose was lower than human dose. In male rats, administration of Vinorelbine resulted in decreased spermatogenesis and prostate/seminal vesicle secretion.	No human data are available.	Rats and rabbits: Teratogenic and embryogenic with adverse fetal effects in animals at lower than human doses.	Category D: No human data are available.	No lactation data are available In rats, offspring growth was restricted.
Vismodegib^397–405	Hedgehog pathway inhibitor	Mixed animals: Fertility data from animal studies have shown that male and female fertility may be irreversibly impaired with Vismodegib treatment.	Amenorrhea has been observed in women of child-bearing potential. Potential is unknown.	Animal studies have revealed evidence of embryo toxicity and teratogenicity. Malformations such as craniofacial anomalies, open perineum, and absent and/or fused digits have been reported.	Category D: There is positive evidence of human fetal risk based on adverse reaction data from post-marketing experience. Malformations reported with the administration of hedgehog pathway inhibitors include severe midline defects, missing digits, and other irreversible malformations in the developing embryo or fetus.	Excreted into human milk. Breast feeding contraindicated.
Veliparib⁴⁰⁶	PARP inhibitor	No animal data are available	No human data are available.	No animal data are available.	Not classified under old FDA category. No human data are available.	No lactation data are available.
Vorinostat^407–410	Histone deacetylase inhibitor	Male animal studies: Treatment of rats with vorinostat had no effect on spermatogenesis or male fertility in one study and produced spermatocyte apoptosis in mice^409,411 and testicular degeneration in dogs. Female rats: Increased resorption and dead fetuses.	No human data are available.	Rats and rabbits: Vorinostat crossed the placenta. Rats: Decreased mean live fetal weights, incomplete ossifications (skull, thoracic vertebra, and sternum), and skeletal variations. Rabbits: the incidence of gall bladder malformations was increased at all doses, reduced fetal weight, and an increased incidence of incomplete ossification of metacarpals.	Category D: No human data are available.	No lactation data are available.
5-Azacitidine (VIDAZA azacitidine)^412–434	Antineoplastic	Male rodents: Gonadal toxicity in male, well below the human daily dose. Female mice: Decreased fertility and increased pre- and post-implantation loss.	No human data are available.	Mice and rats: A number of congenital abnormalities, including CNS and limb abnormalities. Fetal survival and fetal weights were decreased.	Not classified under old FDA category. No human data, but expected based on animal model.	No lactation data are available. The molecular weight (244) and the elimination half-life (about 4 hours) suggest that the drug will be excreted into breast milk.
5-Fluorouracil^{31,165,435–439}	Antimetabolite	5FU has not been adequately studied in animals. Chromosomal changes and spermatogonial differentiation were inhibited in males receiving IV doses resulting in transient infertility. 5FU did not produce any abnormalities at oral doses of up to 80 mg/kg/day. Female rabbits: In limited studies in rabbits, showed no effect. Female rats: Increased pre-implantation lethality and chromosomal anomalies.	Temporary reduction in sperm count, but no appreciable effect on the stem cells. Very low risk in females.⁴⁴⁰	Multispecies animal studies have revealed evidence of embryo lethality and congenital defects.	Category D: The use of intravenous fluorouracil in the first trimester resulted in multiple congenital defects.	No lactation data are available.
6-Mercaptopurine^{56,364,441–449}	Antimetabolite	Male mice: Long-term use does not impair sperm production and sperm morphology.	Available human data show that the risk of gonadotoxic damage is very low.⁴⁵⁰	Mice, rats, hamsters and, rabbits: Causes embryo lethality and severe teratogenic effects. In all species, the degree of embryo toxicity and type of malformations are dependent on the dose and the stage of gestation at the time of administration.	Category D: Substantial transplacental and transamniotic transmission of mercaptopurine and its metabolites from the mother to the fetus have been shown to occur. Risk in third trimester affecting growth and development.	No lactation data are available.

5FU, 5-fluorouracil; AUC, area under the curve; BRAF, proto-oncogene B-Raf; CNS, central nervous system; FEC, fluorouracil, epirubicin, cyclophosphamide; FSH, follicle-stimulating hormone; IV, intravenous; LH, luteinizing hormone; mTOR, mammalian target of rapamycin; PARP, poly ADP ribose polymerase; PD-L1, programmed death-ligand 1; PD1, programmed cell death protein 1; PI3K, phosphoinositide 3-kinase inhibitor; VEGF, vascular endothelial growth factor.

A review of the 68 protocols showed that information about the gonadotoxic risks were only documented in 22 of the 68 protocols (32%). Forty-six of the protocols (68%) did not document the gonadotoxic risk of treatment in the protocol. The only available infant protocol did not have information on the gonadotoxic risk of the treatment. Ten out of the 26 (38%) pediatric and AYA protocols, 6/27 (22%) of the adult protocols, and 6/14 (43%) of the protocols covering the combined pediatric, AYA, and adult age group had information on the gonadotoxic risk of the treatment protocol.

Nine of 68 protocols (13%) were open during 2005–2008 and of these protocols, 5/9 (56%) had gonadotoxic information available, 18/68 protocols (26%) were open during 2009–2012 with 6/18 (33%) having gonadotoxic information included, and 39/68 protocols (57%) were open during 2013–2016, with only 9/38 (23%) having any gonadotoxic information available. There were only 2/68 protocols (3%) that were opened before 2005.

Gonadotoxicity data were available in 3/11 (27%) phase 1 protocols, 1/6 (14%) phase 1/2 protocols, 6/9 (66.67%) phase 2 protocols, 2/3 (67%) phase 2/3 protocols, and 10/38 (26%) phase 3 protocols.

Only 15/68 protocols (22%) documented the teratogenic risk in the protocol and 53/68 of the protocols (78%) did not have any information available regarding the teratogenic risks of treatment. However, 60/68 (88%) protocols had information on the recommendation for contraceptive management during treatment.

Nine of 68 (13%) protocols were opened during 2005–2008 and of these protocols, 2/9 (22%) had teratogenic information available. Eighteen of 68 protocols (26%) were opened during 2009–2012, of which 4/18 (22%) had teratogenic information. Thirty-nine of 68 (57%) protocols were opened during 2013–2016 with 8/38 protocols (21%) providing teratogenic information.

Teratogenic data were available in 4/11 (36.36%) phase 1 protocols, 2/7 (29%) phase 1/2 protocols, 2/9 (22%) phase 2 protocols, 2/3 (66.67%) phase 2/3 protocols, and 5/38 (13%) phase 3 protocols.

There were only 6/68 protocols (9%) that provided recommendations for fertility preservation before cancer treatment (4 pediatric and AYA protocols, 1 adult protocol, and 1 protocol covering the pediatric to adult age range). Three of 68 protocols (4%) gave recommendations for reproductive follow-up in the survivorship period. Only 18/68 protocols (26%) had a section in the protocol that had all the oncofertility information easily identified.

Seventy-one individual chemotherapy and antineoplastic drugs were classified into 19 classes of drugs (10 alkylating agents, 8 monoclonal inhibitors, 8 antimetabolite inhibitors, 6 tyrosine kinase inhibitors, 6 plant alkaloids, 4 immune checkpoint inhibitors, 4 antitumor agents, 4 anthracyclines, 4 poly (ADP-ribose) polymerase (PARP) inhibitors, 3 antineoplastic agents, 2 mechanistic target of rapamycin (mTOR) inhibitors, 2 topoisomerase inhibitors, 2 platinum agents, 2 Vascular endothelial growth factor (VEGF) inhibitors, 2 protease inhibitors and 1, phosphoinositide 3-kinase inhibitor (PI3K inhibitor), 1 proto-oncogene B-Raf (BRAF) inhibitor, 1 histone deacetylase inhibitor, and 1 hedgehog inhibitor).

In every class of drug, there was a significant reduction in the available gonadotoxic and teratogenic information in the clinical trial protocols compared to the available information in the literature (Figs. 1 and 2).

FIG. 1.

Comparison between gonadotoxic information available in the literature and in the clinical trials protocol.

FIG. 2.

Comparison between teratogenic information available in the literature and in the clinical trials protocol.

The research team did not demonstrate any difference in the documentation of reproductive risk in protocols from protocols of different countries.

Limitations

The researchers reviewed all open protocols available during the study time period, which were available in both pediatric and adult oncology units. The research group also reviewed International clinical trial protocols in English available from clinical trials group websites. This reflects a small number of clinical trial protocols used to treat cancer patients in these age groups. However, the results of this study demonstrate a clear lack of clinical care information across both pediatric and adult centers internationally. The researchers only reviewed the initial version of the study protocols; subsequent versions of the protocol were not reviewed.

Discussion

What is currently documented?

This research study has shown a significant difference between what is known about the gonadotoxic and teratogenic risks of treatment compared to what is reported in the literature or in published PI sheets. Data in this study showed that where information is clearly known about the gonadotoxic and teratogenic risk about drugs like alkylating agents, anthracyclines, and platinum agents, the gonadotoxic and teratogenic data are still poorly reported and this has not changed significantly over the past 15 years, despite an improved focus on survivorship care and fertility preservation. The available oncofertility information was often poorly organized within protocols rather than having a section on reproductive risk and management.

To gather clear information about the reproductive concerns of individual drugs required multiple different literature reviews to develop an understanding of the gonadotoxic and teratogenic risk of individual chemotherapy agents. The available data did not consistently follow either the old or new FDA nomenclature or country-specific nomenclature for defining what the risks are during pregnancy, breast feeding, or male or female reproductive potential. The gonadotoxic risks are usually not clearly defined in terms of low, intermediate, or high risk of causing infertility with the exception of the alkylating and anthracycline data, which make recommendations for fertility preservation very difficult.

Many of the novel agents do not have any human data on reproductive risks, but they do report animal data or post-marketing data highlighting a concern. Others have a proposed risk on reproductive health based on the mechanism of action. The clinical trial protocols reviewed do not contain adequate information to sufficiently advise clinicians, patients, and parents about the concerns of these new classes of drugs, and this is even more concerning as fewer clinicians would know the risks of new classes of drugs without reviewing the literature. It is important that either the unknown risk or the potential risk due to the mechanism of action or animal data are included in all clinical trial protocols with some recommendations about oncofertility care.

As more novel and immunotherapy agents are being developed and included in clinical trial protocols, it will be very important for information on the reproductive risk to be collected so that patients and clinicians can make informed decisions about choices of treatments based on the improvements in survival and well as side-effect profiles.

Understanding the risk of the whole protocol

A significant number of patients will have multimodality treatment with surgery, radiotherapy, or bone marrow transplantation, and the combined risk may be higher than the individual risk of individual chemotherapy drugs. Thus, it is important for protocols to give a risk projection for the whole protocol, not just for a component of the treatment regimen, unless the patient's survival does not depend on all phases of treatment. In cases when a treatment protocol has different phases, depending on risk stratification, the gonadotoxic and teratogenic risk of each component should be documented.

Precision medicine

Precision medicine is changing the way in which we treat cancers. Many patients will be taking targeted treatments for longer periods of time and patients will be living with their cancers as a chronic disease rather than being cured and ceasing treatment. Cessation of treatment at a later date, to allow patients to undergo fertility preservation, may not be possible, and even if there was a window of opportunity, it may not be long enough to reduce the teratogenic effects of prior chemotherapy. The patient may have also missed the window of opportunity to have fertility preservation. Therefore, clinicians should participate in international studies to collect fertility preservation data so that the short- and long-term risks of new treatments can be documented and clearer recommendations made about fertility preservation.⁴⁵¹

Oncofertility assessment and management

The reviewed protocols show that oncofertility assessment and management are not being incorporated consistently in the toxicity assessment of cancer patients who are post-pubertal and have fertility preservation choices. Fertility preservation in pre-pubertal patients is still experimental, however, clinicians, patients, and parents need to be aware of the potential risks so that appropriate follow-up can occur or timely consideration can be provided for referral for fertility preservation under research parameters.

What do our patients want?

Consumers have indicated that they would like more data on oncofertility-related risk, better communication, access to fertility-related decision aids, and the availability of oncofertility referral pathways.⁴⁵² The late effects of cancer treatment can impact survivorship immensely, and with increasing cure rates, we must make sure that patients and parents are well informed to be able to make choices for the future. Treatment decisions can be enhanced with the inclusion of more reproductive information and with warnings about the risks of infertility incorporated into the clinical trial protocols and informed consent documents.

It is important that pharmaceutical companies are made aware of the effects that reproductive complications may have on cancer patients and routinely collect information on the reproductive risk of new drugs in all phases of clinical development.

The data reported indicate that gonadotoxic and teratogenic information are not readily available across all phases of development, and phase 3 protocols do not provide any more data compared with early phase protocols. This may arise from the lack of data collected during pre-clinical and clinical development.

Conclusion

The actual or potential reproductive concerns of cancer treatment are poorly documented in clinical trial protocols and limited information is given about oncofertility assessment and follow-up. As these protocols are used by clinicians to base toxicity assessments and follow-up care, it is important for the clinical trials development team to include up-to-date information about reproductive concerns as well as recommendations about oncofertility care. Internationally, a number of guidelines are available that include standard oncofertility assessment, management, and follow-up of pediatric and adult cancer patients, which could be referenced or included in the clinical trial protocols.^453–457 Better clinician knowledge about the reproductive risk of treatment may lead to an increase in discussion about reproductive risk and referral for oncofertility consultation and management.

