Fertility Preservation in young women with Genital Cancer

Approximately 4% of individuals suffering from cancer are under the age of 35 years and a fourth of these are teenagers or young adults (13-25 years).

About 80% of the affected in the age group 13-35 will survive beyond ten years after cancer treatment. These individuals when attempting pregnancy at a later date may find it difficult to conceive. Fertility preservation strategies instituted prior to cancer treatments may help these individuals realize their dream of parenthood subsequently. Hence, it is imperative in all young women undergoing cancer treatment that fertility preservation strategies be discussed and implemented wherever possible.

What types of cancers can afflict young women?

Cancers affecting women can be largely grouped into gynecological and non-gynecological cancers.

The three common gynecological cancers affecting young women are the endometrial, ovarian and breast cancers. Others like the cervical, fallopian tubal, vaginal and vulvar cancers are more common in the older age women and one is less likely to hear of a woman in her twenties or early thirties affected by them.

Non-gynecological cancers affecting young women are in the order of their decreasing frequency, lymphoma, (blood cancer), germ cell tumours (cancers arising in fetal tissue), intracranial malignancies, melanoma (skin cancer), leukaemia (blood cancer), bone tumours and other sarcomas (cancers of the muscle, nerve, blood vessels etc.)

What are the treatments offered to young women with cancer?

Surgery is one of the major treatments for cancer treatments. Sometimes when the tumour has spread way beyond its direct reaches, the doctor decides not to operate. Instead, the treatment then relies on killing the cancer cells that has spread to different parts of the body via the blood and lymph stream using chemotherapy (orally/intravenously administered) and radiotherapy (focused or whole body)

How do these treatments affect the future fertility of women with cancer?

The surgery undertaken for cancer treatment may make future conception difficult.

Uterine cancer: The uterus or its lining involving the cancer is removed. So the woman would lose her ability to carry a pregnancy.

Ovarian cancer: When the ovaries are removed, the natural fertility is lost due to lack of availability of eggs.

Cervical cancer: The uterus and ovaries may both be spared in pre-cancerous lesions of the cervix. The cervix may be partially amputated to ensure complete lesional excision. This may affect sperm movement through the cervix, a necessary pre-requisite in it’s onwards journey to meet the oocyte.

The chemotherapeutic medicines used for blood cancers affect future fertility by acting directly on the germ cells. By destroying the germ cells or reducing their ability to mature and divide, chemotherapy induces massive germ cell depletion. This leads to early cessation of menses. Even in cases where menstrual cyclicity is maintained, fertility is affected as a result of fewer  good quality surviving eggs in the ovary.

 

Radiation can affect gametogenesis by inducing fibrosis and devascularization of gonads or destruction of actively dividing germ cells in the testes or cyclically maturing germ cells in the ovaries. It can also lead to the destruction of the master endocrine gland called the pituitary that drives gonadal function.

 

Is the risk for future infertility the same in all individuals following cancer treatment?

No, the risk varies depending upon individual age, prior fertility status, the organ affected, stage of cancer, surgery performed, type, dose and duration of chemotherapeutic agent used; type (focused or whole body), dose, fractions and duration of radiotherapy given.

Younger individuals have a greater reserve of eggs and hence removal of one or part of the other ovary may reduce their reserve, but may not affect their ability to ovulate each month for several years.

Some types of cancers directly affect the gonads like lymphomas and thus their ability for gametogenesis.

Higher stage of cancer involving a generative organ necessitates its removal.

With chemotherapeutic agents, drugs like cyclophosphamide, melphalan, busulfan, ifosfamide, chlorambucil etc. pose the greatest risks to fertility. Several agents like methotrexate, fluorouracil, vincristine, bleomycin, and dactinomycin are associated with a low risk of infertility.

Total-body irradiation carries a greater risk of loss of ovarian and testicular function. While lesser doses or focused radiation fields have less gonadal toxicity. Radiation doses of >2.5 Gray to the testes induces prolonged azoospermia. Radiation doses of > 40 Gray to the ovaries cause menopause. 

What should be done once the diagnosis of cancer is made?

Young patients with a desire to conceive in future should discuss fertility preservation options with their primary care physician, or an oncologist or a fertility preservation expert. The primary care physician gives primary counseling about the condition, information about investigations needed and treatments offered. He or she also refers the affected individual to the oncologist, a reproductive physician and a psychiatrist.

 

What options do women suffering from cancer have to preserve their fertility?

Fertility-sparing gynaecological surgeries as opposed to surgeries involving complete removal of the reproductive organs should be undertaken wherever possible.

In women under 40 years with cervical cancer, upto 50% have early stage cervical cancer (Stage 1A1 to 1B). In these women, a trachelectomy (cervical amputation procedure) is usually possible. This leaves behind the uterus and the ovary for subsequent childbearing. If the uterus has been spared, a close follow-up every three month would be necessary using cervical smear sampling and colposcopy wherever indicated. Getting pregnant in such cases is possible naturally, but an IUI may be necessary in some cases. Once pregnant, expect complications like mid-trimester loss due to cervical incompetence and difficult labour due to a fibrosed cervix requiring cesarean section. Mid trimester loss is avoidable by a carefully placed cervical stitch at 14 weeks of pregnancy.

If it is necessary to remove the uterus as would sometimes be in this age-group, the ovaries may generally be left behind in young women. This leaves her the option of becoming a biological mother later with use of surrogacy.

If radiotherapy or chemotherapy is also needed, other fertility preservation strategies should be resorted to.

