Fertility Preservation No Longer Experimental for Cancer Patients

Fertility preservation for young women facing cancer therapy has garnered endorsements from leading medical groups in oncology and reproductive medicine, and it isn’t in the experimental stages anymore, interviews with experts suggest.

"There is more literature coming out showing that egg freezing does work," said Dr. Clarisa R. Gracia, director of fertility preservation at the University of Pennsylvania Health System, Philadelphia. "We have more data that we can show patients to say, ‘This is not as experimental as it used to be. It is improving, and it is a real option to offer.’ "

Courtesy Dr. Clarisa R. Gracia

For example, several randomized controlled trials have shown that using frozen eggs is equivalent to using fresh eggs (Hum. Reprod. 2010;25:66-73; Hum. Reprod. 2010;25:2239-46).

The two most common methods of fertility preservation are embryo freezing and egg freezing, according to Dr. Nicole Noyes, a New York City–based reproductive endocrinologist who specializes in infertility, in vitro fertilization (IVF), and egg freezing.

Both procedures involve the use of follicle-stimulating hormone, an injectable medication that causes maturation of multiple eggs in the woman’s ovaries as opposed to a single egg that is naturally ovulated. The stimulated eggs are then gently aspirated from the ovary and placed in a Petri dish.

From this point, either the eggs can be frozen in the unfertilized state or, alternatively, sperm is added, allowing for fertilization and, thus, the creation of embryos prior to freezing. Using either method, eggs or embryos remain cryopreserved until a pregnancy is desired, at which time they are removed from liquid nitrogen for usage. In the case of eggs, fertilization is required post thaw before transfer back to the uterus.

Single girls and women who don’t have a male partner and, thus, don’t have a source of male gamete – other than donor sperm from a bank or "friend" – most often choose egg freezing, whereas women in a committed relationship more often freeze embryos.

"In my patient population, even patients in a committed relationship often choose to freeze some of their gametes unfertilized to increase reproductive autonomy and to lower the relationship pressure – especially given all the stress," she said.

Another fertility preservation option is ovarian tissue freezing, an experimental procedure in which clinicians remove a piece of the ovary via laparoscopy and freeze it. The stored tissue can then be thawed and transplanted back into the pelvis at a later time, in the hope of achieving ovarian function with ovulation and subsequent pregnancy.

"Ovarian tissue freezing is also sometimes offered to prepubertal girls with hopes that it will later function as a source of eggs for that person. To date, there have been no pregnancies or births from tissue transplanted back after being removed at a prepubertal age," Dr. Noyes said.

The advantage of ovarian tissue freezing is that it can be performed in a few hours. The disadvantages are that it requires surgery (general anesthesia and laparoscopy or laparotomy), and there are relatively few successes at this time.

"There have been 17 live births reported worldwide from ovarian tissue freezing and transplantation" in patients who had cancer, Dr. Gracia said "While that’s a limited number, it shows that it can work, and it gives ammunition to keep referring patients to reproductive endocrinologists who are involved in fertility preservation and who are aware of what’s available."

Timing and Cancer Type Are Critical

Young women with breast cancer, gynecologic cancer, or a hematologic malignancy are the patients most often seeking fertility preservation, said Dr. Noyes. It takes an average of 17 days from the day of consult with a reproductive endocrinologist to the day of oocyte retrieval, and this can be an obstacle.

"For some malignancies, that’s too long to wait, such as for hematologic malignancies including non-Hodgkin’s lymphoma – the really sick patients who have a full tumor load," she said.

"In breast cancer cases, we generally do oocyte retrieval between surgery and chemotherapy. There’s usually a 4-6 week window there, so that usually is not an issue. The problem is, sometimes the oncologist doesn’t call you until they’re 5 weeks after their surgery to ask if you can do the oocyte retrieval in 7 days."

