Oncology and Fertility
Infertility Issues in Cancer Patients
To most women faced with the horrific news of a newly diagnosed cancer, issues of fertility and child bearing would be the last thing on their minds. But over the last two decades, as treatment options for a variety of cancers affecting women of reproductive age have improved, issues of preserving fertility have come to the foreground. More and more, oncologists have begun discussions about future fertility potential as part of the routine consultation of men and women newly diagnosed with cancer.
Cancer can affect fertility in a variety of different ways. The cancer itself can alter fertility by affecting organs involved in fertility. This is especially true of the organs of the reproductive tract such as cancers of the cervix, uterus, fallopian tube and ovary. But other cancers such as lymphomas can affect fertility through metastatic involvement of the reproductive tract. Cancers of the central nervous system can affect fertility and reproduction by altering the secretions of brain hormones responsible for reproduction. And most cancers can also affect fertility by creating an environment in-hospitable to embryo development and growth.
But by far, the most important reason why cancer affects fertility is not because of the tumor itself but the treatments for that tumor. Namely, radiation, chemotherapy, and surgical therapy for cancer can all have the undesirable side effect of reducing or eliminating a woman’s ability to conceive. Radiation affects fertility by destroying the eggs in the ovary or scarring the uterus. Chemotherapy can affect fertility by destroying ovarian function. Surgery, especially for tumors of the reproductive tract, can result in the removal of organs involved in pregnancy.
In tackling fertility issues in women with cancer, a multi-disciplinary approach should be undertaken. It is vitally important that the infertility specialist work in conjunction with the members of the oncology team and that a consensus is reached regarding any fertility treatments that a patient may undergo.
In general, women faced with a diagnosis of cancer who desire future fertility should consult with a reproductive endocrinologist before initiating treatment. If the planned treatment for the cancer is found to be particularly injurious to ovarian function, several options do exist.
The most practical of these options is to undergo a rapid cycle of in vitro fertilization (IVF) and freeze the embryos before initiating cancer treatment. The embryos can then be transferred back into the uterus after the completion of treatment. This option can result in pregnancy rates as high as 40-50%, but it does raise several legitimate concerns. Many oncologists fear that delaying chemotherapy for the purpose of undergoing IVF may have a negative impact on survival rates. The effect of this delay on survival is highly dependant on the particular type of cancer. For example, delays of up to 1-2 months in women with Hodgkin’s lymphoma will have little impact on survival rates, while delaying treatment of pancreatic cancer for even a few weeks can have a detrimental effect.
With the introduction of newer medications in IVF, particularly the GnRH antagonists, it is now possible to dramatically shorten the duration of an IVF cycle from several weeks to 10-14 days. Most oncologists agree that a delay of 1-2 weeks will have little impact on survival rates in most cancers.
The other major concern raised is that some of the medications used in IVF may worsen the course of particular cancers. This is most notably true for breast cancer, which may contain receptors for estrogen. In a standard IVF cycle, estrogen levels may rise to levels far above the physiologic range. However, recent studies have shown that IVF cycles employing the drugs letrozle or tamoxifen can maintain low estrogen levels while still allowing for proper extraction of eggs and the freezing of embryos. Researchers from Cornell Medical College have recently published data on survival rates in women with breast cancer who underwent IVF using this modified protocol and found no differences in recurrence rates compared to breast cancer patients who did not undergo IVF treatment.
IVF and embryo freezing is therefore a definite option for women with partners. The option for women without partners is a bit more limited. These women may elect to undergo IVF with embryo freezing using donated sperm. This way, they can ensure that their genetic heritage will be preserved. More recently, the option of oocyte cryopreservation (egg freezing) has been introduced. Over the past few years, more and more IVF clinics are offering this option not only to cancer patients, but to single women who are approaching their mid to late 30’s and face decreased reproductive potential. The costs can be as high as $15,000. This is more than the cost of a standard IVF cycle.
Unlike sperm freezing (which is associate with excellent survivability and pregnancy rates), the data on egg freezing is tenuous at best. The major problem with oocyte cryopreservation is that the freezing process itself can irreversibly damage the fragile egg. The survivability rate after an egg has been thawed has been reported in the literature in the range of 1 to 20 %. This is compared with the thaw rate of frozen embryos which can be as high as 75% in some centers. To date, less than 150 pregnancies have been reported in the world literature from egg freezing. These facts have compelled the American Society for Reproductive Medicine (ASRM) to recently issue a statement that oocyte cryopreservation should not be marketed or offered to healthy women as a means to defer reproductive aging and that it should be offered to cancer patients only under strict research protocols.
Ovarian tissue freezing has also recently been introduced as a means of preserving fertility in cancer patients. The first birth from a transplanted frozen ovarian tissue in a woman with cancer was recently reported in Belgium . Again, it is far too early to recommend routine use of ovarian tissue freezing outside the scope of approved research protocols.