 

In early stage endometrial cancer, sometimes a combination of removing the lesion by a hysteroscopic procedure and high dose hormonal therapy is enough to induce resolution. A close follow up is necessary every three months with ultrasounds and endometrial sampling to look for recurrences. Most women attempting conception after such therapy conceive. The rate of recurrence after one year of stopping medicines is about thirty percent. Once child bearing is complete, the uterus should be removed by a radical surgery.

 

In ovarian cancer, if only one ovary is involved, the other ovary should be sampled and spared. In cases of bilateral ovarian involvement, fertility preservation strategies using ART should be employed.

 

What are the other fertility preservation strategies?

The following three strategies can be employed.

  1. Embryo/oocyte cryopreservation

    This is an established fertility preservation method in experienced centres. It requires a period of delaying cancer treatment for two to six weeks depending upon what phase of menstrual cycle the woman is in. But now, studies have shown that with the use of GnRh antagonist injections, the delay may need not be more than fourteen days. After follicular growth has occurred adequately under the influence of medicines, eggs are extracted and mature eggs are frozen for use later. In the presence of a spouse or partner, the eggs are fertilized with sperm and stored as embryos for later use.

  2. Ovarian tissue cryopreservation

    This is not an established fertility preservation method yet, but scores over the above methods in that a semen donor is not required and ovarian stimulation can be avoided. Ovarian tissue is removed laparoscopically or during laparotomy and frozen. This ovarian tissue is thawed and implanted back in the body when the patient recovers from cancer therapy. Freezing can lead to a loss of a large number of follicles. And hence the efficacy with this technique is really low. The ovarian endocrine function has been shown to be restored in about 20% of re-implanted tissue.

  3. Ovarian transposition

    This is offered when pelvic radiation is used for cancer treatment. It is a technique in which ovaries are surgically moved out of the radiation field. The procedure can be done laparoscopically or by laparotomy. Menstrual function returns in about 50% of patients. However, because of scatter radiation and higher doses of radiation used, sometimes the ovarian function fails to return. After the radiation courses are over, the ovary may need to be repositioned back in the pelvis as egg pick up by fallopian tubes may be a problem, although a few natural pregnancies have been reported in transposed ovaries.

  4. Ovarian suppression

    It is known that chemotherapeutic drugs and radiotherapy affect actively dividing cells the most. If the activity of these cells can be temporarily suspended, damage to these cells by chemotherapy or radiotherapy can be limited. Injections to suppress the pituitary (the master endocrine gland) with the intention to suppress ovarian egg production have been used in the past but results have been very variable. In the absence of any evidence of a clear benefit, most centers do not offer this method of fertility preservation.

Will fertility preservation options decrease chances of successful cancer treatment or increase the risk of cancer recurrence?

Currently, there is no evidence that fertility preservation options would do any of the above. However, three scenarios, mentioned below, need to be considered in women with cancer considering egg or embryo freezing. Possible solutions are mentioned as sub-points.

  1. The cancer stage may increase if chemotherapy is delayed to give time to pursue egg or embryo freezing.
    • Usually, a cleverly chosen way can be found in women who are not in the right phase of their cycle for egg harvesting. Even if ten days can be gained after diagnosis, egg harvesting is possible.
    • Ovarian tissue freezing, suppression or transposition can be offered when waiting is not an option.
  2. Ovarian stimulation for egg harvesting may lead to spread of breast or endometrial cancer.
    • A milder ovarian stimulation regime mitigates the effects of high hormonal levels.
  3. Re-implanting ovarian tissue after ovarian tissue freezing may cause recurrence of ovarian cancer.
    • Xenografting (transplant of tissues in mice, rabbits, guinea-pigs) of such tissue and subsequent egg harvesting from animals avoids the risk of cancer in the patient.

When can conception be attempted after completion of cancer treatment?

 Usually two years after stopping chemotherapeutic regimen or completion of radiotherapy, pregnancy can be attempted after a visit to a reproductive physician.

Will attempting pregnancy subsequently compromise on a cancer survivor’s health?

If cancer therapy has been with drugs that cause organ-toxicity, especially of the heart or lung, then pregnancy may exacerbate this insufficiency. For example, doxorubicin causes cardiac toxicity and its prolonged usage leads to lowered blood pumping ability. Pregnancy may worsen this as a result of imposing increased workload on the heart. But, in other cases, where the general health of women remains unaffected after stopping cancer therapy, pregnancy poses no additional risk to her health.

What effect will a history of cancer treatments have on the progeny?

In pregnant women who have a prior history of endometrial ablation or cervical amputation there appears to be an increased risk of repeated implantation failures, midtrimester losses, prematurity and low birth weight.

Some cancers are heritable like those of the colon associated with congenital polyposis or of the breast associated with BRCA gene mutation and there may be a risk of the same being inherited by the progeny. However, there aren’t enough studies that would suggest that a history of cancer, cancer chemotherapy, radiotherapy, or fertility interventions increase the risk of problems like genetic abnormalities, birth defects, or non-hereditary cancers, in the children of cancer survivors.

 

KEY POINTS

  • 4% of all cancers affect young individuals, desiring parenthood in future.
  • Cancer and cancer therapy can affect future fertility.
  • Medical or surgical interventions undertaken prior to cancer therapy can preserve fertility.
  • Most of the methods are established and few are still in the realm of the experimental.

 (Written by Dr. Ruma Satwik, for Gangaram health series 2016)

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