Toxicity
Medication class
Medication
High
Alkylating agents:
Cyclophosphamide
Chloroethylamine
Chlorambucil
Mechlorethamine
Nitrogen mustard
Nitrosurea
l-phenylalanine mustard
Alkylalkane sulfonate
Carmustine
Methylhydrazine derivative
Lomustine
Busulfan
Procarbazine
Intermediate
Platinum complexes
Anthracyclines
Cisplatinum
Carboplatinum
Doxorubicin
Low
Antimetabolites
Methotrexate
Vinca alkaloids
5-Fluorouracil
Antibiotics
6-Mercaptopurine
Vincristine
Vinblastin
Bleomycin
Dactinomycin
13.9 Predicting Ovarian Failure
Premature ovarian failure does not consistently occur in patients receiving multi-agent chemotherapy, regardless of age or type of chemotherapeutic agent. Most young patients with Hodgkin’s disease treated with multi-agent chemotherapy and radiation to a field that does not include the ovaries will be fertile, although their fertility will begin to decrease at a younger age than matched controls [ 22 ]. Spontaneous conception can occur even in after diagnosis of premature ovarian failure, such as reported in a woman who had completed 14 courses of an alkylating agent combined with pelvic irradiation for treatment of Ewing’s sarcoma of the pelvis [ 23 ]. This exemplifies the difficulties in predicting the probability of ovarian failure after chemotherapy, which also makes it difficult to evaluate the efficacy of treatment aimed at preserving ovarian function.
13.10 Markers for Gonadal Damage
Ovarian reserve testing, which was discussed earlier in the chapter, should be offered both pre- and post-treatment. Basal FSH levels (if the patient has menstrual cycles), AMH, inhibin-B, and transvaginal ultrasound measured AFC are useful markers for ovarian function after chemotherapy [ 24 ].
13.11 Radiation Therapy and Ovarian Damage
Ovarian damage from radiotherapy can lead to diminished ovarian reserve and premature ovarian failure [ 25 – 33 ]. The ovarian follicles are remarkably vulnerable to DNA damage from ionizing radiation. Irradiation results in ovarian atrophy and reduced follicle stores [ 30 ]. As a result, serum FSH and LH levels progressively rise and estradiol levels decline within 4–8 weeks following radiation exposure. On the cellular level, irradiation of oocytes results in rapid onset of pyknosis, chromosome condensation, disruption of the nuclear envelope, and cytoplasmic vacuolization.
13.12 Risk Factors for Ovarian Damage
Cancer patients are at high risk for premature ovarian failure after treatment with pelvic or total body irradiation. The degree of ovarian damage is related to the patient’s age and the total dose of radiation to the ovaries. It is generally estimated that a single dose of 5.0 Gy will cause permanent ovarian failure in over 90% of postpubertal women [ 34 ]. When looking at specific age groups, a prepubertal girl may have permanent ovarian failure if exposed to 12 Gy, but only 2 Gy may cause the same result in women over the age of 45 [ 29 ].
The dose response of the ovaries to irradiation has been demonstrated in several studies [ 27 , 31 , 33 ]. It is estimated that as little as 3 Gy is enough to destroy 50% of the oocyte population in young, reproductive-age women [ 32 ]. When the mean radiation dose to the ovary was 1.2 Gy, 90% of patients retained their ovarian function. When mean dose was 5.2 Gy, only 60% retained ovarian function.
Ovarian failure will occur in virtually all patients exposed to pelvic radiation at the doses necessary to treat cervical cancer (85 Gy), rectal cancer (45 Gy), or total body radiation for bone marrow transplantation (8–12 Gy exposed to the ovaries). The addition of chemotherapy to radiotherapy further decreases the dose required to induce premature ovarian failure.
Even if the ovaries are not directly in the radiation field, radiation scatter can reduce ovarian function. Given this risk, it is very important to discuss with the radiation oncologist the expected dose that will be delivered to the ovary either directly or through scatter.
13.13 Radiotherapy and Uterine Damage
Irradiation-induced uterine damage can result in impaired endometrial function and uterine blood flow [ 35 ]. Young women exposed to radiotherapy below the diaphragm are at risk of impaired development of the uterus, in addition to ovarian failure. Long-term cancer survivors treated with total body irradiation and marrow transplantation are at risk of impaired uterine growth and blood flow. Despite standard estrogen replacement, the uterine size of young girls is often reduced to 40% of the normal adult size. The younger the girl is when irradiated, the more the uterus appears to be affected.
It has been demonstrated in women treated with total body irradiation that sex steroid replacement in physiological doses significantly increases uterine volume and endometrial thickness, as well as reestablishes uterine blood flow. However, it is not known whether standard regimens of estrogen replacement therapy are sufficient to facilitate uterine growth in adolescent women treated with total body irradiation in childhood.