Women faced with cancers that require radiation to the abdomen and pelvis are at particular risk for ovarian failure. Common cancers which require pelvic radiation include cervical cancer and some lymphomas. The dose required to render an ovary non functional is dependant on the age of the woman, but has been reported in the range 800 to 2000 cGray. Women undergoing abdominal or pelvic radiation may benefit from undergoing a procedure called ovarian transposition in which the ovaries are moved higher up into the abdomen and out of the radiation field. This procedure should be performed by an experienced gynecological surgeon as there is a risk of compromising the blood supply to the ovary as it is being moved.
These are all steps that can be taken to preserve fertility in women before they initiate treatment for their cancer. But further steps can be taken during the treatment process itself to help improve the chances of preserving fertility. Chemotherapy is one of the biggest culprits in affecting fertility in cancer patients. The chance that a woman’s fertility will be affected by chemotherapy is dependant on a variety of factors. Chief among them is the woman’s age at the time of treatment. Children and younger women tend to survive the reproductive impact of chemotherapy much better than women in their 30’s and 40’s.
Although chemotherapy may not immediately cause a woman to enter menopause, it does shorten the time it will take for a woman to reach menopause. For example, a 30 year old woman receiving chemotherapy may reach menopause at the age of 40 whereas she would have otherwise reached menopause at the age of 50 if she had not received chemotherapy. The type of chemotherapy used can also have a dramatic effect on fertility potential. In general, alkylating agents such as cyclophosphamide have a more profound affect on ovarian function, compared to other chemotherapeutic agents. Therefore, modifying the chemotherapy treatment, as long as it does not have an impact on survival, may help improve reproductive outcome. This has been demonstrated in women with lymphoma.
The long standing chemotherapy regimen for patients with lymphoma, called CHOPP, has been associated with a high rate of ovarian failure and infertility. A newer regimen, called ABVD, has been shown to be as effective as CHOPP in treating lymphoma, while dramatically reducing the rate of ovarian failure and infertility. Patients should discuss the effects of chemotherapy with their oncologist and formulate a regimen which would be “friendly” to reproductive function.
In addition to modifying the type of chemotherapy, it is also possible to use adjunctive medication to help protect the ovaries from the effects of any chemotherapeutic drug. Chemotherapy tends to work on cells in the body that are rapidly dividing. This of course includes the cancer cells, but also normal cells in the body such as blood cells in the bone marrow, cells in the hair follicles and the granulosa cells which surround and nourish the eggs inside the ovary. A class of drugs called GnRH agonists work by suppressing the production of the sex hormones LH and FSH which are responsible for the growth and division of the granulosa cells. GnRH agonists therefore slow down the growth and division of these granulosa cells and make them less susceptible to the harmful effects of chemotherapy.
Recent studies from Israel have shown that women who take GnRH agonists with their chemotherapy retain their ovarian function at much higher rates than those who do not. In the United States , a GnRH agonist called lupron can be administered in the form of a depot injection which can last 3 months. The typical duration of a chemotherapy regimen lasts three to six months.
Historically, women faced with cancers of the female reproductive tract, had little option in preserving their fertility. The principle treatment of these cancers has been the surgical removal of the effected reproductive organ. Over the past 10 years, more attention has been focused on approaches that treat these gynecological cancers while maintaining fertility. For example, some women with cervical cancer now have the option to undergo a procedure called radical trachelectomy in which only the cervix and adjacent tissues are removed. This allows for the preservation of the uterus which has traditionally been removed as part of the surgery for cervical cancer.
The standard treatment for ovarian cancer is the removal of both ovaries, uterus and lymph nodes. Some women with Stage I ovarian cancer or with a particular type of ovarian tumor called Low Malignant Potential tumors can undergo fertility sparing surgery with the removal of only one ovary. Women faced with the diagnosis of reproductive tract cancers should discuss these and other fertility sparing options with their physicians and, when appropriate, seek a second opinion.
After completion of cancer treatment, many women cease to menstruate for some time. For some women, this may be permanent and herald the onset of menopause. Most women however do regain some reproductive function. Some can even become pregnant spontaneously. Most women do need some form of advanced reproductive techniques to help them in this endeavor, be it insemination with medications or IVF. As most cancer recurrences occur within the first 2 years after treatment, it is generally recommended that women wait at least that long before attempting pregnancy.
Pregnancy itself and its associated hormone changes can at times have an effect on recurrences of some cancers. A thorough discussion with one’s oncologist should be undertaken. Ideally, a consultation with an obstetrician and reproductive endocrinologist would also be advised. The risk and benefits of the pregnancy should be seriously weighed before any attempt at treatment is undertaken. With breast cancer patients in particular, treatment protocols which increase estrogen levels should be avoided. Again, the use of Tamoxifen or leptosome may help reduce or eliminate this risk.
Given that cancer incidence increases with age, more women are either diagnosed with cancer during the course of gestation or inquire into the feasibility and safety of pregnancy following cancer diagnosis. Here, we provide the ESMO Clinical Practice Guidelines for managing patients diagnosed with cancer during pregnancy. Also, we provide guidance on fertility considerations for women desiring pregnancy following cancer diagnosis