Bone marrow transplant patients face almost a 100% chance of ovarian failure from the pretreatment for the transplant. "Those patients are great candidates for fertility preservation," Dr. Noyes said. "Any regimen that has an alkylating agent such as cyclophosphamide (Cytoxan), those patients are at high risk. Almost all breast cancer patients get Cytoxan."

Not all female cancer patients opt for fertility preservation, however. For example, the initial treatment for Hodgkin’s lymphoma, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin, vinblastine, and dacarbazine), is a chemotherapeutic regimen with low toxicity that usually does not cause infertility.

"Many of those patients do not end up doing fertility preservation, because ultimately 90% of women with Hodgkin’s lymphoma get cured and will be able to get pregnant without a problem, as long as they try before the age of 35," Dr. Gracia said.

The problem is that "10% of women who relapse will then require a bone marrow transplant as the subsequent therapy," she continued, and no one knows who they will be. "That treatment causes infertility in over 95% of patients."

Many oncologists do not refer Hodgkin’s lymphoma patients on the assumption that all will be fine after ABVD therapy. "But if the chemotherapy regimen fails and [the patients] come back to see me, at that point the options are more limited in terms of what you can offer them. ... Their ovaries may not respond as well to treatment in order to stimulate the ovaries with injections of gonadotropin, and then retrieve eggs in order to freeze eggs or embryos."

Providing fertility preservation for patients with leukemia can be challenging, Dr. Gracia added, because they sometimes are so sick "that it’s not really safe to put them through procedures like ovarian stimulation, or egg or embryo freezing. Those are patients we are often not able to help."

Cancer prognosis also can be a factor in deciding whether a patient is a good candidate for fertility preservation, although Dr. Noyes urged caution on that issue. "Even if a patient has stage III cancer and the survival rate is 20%, I don’t think it’s my place to judge that. ... If she is in the 20% who survive, she will not be happy if you say, ‘I didn’t do oocyte retrieval because I didn’t figure you would make it,’ " she explained.

In a survey answered by 516 oncologists, slightly less than half of respondents took "a neutral stance" on the advisability of poor-prognosis patients pursuing fertility preservation. While 23% agreed that these patients should not pursue fertility preservation, 32% disagreed; data were missing for 1%. Similarly, 51% had no opinion on posthumous parenting, only 16% expressed support, and 32% were opposed. Again, data were missing for 1%.

"Oncologists’ personal attitudes regarding posthumous reproduction were related to referral of patients with a poor prognosis," the authors wrote, noting that religious beliefs can influence physician attitudes (J. Support. Oncol. 2011 [doi: 10.1016/j.suponc.2011.09.006]).

How Old, How Young, and With Whom?

Age cutoffs for fertility preservation vary from practice to practice, but most physicians won’t perform the practice in patients older than age 46. When providing counseling about fertility preservation options, Dr. Noyes makes it a point to ask the patient if she is in a committed relationship with someone with whom she can rear a child.

"Oftentimes rather than just freezing all embryos, I’ll freeze half as unfertilized eggs and half as embryos, even if the woman is in a committed relationship," Dr. Noyes said. "This creates less pressure on the couple, and there is some reproductive autonomy if things don’t work out. The woman could still use those eggs with someone else."

Dr. Gracia once had a 49-year-old cancer patient seek her assistance with fertility preservation. "I told her, ‘You’re close to menopause and unfortunately, fertility preservation technologies will not work at your age.’ Even in situations where a woman’s fertility is already compromised, a cancer diagnosis often makes individuals even more aware of their future fertility, since treatments may take away their ability to have children."

©Monkey Business/Fotolia.com

With IVF, the efficiency is about a 6%-7% live birth rate per egg. With egg freezing, the efficiency stands at about 5% per egg, "so it’s similar to IVF, which is good," Dr. Noyes said. "We know from years and years of IVF that every egg isn’t meant to be a baby. Otherwise, the pregnancy success rate would have gone from about 30%, which it was in 1990, to almost 100% now. It improved from about 30% in 1990 to 50%-60% now."