It is also important for the clinical trial teams and pharmaceutical groups to collect data on the reproductive concerns of new novel agents, so that successful drugs, included in phase 2–3 studies, have animal and human data on reproductive concerns. Our study showed that reproductive knowledge about chemotherapy agents was not reported adequately in phase 3 trials. This is important as a large number of the new novel agents have limited data available in this area and are currently being used in phase 1 and 2 trials.

Recommendations

The research team proposes a number of recommendations that should be required for clinicians and pharmaceutical companies developing new trials. These recommendations will enable clearer information and recommendations for oncofertility care, which will lead to improved reproductive outcomes:

(1) The gonadotoxic and teratogenic risk of individual chemotherapy drugs and combined effect of the treatment protocol should be clearly documented in every new protocol that is developed as per the new FDA recommendations.

(2) If gonadotoxic and teratogenic information are not available for individual chemotherapy agents, then this should also be documented and guidance provided regarding the class or mechanism of action of the chemotherapy drug.

(3) Protocols should include recommendations for oncofertility management at diagnosis and follow-up within the toxicity assessment section of a protocol so that doctors can ensure that, when necessary, fertility preservation is included as part of follow-up and standard practice in the same way that audiology, echocardiograms, and glomerular filtration rate assessments are recommended based on the toxicity profile of a protocol.

(4) Clinical trial protocols focusing on new drugs should collect short- and long- term data on the reproductive effects of treatment for all phases of clinical trials. This will help define the reproductive risks of treatment and will allow doctors to make recommendations on oncofertility assessment and management in the future.

(5) Cancer clinicians should participate in the collection of oncofertility data so that the reproductive concerns of treatment can be documented consistently and data collected on the benefits of fertility preservation strategies.

Future directions

The researchers believe that the information from this study has significant relevance for both clinicians and researchers to address the gaps in oncofertility knowledge and care provided. The next phase will be to develop resources using our data for clinicians and patients so that information about the reproductive concerns can be identified quickly and recommendations made.

The researchers are also looking at the development of animal model trials for new novel agents to provide more extensive knowledge in this area.

Footnotes

Acknowledgments

The authors express their gratitude for the New York University at Sydney faculty, Ms. Sarah Naderi and staff at the University of New South Wales who made this internship possible. We also thank the FUTuRE Fertility Research team, Joanne O'Brien from the Prince of Wales Hospital Pharmacy, Dr. Dan Stark Adolescent Oncologist at St. James's Institute of Oncology, St. James's University Hospital, and Dr. Lorna Fern, NCRI Teenage and Young Adult Clinical Studies Group.

Author Disclosure Statement

No competing financial interests exist.

Appendix 1. Old FDA Pregnancy Categories: 21 CFR 201.57 (c)(8)(i)

(A) Generally acceptable. Controlled studies in pregnant women show no evidence of fetal risk.

“If adequate and well-controlled studies in pregnant women have failed to demonstrate a risk to the fetus in the first trimester of pregnancy (and there is no evidence of a risk in later trimesters).”

(B) May be acceptable. Either animal studies show no risk, but human studies not available, or animal studies showed minor risks and human studies done and showed no risk.

“If animal reproduction studies have failed to demonstrate a risk to the fetus and there are no adequate and well-controlled studies in pregnant women.”

(C) Use with caution if benefits outweigh risks. Animal studies show risk and human studies not available or neither animal nor human studies done.

“If animal reproduction studies have shown an adverse effect on the fetus, if there are no adequate and well-controlled studies in humans, and if the benefits from the use of the drug in pregnant women may be acceptable despite its potential risks.”

(D) Use in LIFE-THREATENING emergencies when no safer drug available. Positive evidence of human fetal risk.

“If there is positive evidence of human fetal risk based on adverse reaction data from investigational or marketing experience, or studies in humans, but the potential benefits from the use of the drug in pregnant women may be acceptable despite its potential risks (for example, if the drug is needed in a life-threatening situation or serious disease for which safer drugs cannot be used or are ineffective).”

(X) Do not use in pregnancy. Risks involved outweigh potential benefits. Safer alternatives exist.

“If studies in animals or humans have demonstrated fetal abnormalities or if there is positive evidence of fetal risk based on adverse reaction reports from investigational or marketing experience, or both, and the risk of the use of the drug in a pregnant woman clearly outweighs any possible benefit (for example, safer drugs or other forms of therapy are available).”

(NA) Information not available.

Appendix 2. The Pregnancy and Lactation Labeling Final Rule: 21 CFR 201.57 (c)(9)

Prescription drugs submitted for FDA approval after June 30, 2015, will use the new format immediately.

Labeling for prescription drugs approved on or after June 30, 2001, will be phased in gradually.

Medications approved before June 29, 2001, are not subject to the Pregnancy and Lactation Labeling Final Rule (PLLR) rule, however, the pregnancy letter category must be removed by June 29, 2018.

The A, B, C, D, and X risk categories are now replaced with narrative sections and subsections to include the following:

Pregnancy (includes Labor and Delivery)

Pregnancy Exposure Registry

Risk Summary

Clinical Considerations

Data

Lactation (includes Nursing Mothers)

Risk Summary

Clinical Considerations

Data

Females and Males of Reproductive Potential

Pregnancy Testing

Contraception

Infertility

References

Cancer in Australia an overview 2012. Canberra, Australia: Australian Institute of Health Welfare; 2012; vol. 56.

U.S. Cancer Statistics Working Group. United States cancer statistics: 1999–2013 incidence and mortality web-based report. Atlanta: U.S. Department of Health and Human Services, Centers for Disease Control and Prevention and National Cancer Institute; 2016. Accessed January 30, 2017 from: www.cdc.gov/uscs

Cancer Research UK. Accessed August 1, 2016 from: www.cancerresearchuk.org/health-professional/cancer-statistics#oePfLUDs4oi186hm.99

Schur

, Wild

, Amann

, et al. Sarcoma of the Ewing family in pregnancy: a case report of intrauterine fetal death after induction of chemotherapy. Case Rep Oncol. 2012; 5(3):633–8.

Meistrich

. Male gonadal toxicity. Pediatr Blood Cancer. 2009; 53(2):261–6.

Meistrich

, Wilson

, Mathur

, et al. Rapid recovery of spermatogenesis after mitoxantrone, vincristine, vinblastine, and prednisone chemotherapy for Hodgkin's disease. J Clin Oncol. 1997; 15(12):3488–95.

Maltaris

, Seufert

, Fischl

, et al. The effect of cancer treatment on female fertility and strategies for preserving fertility. Eur J Obstet Gynecol Reprod Biol. 2007; 130(2):148–55.

Prescribing medicines in pregnancy database. Accessed December 8, 2016 from: www.tga.gov.au/prescribing-medicines-pregnancy-database

Directorate-General Eceai. A guideline on summary of product characteristics (SmPC). European Commission Enterprise and Industry September, 2009;(2):1–29.

10.

Mosley

, Smith

, Dezan

. An overview of upcoming changes in pregnancy and lactation labeling information. Pharm Pract (Granada). 2015; 13(2):605.

11.

Woodruff

. Oncofertility: a grand collaboration between reproductive medicine and oncology. Reproduction. 2015; 150(3):S1–10.

12.

Kondapalli

. Oncofertility: a new medical discipline and the emerging scholar. In: Oncofertility fertility preservation for cancer survivors. Berlin: Springer; 2007; pp. 221–234.

13.

Woodruff

, Snyder

. Oncofertility: fertility preservation for cancer survivors, vol. 138. Berlin: Springer Science & Business Media; 2007.

14.

Wallace

WHB

, Anderson

, Irvine

. Fertility preservation for young patients with cancer: who is at risk and what can be offered?. Lancet Oncol. 2005; 6(4):209–18.

15.

Stern

, Conyers

, Orme

, et al. Reproductive concerns of children and adolescents with cancer: challenges and potential solutions. Clin Oncol Adolesc Young Adult. 2013; 3:63–78.

16.

Levine

, Stern

. Fertility preservation in adolescents and young adults with cancer. J Clin Oncol. 2010; 28(32):4831–41.

17.

Jeruss

, Woodruff

. Preservation of fertility in patients with cancer. N Engl J Med. 2009; 360(9):902–11.

18.

Hovatta

. Cryopreservation of testicular tissue in young cancer patients. Hum Reprod Update. 2001; 7(4):378–83.

19.

Schover

, Rybicki

, Martin

, Bringelsen

. Having children after cancer. Cancer. 1999; 86(4):697–709.

20.

Schover

, Brey

, Lichtin

, et al. Knowledge and experience regarding cancer, infertility, and sperm banking in younger male survivors. J Clin Oncol. 2002; 20(7):1880–89.

21.

Wenzel

, Dogan-Ates

, Habbal

, et al. Defining and measuring reproductive concerns of female cancer survivors. J Natl Cancer Inst Monogr., 2005(34):94–8.

22.

Smith

. Medicare and assisted reproductive technologies. [document on the internet] Australian Health Policy Institute; 2006. Assessed August 5, 2008 from: www.ahpi.health.usyd.edu.au/research/publish/ivfbrief.pdf

23.

Quinn

, Vadaparampil

, Bell-Ellison

, et al. Patient–physician communication barriers regarding fertility preservation among newly diagnosed cancer patients. Soc Sci Med. 2008; 66(3):784–9.

24.

Achille

, Rosberger

, Robitaille

, et al. Facilitators and obstacles to sperm banking in young men receiving gonadotoxic chemotherapy for cancer: the perspective of survivors and health care professionals. Hum Reprod. 2006; 21(12):3206–16.

25.

Palmer

, Mitchell

, Thompson

, Sexton

. Unmet needs among adolescent cancer patients: a pilot study. Palliat Support Care. 2007; 5(02):127–34.

26.

Robbins

, Zahoor

, Jones

. Fertility preservation in young cancer patients—too little, too late?. Support Care Cancer. 2015; 23(12):3395–7.

27.

Holson

, Stump

, Clevidence

, et al. Evaluation of the prenatal developmental toxicity of orally administered arsenic trioxide in rats. Food Chem Toxicol. 2000; 38(5):459–66.

28.

Stump

, Holson

, Fleeman

, et al. Comparative effects of single intraperitoneal or oral doses of sodium arsenate or arsenic trioxide during in utero development. Teratology. 1999; 60(5):283–91.

29.

Green

, Hall

, Zevon

. Pregnancy outcome after treatment for acute lymphoblastic leukemia during childhood or adolescence. Cancer. 1989; 64(11):2335–9.

30.

Okun

, Groncy

, Sieger

, Tanaka

. Acute leukemia in pregnancy: transient neonatal myelosuppression after combination chemotherapy in the mother. Med Pediatr Oncol. 1979; 7(4):315–19.

31.

Cardonick

, Iacobucci

. Use of chemotherapy during human pregnancy. Lancet Oncol. 2004; 5(5):283–91.

32.

Blatt

, Mulvihill

, Ziegler

, et al. Pregnancy outcome following cancer chemotherapy. Am J Med. 1980; 69(6):828–32.

33.

Jaccard

, Gachard

, Marin

, et al. Efficacy of L-asparaginase with methotrexate and dexamethasone (AspaMetDex regimen) in patients with refractory or relapsing extranodal NK/T-cell lymphoma, a phase 2 study. Blood. 2011; 117(6):1834–9.

34.

Awidi

, Tarawneh

, Shubair

, et al. Acute leukemia in pregnancy: report of five cases treated with a combination which included a low dose of adriamycin. Eur J Cancer Clin Oncol. 1983; 19(7):881–4.

35.

Leonard

, Kay

JDS

. Acute encephalopathy and hyperammonaemia complicating treatment of acute lymphoblastic leukaemia with asparaginase. Lancet. 1986; 327(8473):162–3.

36.

Bottsford-Miller

, Haeri

, Baker

, et al. B cell acute lymphocytic leukemia in pregnancy. Arch Gynecol Obstet. 2011; 284(2):303–6.

37.

Campisi

, Nicotra

, Livrea

. Action of some steroid hormones on hepatic asparaginase in the rat. Boll Soc Ital Biol Sper. 1971; 47(10):294.

38.

Berrington

, Shafiq

, Dimmick

, Embleton

. 168 serum Veg F levels in preterm infants: effects of gestation and laser or bevacizumab therapy for retinopathy of prematurity. Arch Dis Child. 2012; 97(Suppl 2):A48–8.

39.

Georgalas

, Petrou

, Koutsandrea

. Safety of intravitreal anti-VEGFs during pregnancy is unclear. BMJ. 2012; 345:e4526.

40.

Han

, Amant

. Trastuzumab, lapatinib and bevacizumab during pregnancy. Breast Cancer. 2013; 2(1):5–7.

41.

Logerot

, Allouchery

, Stuck

, Coston

. Intravitreal injection of bevacizumab during pregnancy: a case report. Fundam Clin Pharmacol. 2015; 29:57.

42.

Peracha

, Rosenfeld

. Anti–vascular endothelial growth factor therapy in pregnancy: what we know, what we don't know, and what we don't know we don't know. Philadelphia: Lippincott Williams & Wilkins. 2016.

43.