13.14 Pregnancy After Radiation Therapy
Pregnancies achieved by survivors of childhood cancer who have received pelvic irradiation must be considered high risk [ 34 – 36 ]. Radiation damage to the uterine musculature and vasculature can adversely affect pregnancy outcomes in these women. Even if the uterus is able to respond to exogenous sex steroid stimulation, and appropriate ARTs are available, pregnancy prognosis remains guarded. Common obstetric problems reported in these patients include early pregnancy loss, premature labor, and low-birth-weight infants [ 37 , 38 ].
13.15 Fertility Preservation Strategies
A wide variety of strategies have been reported in an effort to preserve ovarian function and fertility in women undergoing chemotherapy and/or radiotherapy. Fertility-sparing procedures, pharmacologic options, and ARTs will be discussed ( ◘ Table 13.2 ).
Table 13.2
Fertility preservation strategies
Technique | Pros | Cons | Experimental vs. Established | |
|---|---|---|---|---|
Surgical | Fertility-preserving surgery | May be able to conceive and carry future pregnancy Less aggressive Usually covered by insurance | May leave residual disease Requires close follow-up May still require ART | Established |
Ovarian transposition | Reduces ovarian exposure to radiation | Requires surgery May still be affected by radiation (Scatter/fall into field) Can cause pain | Established | |
Pharmacologic | GnRH agonists | Minimal delay in treatment | Not proven Side effects similar to menopause | Experimental |
Assisted reproductive technology | Embryo cryopreservation | Commonly performed, good success rates | Elevated hormone levels Time-consuming Requires a sperm source May not be covered by insurance | Established |
Oocyte cryopreservation | Good success rates, no longer experimental Does not require a sperm source | Elevated hormone levels Time-consuming May not be covered by insurance | Established | |
Ovarian tissue cryopreservation | No delay in treatment Does not require a sperm source Option for prepubertal females | Requires surgery Ovarian tissue ischemia Possible reexposure to cancer cells May not be covered by insurance | Experimental | |
In vitro maturation | Minimal delay in treatment Does not require a sperm source | Limited experience with this procedure | Experimental |
13.16 Surgical Techniques
In general, the conventional therapy for a gynecologic malignancy consists of removal of the uterus, tubes, and ovaries. However, there are specific circumstances that may allow a more conservative surgical approach.
13.17 Cervical Cancer
Cervical cancer is typically treated with surgery or radiation therapy, depending on the stage at presentation. Those with early stage disease, Stage IA1, may be treated with cervical conization and close follow-up. Women who desire future fertility and are diagnosed with Stage IA2 and Stage IB disease may opt for a radical trachelectomy, which involves removal of the cervix, surrounding tissues, and lymph node dissection [ 39 ]. Patients treated with trachelectomy may require ART to achieve a future pregnancy, and should be aware that they are at increased risk of second-trimester loss and preterm birth after this procedure [ 40 ]. A recent study described successful fertility preservation and spontaneous pregnancies achieved with robotic trachelectomy [ 41 ].
13.18 Ovarian Cancer
Ovarian tumors classified as low malignant potential, germ cell, sex cord-stromal, or early epithelial malignancies have the potential to be treated with conservative surgery. Most ovarian cancers diagnosed in the reproductive years tend to be unilateral and are less likely to have metastasized. The surgical option most likely to succeed in removing the cancerous tissue, as well as preserve fertility potential, is unilateral oophorectomy with conservation of the remaining normal ovary and the uterus. These women should still undergo complete staging and be monitored closely by a gynecologic oncologist for possible recurrence [ 42 ].
13.19 Endometrial Cancer
Both complex endometrial hyperplasia with atypia and early stage endometrial adenocarcinoma (Stage IA1) can be treated conservatively. A hysteroscopy with dilatation and curettage, followed by high-dose progesterone therapy, is the standard treatment for those women who desire fertility preservation. Unfortunately, recurrence is common and close periodic evaluation is required to avoid progression. It is also important to stress to these patients that they should pursue child-rearing sooner rather than later, and then have a complete hysterectomy and bilateral salpingo-oophorectomy to ensure a disease-free survival.
13.20 Ovarian Transposition
Transposition of the ovaries out of the field of radiation appears to help maintain ovarian function in patients scheduled to undergo gonadotoxic radiation therapy. This technique can be utilized for gynecologic, colon, rectal, and anal cancers. Transposition of the ovaries has been reported to reduce the radiation dose to each ovary by approximately 90–95% compared to ovaries left in their original location [ 38 ].
There are two techniques available, lateral and medial transposition. Lateral transposition appears to be more effective than medial transposition. A compilation of ten case reports and a small series showed an ovarian failure rate of 14% after lateral transposition compared to 50% after medial transposition [ 43 ].