To date, Dr. Noyes has performed fertility preservation in about 125 cancer patients, and 6 of them have returned to use the frozen eggs or embryos. "On average, they are using their preserved eggs or embryos about 3 years after preserving them," she said. "It depends on their age when they freeze the eggs or embryos. The very young girls aren’t going to be back for a decade or more."

The best candidates for ovarian tissue freezing are children, "because it’s not possible to stimulate the ovaries of a girl who hasn’t gone through puberty yet," Dr. Gracia said. "That’s really the only option they have. We also offer it to patients who are at extremely high risk for going through ovarian failure or infertility, like patients who need to get transplants or those who receive high doses of alkylating agents."

Fears of Recurrence

Some breast cancer patients ask Dr. Karine Chung, director of the Fertility Preservation Program at the University of Southern California, Los Angeles, if fertility treatments or becoming pregnant will increase the risk that the cancer may return. She tells them that "while theoretically it is a concern that becoming pregnant after breast cancer could increase the rate of recurrence, there have been a number of very well-designed, large studies that have shown that that is not the case."

"As far as whether going through IVF or ovarian stimulation increases the risk of recurrence, we don’t think so. There is very limited data looking at that, but if you compare what happens during an IVF cycle and what happens during pregnancy, an IVF cycle is a very short period of time in which a woman is exposed to high levels of estrogen, whereas pregnancy is a relatively long time in which a woman is exposed to high levels of estrogen. If pregnancy has not turned out increased recurrence, we don’t think that IVF will, either," she said.

Dr. Alison W. Loren, fellowship program director in the division of hematology/oncology at the University of Pennsylvania, Philadelphia, tells her hematology patients that there is "really no increased risk of recurrence of blood cancers, if they choose to become pregnant after their cancer treatment."

On the other hand, women who have hormone receptor–positive cancers "are generally counseled to wait at least 5 years after their cancer treatment is complete to become pregnant, but that’s not evidence based. There are concerns in cases where the fertility window is shortened. For example, if you advise a 32-year-old woman to wait 5 years after her last cancer treatment to get pregnant, you could be jeopardizing her ability to get pregnant."

Increased recurrence rates for certain types of cancer following fertility preservation were reported at the March 2102 annual meeting of the Society of Gynecologic Oncology in Austin, Tex. A study from Japan reported a recurrence rate of 24% after use of high-dose medroxyprogesterone acetate in young patients with endometrial cancer. The total number of pregnancies was 42; delivery outcomes were 19 normal deliveries, 11 cesarean sections, 2 premature deliveries, 5 spontaneous abortions, 2 induced abortions, 1 unknown, and 2 ongoing pregnancies (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.006]). A separate, multicenter study in the United States found that the risk of recurrence in patients with serous borderline ovarian tumors was 35% among patients who underwent fertility-sparing surgery, compared with 15% in other patients; at least 7 healthy infants were delivered (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.007]).

©Monkey Business/Fotolia.com

The data have not yet been published in a medical journal except as meeting abstracts, however, and Dr. Loren was reluctant to comment until more information becomes available.

Cost Can Be an Obstacle

Insurance rarely covers the cost of fertility preservation for cancer patients, and the costs can reach $20,000. Fertile Hope’s Sharing Hope Program for Women, an initiative of the Lance Armstrong Foundation, invites cancer patients to apply for discounted services and donated medications (www.fertilehope.org). Eligibility requirements include being a U.S. citizen or permanent resident with an annual household income of less than $75,000 (single) or $100,000 (married), and having not yet started fertility-damaging cancer treatments.

Other resources for patients include Fertile Action (http://fertileaction.org), which was founded by a breast cancer survivor, and MyOncofertility.org (http://myoncofertility.org), an education resource provided by the Oncofertility Consortium.

Who Has Expertise in Fertility Preservation?