Polizzi

, Mahajan

. Intravitreal anti-VEGF injections in pregnancy: case series and review of literature. J Ocul Pharmacol Ther. 2015; 31(10):605–10.

44.

Rosen

, Rubowitz

, Ferencz

. Exposure to verteporfin and bevacizumab therapy for choroidal neovascularization secondary to punctate inner choroidopathy during pregnancy. Eye. 2009; 23(6):1479.

45.

Sarno

, Mancari

, Azim

, et al. Are monoclonal antibodies a safe treatment for cancer during pregnancy?. Immunotherapy. 2013; 5(10):1146.

46.

Steeples

, Bonshek

, Morgan

. Intralesional bevacizumab for cutaneous capillary haemangioma associated with pregnancy. Clin Exp Ophthalmol. 2013; 41(4):413–14.

47.

Tarantola

, Folk

, Boldt

, Mahajan

. Intravitreal bevacizumab during pregnancy. Retina. 2010; 30(9):1405–11.

48.

, Huang

, Sadda

. Inadvertent use of bevacizumab to treat choroidal neovascularisation during pregnancy: a case report. Ann Acad Med Singapore. 2010; 39(2):143–5.

49.

Susan Blumel

, Cheryl Martin

, Dang

. Bendamustine: a novel cytotoxic agent for hematologic malignancies. Clin J Oncol Nurs. 2008; 12(5):799.

50.

Leonard

, Lauwerys

. Carcinogenicity, teratogenicity and mutagenicity of arsenic. Mutat Res. 1980; 75(1):49–62.

51.

Mathews

, George

, Chendamarai

, et al. Single-agent arsenic trioxide in the treatment of newly diagnosed acute promyelocytic leukemia: long-term follow-up data. J Clin Oncol. 2010; 28(24):3866–71.

52.

DeSesso

. Teratogen update: inorganic arsenic. Teratology. 2001; 64(3):170–3.

53.

Ferm

. Arsenic as a teratogenic agent. Environ Health Perspect. 1977; 19:215.

54.

Zarchi

, Behtash

, Gilani

. Good pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for ovarian immature teratoma: a case report and literature review. Arch Gynecol Obstet. 2008; 277(1):75–8.

55.

Adler

. New approaches to mutagenicity studies in animals for carcinogenic and mutagenic agents. II. Clastogenic effects determined in transplacentally treated mouse embryos. Teratog Carcinog Mutagen., 1983; 3(4):321–34.

56.

Arnon

, Meirow

, Lewis-Roness

, Ornoy

. Genetic and teratogenic effects of cancer treatments on gametes and embryos. Hum Reprod Update. 2001; 7(4):394–403.

57.

Povirk

, Austin

MJF

. Genotoxicity of bleomycin. Mutat Res. 1991; 257(2):127–43.

58.

Stammberger

, Tempel

. Absence of O 6-alkylguanine-DNA alkyltransferase induction in chick embryo liver and brain following X-irradiation or treatment with bleomycin. Comp Biochem Physiol C. 1991; 100(3):573–6.

59.

Han

J-Y

, Nava-Ocampo

, Kim

T-J

, et al. Pregnancy outcome after prenatal exposure to bleomycin, etoposide and cisplatin for malignant ovarian germ cell tumors: report of 2 cases. Reprod Toxicol. 2005; 19(4):557–61.

60.

Petite

. mTOR inhibitor interactions with azole antifungals. Formulary. 2015; 3(2):1–7.

61.

Baumann

, Flagella

, Forster

, et al. New challenges and opportunities in nonclinical safety testing of biologics. Regul Toxicol Pharmacol. 2014; 69(2):226–33.

62.

Roboz

, Jabbour

, Faderl

, Douer

. Advances in the treatment of relapsed/refractory acute lymphoblastic leukemia: a case study compendium. Clin Adv Hematol Oncol. 2014; 12(12 Suppl 20):8–18.

63.

Gharwan

, Groninger

. Kinase inhibitors and monoclonal antibodies in oncology: clinical implications. Nat Rev Clin Oncol. 2016; 13(4):209–27.

64.

Schnaiter

, Stilgenbauer

. Refractory chronic lymphocytic leukemia–new therapeutic strategies. Oncotarget. 2010; 1(7):472–82.

65.

Bross

, Kane

, Farrell

, et al. Approval summary for bortezomib for injection in the treatment of multiple myeloma. Clin Cancer Res. 2004; 10(12):3954–64.

66.

Smith

, Stevens

, Quinn

, et al. Myeloma presenting during pregnancy. Hematol Oncol. 2014; 32(1):52–5.

67.

Chen

, Tu

, Cao

, et al. Bortezomib-dexamethasone or vincristine-doxorubicin-dexamethasone as induction therapy followed by thalidomide as maintenance therapy in untreated multiple myeloma patients. J Int Med Res. 2011; 39(5):1975–84.

68.

de Claro

, McGinn

, Kwitkowski

, et al. US Food and Drug Administration approval summary: brentuximab vedotin for the treatment of relapsed Hodgkin lymphoma or relapsed systemic anaplastic large-cell lymphoma. Clin Cancer Res. 2012; 18(21):5845–9.

69.

Alexander

, King

, Bajel

, et al. Australian consensus guidelines for the safe handling of monoclonal antibodies for cancer treatment by healthcare personnel. Intern Med J, 2014; 44(10):1018–26.

70.

Jacob

, Raveendran

. Marine pharmacognosy: turning the tide in drug discovery. Int J Appl Biol Pharm Technol. 2016; 7(4):107–117.

71.

Bachanova

, Connors

. Hodgkin lymphoma in the elderly, pregnant, and HIV infected. Semin Hematol. 2016; 53(3):203–8.

72.

Bishop

, Wassom

. Toxicological review of busulfan (Myleran). Mutat Res. 1986; 168(1):15–45.

73.

Abramovici

, Shaklai

, Pinkhas

. Myeloschisis in a six weeks embryo of a leukemic woman treated by busulfan. Teratology. 1978; 18(2):241–5.

74.

DiPaolo

. Teratogenic agents: mammalian test systems and chemicals. Ann N Y Acad Sci. 1969; 163(2):801–12.

75.

Williams

. Busulfan in early pregnancy. Obstet Gynecol. 1966; 27(5):738–40.

76.

Dodo

, Uchida

, Hirose

, et al. Increases in discontinuous rib cartilage and fused carpal bone in rat fetuses exposed to the teratogens, busulfan, acetazolamide, vitamin A, and ketoconazole. Hum Exp Toxicol. 2010; 29(6):439–50.

77.

Otsuji

, Takahara

, Naruse

, et al. Developmental abnormalities in rat embryos leading to tibial ray deficiencies induced by busulfan. Birth Defects Res A Clin Mol Teratol. 2005; 73(6):461–7.

78.

, Wang

. Toxicity and teratogenic effects of busulfan in early developing embryo and larva of Zebrafish (Danio rerio). Ecol Sci. 2008; 27(5):368–75.

79.

Krause

. [Teratogenic effect of busulfan on testis cells of the rat (postnatal development)]. Arzneimittelforschung. 1975; 25(4):644–5.

80.

Deshpande

, Sheth

, Sosa

, Roman

. Efficacy and tolerability of pharmacotherapy options for the treatment of medullary thyroid cancer. Clin Med Insights Oncol. 2012; 6:355.

81.

Cooper

, Yi

, Alghamdi

, et al. Vandetanib for the treatment of medullary thyroid carcinoma. Ann Pharmacother., 2013:1060028013512791.

82.

Mazer-Amirshahi

, Samiee-Zafarghandy

, Gray

, van den Anker

. Trends in pregnancy labeling and data quality for US-approved pharmaceuticals. Am J Obstet Gynecol. 2014; 211(6):690.e1–11.

83.

Gharwan

, Groninger

. Targeted cancer therapies part 1 #276. J Palliat Med. 2014; 17(2):236–40.

84.

Kyriacou

, Kottaridis

, Eliahoo

, et al. Germ cell damage and Leydig cell insufficiency in recipients of nonmyeloablative transplantation for haematological malignancies. Bone Marrow Transplant. 2003; 31(1):45–50.

85.

Colpi

, Contalbi

, Nerva

, et al. Testicular function following chemo–radiotherapy. Eur J Obstet Gynecol Reprod Biol. 2004; 113:S2–6.

86.

Havrdova

, Horakova

, Kovarova

. Alemtuzumab in the treatment of multiple sclerosis: key clinical trial results and considerations for use. Ther Adv Neurol Disord. 2015; 8(1):31–45.

87.

Levi

, Hasky

, Stemmer

, et al. Anti-mullerian hormone is a marker for chemotherapy-induced testicular toxicity. Endocrinology. 2015; 156(10):3818–27.

88.

Ghezzi

, Berretta

, Bottacin

, et al. Impact of Bep or carboplatin chemotherapy on testicular function and sperm nucleus of subjects with testicular germ cell tumor. Front Pharmacol. 2016; 7:122.

89.

Tabata

, Nishiura

, Tanida

, et al. Carboplatin chemotherapy in a pregnant patient with undifferentiated ovarian carcinoma: case report and review of the literature. Int J Gynecol Cancer. 2008; 18(1):181–4.

90.

Mendez

, Mueller

, Salom

, Gonzalez-Quintero

. Paclitaxel and carboplatin chemotherapy administered during pregnancy for advanced epithelial ovarian cancer. Obstet Gynecol. 2003; 102(5 Pt 2):1200–2.

91.

Serkies

, Węgrzynowicz

, Jassem

. Paclitaxel and cisplatin chemotherapy for ovarian cancer during pregnancy: case report and review of the literature. Arch Gynecol Obstet. 2011; 283(Suppl 1):97–100.

92.

BC Cancer Agency Cancer Drug Manual. Carfilzomib (interim monograph). 2015:1–5.

93.

Jurczyszyn

, Olszewska-Szopa

, Vesole

, et al. Multiple myeloma in pregnancy—a review of the literature and a case series. Clin Lymphoma Myeloma Leuk. 2016; 16(3):e39–45.

94.

Sedlarikova

, Kubiczkova

, Sevcikova

, Hajek

. Mechanism of immunomodulatory drugs in multiple myeloma. Leuk Res. 2012; 36(10):1218–24.

95.

, Middleton

, Sun

, et al. The myeloma drug lenalidomide promotes the cereblon-dependent destruction of Ikaros proteins. Science. 2014; 343(6168):305–9.

96.

Herndon

, Deisseroth

, Kaminskas

, et al. US Food and Drug Administration approval: carfilzomib for the treatment of multiple myeloma. Clin Cancer Res. 2013; 19(17):4559–63.

97.

Hanaizi

, Flores

, Hemmings

, et al. The European medicines agency review of pomalidomide in combination with low-dose dexamethasone for the treatment of adult patients with multiple myeloma: summary of the scientific assessment of the committee for medicinal products for human use. Oncologist. 2015; 20(3):329–34.

98.

Schrader

, Heicappell

, Muller

, et al. Impact of chemotherapy on male fertility. Onkologie. 2001; 24(4):326–30.

99.

Cohen

. Targeting the hedgehog pathway: role in cancer and clinical implications of its inhibition. Hematol Oncol Clin North Am. 2012; 26(3):565–88.

100.

Aftab

, Rudin

. Therapeutic potential of Hedgehog signaling inhibitors in cancer: rationale and clinical data. Clin Invest. 2012; 2(4):371–85.

101.

Borden

, Culjkovic

. Combinatory cancer treatment. In: Google Patents; 2011.

102.

, Connell

, Bazhenova

. Ovarian stimulation in young adult cancer survivors on targeted cancer therapies. Fertil Steril. 2016; 106(6):1475–8.

103.

Cao

, Wang

, Li

, Wang

, Yu

, Wang

. The Effects of l-Carnitine Against Cyclophosphamide-Induced Injuries in Mouse Testis. Basic Clin Pharmacol Toxicol., 120(2):152–158.

104.

Chen

, Xia

, Guan

, et al. Follicle loss and apoptosis in cyclophosphamide-treated mice: what's the matter?. Int J Mol Sci., 2016; 17(6).

105.

Huong

, Amoura

, Duhaut

, et al. Risk of ovarian failure and fertility after intravenous cyclophosphamide. A study in 84 patients. J Rheumatol., 2002; 29(12):2571–6.

106.

Ritter

, Scott

, Wilson

. Teratogenesis and inhibition of DNA synthesis induced in rat embryos by cytosine arabinoside. Teratology. 1971; 4(1):7–13.

107.

Percy

. Teratogenic effects of the pyrimidine analogues 5‐lododeoxyuridine and cytosine arabinoside in late fetal mice and rats. Teratology. 1975; 11(1):103–17.

108.

Chiang

, Wu

, Shao

, et al. Pulsed magnetic field from video display terminals enhances teratogenic effects of cytosine arabinoside in mice. Bioelectromagnetics. 1995; 16(1):70–4.

109.

Chaube

, Murphy

. Teratogenic effects of cytosine arabinoside (CA) in the rat fetus. Proc Am Assoc Cancer Res., 1965; 6(11).

110.

Scott

, Ritter

, Wilson

. Studies on induction of polydactyly in rats with cytosine arabinoside. Dev Biol. 1975; 45(1):103–11.

111.

Goto

, Endo

. Dose‐and stage‐related sex difference in the incidence of cytosine arabinoside induced digit anomalies in the mouse fetus. Teratology. 1987; 35(1):35–40.

