Introduction

Cancer affects 1 in 500 children up to the age of 14, and cancer incidence rises with age. Each year in the United States approximately 15,780 children between birth and age 19 are diagnosed with cancer. The commonest cancers occurring in childhood are leukemia, brain/CNS tumors, and lymphoma, and in teenagers, in addition to these, sarcomas of bone and soft tissue, carcinomas, germ cell tumors, and malignant melanoma. Early diagnosis and advancements in treatments have resulted in survival rates of 83 percent and 84 percent respectively for childhood (ages 0–14) and adolescent (15–19) cancer survivors [1,2]. As a result of improved therapies, it is predicted that 1 in 800 women will be childhood cancer survivors by 2020 and therefore at risk of long-term sequelae, or “late effects” of therapy. To appropriately address late effects, comprehensive care of the cancer survivor should be provided to include counseling regarding fertility preservation, contraception, and menstrual suppression prior to therapy and assessment of reproductive function, hormonal status, and sexual dysfunction in survivorship [3,4,5]. Reproductive late effects to be addressed include ovarian insufficiency and its sequelae of delayed puberty, impaired fertility, decreased bone mass, and impaired vaginal health, as well as increased risk of cardiovascular disease, early onset dementia, and Parkinson’s. Sexual dysfunction is an important late effect of pelvic radiation and surgery that is often not addressed. This chapter reviews the late effects of childhood cancer in the pediatric and adolescent gynecology practice and provides evidence-based guidance to care in a problem-based approach.

Effects of Cancer Treatment

Acute ovarian failure in childhood cancer survivors has been reported at 6 percent in the Childhood Cancer Survivor Study as compared to 0.8 percent of their siblings [6]. Moreover, the risk of diminished ovarian reserve remains with the risk of imminent ovarian failure reported to be as high as 22.6 percent and the risk of premature menopause 8 percent after alkylating agent therapy, depending on the age at diagnosis [7,8]. Premature menopause is associated with sequelae of osteoporosis, early onset dementia, and morbidity and mortality related to cardiovascular disease [9,10].

The degree of ovarian injury depends on the age at therapy, treatment type, with alkylating agents being especially gonadotoxic, and total cumulative dose, with multi-dose therapies having a cumulative toxic effect on ovarian function [11](Table 10.1). Green and colleagues developed the “cyclophosphamide equivalent dose” scoring system to stratify survivors at high risk of ovarian failure. A CED ≥ 7.5 gm/m² is associated with a relative risk of premature menopause of 4.19 and may be used to counsel survivors regarding fertility preservation options [12]. It is well established that radiation doses to the ovary > 2 Gy result in a loss of 50 percent of follicles and impaired fertility [13]. Pelvic radiation doses ≥ 15 Gy in prepubertal and 10 Gy in postpubertal females have permanent effects on the ovary and are associated with a high risk of ovarian failure. Craniospinal radiation ≥ 25 Gy is associated with diminished function of the hypothalamic-pituitary axis, which can develop several years after treatment, leading to secondary ovarian insufficiency. Pelvic radiation doses ≥ 30 Gy are associated with irreversible injury to the uterus. Pelvic radiation and total body irradiation (TBI) result in impaired uterine growth in prepubertal children and restricted uterine blood flow with the consequences of spontaneous abortion, premature birth and low birth weight offspring [14,15].

Predicting the extent of reproductive impairment and the window of fertility for family planning has proven challenging. Assessment of ovarian reserve with anti-Müllerian hormone (AMH) and antral follicle count (AFC) is useful in predicting response and pregnancy rates from assisted reproduction in infertile women; however, there is limited data on how to best use ovarian reserve markers in counseling young cancer survivors [16,17]. Nomograms to predict the age of menopause in healthy women have been reported showing that AMH and age were significantly correlated with the time to menopause and useful as predictors [18,19]. However, such nomograms have not been used to predict loss of the fertility window in survivors of childhood cancers (Figure 10.1).

Figure 10.1 AMH normal values by age

Kelsey TW, Wright P, Nelson SM, Anderson RA, Wallace WH. A validated model of serum anti-Müllerian hormone from conception to menopause.

http://journals.plos.org/plosone/article?id=10.1371/journal.pone.0022024

Intracranial cancers (and benign tumors) may affect the hypothalamic-pituitary-ovarian (HPO) axis function due to mass effect, hormonal production, and the treatment itself. The radiation dose to the hypothalamus and pituitary that confers damage is >30 Gy of radiation. Scatter effect may also affect the hypothalamic-pituitary function. Disruption of the HPO axis results in decreased gonadotropins with resultant estrogen insufficiency. Disruption of the anterior pituitary may cause a decrease in adrenocorticotropic hormone, growth hormone, luteinizing hormone, follicle stimulating hormone, prolactin, and thyroid hormone. Disruption of the posterior pituitary results in decreased anti-diuretic hormone and oxytocin. These hormone deficiencies are typically identified and managed by pediatric endocrinologists. Pediatric gynecologists may co-manage hormone replacement therapy of survivors with estrogen insufficiency. With permanent damage to the HPO axis, estrogen replacement is required until the expected age of menopause.