New guidelines from the National Comprehensive Cancer Network establish young adult and adolescent cancer patients as a distinct group whom oncologists should routinely send for fertility counseling. Will they?

Oncologists are not necessarily knowledgeable about the options or in the habit of referring patients to reproductive endocrinologists or other clinicians who specialize in fertility, according to Dr. Chung.

"Because [the oncologists’] knowledge of fertility and ovarian function in general is somewhat limited, to have a meaningful discussion about fertility preservation options with these patients is difficult," she said.

The American Society of Clinical Oncology (J. Clin. Oncol 2006:24:2917-31). and the American Society for Reproductive Medicine (Fertil. Steril. 2005;83:1622-8) have previously recommended that all women be offered counseling and an opportunity to preserve their fertility before cancer therapy, but implementation appears to be mixed.

According to a 2009 survey of 249 oncologists who practice at academic medical centers, 95% reported routinely discussing a cancer treatment’s impact on fertility (Fertil. Steril. 2010;94:1652-6). Only 39% said they routinely referred female cancer patients to a reproductive endocrinologist or ob.gyn. who specializes in fertility, however, while 18% said they never refer their patients. Reasons most commonly cited for not referring included lack of patient interest in fertility preservation (38%), lack of time because of emergent need to start therapy (28%), and poor prognosis for future fertility (6%).

Three key factors contribute to a lack of referrals by oncologists, according to Dr. Loren: a lack of time, a lack of access to reproductive endocrinologists in the oncologist’s network/institution, and a lack of baseline knowledge about fertility preservation options.

"Many oncologists don’t know a lot about this; so they worry if they bring this up, patients are going to start asking, ‘What are my options?’ " Dr. Loren said.

"We have studied this issue specifically among clinicians who provide bone marrow transplantation to cancer patients. Lack of knowledge and lack of access to a provider are the biggest reasons that people don’t refer patients for fertility preservation," she added.

Dr. Loren advises gynecology specialists to make networking inroads with oncologists by offering to be their referral source for patients with questions about fertility preservation. This may include speaking at grand rounds and at occasional meetings of oncology faculty and staff – anything to increase awareness of options for patients. "A key to this is good communication," she said.

In a year-long pilot study carried out at the Tampa, Fla.–based Lee Moffitt Cancer Center to develop a referral system for fertility preservation in patients with newly diagnosed cancer, measures that included placement of informational brochures in the waiting room and establishment of a dedicated telephone line for referrals led to a ninefold increase in the number of calls received (J. Natl. Compr. Canc. Netw. 2011;9:1219-25). The researchers concluded that such a referral system "allows oncologists to fulfill their obligation and make informed decisions about fertility preservation, thereby improving the full cancer care continuum."

Dr. Chung, Dr. Loren, Dr. Noyes and Dr. Gracia said that they had no relevant financial disclosures.

Fertility preservation for young women facing cancer therapy has garnered endorsements from leading medical groups in oncology and reproductive medicine, and it isn’t in the experimental stages anymore, interviews with experts suggest.

"There is more literature coming out showing that egg freezing does work," said Dr. Clarisa R. Gracia, director of fertility preservation at the University of Pennsylvania Health System, Philadelphia. "We have more data that we can show patients to say, ‘This is not as experimental as it used to be. It is improving, and it is a real option to offer.’ "

Courtesy Dr. Clarisa R. Gracia

For example, several randomized controlled trials have shown that using frozen eggs is equivalent to using fresh eggs (Hum. Reprod. 2010;25:66-73; Hum. Reprod. 2010;25:2239-46).

The two most common methods of fertility preservation are embryo freezing and egg freezing, according to Dr. Nicole Noyes, a New York City–based reproductive endocrinologist who specializes in infertility, in vitro fertilization (IVF), and egg freezing.