112.

Selig

, Furr

, Huey

, et al. Cancer chemotherapeutic agents as human teratogens. Birth Defects Res A Clin Mol Teratol. 2012; 94(8):626–50.

113.

Tamaro

, Dolzani

, Monti-bragadin

, Sava

. Mutagenic activity of the dacarbazine analog p-(3, 3-dimethyl-l-triazeno) benzoic acid potassium salt in bacterial cells. Pharmacol Res Commun. 1986; 18(5):491–501.

114.

Cartes

WRE

. Teratogenic action of an antibiotic, actinomycin, in mice embryos. Odontol Chil. 1976; 24(115):29.

115.

Baranov

, Karpov

, Repin

, et al. The distribution of C-14-actinomycin in rat embryos at different developmental stages (to the problem of the mechanism of the teratogenic effect of actinomycin D). Tsitologiia. 1969; 11(8):973.

116.

Byrne

, Nicholson

, Mulvihill

. Absence of birth defects in offspring of women treated with dactinomycin. N Engl J Med. 1992; 326(2):137.

117.

Tuchmann-Duplessis

, Mercier-Parot

. Attempted prevention of the embryotoxic and teratogenic effects of actinomycin D. II. Influence of the lactogenic hormone. C R Séances Soc Biol Fil., 1970; 164(1):60–3.

118.

Juhr

, Ratsch

. [Modification of the teratogenesis of actinomycin D and cyclophosphamide by a mycoplasma pulmonis infection in rats]. Z Versuchstierkd. 1989; 33(6):265–70.

119.

Henderson

. Single versus multiple dactinomycin therapy in Wilms' tumor. A controlled cooperative study conducted by the children's cancer study group a (formerly acute leukemia cooperative chemotherapy group A): Prepared by Writing Committee: JA Wolff (Chairman), W. Krivit, WA Newton, Jr., and GJ D'Angio. New Eng. J. Med., 279:290–294 (August) 1968. J Pediatr Surg., 1969; 4(1):172–3.

120.

Bayraktar

, Morency

, Escalon

. Successful pregnancy in a patient with chronic myeloid leukaemia exposed to dasatinib during the first trimester. BMJ Case Rep., 2010; 2010:pii: bcr052010297.

121.

Berveiller

, Andreoli

, Mir

, et al. A dramatic fetal outcome following transplacental transfer of dasatinib. Anticancer Drugs. 2012; 23(7):754–7.

122.

Conchon

, Sanabani

, Serpa

, et al. Successful pregnancy and delivery in a patient with chronic myeloid leukemia while on dasatinib therapy. Adv Hematol. 2010; 2010:136252.

123.

Kroll

, Ames

, Pruett

, Fenske

. Successful management of pregnancy occurring in a patient with chronic myeloid leukemia on dasatinib. Leuk Lymphoma. 2010; 51(9):1751–3.

124.

, Lago

, Iyer

, et al. Lacteal secretion, fetal and maternal tissue distribution of dasatinib in rats. Drug Metab Dispos. 2008; 36(12):2564–70.

125.

Cortes

, Abruzzese

, Chelysheva

, et al. The impact of dasatinib on pregnancy outcomes. Am J Hematol. 2015; 90(12):1111–15.

126.

Yassin

, Soliman

, Elawa

, et al. Effects of tyrosine kinase inhibitors on spermatogenesis and pituitary gonadal axis in males with chronic myeloid leukemia. Blood. 2012; 120(21):1688.

127.

Oweini

, Otrock

, Mahfouz

, Bazarbachi

. Successful pregnancy involving a man with chronic myeloid leukemia on dasatinib. Arch Gynecol Obstet. 2011; 283(1):133–4.

128.

Gentile

, Guido

, Lucia

, et al. Favorable conception and pregnancy involving a male patient affected by chronic myeloid leukemia while taking dasatinib. Leuk Lymphoma. 2014; 55(3):709–10.

129.

Matthews

, Wood

. Male fertility during chemotherapy for acute leukemia. N Engl J Med. 1980; 303(21):1235.

130.

Green

, Kawashima

, Stovall

, et al. Fertility of female survivors of childhood cancer: a report from the childhood cancer survivor study. J Clin Oncol. 2009; 27(16):2677–85.

131.

Peccatori

, Azim

, Orecchia

, et al.; ESMO Guidelines Working Group. Cancer, pregnancy and fertility: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. Ann Oncol. 2013; 24 Suppl 6:vi160–70.

132.

Donnez

, Dolmans

. Preservation of fertility in females with haematological malignancy. Br J Haematol. 2011; 154(2):175–84.

133.

Nurmio

, Keros

, Lähteenmäki

, et al. Effect of childhood acute lymphoblastic leukemia therapy on spermatogonia populations and future fertility. J Clin Endocrinol Metab. 2009; 94(6):2119–22.

134.

van der Kaaij

MAE

, van Echten‐Arends

, Simons

AHM

, Kluin‐Nelemans

. Fertility preservation after chemotherapy for Hodgkin lymphoma. Hematol Oncol. 2010; 28(4):168–79.

135.

Yoshinaka

, Fukasawa

, Sakamoto

, et al. The fertility and pregnancy outcomes of the patients who underwent preservative operation followed by adjuvant chemotherapy for malignant ovarian tumors. Arch Gynecol Obstet. 2000; 264(3):124–7.

136.

Chasle

, How

. The effect of cytotoxic chemotherapy on female fertility. Eur J Oncol Nurs. 2003; 7(2):91–8.

137.

Saunthararajah

. Decitabine and sickle cell disease: molecular therapy for a molecular disease. Pediatr Hematol Oncol. 2007; 24(7):465–8.

138.

Saunthararajah

, Molokie

, Saraf

, et al. Clinical effectiveness of decitabine in severe sickle cell disease. Br J Haematol. 2008; 141(1):126–9.

139.

Olivieri

, Saunthararajah

, Thayalasuthan

, et al.; Thalassemia Clinical Research Network. A pilot study of subcutaneous decitabine in β-thalassemia intermedia. Blood. 2011; 118(10):2708–11.

140.

DeSimone

, Saunthararajah

. Compositions comprising decitabine and tetrahydrouridine and uses thereof. In: Google Patents; 2016.

141.

Lal

, Vichinsky

. The role of fetal hemoglobin–enhancing agents in thalassemia. Semin Hematol. 2004; 41(4 Suppl 6):17–22.

142.

Lijzmran

, Hong

, Xinhua

WJZ

. Clinical observation of decitabine treatment for patients with myelodysplastic syndrome and refractory acute myeloid leukemia. J Clin Hematol. 2013; 1:008.

143.

De Santis

, Lucchese

, De Carolis

, et al. Metastatic breast cancer in pregnancy: first case of chemotherapy with docetaxel. Eur J Cancer Care. 2000; 9(4):235–7.

144.

Kim

, Kim

, Sung

, et al. Docetaxel, gemcitabine, and cisplatin administered for non-small cell lung cancer during the first and second trimester of an unrecognized pregnancy. Lung Cancer. 2008; 59(2):270–3.

145.

Hongjian

. Study of docetaxel injection on vascular irritation and hemolysis test. Heilongjiang Med J. 2012; 1:016.

146.

Paskulin

, Zen

, Ricardo

, et al. Combined chemotherapy and teratogenicity. Birth Defects Res A Clin Mol Teratol. 2005; 73(9):634–7.

147.

Kun

, Yong

, Jinqi

, Bo

. Weekly and three-weeks' docetaxel single-treatment in advanced cancer of elderly patients. J Basic Clin Oncol. 2009; 4:028.

148.

Imahie

, Adachi

, Nakagawa

, et al. Effects of adriamycin, an anticancer drug showing testicular toxicity, on fertility in male rats. J Toxicol Sci. 1995; 20(3):183–93.

149.

Takayama

, Akaike

, Kawashima

, et al. A collaborative study in Japan on optimal treatment period and parameters for detection of male fertility disorders induced by drugs in rats. Int J Toxicol. 1995; 14(4):266–92.

150.

Kim

J-C

, Kim

K-H

, Chung

M-K

. Testicular cytotoxicity of DA-125, a new anthracycline anticancer agent, in rats. Reprod Toxicol. 1999; 13(5):391–7.

151.

Fantel

, Greenaway

, Juchau

. The embryotoxicity of adriamycin in rat embryos in vitro. Toxicol Appl Pharmacol. 1985; 80(1):155–65.

152.

Willcocks

, Jones

, Jayne

. Lupus nephropathy and vasculitis. Medicine. 2015; 43(9):538–44.

153.

Amissah-Arthur

, Gordon

. Contemporary treatment of systemic lupus erythematosus: an update for clinicians. Ther Adv Chronic Dis. 2010; 1(4):163–75.

154.

Hodby

, Fields

. Management of lymphoma in pregnancy. Obstet Med. 2009; 2(2):46–51.

155.

WiIlcocks

, Jones

, Jayne

. Lupus nephropathy and vasculitis. Medicine. 2011; 39(8):486–91.

156.

, Wang

, Han

. Neoadjuvant chemotherapy for osteosarcoma: three-year results of ifosfamide, methotrexate and epirubicin. Chin J Bone Tumor Bone Dis. 2008; 6:004.

157.

Gziri

, Pokreisz

, De Vos

, et al. Fetal rat hearts do not display acute cardiotoxicity in response to maternal doxorubicin treatment. J Pharmacol Exp Ther. 2013; 346(3):362–9.

158.

Menegola

, Broccia

, Prati

, et al. Comparative embryotoxicity of four anthracyclines: in vitro study on their effects on glutathione status. Toxicol in vitro. 1997; 11(1):33–41.

159.

Zhang

, Willett

, Fremgen

. Zebrafish: an animal model for toxicological studies. Curr Protoc Toxicol., 2003:1–7.

160.

Kelly

, Collichio

, Dees

. Concomitant pregnancy and breast cancer: options for systemic therapy. Breast Dis. 2005; 23(1):95–101.

161.

Jaeger

, Rubin

. Migration of a phthalate ester plasticizer from polyvinyl chloride blood bags into stored human blood and its localization in human tissues. N Engl J Med. 1972; 287(22):1114–18.

162.

Chung

M-K

, Kim

J-C

, Han

S-S

. Embryotoxic effects of CKD-602, a new camptothecin anticancer agent, in rats. Reprod Toxicol. 2005; 20(1):165–73.

163.

Mailhes

, Marchetti

, Phillips

, Barnhill

. Preferential pericentric lesions and aneuploidy induced in mouse oocytes by the topoisomerase II inhibitor etoposide. Teratog Carcinog Mutagen. 1994; 14(1):39–51.

164.

Nam

, Yamauchi

, Nakayama

, Doi

. Etoposide induces apoptosis and cell cycle arrest of neuroepithelial cells in a p53-related manner. Neurotoxicol Teratol. 2006; 28(6):664–72.

165.

Hyoun

, Običan

, Scialli

. Teratogen update: methotrexate. Birth Defects Res A Clin Mol Teratol. 2012; 94(4):187–207.

166.

Lorenzi

, Simonelli

, Santoro

. Infertility risk and teratogenicity of molecularly targeted anticancer therapy: a challenging issue. Crit Rev Oncol/Hematol. 2016; 107:1–13.

167.

Baumgärtner

, Oberhoffer

, Jacobs

, et al. Reversible foetal cerebral ventriculomegaly and cardiomyopathy under chemotherapy for maternal AML. Oncol Res Treat. 2009; 32(1–2):40–3.

168.

Hamad

, Kliman

, Best

, et al. Chronic lymphocytic leukaemia, monoclonal B-lymphocytosis and pregnancy: five cases, a literature review and discussion of management. Br J Haematol. 2015; 168(3):350–60.

169.

Faraci

, Matthes-Martin

, Lanino

, Morreale

, Ferretti

, Giardino

, Micalizzi

, Balduzzi

. Two pregnancies shortly after transplantation with reduced intensity conditioning in chronic myeloid leukemia. Pediatr Transplant. 2016; 20(1):158-61.

170.

Yabe

, Koike

, Shimizu

, et al. Natural pregnancy and delivery after unrelated bone marrow transplantation using fludarabine-based regimen in a Fanconi anemia patient. Int J Hematol. 2010; 91(2):350–1.

171.

Papageorgiou

, Ahmed

, Narvekar

, et al. Preservation of fertility in women undergoing reduced-intensity conditioning allogeneic transplantation with a fludarabine-based regime. Transplantation. 2012; 94(5):e29–30.

172.

Chatterjee

, Haines

, Perera

DMD

, et al. Testicular and sperm DNA damage after treatment with fludarabine for chronic lymphocytic leukaemia. Hum Reprod. 2000; 15(4):762–6.

173.

Chatterjee

, Kottaridis

, McGarrigle

, Goldstone

. Reversal of fludarabine induced testicular damage in a patient with chronic lymphocytic leukaemia (CLL), by suppression of pituitary-testicular axis using gonadotrophin releasing hormone (GnRH). Leuk Lymphoma. 2001; 41(1–2):213–15.

174.

Baker

SOA

. Gemcitabine impacts histological structure of mice testis and embryonic organs. Pak J Biol Sci. 2009; 12(8):607.

175.