Ovarian transposition can be performed by either laparotomy or laparoscopy. When surgery is required for the treatment of cervical cancer or during staging and treatment of ovarian cancer, lateral ovarian transposition can be performed simultaneously. However, if a surgical procedure is not required for treatment, the transposition can easily be performed as an outpatient procedure. The ovaries have a tendency to migrate back to their original position, so it is recommended to complete the procedure immediately prior to the initiation of radiation therapy [ 33 , 44 , 45 ].
Most ovaries will maintain function if they are transposed at least 3 cm from the upper edge of the field [ 46 ]. It has been shown that approximately 80% of women undergoing laparoscopic ovarian transposition will maintain ovarian function after radiation therapy for various indications [ 47 ].
Ovarian failure following transposition can occur because of several different mechanisms. Ovarian failure may result if the ovaries are not moved far enough out of the radiation field. Another reason for failure would be ovarian migration back to their original position. Ovarian failure following transposition may also be due to compromised ovarian blood flow from surgical technique or radiation injury to the vascular pedicle [ 48 ].
Pregnancies have been reported after ovarian transposition. Some have occurred spontaneously, but others required reversal of the procedure.
13.21 Pharmacologic Protection
13.21.1 Gonadotropin-Releasing Hormone Agonists
The ideal approach to decrease or eliminate gonadal damage from chemotherapy is pharmacologic. The patient can take a medication and proceed with her cancer treatment without undergoing an invasive procedure. The critical step in the development of such a drug is an understanding on how chemotherapy actually causes ovarian follicle destruction. The impact, as stated earlier, depends not only on the type of chemotherapeutic agents but on age, ovarian reserve, dose, and duration of treatment. The unique feature of chemotherapy induced gonadal damage is the predilection towards damage of the primordial follicle, which consists of non-growing cells. Growing follicles are immediately impacted resulting in amenorrhea. Chemotherapeutic agents can directly cause apoptosis of follicles, with the dividing granulosa cells being particularly susceptible to damage [ 49 – 51 ]. This latter phenomenon leads to the theory of “follicle burn out” [ 49 ]. Since growing follicles have a direct effect in dampening the initiation of primordial follicle growth, the immediate and complete loss of growing follicles causes an accelerated recruitment of primordial follicles and a decrease in the total ovarian follicular reserve. In addition to these effects chemotherapy can cause stromal fibrosis and damage to intra-ovarian vessels. The ideal drug would impede these effects. Drugs that act on apoptotic pathways such as sphingosine-1-phosphate or drugs that impede follicle activation pathways such as AMH would be ideal. Most are in pre-clinical trials and not available clinically. While testing these drugs it is important not to interfere with the efficacy of the cancer treatment. The only drug clinically available for use in patients undergoing gonado-toxic treatment is Gonadotropin-releasing hormone agonists (GnRHa) .
Protection of gonadal function is more than just preservation of fertility. Many aspects of quality of life are related to gonadal function. Hypogonadal symptoms such as hot flashes, insomnia, vaginal dryness, dyspareunia, and impaired sexual function are equally important. Ovarian failure is associated with osteoporosis, cardiovascular disease, and neurocognitive decline. Therefore drugs that prevent chemotherapeutic damage can be efficacious in maintaining an estrogenic environment and quality of life without necessarily protecting fertility.
It is unclear how GnRHa can impede the gonadotoxic effects of chemotherapy. Its effect on suppressing the pituitary gonadotropin secretion is well described. This aspect of the drug cannot be solely responsible for its observed effects as primordial follicle activation is independent of gonadotropins. It may be acting on impeding follicle recruitment by different mechanisms [49]. GnRHa are thought to decrease vascularity at the level of the ovary, thereby reducing the concentration of chemotherapy acting directly on the ovary [49].
The use of GnRHa during chemotherapy is still a controversial and considered experimental. In some circumstances such as preventing the severe menstrual bleeding associated with some chemotherapeutic drugs it is quite effective. GnRHa can be useful for preservation of gonadal function to alleviate hypogonadal consequences. It seems to be more effective when used in conjunction with chemotherapy in breast cancer patients than lymphoma patients [52–54]. This may be due to the temporal relationship of the diagnosis and initiation of treatment in breast cancer patients which is often delayed until after surgery as compared with lymphoma patients which is often immediate. A review of 14 previously published meta-analyses evaluating RCTs on this subject showed mixed results [55]. The majority showed a favorable impact on gonadal protection but others did not. This is most probably the result of the heterogeneous population of patients with different cancers and different chemotherapy protocols.