Both procedures involve the use of follicle-stimulating hormone, an injectable medication that causes maturation of multiple eggs in the woman’s ovaries as opposed to a single egg that is naturally ovulated. The stimulated eggs are then gently aspirated from the ovary and placed in a Petri dish.

From this point, either the eggs can be frozen in the unfertilized state or, alternatively, sperm is added, allowing for fertilization and, thus, the creation of embryos prior to freezing. Using either method, eggs or embryos remain cryopreserved until a pregnancy is desired, at which time they are removed from liquid nitrogen for usage. In the case of eggs, fertilization is required post thaw before transfer back to the uterus.

Single girls and women who don’t have a male partner and, thus, don’t have a source of male gamete – other than donor sperm from a bank or "friend" – most often choose egg freezing, whereas women in a committed relationship more often freeze embryos.

"In my patient population, even patients in a committed relationship often choose to freeze some of their gametes unfertilized to increase reproductive autonomy and to lower the relationship pressure – especially given all the stress," she said.

Another fertility preservation option is ovarian tissue freezing, an experimental procedure in which clinicians remove a piece of the ovary via laparoscopy and freeze it. The stored tissue can then be thawed and transplanted back into the pelvis at a later time, in the hope of achieving ovarian function with ovulation and subsequent pregnancy.

"Ovarian tissue freezing is also sometimes offered to prepubertal girls with hopes that it will later function as a source of eggs for that person. To date, there have been no pregnancies or births from tissue transplanted back after being removed at a prepubertal age," Dr. Noyes said.

The advantage of ovarian tissue freezing is that it can be performed in a few hours. The disadvantages are that it requires surgery (general anesthesia and laparoscopy or laparotomy), and there are relatively few successes at this time.

"There have been 17 live births reported worldwide from ovarian tissue freezing and transplantation" in patients who had cancer, Dr. Gracia said "While that’s a limited number, it shows that it can work, and it gives ammunition to keep referring patients to reproductive endocrinologists who are involved in fertility preservation and who are aware of what’s available."

Timing and Cancer Type Are Critical

Young women with breast cancer, gynecologic cancer, or a hematologic malignancy are the patients most often seeking fertility preservation, said Dr. Noyes. It takes an average of 17 days from the day of consult with a reproductive endocrinologist to the day of oocyte retrieval, and this can be an obstacle.

"For some malignancies, that’s too long to wait, such as for hematologic malignancies including non-Hodgkin’s lymphoma – the really sick patients who have a full tumor load," she said.

"In breast cancer cases, we generally do oocyte retrieval between surgery and chemotherapy. There’s usually a 4-6 week window there, so that usually is not an issue. The problem is, sometimes the oncologist doesn’t call you until they’re 5 weeks after their surgery to ask if you can do the oocyte retrieval in 7 days."

Bone marrow transplant patients face almost a 100% chance of ovarian failure from the pretreatment for the transplant. "Those patients are great candidates for fertility preservation," Dr. Noyes said. "Any regimen that has an alkylating agent such as cyclophosphamide (Cytoxan), those patients are at high risk. Almost all breast cancer patients get Cytoxan."

Not all female cancer patients opt for fertility preservation, however. For example, the initial treatment for Hodgkin’s lymphoma, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin, vinblastine, and dacarbazine), is a chemotherapeutic regimen with low toxicity that usually does not cause infertility.

"Many of those patients do not end up doing fertility preservation, because ultimately 90% of women with Hodgkin’s lymphoma get cured and will be able to get pregnant without a problem, as long as they try before the age of 35," Dr. Gracia said.

The problem is that "10% of women who relapse will then require a bone marrow transplant as the subsequent therapy," she continued, and no one knows who they will be. "That treatment causes infertility in over 95% of patients."

Many oncologists do not refer Hodgkin’s lymphoma patients on the assumption that all will be fine after ABVD therapy. "But if the chemotherapy regimen fails and [the patients] come back to see me, at that point the options are more limited in terms of what you can offer them. ... Their ovaries may not respond as well to treatment in order to stimulate the ovaries with injections of gonadotropin, and then retrieve eggs in order to freeze eggs or embryos."