Eudaly

, Tizzano

, Higdon

, Todd

. Developmental toxicity of gemcitabine, an antimetabolite oncolytic, administered during gestation to CD‐1 mice. Teratology. 1993; 48(4):365–81.

176.

Gurumurthy

, Koh

, Singh

, et al. Metastatic non-small-cell lung cancer and the use of gemcitabine during pregnancy. J Perinatol. 2009; 29(1):63–5.

177.

Kilic

, Sahin

, Karanfil

, et al. Antimetabolite cancer drug gemcitabine selectively impacts preantral and antral follicle cohorts in the ovary as evidenced by quantitatively histomorphometric, hormonal and cell viability markers. Human Reproduction. 2014; 1(29):166–169.

178.

Rai

, Mj

, Kademane

, et al. Effect of gemcitabine on female fertilty—an animal model study. J Drug Deliv Ther. 2014; 4(1):45–8.

179.

Bayir

, Bilgi

, Urkmez

. Implementation of nanoparticles in cancer therapy. In: Handbook of research on nanoscience, nanotechnology, and advanced materials. 2014; 447–491.

180.

Amneal-Agila

LLC

. Injection IH. For intravenous use only warnings. Accessed January 30, 2017 from: www.dailymed.nlm.nih.gov/dailymed/fda/fdaDrugXsl.cfm?setid=31c9691c-aa14-426d-b67f-f8d25e7200ce&type=display

181.

Pentheroudakis

, Pavlidis

. Cancer and pregnancy: poena magna, not anymore. Eur J Cancer. 2006; 42(2):126–40.

182.

Bose

, Grant

. Rational combinations of targeted agents in AML. J Clin Med. 2015; 4(4):634–64.

183.

D'Cruz

, Uckun

. Protein kinase inhibitors against malignant lymphoma. Expert Opin Pharmacother. 2013; 14(6):707–21.

184.

Hamad

, Kliman

, Best

, et al. Chronic lymphocytic leukaemia, monoclonal B-lymphocytosis and pregnancy: five cases, a literature review and discussion of management. Br J Haematol. 2015; 168(3):350–60.

185.

Miller

, Przepiorka

, de Claro

, et al. FDA approval: idelalisib monotherapy for the treatment of patients with follicular lymphoma and small lymphocytic lymphoma. Clin Cancer Res. 2015; 21(7):1525–9.

186.

Barrientos

. Idelalisib for the treatment of chronic lymphocytic leukemia/small lymphocytic lymphoma. Future Oncol. 2016; 12(18):2077–94.

187.

Zamlauskitucker

, Morris

, Springate

. Ifosfamide metabolite chloroacetaldehyde causes Fanconi syndrome in the perfused rat kidney. Toxicol Appl Pharmacol. 1994; 129(1):170–5.

188.

Slott

, Hales

. Teratogenicity and embryolethality of acrolein and structurally related compounds in rats. Teratology. 1985; 32(1):65–72.

189.

Mirkes

. Cyclophosphamide teratogenesis: a review. Teratog Carcinog Mutagen. 1985; 5(2):75–88.

190.

Hales

. Comparison of the mutagenicity and teratogenicity of cyclophosphamide and its active metabolites, 4-hydroxycyclophosphamide, phosphoramide mustard, and acrolein. Cancer Res. 1982; 42(8):3016–21.

191.

Bus

, Gibson

. Teratogenicity and neonatal toxicity of ifosfamide in mice. Exp Biol Med. 1973; 143(4):965–70.

192.

Siebert

. Comparison of the genetic activity of cyclophosphamide, ifosfamide and trofosfamide in host-mediated assays with the gene conversion system of yeast. Z Krebsforsch Klin Onkol. 1974; 81(3):261–7.

193.

Slott

, Hales

. Sodium 2-mercaptoethane sulfonate protection against cyclophosphamide-induced teratogenicity in rats. Toxicol Appl Pharmacol. 1986; 82(1):80–6.

194.

Hensley

, Ford

. Imatinib treatment: specific issues related to safety, fertility, and pregnancy. Semin Hematol. 2003; 40(2 Suppl 2):21–5.

195.

Heartin

, Walkinshaw

, Clark

. Successful outcome of pregnancy in chronic myeloid leukaemia treated with imatinib. Leuk Lymphoma. 2004; 45(6):1307–8.

196.

Cohen

, Williams

, Johnson

, et al. Approval summary for imatinib mesylate capsules in the treatment of chronic myelogenous leukemia. Clin Cancer Res. 2002; 8(5):935–42.

197.

Ali

, Özkalemkaş

, Özçelik

, et al. Pregnancy under treatment of imatinib and successful labor in a patient with chronic myelogenous leukemia (CML): outcome of discontinuation of imatinib therapy after achieving a molecular remission. Leuk Res. 2005; 29(8):971–3.

198.

Ault

, Kantarjian

, O'Brien

, et al. Pregnancy among patients with chronic myeloid leukemia treated with imatinib. J Clin Oncol. 2006; 24(7):1204–8.

199.

Pye

, Cortes

, Ault

, et al. The effects of imatinib on pregnancy outcome. Blood. 2008; 111(12):5505–8.

200.

Choudhary

, Mishra

, Kumar

, et al. Pregnancy on imatinib: fatal outcome with meningocele. Ann Oncol. 2006; 17(1):178.

201.

Prabhash

, Sastry

, Biswas

, et al. Pregnancy outcome of two patients treated with imatinib. Ann Oncol. 2005; 16(12):1983–4.

202.

Buyukbayrak

, Ergen

, Karsidag

, et al. Pregnancy complicated with chronic myelogeneous leukemia (CML) successfully treated with imatinib: a case report. Arch Gynecol Obstet. 2008; 278(2):161–3.

203.

Ali

, Özkalemkas

, Özkocaman

, et al. Successful pregnancy and delivery in a patient with chronic myelogenous leukemia (CML), and management of CML with leukapheresis during pregnancy: a case report and review of the literature. Jpn J Clin Oncol. 2004; 34(4):215–17.

204.

Zamah

, Mauro

, Druker

, et al. Will imatinib compromise reproductive capacity?. Oncologist. 2011; 16(10):1422–7.

205.

Taylor

, Amanze

, Di Federico

, Verschraegen

. Irinotecan use during pregnancy. Obstet Gynecol. 2009; 114(2, Part 2):451–2.

206.

Wang

W-M

, Li

, Zhang

. Serum level of IL-15 in mice after delayedonset diarrhea receiving irinotecan effected by jiaweibanxiaxiexin soup. Anhui Med Pharm J. 2008; 7:006.

207.

Chung

M-K

, Kim

C-Y

, Kim

J-C

. Reproductive toxicity evaluation of a new camptothecin anticancer agent, CKD-602, in pregnant/lactating female rats and their offspring. Cancer Chemother Pharmacol. 2007; 59(3):383–95.

208.

Georgalas

, Petrou

, Koutsandrea

. Safety of intravitreal anti-VEGFs during pregnancy is unclear. BMJ. 2012; 345:e4526.

209.

Kato

, Matsuhashi

, Shimomura

, et al. Examination of meningocele induced by the antitumor agent DE-310 in rat fetuses. Reprod Toxicol. 2005; 20(4):495–502.

210.

Beghin

, Delongeas

, Claude

, et al. Comparative effects of drugs on P-glycoprotein expression and activity using rat and human trophoblast models. Toxicol In Vitro. 2010; 24(2):630–7.

211.

Z-M

, Sun

Z-X

. The effect and the synergistic mechanism of irinotecan combined with norcantharidin in human gastric cancer cell line BGC-823. Prog Biochem Biophys. 2015; 2:009.

212.

Moon-Koo

, Choong-Yong

, Jong-Choon

. Reproductive toxicity evaluation of a new camptothecin anticancer agent, CKD-602, in pregnant/lactating female rats and their offspring. Cancer Chemother Pharmacol. 2007; 59(3):383.

213.

Dose B-DTMF: Prescribing Information.

214.

Kim

D-H

. Gut microbiota-mediated drug-antibiotic interactions. Drug Metab Dispos. 2015; 43(10):1581–9.

215.

Hamanishi

, Mandai

, Matsumura

, et al. PD-1/PD-L1 blockade in cancer treatment: perspectives and issues. Int J Clin Oncol. 2016; 21(3):462–73.

216.

Glantz

. Reproductive toxicology of alkylating agents. Obstet Gynecol Surv. 1994; 49(10):709–15.

217.

Vinson

, Hales

. Genotoxic stress response gene expression in the mid-organogenesis rat conceptus. Toxicol Sci. 2003; 74(1):157–64.

218.

Hottendorf

. Carcinogenicity testing of antitumor agents. Toxicol Pathol. 1985; 13(3):192–9.

219.

Nicholson

. Cytotoxic drugs in pregnancy. Review of reported cases. J Obstet Gynaecol Br Commonw., 1968; 75(3):307.

220.

Skalko

, Gold

. Teratogenicity of methotrexate in mice. Teratology. 1974; 9(2):159–63.

221.

Lloyd

, Carr

, McElhatton

, et al. The effects of methotrexate on pregnancy, fertility and lactation. QJM. 1999; 92(10):551–63.

222.

Nguyen

, Duhl

, Escallon

, Blakemore

. Multiple anomalies in a fetus exposed to low‐dose methotrexate in the first trimester. Obstet Gynecol. 2002; 99(4):599–602.

223.

Bawle

, Conard

, Weiss

. Adult and two children with fetal methotrexate syndrome. Teratology. 1998; 57(2):51–5.

224.

Chapa

, Hibbard

, Weber

, et al. Prenatal diagnosis of methotrexate embryopathy. Obstet Gynecol. 2003; 101(5, Part 2):1104–7.

225.

Jordan

, Wilson

, Schumacher

. Embryotoxicity of the folate antagonist methotrexate in rats and rabbits. Teratology. 1977; 15(1):73–9.

226.

Lewden

, Vial

, Elefant

, et al.; French Network of Regional Pharmacovigilance Centers: Low dose methotrexate in the first trimester of pregnancy: results of a French collaborative study. J Rheumatol., 2004; 31(12):2360–5.

227.

Bantle

, Fort

, Rayburn

, et al. Further validation of FETAX: evaluation of the developmental toxicity of five known mammalian teratogens and non-teratogens. Drug Chem Toxicol. 1990; 13(4):267–82.

228.

Del Campo

, Kosaki

, Bennett

, Jones

. Developmental delay in fetal aminopterin/methotrexate syndrome. Teratology. 1999; 60(1):10–2.

229.

Feldkamp

, Carey

. Clinical teratology counseling and consultation case report: low dose methotrexate exposure in the early weeks of pregnancy. Teratology. 1993; 47(6):533–9.

230.

Adam

, Manning

, Beck

, et al. Methotrexate/misoprostol embryopathy: report of four cases resulting from failed medical abortion. Am J Med Genet A. 2003; 123(1):72–8.

231.

Desesso

. Comparative ultrastructural alterations in rabbit limb‐buds after a teratogenic dose of either hydroxyurea or methotrexate. Teratology. 1981; 23(2):197–215.

232.

Poggi

, Ghidini

. Importance of timing of gestational exposure to methotrexate for its teratogenic effects when used in setting of misdiagnosis of ectopic pregnancy. Fertil Steril. 2011; 96(3):669–71.

233.

Donnenfeld

, Pastuszak

, Noah

, et al. Methotrexate exposure prior to and during pregnancy. Teratology. 1994; 49(2):79–81.

234.

Perry

. Methotrexate and teratogenesis. Arch Dermatol. 1983; 119(11):874.

235.

Sutton

, McIvor

, Vagt

, et al. Methotrexate-resistant form of dihydrofolate reductase protects transgenic murine embryos from teratogenic effects of methotrexate. Pediatr Dev Pathol. 1998; 1(6):503–12.

236.

Cicurel

, Schmid

. Post-implantation embryo culture: validation with selected compounds for teratogenicity testing. Xenobiotica. 1988; 18(6):617–24.

237.

Warkany

. Aminopterin and methotrexate: folic acid deficiency. Teratology. 1978; 17(3):353–7.

238.

Nurmohamed

, Moretti

, Schechter

, et al. Outcome following high-dose methotrexate in pregnancies misdiagnosed as ectopic. Am J Obstet Gynecol. 2011; 205(6):533.e1–3.

239.

Leeman

, Wendland

. Cervical ectopic pregnancy: diagnosis with endovaginal ultrasound examination and successful treatment with methotrexate. Arch Fam Med. 2000; 9(1):72.

240.

De Santis

, Straface

, Cavaliere

, et al. The first case of mitoxantrone exposure in early pregnancy. Neurotoxicology. 2007; 28(3):696–7.

241.

Frau

, Coghe

, Lorefice

, et al. Mitoxantrone exposure in pregnancy: a new case report in a multiple sclerosis patient. Case Rep Perinat Med. 2016; 5(2):125–6.

242.

Schwarz

, Maselli

, Norton

, Gonzales

. Prescription of teratogenic medications in United States ambulatory practices. Am J Med. 2005; 118(11):1240–9.

243.

Frau

, Coghe

, Lorefice

, et al. Mitoxantrone exposure in pregnancy: a new case report in a multiple sclerosis patient. Case Reports in Perinatal Medicine. 2016; 5(2):125–6.

244.

Baird

, Dalton

. Multiple sclerosis in pregnancy. J Perinat Neonatal Nurs. 2013; 27(3):232–41.