Additionally, GnRHa are often beneficial as adjuvant treatment in combination with chemotherapy for a subset of patients. Certainly it is clear that it is not deleterious to chemotherapy outcomes. Breast cancer patients, including those with estrogen receptor positive tumors, who received GnRHa co-treatment had increased or no impact on disease free survival and overall survival compared to chemotherapy alone [52, 53]. In the Prevention of Early Menopause Study [52], a trend towards a higher rate of disease free survival in those individuals treated with GnRHa was observed, as well as a statistically significant higher rate of overall survival in this group compared to those treated with chemotherapy alone [52]. Similarly, in the Lambertini et al. study, a trend towards improved 5-year disease free survival was observed in the GnRHa group versus controls [53].
The impact of GnRHa on improving fertility potential is less clear. It is especially difficult because spontaneous pregnancy rates in women after breast cancer treatment are high enough to make clinical studies difficult to interpret. To date the ASRM recommends use of GnRHa in concert with other fertility preservation methods for patients who desire future pregnancies [56]. The use of GnRHa does not impede the use of other strategies for fertility preservation [55]. Additionally, the National Comprehensive Cancer Network and the St. Gallen International Expert Consensus panel guidelines support the use of GnRHa for the prevention of ovarian failure secondary to gonadotoxic chemotherapy [42]. For individuals who have completed childbearing but are still far from menopause, GnRHa can be considered with the goal of preserving of ovarian function .
13.22 Assisted Reproductive Technology
The application of ART for patients interested in fertility preservation depends on multiple factors, such as the type of cancer, treatment planned, time until treatment will start, and presence of a partner. There are multiple options available to the patient; some are considered established practices and others are experimental techniques. The overall goal is to preserve embryos, oocytes, or ovarian tissue for these women prior to treatment, so they may have options to reproduce in the future.
13.23 Embryo Cryopreservation
For postpubertal patients who have a committed male partner, embryo cryopreservation is an established technique for fertility preservation [ 56 ]. The age of the patient, number, stage and quality of the frozen embryos mainly determine the likelihood of success with embryo cryopreservation. The chances of a live birth from a cryopreserved embryo in a woman under the age of 40 years old are 28.5–38.7% . In general, the post-thaw survival rate of embryos ranges between 76 and 93%, and the clinical pregnancy rate is 37.5–62.5% [ 57 ].
A typical IVF cycle for fertility preservation can be done in a few weeks from start to finish; with traditional protocols, the time constraint has sometimes been dependent on where the patient is in her menstrual cycle. Some centers have offered natural cycle-IVF for breast cancer patients. During this process, a single oocyte is aspirated during a woman’s spontaneous menstrual cycle. Unfortunately, cancellation rates are high and the pregnancy rates are very low for this protocol (7.2% per cycle and 15.8% per embryo transfer) [ 58 , 59 ].
Most centers will use mild ovarian stimulation with a GnRH antagonist to prevent ovulation [ 60 ]. A new protocol in the starting time of ovarian stimulation has been reported. In those patients who present in the luteal phase of the menstrual cycle, a GnRH antagonist can be started immediately to help down-regulate LH and initiate luteolysis. Ovarian stimulation is started at the same time, thereby reducing the time to retrieval to less than 2 weeks. Reports in the literature have identified similar dosage requirements, numbers of oocytes retrieved, and fertilization rates in women who started in the luteal phase compared to those who started at in the follicular phase of their menstrual cycle [ 60 , 61 ].
13.24 Oocyte Cryopreservation
Postpubertal female patients who do not have a male partner or do not wish to fertilize their eggs have the possibility to cryopreserve their oocytes for future use. The option of oocyte cryopreservation is no longer considered an experimental technique by the ASRM [ 62 ]. Freezing gametes, rather than embryos, also avoid ethical and legal considerations of embryo storage and disposal, which is of concern for some patients. The greatest concern about utilizing oocyte cryopreservation is that the success rate in the past was significantly lower than with embryo cryopreservation. Early studies reported a low survival, fertilization, and pregnancy rate with thawed oocytes [ 63 ].
The structural complexity of the oocyte is most likely responsible for the reduced success rate in oocyte cryopreservation. Unlike fertilized embryos, the subcellular organelles in oocytes are far more complex and more sensitive to thermal injury [ 64 , 65 ]. Improvements in the cryopreservation technique have led to significant improvements in the overall outcome of oocyte cryopreservation. The advent of vitrification for cryopreservation, rather than the slow-freeze protocol, has reduced the damage caused from ice-crystal formation and subsequent cellular damage [ 66 ]. Recent reports have seen survival rates after a thaw of 75–86%, fertilization rates of 77%, and live birth rates of 38% [ 67 ]. In those pregnancies that have resulted from oocyte cryopreservation, there appears to be no increase in chromosomal abnormalities, birth defects, or developmental deficits [ 68 ].
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