Providing fertility preservation for patients with leukemia can be challenging, Dr. Gracia added, because they sometimes are so sick "that it’s not really safe to put them through procedures like ovarian stimulation, or egg or embryo freezing. Those are patients we are often not able to help."

Cancer prognosis also can be a factor in deciding whether a patient is a good candidate for fertility preservation, although Dr. Noyes urged caution on that issue. "Even if a patient has stage III cancer and the survival rate is 20%, I don’t think it’s my place to judge that. ... If she is in the 20% who survive, she will not be happy if you say, ‘I didn’t do oocyte retrieval because I didn’t figure you would make it,’ " she explained.

In a survey answered by 516 oncologists, slightly less than half of respondents took "a neutral stance" on the advisability of poor-prognosis patients pursuing fertility preservation. While 23% agreed that these patients should not pursue fertility preservation, 32% disagreed; data were missing for 1%. Similarly, 51% had no opinion on posthumous parenting, only 16% expressed support, and 32% were opposed. Again, data were missing for 1%.

"Oncologists’ personal attitudes regarding posthumous reproduction were related to referral of patients with a poor prognosis," the authors wrote, noting that religious beliefs can influence physician attitudes (J. Support. Oncol. 2011 [doi: 10.1016/j.suponc.2011.09.006]).

How Old, How Young, and With Whom?

Age cutoffs for fertility preservation vary from practice to practice, but most physicians won’t perform the practice in patients older than age 46. When providing counseling about fertility preservation options, Dr. Noyes makes it a point to ask the patient if she is in a committed relationship with someone with whom she can rear a child.

"Oftentimes rather than just freezing all embryos, I’ll freeze half as unfertilized eggs and half as embryos, even if the woman is in a committed relationship," Dr. Noyes said. "This creates less pressure on the couple, and there is some reproductive autonomy if things don’t work out. The woman could still use those eggs with someone else."

Dr. Gracia once had a 49-year-old cancer patient seek her assistance with fertility preservation. "I told her, ‘You’re close to menopause and unfortunately, fertility preservation technologies will not work at your age.’ Even in situations where a woman’s fertility is already compromised, a cancer diagnosis often makes individuals even more aware of their future fertility, since treatments may take away their ability to have children."

©Monkey Business/Fotolia.com

With IVF, the efficiency is about a 6%-7% live birth rate per egg. With egg freezing, the efficiency stands at about 5% per egg, "so it’s similar to IVF, which is good," Dr. Noyes said. "We know from years and years of IVF that every egg isn’t meant to be a baby. Otherwise, the pregnancy success rate would have gone from about 30%, which it was in 1990, to almost 100% now. It improved from about 30% in 1990 to 50%-60% now."

To date, Dr. Noyes has performed fertility preservation in about 125 cancer patients, and 6 of them have returned to use the frozen eggs or embryos. "On average, they are using their preserved eggs or embryos about 3 years after preserving them," she said. "It depends on their age when they freeze the eggs or embryos. The very young girls aren’t going to be back for a decade or more."

The best candidates for ovarian tissue freezing are children, "because it’s not possible to stimulate the ovaries of a girl who hasn’t gone through puberty yet," Dr. Gracia said. "That’s really the only option they have. We also offer it to patients who are at extremely high risk for going through ovarian failure or infertility, like patients who need to get transplants or those who receive high doses of alkylating agents."

Fears of Recurrence

Some breast cancer patients ask Dr. Karine Chung, director of the Fertility Preservation Program at the University of Southern California, Los Angeles, if fertility treatments or becoming pregnant will increase the risk that the cancer may return. She tells them that "while theoretically it is a concern that becoming pregnant after breast cancer could increase the rate of recurrence, there have been a number of very well-designed, large studies that have shown that that is not the case."