245.

Raedler

. Tecentriq (atezolizumab) first PD-L1 inhibitor approved for patients with advanced or metastatic urothelial carcinoma.

246.

Inman

, Longo

, Ramalingam

, Harrison

. Atezolizumab: a PD-L1 blocking antibody for bladder cancer. Clin Cancer Res., 2016:clincanres. 1417.2016.

247.

McGahan

. HASH (0xd2919e0). 2016.

248.

Fromer

. ODAC recommends lenalidomide (Revlimid) for small subset of patients with MDS. Oncol Times. 2005; 27(19):10–11.

249.

Wilmott

. International symposium on oncology pharmacy practice. J Pharm Pract Res. 2007; 37(1):47.

250.

Kümmerer

, Haiß

, Schuster

, et al. Antineoplastic compounds in the environment—substances of special concern. Environ Sci Pollut Res., 2014:1–14.

251.

Gupta

, Sung

, Prasad

, et al. Cancer drug discovery by repurposing: teaching new tricks to old dogs. Trends Pharmacol Sci. 2013; 34(9):508–17.

252.

Harned

, Gaynon

. Treating refractory leukemias in childhood, role of clofarabine. Ther Clin Risk Manage. 2008; 4(2):327.

253.

Zwaan

, Kearns

, Caron

, et al. The role of the ‘innovative therapies for children with cancer’(ITCC) European consortium. Cancer Treat Rev. 2010; 36(4):328–34.

254.

McCune

, Cpon

. Biotherapy update. America, 40:77–94.

255.

Kim

, Ison

, McKee

, et al. FDA approval summary: olaparib monotherapy in patients with deleterious germline BRCA-mutated advanced ovarian cancer treated with three or more lines of chemotherapy. Clin Cancer Res. 2015; 21(19):4257–61.

256.

Wilczyński

, Makuła

. Alternative treatment of chemoresistant, recurrent or advanced ovarian cancer. Part II.

257.

Furusawa

. An isocratic toxic chemical-free mobile phase HPLC-PDA analysis of malachite green and leuco-malachite green. Chromatography. 2014; 1(2):75–81.

258.

Bonanni

, Lazzeroni

. Acceptability of chemoprevention trials in high-risk subjects. Ann Oncol. 2013; 24(suppl 8):viii42–6.

259.

Gore

, DeGregori

, Porter

. Targeting developmental pathways in children with cancer: what price success?. Lancet Oncol. 2013; 14(2):e70–8.

260.

Cavero

. 2012 Annual Meeting of the Safety Pharmacology Society: spotlight on targeted oncology medicines. Expert Opin Drug Saf. 2013; 12(4):589–603.

261.

Maugeri-Saccà

, Zeuner

, De Maria

. Therapeutic targeting of cancer stem cells. Front Oncol. 2011; 1:10.

262.

Lanowska

, Mangler

, Speiser

, et al. Radical vaginal trachelectomy after laparoscopic staging and neoadjuvant chemotherapy in women with early-stage cervical cancer over 2 cm: oncologic, fertility, and neonatal outcome in a series of 20 patients. Int J Gynecol Cancer. 2014; 24(3):586–93.

263.

Lansita

, Mounho-Zamora

. The development of therapeutic monoclonal antibodies: overview of the nonclinical safety assessment. Curr Pain Headache Rep. 2015; 19(2):1–9.

264.

Perry

(ed). The chemotherapy source book, 4th ed. Philadelphia: Lippincott Williams & Wilkins; 2008.

265.

Yildiz

, Kacan

, Akkar

, et al. Effects of pazopanib, sunitinib, and sorafenib, anti-VEGF agents, on the growth of experimental endometriosis in rats. Reprod Sci. 2015; 22(11):1445–51.

266.

Rogers

, Dasari

, Eng

. The treatment of colorectal cancer during pregnancy: cytotoxic chemotherapy and targeted therapy challenges. Oncologist. 2016; 21(5):563–70.

267.

Sultan

, Kaleem

, Radhi

. Treatment of metastatic colorectal cancer in a pregnant woman with lynch syndrome-a case report. J Integr Oncol. 2016; 5:175.

268.

Amini

, Masoumi Moghaddam

, Morris

, Pourgholami

. Utility of vascular endothelial growth factor inhibitors in the treatment of ovarian cancer: from concept to application. J Oncol. 2012; 2012:540791.

269.

Fushida

, Kinoshita

, Kaji

, et al. Paclitaxel plus valproic acid versus paclitaxel alone as second-or third-line therapy for advanced gastric cancer: a randomized Phase II trial. Drug Des Devel Ther. 2016; 10:2353.

270.

Muyaba

, Liu

, Si

, et al. Recent advances in vascular targeting agents as anticancer drugs. World J Pharm Res. 2015; 4(4):241–271.

271.

Stratigos

, Matikas

, Voutsina

, et al. Targeting angiogenesis in small cell lung cancer. Transl Lung Cancer Res. 2016; 5(4):389.

272.

Ettrich

, Seufferlein

. Regorafenib. Recent Results Cancer Res, 2014; 201:185–196.

273.

Pal

, De

, Baral

, Kumar

. Regorafenib (stivarga): a new option in the treatment of patients with metastatic colorectal cancer (CRC). Int J Pharm Pharm Sci. 2013; 5:3.

274.

Rey

J-B

, Launay-Vacher

, Tournigand

. Regorafenib as a single-agent in the treatment of patients with gastrointestinal tumors: an overview for pharmacists. Target Oncol. 2015; 10(2):199–213.

275.

Muthukumarasamy

, Handore

, Kakade

, et al. Identification of noreremophilane-based inhibitors of angiogenesis using zebrafish assays. Org Biomol Chem. 2016; 14(5):1569–78.

276.

Entschladen

, Thyssen

, Drell

. Re-use of established drugs for anti-metastatic indications. Cells. 2016; 5(1):2.

277.

Zarkavelis

, Petrakis

, Fotopoulos

, et al. Bone and soft tissue sarcomas during pregnancy: a narrative review of the literature. J Adv Res. 2016; 7(4):581–7.

278.

Perkins

, Cole

. Ziv-aflibercept (Zaltrap) for the treatment of metastatic colorectal cancer. Ann Pharmacother. 2014; 48(1):93–8.

279.

Chakravarty

, Murray

, Kelman

, Farmer

. Pregnancy outcomes after maternal exposure to rituximab. Blood. 2011; 117(5):1499–506.

280.

Rey

, Coso

, Roger

, et al. Rituximab combined with chemotherapy for lymphoma during pregnancy. Leuk Res. 2009; 33(3):e8–9.

281.

Kimby

, Sverrisdottir

, Elinder

. Safety of rituximab therapy during the first trimester of pregnancy: a case history. Eur J Haematol. 2004; 72(4):292–5.

282.

Daver

, Nazha

, Kantarjian

, et al. Treatment of hairy cell leukemia during pregnancy: are purine analogues and rituximab viable therapeutic options. Clin Lymphoma Myeloma Leuk. 2013; 13(1):86.

283.

Ojeda-Uribe

, Gilliot

, Jung

, et al. Administration of rituximab during the first trimester of pregnancy without consequences for the newborn. J Perinatol. 2006; 26(4):252–5.

284.

Ton

, Tekstra

, Hellmann

, et al. Safety of rituximab therapy during twins' pregnancy. Rheumatology. 2011; 50(4):806–8.

285.

Maria

, Schioppo

, Meroni

. Challenges and treatment options for rheumatoid arthritis during pregnancy. Expert Opin Pharmacother. 2016; 17(11):1539–47.

286.

Vaidyanathan

, McKeever

, Anand

, et al. Developmental immunotoxicology assessment of rituximab in cynomolgus monkeys. Toxicol Sci. 2011; 119(1):116–25.

287.

Ojeda-Uribe

, Afif

, Dahan

, et al. Exposure to abatacept or rituximab in the first trimester of pregnancy in three women with autoimmune diseases. Clin Rheumatol. 2013; 32(5):695–700.

288.

Girotra

, Baki

, Grover

. Rituximab for refractory myasthenia gravis in a pregnant patient (P2. 165). Neurology., 2016; 86(16 Supplement):P2–165.

289.

Cree

. Update on reproductive safety of current and emerging disease-modifying therapies for multiple sclerosis. Mult Scler J. 2013; 19(7):835–43.

290.

Brenner

, Avivi

. Lymphoma and leukemia during pregnancy. Womens Health. 2013; 9(2):127–9.

291.

Ostensen

, Lockshin

, Doria

, et al. Update on safety during pregnancy of biological agents and some immunosuppressive anti-rheumatic drugs. Rheumatology (Oxford). 2008; 47(Suppl 3):iii28–31.

292.

Cheung

, Hamm

, Suga

, Adie

. 25 year old female conceiving 6 months after last dose of rituximab: a case report. Blood. 2010; 116(21):4924.

293.

Florea

, Job-Deslandre

. [Rheumatoid arthritis and pregnancy]. Presse Med. 2008; 37(11):1644–51.

294.

Watson

, Beresford

, Maynes

, et al. The indications, efficacy and adverse events of rituximab in a large cohort of patients with juvenile-onset SLE. Lupus. 2015; 24(1):10–7.

295.

Lee

, Ahn

, Hong

, et al. Rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) chemotherapy for diffuse large B-cell lymphoma in pregnancy may be associated with preterm birth. Obstet Gynaecol Sci. 2014; 57(6):526–9.

296.

Østensen

, Förger

. How safe are anti-rheumatic drugs during pregnancy?. Curr Opin Pharmacol. 2013; 13(3):470–5.

297.

Østensen

, Förger

. Treatment with biologics of pregnant patients with rheumatic diseases. Curr Opin Rheumatol. 2011; 23(3):293–8.

298.

Partlett

, Roussou

. The treatment of rheumatoid arthritis during pregnancy. Rheumatol Int. 2011; 31(4):445–9.

299.

Østensen

. Safety issues of biologics in pregnant patients with rheumatic diseases. Ann N Y Acad Sci. 2014; 1317(1):32–8.

300.

Magloire

, Pettker

, Buhimschi

, Funai

. Burkitt's lymphoma of the ovary in pregnancy. Obstet Gynecol. 2006; 108(3, Part 2):743–5.

301.

Levy

. Use of anti-rheumatic drugs in pregnancy. Handbook of Systemic Autoimmune Diseases. 2005; 31(4):101–10.

302.

Abadi

, Koren

, Lishner

. Leukemia and lymphoma in pregnancy. Hematol Oncol Clin North Am. 2011; 25(2):277–91.

303.

Indolent

NHL

. Diagnosis and staging. In: Cancer in pregnancy and lactation: the motherisk guide. 2011; p. 49.

304.

Ray

. Archive for the ‘pharmaceutical industry competitive intelligence'category.

305.

Beedie

, Mahony

, Walker

, et al. Shared mechanism of teratogenicity of anti-angiogenic drugs identified in the chicken embryo model. Sci Rep. 2016; 6:30038.

306.

Patyna

, Haznedar

, Morris

, et al. Evaluation of the safety and pharmacokinetics of the multi‐targeted receptor tyrosine kinase inhibitor sunitinib during embryo–fetal development in rats and rabbits. Birth Defects Res B Dev Reprod Toxicol. 2009; 86(3):204–13.

307.

Fallon

, Nehra

, Carlson

, et al. Evaluation of anastomotic strength and drug safety after short-term sunitinib administration in rabbits. J Surg Res. 2014; 187(1):101–6.

308.

Everaus

. Sterility, infertility, and teratogenicity. In: The MASCC textbook of cancer supportive care and survivorship. Springer; 2010; pp. 133–44.

309.

Lambertini

, Peccatori

, Azim

. Targeted agents for cancer treatment during pregnancy. Cancer Treat Rev. 2015; 41(4):301–9.

310.

Mitrou

, Zarkavelis

, Fotopoulos

, et al. Pregnant mothers with cancer: a paradoxical coexistence (Mini Review). J Adv Res. 2016; 7(4): 559–63.

311.

Pentheroudakis

, Pavlidis

, Castiglione

, Group

EGW

. Cancer, fertility and pregnancy: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009; 20(suppl 4):iv178–81.

312.

Kolaja

. Stem cells and stem cell-derived tissues and their use in safety assessment. J Biol Chem. 2014; 289(8):4555–61.

313.

Harshman

, Li

, Srinivas

. The combination of thalidomide and capecitabine in metastatic renal cell carcinoma-is not the answer. Am J Clin Oncol. 2008; 31(5):417–23.

314.

Rashid

, Hasan

. Cardiotoxicity of non cardiovascular drugs: a mechanistic point of view. BIRDEM Med J. 2013; 3(1):35–43.

315.

Sicklick

. Reassessing risk and prognostic factors in GIST: updated histology codes redefine epidemiology of the disease. Looking Beyond the ‘Media Hype'on Immunotherapy and Assessing Implications for GIST. GIST Cancer J., 2014; 1(4):102–103.

316.

Hoellen

, Reibke

, Hornemann

, et al. Cancer in pregnancy. Part I: basic diagnostic and therapeutic principles and treatment of gynecological malignancies. Arch Gynecol Obstet., 2012; 285(1):195–205.

317.

