Fig. 23.1
Imaging of femur . (a) X-ray. (b) MRI
The young woman is otherwise healthy, with no significant past medical history . She has never been hospitalized nor had surgery. She has not been taking any medications , vitamins, or supplements. She lives at home with her parents and two younger siblings. There is no family history of childhood cancers. She is sexually active with one partner, and they use condoms for birth control. She experienced menarche at 13 years of age. Although her menses were irregular in frequency, intensity, and duration for the first 2 years, she has had regular, monthly menses for the last 3 years that have occurred every 28 days and last for 5 days. She has never used any form of tobacco and does not drink alcohol, although she has been smoking marijuana one–two times per week.
Her pediatric oncologist discussed her diagnosis, prognosis, and the treatment plan in detail. She learned that there is a 75% chance that she will be cured, meaning the cancer will go away, stay away, and never come back. In order to accomplish that, she will receive 12 weeks of neoadjuvant chemotherapy given in six two-week cycles and then will have surgery to remove the tumor. Following surgery, she will receive an additional 22 weeks of adjuvant chemotherapy in 11 two-week cycles. In total, she will be treated for ~36 weeks and will receive:
375 mg/m2 doxorubicin
3500 mg/m2 etoposide
27 mg/m2 vincristine
8400 mg/m2 of cyclophosphamide
63 g/m2 of ifosfamide
The plan is to start treatment as soon as possible.
After learning the treatment plan , the patient and her parents ask several questions about the potential impact of the cancer treatment on her fertility, including:
- 1.
Will the treatment affect her ability to have children?
- 2.
If there is a chance that the treatment will make her infertile, is there anything that can be done before treatment to preserve her fertility?
- 3.
If she were to have biological children in the future, are there any additional risks to them?
Discussion
With an overall cure rate exceeding 80%, most adolescents and young adults (AYA) diagnosed with cancer will live many decades after their diagnosis. This remarkable success has been achieved mostly through the refinement of cancer treatments comprised of chemotherapy, radiation, and surgery. Despite the excellent oncologic prognosis, long-term survivors experience a high burden of morbidity from the late effects of cancer treatment . Over 70% experience at least one chronic disease as a consequence of cancer therapy [1, 2], and mortality among survivors greatly exceeds that of their peers [3]. With over 400,000 survivors of childhood cancer living in the United States, the health of this prevalent and medically complex patient population is a public health concern.
Among the late effects of cancer therapy, the possibility of infertility is among the most distressing aspects of survivorship for AYA, especially young women [4]. In 1975, a radiation oncologist named Giulio D’Angio coined the motto of survivorship “cure is not enough” [5]. To that end, it is imperative that young women such as the adolescent in the vignette receive accurate counseling as to the potential impact of their cancer treatment on fertility and be offered the opportunity to undergo fertility preservation techniques if fertility is threatened.
The Impact of Cancer Therapy on Fertility
Cancer treatment can affect female fertility by impacting the function of the ovaries, fallopian tubes, uterus, vagina, or hypothalamic-pituitary axis. While ovarian function can be affected by chemotherapy, radiation, or surgery, the uterus, vagina, and hypothalamic-pituitary axis are primarily at risk only from radiation and surgery. For the young woman in the vignette, there is no plan to radiate the pelvis nor would any surgery impact the reproductive structures. The greatest risk to her fertility is therefore the potential impact of chemotherapy on her ovaries.
Of the chemotherapeutics commonly used to treat childhood cancer, the group with by far the greatest impact on ovarian function is the alkylating agents. The risk for ovarian dysfunction is directly proportional to the cumulative lifetime alkylator dose, as measured in mg/m2 (i.e., the dose based on the m2 at the time it is delivered). The best studied alkylator in terms of its impact on ovarian function is cyclophosphamide. In order to better assess the impact of alkylator therapy on a given patient’s fertility, each alkylator can be given a cyclophosphamide equivalence score as reported by Green et al. [6]. Common alkylators and their cyclophosphamide equivalence are shown in Table 23.1.
Table 23.1
Common alkylating agents and their cyclophosphamide equivalence
Cyclophosphamide | 1 |
|---|---|
Ifosfamide | 0.244 |
Procarbazine | 0.857 |
Busulfan | 8.823 |
Chlorambucil | 14.286 |
BCNU | 15 |
CCNU | 16 |
Melphalan | 40 |
Thiotepa | 50 |
Nitrogen mustard | 100 |
Ovarian dysfunction after cancer therapy can manifest in two forms:
- 1.
Acute ovarian failure (AOF) occurs when women lose ovarian function during cancer treatment or soon after the completion of treatment.
- 2.
Premature ovarian insufficiency (POI) occurs when women maintain ovarian function after cancer treatment but experience menopause before the age of 40.
Women less than 20 years of age who receive >7.5 g/m2 of cyclophosphamide equivalents are at the highest risk for ovarian dysfunction. For the young woman in the vignette, the treatment protocol she has been presented with contains 8400 mg/m2 cyclophosphamide + 63,000 mg/m2 ifosfamide, for a total cyclophosphamide equivalence of 23,772 mg/m2. She is thus at increased risk for ovarian dysfunction after the completion of treatment .
Methods of Fertility Preservation
For women at risk for ovarian dysfunction after cancer therapy, there are several approaches available for fertility preservation [7] (Table 23.2).
Table 23.2
Methods of fertility preservation in order of preference
Prepubertal girls | 1. Ovarian tissue cryopreservation 2. Oophoropexy for girls receiving pelvic radiation |
Postpubertal adolescents | 1. Oocyte cryopreservation 2. Embryo cryopreservation for women who have identified a male partner 3. Ovarian tissue cryopreservation if unable to harvest oocytes 4. Oophoropexy for women receiving pelvic radiation |
Young adult women | 1. Embryo cryopreservation for women who have identified a male partner 2. Oocyte cryopreservation if embryo cryopreservation is not feasible 3. Ovarian tissue cryopreservation if unable to harvest oocytes 4. Oophoropexy for females receiving pelvic radiation |
Embryo cryopreservation is the oldest and most successfully form of fertility preservation. It involves harvesting oocytes from the woman, collecting sperm from a male partner and generating embryos through in vitro fertilization (IVF). These embryos can then be safely and effectively cryopreserved for future use. Embryo cryopreservation has proven effective, with cancer survivors experiencing a 30% rate of live births versus 32% for patients who never had cancer [8]. Nonetheless, for AYA in particular, there are potential barriers to this approach. First, it requires that the young woman have an identified male partner with whom she wants to have biologic children. Second, oocyte harvesting requires time and ovarian stimulation, which may be challenging if there is a sense of urgency to begin cancer treatment. Newer methods of ovarian stimulation can be undertaken independent of menstrual cycle, which reduces the risk of delaying cancer treatment and allows for cancer therapy to start the day after oocyte harvest.
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