Fertility Preservation

Professional bodies (including the American Society of Clinical Oncology, American Society for Reproductive Medicine, Canadian Fertility and Andrology Society, and the Royal Colleges in the UK) recommend fertility preservation (FP) counseling prior to initiating cancer treatment in order to provide all available options to survivors [25,26,27,28]. Standard options include oocyte, embryo, and sperm freezing for adult females and males, respectively [29]. Oocyte and sperm freezing in adolescents requires knowledgeable discussions between the patient, parent, oncologist, and reproductive specialist. Oocyte freezing in adolescent girls is not standard care but may be performed at specialized centers [30]. Sperm freezing in adolescent boys may be challenging depending on the degree of sexual maturity and may require invasive techniques to procure sperm such as testicular aspiration under anesthesia [31]. Testicular and ovarian tissue freezing in prepubertal children is an investigational option performed under research protocols for pediatric patients at high risk of infertility [32]. There are ethical considerations in undertaking procedures that are not of immediate therapeutic value in young patients who may not have a full understanding of the future implications.

Pregnancies following regrafting of frozen-thawed ovarian tissue have been reported worldwide, making this a viable option for adolescent and adult patients who decline standard therapies or cannot delay cancer treatment to pursue those options [33,34,35,36]. Laparoscopy carries the risks of a surgical procedure. In prepubertal girls, this is the only FP option, but outcomes are still unknown.

Ovarian transposition or oophoropexy may be considered for individual cases to move the ovaries out of the field of localized radiation. Subsequently a second laparoscopy may be performed to release them and allow natural conception, or IVF may be required with egg pickup from the transposed ovary [37].

Despite our knowledge of FP options, only a minority of adult patients undertake FP therapies. Unfortunately, discussions simply may not occur, due to physicians’ lack of awareness about options and concerns for treatment delay and cost of therapies [38]. At the time of diagnosis, patients receive a great amount of information. Many patients do not “hear” or are unable to process discussions about future fertility at that time. For these reasons, after an initial discussion by the oncologist, a separate conversation with a reproductive specialist is recommended. In fact, women counseled about their risk of infertility by both an oncologist and a fertility specialist had significantly less regret about their decision to preserve fertility than those counseled only by an oncologist [39].

Decision aids may assist the patient in deciding on the best option; however, few standard aids currently exist [40]. The optimal timing for discussion is prior to chemotherapy and radiation, as early referral has been reported to decrease decisional conflict by allowing time to pursue options if desired [41]. Additionally, studies suggests that adolescents desire to be a part of the decision-making process [42]. There are fewer options available once cancer treatments have started. For those patients at high risk of ovarian failure who have undergone one cycle of chemotherapy, ovarian tissue freezing remains an option. Additionally, recent studies have shown that Goserelin, a gonadotropin-releasing hormone agonist, improves pregnancy rates and long-term survival rates in patients with certain types of breast cancer [43]. Unfortunately, Goserelin has not been confirmed as an ovarian protection agent during treatment of other cancer types.

Many patients express concern that pursuing fertility options may delay cancer treatment. Ovarian stimulation for oocyte and embryo freezing require a minimum of 2 weeks. Historically, the onset of menses was required prior to initiating therapy. However, newer ovarian stimulation protocols have been developed to “quick start” stimulation during any phase of the menstrual cycle, minimizing treatment delays. Ovarian tissue freezing can be combined with cancer-related procedures and results in no delay. To optimize time to cancer therapies, FP counseling and development of a “fertility road map” should occur within days of the cancer diagnosis so that FP options can be implemented in a timely fashion. Specialist nurses to help families navigate the process, assist with financial considerations, and minimize barriers are becoming a standard and integral part of treatment teams.

Menstrual Suppression

Menstrual suppression during chemotherapy is not necessary for all cancers. However, patients receiving myeloablative agents are more likely to experience bleeding secondary to thrombocytopenia that may require transfusion and blood products; therefore, they may be candidates for menstrual suppression [44].

Menstrual suppression may be achieved in several ways. Combined oral contraceptives carry a theoretical risk of thrombosis; therefore, progestin-only options may be better. Progestin-only contraceptive pills may result in breakthrough bleeding if not taken at the same time each day. Higher doses of progestin to achieve amenorrhea may result in side effects, and in the case of norethindrone acetate, paradoxical breakthrough bleeding as estradiol is a metabolite of norethindrone acetate. Episodes of nausea and emesis during chemotherapy make oral therapy less than ideal for many patients.

Injectable medroxyprogesterone may result in breakthrough bleeding during the first 3 months. This may be difficult to control and may require additional oral progestin therapy. Additionally, an intramuscular injection in the setting of thrombocytopenia may cause hematoma formation. The dual benefit of IM medroxyprogesterone for menstrual suppression is contraception. Gonadotropin-releasing hormone agonist (GnRHa) therapy during chemotherapy downregulates the HPO axis after the initial release of gonadotropins, resulting in suppressed estradiol levels and amenorrhea. A withdrawal bleed typically occurs within 2 weeks of administration; to minimize bleeding, the ideal time to give GnRHa is during the luteal phase of the menstrual cycle or after 2 weeks of suppression with oral progestins. Unfortunately, due to the urgency surrounding initiation of chemotherapy, neither of these regimens may be ideal. Concurrent administration of oral progestin with initiation of GnRHa therapy may be the best option. Continuing hormonal add-back therapy is advisable with prolonged administration of GnRHa therapy to minimize loss of bone mineral density [45]. Add-back therapy may be given in the form of progestin, transdermal estradiol, conjugated equine estrogen, and combined low-dose oral contraceptives. The drawbacks with estrogen therapy are breakthrough bleeding and in the case of oral contraceptives, potential for thrombosis.