Mitrou

, Zarkavelis

, Fotopoulos

, et al. A mini review on pregnant mothers with cancer: a paradoxical coexistence. J Adv Res. 2016; 7(4):559–63.

318.

Wachter

. Stopping trials early: do results get clouded?. Int Med News. 2010; 43(6):54.

319.

Malton

. How to counsel cancer patients about their oral chemotherapy.

320.

Carrington

. Safe use of oral cytotoxic medicines. Aust Prescr. 2013; 36:9–12.

321.

Ruedi

, Murphy

. Principles of fracture management. Thieme Stuttgart; 2000.

322.

Brown

, de Souza

, Cohen

. Thyroid cancer: burden of illness and management of disease. J Cancer. 2011; 2:193–9.

323.

Carrington

. Oral targeted therapy for cancer. Aust Prescr. 2015; 38(5):171.

324.

Cheng

, Kari

, Dicker

, et al. A novel preclinical strategy for identifying cardiotoxic kinase inhibitors and mechanisms of cardiotoxicity. Circ Res. 2011; 109(12):1401–9.

325.

Nolan

, Balakrishna

, George

. Exposure to temozolmide in the first trimester of pregnancy in a young woman with glioblastoma multiforme. World J Oncol. 2013; 3(6):286–7.

326.

Blagosklonny

. Teratogens as anticancer drugs. Cell Cycle. 2005; 4(11):1518–21.

327.

Son

, Kim

J-S

, Kim

, et al. Combination treatment with temozolomide and thalidomide inhibits tumor growth and angiogenesis in an orthotopic glioma model. Int J Oncol. 2006; 28(1):53–60.

328.

Watanabe

, Kuwabara

, Suehiro

, et al. Valproic acid reduces hair loss and improves survival in patients receiving temozolomide-based radiation therapy for high-grade glioma. Eur J Clin Pharmacol. 2016; 26:1–7.

329.

Ambados

, Crea

, Chin

, Lee

. Preparation method and stability of a temozolomide suspension: a pilot study. J Pharm Pract Res. 2012; 42(2):111–14.

330.

Evans

, Nelson

, Dhall

. Pregnancy in a patient with a malignant brain tumor taking temozolomide: case report and review of the literature. J Pediatr Oncol Nurs. 2015; 32(5):326–8.

331.

Wang

, Sun

, Wang

. Fluoxetine synergizes with temozolomide to induce the CHOP-dependent endoplasmic reticulum stress-related apoptosis pathway in glioma cells. Oncol Rep. 2016; 36(2):676–84.

332.

Blumenthal

, Parreño

MGH

, Batten

, Chamberlain

. Management of malignant gliomas during pregnancy. Cancer. 2008; 113(12):3349–54.

333.

Lin

, Sum

, DeAngelis

. Is there a role for early chemotherapy in the management of pituitary adenomas?. Neuro Oncol. 2016; 18:1350–6.

334.

Sengupta

, Gerstner

. Brain tumors and pregnancy. In: Neurological illness in pregnancy: principles and practice. 2015; p. 191.

335.

Eisen

. Thalidomide in solid malignancies. J Clin Oncol. 2002; 20(11):2607–9.

336.

Teo

, Stirling

, Zeldis

. Thalidomide as a novel therapeutic agent: new uses for an old product. Drug Discov Today. 2005; 10(2):107–14.

337.

Lee

, Kuhn

, Lamborn

, et al. Phase I/II study of sorafenib in combination with temsirolimus for recurrent glioblastoma or gliosarcoma: North American Brain Tumor Consortium study 05–02. Neuro Oncol. 2012; 14(12):1511–18.

338.

Sherbet

. Therapeutic potential of thalidomide and its analogues in the treatment of cancer. Anticancer Res. 2015; 35(11):5767–72.

339.

Briggs

. Estimating pregnancy risk in the absence of human data. Ob Gyn News. 2008; 43(16):12.

340.

Johnson

, Dreyling

, Colomer

, et al. Molecular targets in malignant lymphomas: from basic science to clinical practice. Ann Oncol. 2012; 23(suppl 9):ix44–5.

341.

Amato

. Current immunotherapeutic strategies in renal cell carcinoma. Surg Oncol Clin N Am. 2007; 16(4):975–86.

342.

Lynch

, Lee

M-J

, Del Priore

. Chemotherapy in pregnancy. In: Clinical pharmacology during pregnancy. 2012; p. 201.

343.

Cherrier-De Wilde

. Lymphoma. In: Side effects of medical cancer therapy. Springer; 2013; pp. 447–57.

344.

Huyghe

, Zairi

, Nohra

, et al. Gonadal impact of target of rapamycin inhibitors (sirolimus and everolimus) in male patients: an overview. Transpl Int. 2007; 20(4):305–11.

345.

Beverhi

, Flamant

, Martinez

, et al. Rapamycin induced oliospermia. Transplantation. 2003;(76):885–6.

346.

Schafer

. Teratogenic effects of antileukemic chemotherapy. Arch Intern Med. 1981; 141(4):514–15.

347.

Artlich

, Möller

, Kruse

, et al. Teratogenic effects in a case of maternal treatment for acute myelocytic leukaemia—neonatal and infantile course. Eur J Pediatr. 1994; 153(7):488–91.

348.

De Boer

NKH

, Van Elburg

, Wilhelm

, et al. 6-Thioguanine for Crohn's disease during pregnancy: thiopurine metabolite measurements in both mother and child. Scand J Gastroenterol. 2005; 40(11):1374–7.

349.

Bragonier

, Roesky

, Carver

. Teratogenesis effects of substituted purines and the influence of 4-hydroxypyrazolopyrimidine in the rat. Exp Biol Med. 1964; 116(3):685–8.

350.

Welsch

, Stedman

. Inhibition of metabolic cooperation between Chinese hamster V79 cells by structurally diverse teratogens. Teratog Carcinog Mutagen. 1984; 4(3):285–301.

351.

Tompa

, Sapi

. Detection of 6-thioguanine resistance in human peripheral blood lymphocytes (PBL) of industrial workers and lung cancer patients. Mutat Res. 1989; 210(2):345–51.

352.

Platzek

, Schwabe

. Combined prenatal toxicity of 6‐mercaptopurine riboside and hydroxyurea in mice. Teratog Carcinog Mutagen. 1999; 19(3):223–32.

353.

Seinen

, Van Asseldonk

, Mulder

, De Boer

. Dosing 6-thioguanine in inflammatory bowel disease: expert-based guidelines for daily practice. J Gastrointestin Liver Dis. 2010; 19(3):291–4.

354.

Hirsch

, Hurley

. Relationship of dietary zinc to 6‐mercaptopurine teratogenesis and DNA metabolism in the rat. Teratology. 1978; 17(3):303–13.

355.

Ochi

, Ohsawa

. Induction of 6-thioguanine-resistant mutants and single-strand scission of DNA by cadmium chloride in cultured Chinese hamster cells. Mutat Res. 1983; 111(1):69–78.

356.

De Boer

NKH

, Reinisch

, Teml

, et al. 6-Thioguanine treatment in inflammatory bowel disease: a critical appraisal by a European 6-TG working party. Digestion. 2006; 73(1):25–31.

357.

Tsuchiya

, Matuoka

, Sekita

, et al. Human embryonic cell growth assay for teratogens with or without metabolic activation system using microplate. Teratog Carcinog Mutagen. 1988; 8(5):265–72.

358.

Fischer

, Clyne

. Circulating factor XI antibody and disseminated intravascular coagulation. Arch Intern Med. 1981; 141(4):515–17.

359.

Connors

. Cytotoxic agents in teratogenic research. In: Teratology. Springer; 1975:49–79.

360.

Loch-Caruso

, Trosko

, Corcos

. Interruption of cell-cell communication in Chinese hamster V79 cells by various alkyl glycol ethers: implications for teratogenicity. Environ Health Perspect. 1984; 57:119.

361.

Woollam

DHM

. Principles of teratogenesis: mode of action of thalidomide. Proc R Soc Med. 1965; 58(7):497.

362.

Lowenthal

, Marsden

, Newman

, et al. Normal infant after treatment of acute myeloid leukaemia in pregnancy with daunorubicin. Aust N Z J Med. 1978; 8(s3):431–2.

363.

Artlich

. Cytarabine/thioguanine. Reactions. 1994; 527:12.

364.

De Boer

NKH

, Jarbandhan

SVA

, De Graaf

, et al. Azathioprine use during pregnancy: unexpected intrauterine exposure to metabolites. Am J Gastroenterol. 2006; 101(6):1390–2.

365.

Elberg

, Brok

. [Teratogen effect of Thiotepa]. Ugeskr Laeger. 1988; 150(43):2602.

366.

Krarup-Hansen

. Teratogenic effect of thiotepa. Ugeskr Laeger. 1989; 151(6):397.

367.

Brok

, Elberg

. [Teratogenic effect of thiotepa despite observation of safety regulations]. Ugeskr Laeger. 1988; 150(31):1898–9.

368.

Korogodina

, Kaurov

. Teratogenic action of thiophosphamide on mice of different genotypes. Bull Exp Biol Med. 1984; 97(3):318–20.

369.

Krarup-Hansen

. Teratogenic effect of thio-tepa despite use of safety rules. Ugeskr Laeger. 1988; 150(40):2416.

370.

Muggia

, Ziegler

. Comments on the carcinogenic, mutagenic, and teratogenic properties of anticancer drugs. In: Cancer chemo-and immunopharmacology. Springer; 1980; pp. 306–11.

371.

Heinemann

. Prophage induction in lysogenic bacteria as a method of detecting potential mutagenic, carcinogenic, carcinostatic, and teratogenic agents. In: Chemical mutagens. Springer; 1971; pp. 235–66.

372.

Murphy

. A comparison of the teratogenic effects of five polyfunctional alkylating agents on the rat fetus. Pediatrics. 1959; 23(1):231–44.

373.

Nishikawa

. [Teratogenic effect of a combination of fasting and thio-tepa administration in pregnant mice]. Kaibogaku Zasshi. 1964; 39:252–7.

374.

Weihong

, Daidi

, Yihong

. Embryotoxicity and teratogenicity study of topotecan in rats. China Pharmaceuticals. 2004; 6:025.

375.

Leslie

, Koil

, Rayburn

. Chemotherapeutic drugs in pregnancy. Obstet Gynecol Clin North Am. 2005; 32(4):627–40.

376.

Downs

, Judson

, Argenta

, et al. A prospective randomized trial of thalidomide with topotecan compared with topotecan alone in women with recurrent epithelial ovarian carcinoma. Cancer. 2008; 112(2):331–9.

377.

Jiang

, Wei

, Ping

, et al. Study of xueerbao complement protein chewing tablet on the embryo teratogenicity of the SD rats. J Shanghai Jiaotong Univ (Agric Sci). 2003; 2:008.

378.

Kasperaviciute

, Sisodiya

. Epilepsy pharmacogenetics. Pharmacogenomics. 2009; 10(5):817–36.

379.

Loibl

. Adjuvant therapy in patients with breast cancer during pregnancy. In: Adjuvant therapy for breast cancer. Springer; 2009; pp. 317–28.

380.

Lacher

, Geller

. Cyclophosphamide and vinblastine sulfate in Hodgkin's disease during pregnancy. JAMA. 1966; 195(6):486–8.

381.

Nordlund

, Devita

, Cabbone

. Severe vinblastine-induced leukopenia during late pregnancy with delivery of a normal infant. Ann Intern Med. 1968; 69(3):581–2.

382.

Joneja

, LeLiever

. Effects of vinblastine and podophyllin on DBA mouse fetuses. Toxicol Appl Pharmacol. 1974; 27(2):408–14.

383.

Joneja

, LeLiever

. In vivo effects of vinblastine and podophyllin on dividing cells of DBA mouse fetuses. Can J Genet Cytol. 1973; 15(3):491–5.

384.

Wyrobek

, Bruce

. Chemical induction of sperm abnormalities in mice. Proc Natl Acad Sci U S A. 1975; 72(11):4425–9.

385.

Naruse

, Shoji

. Whole embryo culture as a primary screening system for teratogens. Proc Jpn Acad Ser B Phys Biol Sci. 1986; 62(1):31–4.

386.

Naruse

, Kano

, Shoji

. Experimental induction of two inner cell masses in mouse embryos by vinblastine treatment in vitro. Teratology. 1983; 28(2):215–18.

387.

Kirshon

, Wasserstrum

, Willis

, et al. Teratogenic effects of first-trimester cyclophosphamide therapy. Obstet Gynecol. 1988; 72(3):462–3.

388.

Chun

, Johnson

, Gabel

BEG

. Relationship of developmental stage to effects of vinblastine on the artificial “embryo” of hydra. Teratology. 1983; 27(1):95–100.

389.

Carboxylesterases

. Hyperplasia and neoplasia, detectionyof, 27,680 sulfhydryl resin effect on (rat), 27,621 Bromobenzene, toxicity of dibenamine effect on (rat), 27,380. measurement (mouse), 27:537.

390.

Joneja

, Ungthavorn

. Teratogenic effects of vincristine in three lines of mice. Teratology. 1969; 2(3):235–40.

391.

Ungthavorn

, Joneja

. Effects of teratogenic doses of vincristine on mitotic cells in the fetuses of DBA mice. Am J Anat. 1969; 126(3):291–7.

392.

Cicurel

, Schmid

. Postimplantation embryo culture for the assessment of the teratogenic potential and potency of compounds. Experientia. 1988; 44(10):833–40.

393.

Zemlickis

, Lishner

, Erlich

, Koren

. Teratogenicity and carcinogenicity in a twin exposed in utero to cyclophosphamide. Teratog Carcinog Mutagen. 1993; 13(3):139–43.

394.

Burdett

, Shah

. Effects of vincristine on developing hamster embryos. Anticancer Drugs. 1994; 5(3):309–12.

395.

Hayes

, Hood

, Lee

. Teratogenic effects of ochratoxin A in mice. Teratology. 1974; 9(1):93–7.

396.

Cuvier

, Espie

, Extra

, Marty

. Vinorelbine in pregnancy. Eur J Cancer. 1997; 33(1):168–9.

397.

Scales

, de Sauvage

. Mechanisms of Hedgehog pathway activation in cancer and implications for therapy. Trends Pharmacol Sci. 2009; 30(6):303–12.

398.

Binns

, James

, Keeler

, Balls

. Effects of teratogenic agents in range plants. Cancer Res. 1968; 28(11):2323–6.

399.

Chen

, Taipale

, Cooper

, Beachy

. Inhibition of Hedgehog signaling by direct binding of cyclopamine to smoothened. Genes Dev. 2002; 16(21):2743–8.

400.

Lipinski

, Hutson

, Hannam

, et al. Dose-and route-dependent teratogenicity, toxicity, and pharmacokinetic profiles of the hedgehog signaling antagonist cyclopamine in the mouse. Toxicol Sci. 2008; 104(1):189–97.

401.

Sekulic

, Migden

, Oro

, et al. Efficacy and safety of vismodegib in advanced basal-cell carcinoma. N Engl J Med. 2012; 366(23):2171–9.

402.

Basset-Seguin

, Hauschild

, Grob

J-J

, et al. Vismodegib in patients with advanced basal cell carcinoma (STEVIE): a pre-planned interim analysis of an international, open-label trial. Lancet Oncol. 2015; 16(6):729–36.

403.

Chang

ALS

, Solomon

, Hainsworth

, et al. Expanded access study of patients with advanced basal cell carcinoma treated with the Hedgehog pathway inhibitor, vismodegib. J Am Acad Dermatol. 2014; 70(1):60–9.

404.

Sekulic

, Weiss

, Solomon

, et al. Amenorrhea or irregular menses in patients treated with vismodegib. 2014.

405.

Strasswimmer

, Latimer

, Ory

. Amenorrhea secondary to a vismodegib-induced blockade of follicle-stimulating hormone–receptor activation. Fertil Steril. 2014; 102(2):555–7.

406.

Walbi

. Pharmacokinetics of the combination of veliparib and temozolomide in leukemia. University of Pittsburgh; 2014.

407.

Giavini

, Menegola

. Teratogenic activity of HDAC inhibitors. Curr Pharm Des. 2014; 20(34):5438–42.

408.

Wise

, Turner

, Kerr

. Assessment of developmental toxicity of vorinostat, a histone deacetylase inhibitor, in Sprague‐Dawley rats and Dutch Belted rabbits. Birth Defects Res B Dev Reprod Toxicol. 2007; 80(1):57–68.

409.

Wise

, Spence

, Saldutti

, Kerr

. Assessment of female and male fertility in Sprague–Dawley rats administered vorinostat, a histone deacetylase inhibitor. Birth Defects Res B Dev Reprod Toxicol. 2008; 83(1):19–26.

410.

Wise

. Numeric estimates of teratogenic severity from embryo–fetal developmental toxicity studies. Birth Defects Res B Dev Reprod Toxicol. 2016; 107(1):60–70.

411.

Fenic

, Hossain

, Sonnack

, et al. In vivo application of histone deacetylase inhibitor trichostatin-a impairs murine male meiosis. J Androl. 2008; 29(2):172–85.

412.

Doerksen

, Trasler

. Developmental exposure of male germ cells to 5-azacytidine results in abnormal preimplantation development in rats. Biol Reprod. 1996; 55(5):1155–62.

413.

Pennarossa

, Maffei

, Gandolfi

, Brevini

TAL

. 194 epigenetic remodeling of adult somatic cells. Reprod Fertil Dev. 2014; 26(1):211.

414.

Takeuchi

, Takeuchi

. 5-Azacytidine-induced exencephaly in mice. J Anat. 1985; 140(Pt 3):403.

415.

Zhao

, Shao

, Li

, et al. 5-Azacytidine induces early stage apoptosis and promotes in vitro maturation by changing chromosomal construction in murine oocytes. Reprod Toxicol. 2013; 37:56–61.

416.

S-y

, Li

, Chen

Y-l

, et al. Aberrant PTPRO methylation in tumor tissues as a potential biomarker that predicts clinical outcomes in breast cancer patients. BMC Genet. 2014; 15(1):1.

417.

Rothrock

, Perry

, Isham

, et al. Activation of tyrosine aminotransferase expression in fetal liver by 5-azacytidine. Biochem Biophys Res Commun. 1983; 113(2):645–9.

418.

Abbey

, Seshagiri

. Aza-induced cardiomyocyte differentiation of P19 EC-cells by epigenetic co-regulation and ERK signaling. Gene. 2013; 526(2):364–73.

419.

Ong

C-N

, Shen

H-M

, Chia

S-E

. Biomarkers for male reproductive health hazards: are they available?. Toxicol Lett. 2002; 134(1):17–30.

420.

Zhou

, Chen

, Love

. Cellular DNA methylation program during neurulation and its alteration by alcohol exposure. Birth Defects Res A Clin Mol Teratol. 2011; 91(8):703–15.

421.

Serman

. Changes in the placenta and in the rat embryo caused by the demethylating agent 5-azacytidine. Int J Dev Biol. 2002; 43(8):843–6.

422.

San-Miguel

. Consolidation therapy in myeloma: a consolidated approach?. Blood. 2012; 120(1):2–3.

423.

Powers

, Korgaonkar

, Fliedner

, et al. Cytocidal activities of topoisomerase 1 inhibitors and 5-azacytidine against pheochromocytoma/paraganglioma cells in primary human tumor cultures and mouse cell lines. PLoS One. 2014; 9(2):e87807.

424.

Doerksen

, Benoit

, Trasler

. Deoxyribonucleic acid hypomethylation of male germ cells by mitotic and meiotic exposure to 5-azacytidine is associated with altered testicular histology 1. Endocrinology. 2000; 141(9):3235–44.

425.

Mužić

, Jurić-Lekić

, Himelreich

, et al. Demethylating agent 5-azacytidine negatively affects proliferation of mammalian limb bud cells in an organ-culture system. 2014.

426.

, Jiang

, Li

, et al. Down-regulation of TCF21 is associated with poor survival in clear cell renal cell carcinoma. Neoplasma. 2011; 59(6):599–605.

427.

Cummings

. Effect of 5-azacytidine administration during very early pregnancy. Toxicol Sci. 1994; 23(3):429–33.

428.

Zhang

, Chu

, Shen

, Dou

. Effect of 5-azacytidine induction duration on differentiation of human first-trimester fetal mesenchymal stem cells towards cardiomyocyte-like cells. Interact Cardiovasc Thorac Surg. 2009; 9(6):943–6.

429.

Ravindran

CRM

, Ticku

. Effect of 5-azacytidine on the methylation aspects of NMDA receptor NR2B gene in the cultured cortical neurons of mice. Neurochem Res. 2009; 34(2):342–50.

430.

Penkov

, Platonov

, Mironova

, Konyukhov

. Effects of 5‐azacytidine on the development of parthenogenetic mouse embryos. Dev Growth Differ. 1996; 38(3):263–70.

431.

Kim

, Jeong

, Kim

, et al. 38 effects of 5-azacytidine on DNA hypermethylation status of cloned miniature pig embryo. Reprod Fertil Dev. 2008; 21(1):119.

432.

Artigas

, Iriarte

, et al. Effects of 5-azacytidine on lymphocyte-metaphases of Creole cows carrying the rob (1; 29). Res Vet Sci. 2010; 88(2):263–6.

433.

Schmahl

, Török

, Kriegel

. Embryotoxicity of 5-azacytidine in mice phase-and dose-specificity studies. Arch Toxicol. 1984; 55(2):143–7.

434.

Seifertova

, Veselý

, Cihak

. Enhanced mortality in offsprings of male mice treated with 5-azacytidine prior to mating. Morphological changes in testes. Neoplasma., 1975; 23(1):53–60.

435.

Zur Nieden

, Kempka

, Ahr

. Molecular multiple endpoint embryonic stem cell test—a possible approach to test for the teratogenic potential of compounds. Toxicol Appl Pharmacol. 2004; 194(3):257–69.

436.

Moudgal

, Sobel

. Antifungal drugs in pregnancy: a review. Expert Opin Drug Saf. 2003; 2(5):475–83.

437.

Kopelman

, Miyazawa

. Inadvertent 5-fluorouracil treatment in early pregnancy: a report of three cases. Reprod Toxicol. 1990; 4(3):233–5.

438.

Odom

, Plouffe

Jr. , Butler

. 5-fluorouracil exposure during the period of conception: report on two cases. Am J Obstet Gynecol. 1990; 163(1 Pt 1):76–7.

439.

Van Le

, Pizzuti

, Greenberg

, Reid

. Accidental use of low-dose 5-fluorouracil in pregnancy. J Reprod Med. 1991; 36(12):872–4.

440.

Levine

. Gonadotoxicity of cancer therapies in pediatric and reproductive-age females. In: Oncofertility medical practice. Springer; 2012; pp. 3–14.

441.

Polifka

, Friedman

. Teratogen update: azathioprine and 6‐mercaptopurine. Teratology. 2002; 65(5):240–61.

442.

Furukawa

, Usuda

, Abe

, et al. Effect of 6-mercaptopurine on rat placenta. J Vet Med Sci. 2008; 70(6):551–6.

443.

Francella

, Dyan

, Bodian

, et al. The safety of 6-mercaptopurine for childbearing patients with inflammatory bowel disease: a retrospective cohort study. Gastroenterology. 2003; 124(1):9–17.

444.

Zlatanic

, Korelitz

, Rajapakse

, et al. Complications of pregnancy and child development after cessation of treatment with 6-mercaptopurine for inflammatory bowel disease. J Clin Gastroenterol. 2003; 36(4):303–9.

445.

Goldstein

, Dolinsky

, Greenberg

, et al. Pregnancy outcome of women exposed to azathioprine during pregnancy. Birth Defects Res A Clin Mol Teratol. 2007; 79(10):696–701.

446.

Alstead

, Nelson-Piercy

. Inflammatory bowel disease in pregnancy. Gut. 2003; 52(2):159–61.

447.

Moskovitz

, Bodian

, Chapman

, et al. The effect on the fetus of medications used to treat pregnant inflammatory bowel-disease patients. Am J Gastroenterol. 2004; 99(4):656–61.

448.

Kane

. What's good for the goose should be good for the gander—6-MP use in fathers with inflammatory bowel disease. Am J Gastroenterol. 2000; 95(3):581–2.

449.

Coelho

, Beaugerie

, Colombel

, et al. Pregnancy outcome in patients with inflammatory bowel disease treated with thiopurines: cohort from the CESAME Study. Gut. 2011; 60(2):198–203.

450.

Ligumsky

, Badaan

, Lewis

, Meirow

. Effects of 6-mercaptopurine treatment on sperm production and reproductive performance: a study in male mice. Scand J Gastroenterol. 2005; 40(4):444–9.

451.

Anazodo

, Stern

, McLachlan

, et al. A study protocol for the Australasian Oncofertility Registry: monitoring referral patterns and the uptake, quality, and complications of fertility preservation strategies in Australia and New Zealand. J Adolesc Young Adult Oncol. 2016; 5(3):215–25.

452.

Anazodo

, Gerstl

, Stern

, et al. Utilising the experience of consumers in consultation to develop the Australasian Oncofertility Consortium Charter. J Adolesc Young Adult Oncol. 2016; 5(3):232–9.

453.

Pentheroudakis

, Pavlidis

, Castiglione

. Cancer, fertility and pregnancy: ESMO clinical recommendations for diagnosis, treatment and follow-up. Ann Oncol. 2009; 20 Suppl 4:178–81.

454.

Loren

, Mangu

, Beck

, et al. Fertility preservation for patients with cancer: American Society of Clinical Oncology clinical practice guideline update. J Clin Oncol. 2013; 31(19):2500–10.

455.

Multidisciplinary Working Group convened by the British Fertility Society. A strategy for fertility services for survivors of childhood cancer. Hum Fertil (Camb), 2003; 6(2):A1–39.

456.

AYA cancer fertility preservation guidance working group. Fertility preservation for AYAs diagnosed with cancer: Guidance for health professionals. Sydney: Cancer Council Australia. [Version URL: http://wiki.cancer.org.au/australiawiki/index.php?oldid=110662, Accessed January 29, 2017 from: www.wiki.cancer.org.au/australia/COSA:AYA_cancer_fertility_preservation

457.

National Collaborating Centre for Women's and Children's Health. Fertility: assessment and treatment for people with fertility problems. In: Commissioned by the National Institute for Health and Clinical Excellence. 2013.