"As far as whether going through IVF or ovarian stimulation increases the risk of recurrence, we don’t think so. There is very limited data looking at that, but if you compare what happens during an IVF cycle and what happens during pregnancy, an IVF cycle is a very short period of time in which a woman is exposed to high levels of estrogen, whereas pregnancy is a relatively long time in which a woman is exposed to high levels of estrogen. If pregnancy has not turned out increased recurrence, we don’t think that IVF will, either," she said.

Dr. Alison W. Loren, fellowship program director in the division of hematology/oncology at the University of Pennsylvania, Philadelphia, tells her hematology patients that there is "really no increased risk of recurrence of blood cancers, if they choose to become pregnant after their cancer treatment."

On the other hand, women who have hormone receptor–positive cancers "are generally counseled to wait at least 5 years after their cancer treatment is complete to become pregnant, but that’s not evidence based. There are concerns in cases where the fertility window is shortened. For example, if you advise a 32-year-old woman to wait 5 years after her last cancer treatment to get pregnant, you could be jeopardizing her ability to get pregnant."

Increased recurrence rates for certain types of cancer following fertility preservation were reported at the March 2102 annual meeting of the Society of Gynecologic Oncology in Austin, Tex. A study from Japan reported a recurrence rate of 24% after use of high-dose medroxyprogesterone acetate in young patients with endometrial cancer. The total number of pregnancies was 42; delivery outcomes were 19 normal deliveries, 11 cesarean sections, 2 premature deliveries, 5 spontaneous abortions, 2 induced abortions, 1 unknown, and 2 ongoing pregnancies (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.006]). A separate, multicenter study in the United States found that the risk of recurrence in patients with serous borderline ovarian tumors was 35% among patients who underwent fertility-sparing surgery, compared with 15% in other patients; at least 7 healthy infants were delivered (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.007]).

©Monkey Business/Fotolia.com

The data have not yet been published in a medical journal except as meeting abstracts, however, and Dr. Loren was reluctant to comment until more information becomes available.

Cost Can Be an Obstacle

Insurance rarely covers the cost of fertility preservation for cancer patients, and the costs can reach $20,000. Fertile Hope’s Sharing Hope Program for Women, an initiative of the Lance Armstrong Foundation, invites cancer patients to apply for discounted services and donated medications (www.fertilehope.org). Eligibility requirements include being a U.S. citizen or permanent resident with an annual household income of less than $75,000 (single) or $100,000 (married), and having not yet started fertility-damaging cancer treatments.

Other resources for patients include Fertile Action (http://fertileaction.org), which was founded by a breast cancer survivor, and MyOncofertility.org (http://myoncofertility.org), an education resource provided by the Oncofertility Consortium.

Who Has Expertise in Fertility Preservation?

New guidelines from the National Comprehensive Cancer Network establish young adult and adolescent cancer patients as a distinct group whom oncologists should routinely send for fertility counseling. Will they?

Oncologists are not necessarily knowledgeable about the options or in the habit of referring patients to reproductive endocrinologists or other clinicians who specialize in fertility, according to Dr. Chung.

"Because [the oncologists’] knowledge of fertility and ovarian function in general is somewhat limited, to have a meaningful discussion about fertility preservation options with these patients is difficult," she said.

The American Society of Clinical Oncology (J. Clin. Oncol 2006:24:2917-31). and the American Society for Reproductive Medicine (Fertil. Steril. 2005;83:1622-8) have previously recommended that all women be offered counseling and an opportunity to preserve their fertility before cancer therapy, but implementation appears to be mixed.

According to a 2009 survey of 249 oncologists who practice at academic medical centers, 95% reported routinely discussing a cancer treatment’s impact on fertility (Fertil. Steril. 2010;94:1652-6). Only 39% said they routinely referred female cancer patients to a reproductive endocrinologist or ob.gyn. who specializes in fertility, however, while 18% said they never refer their patients. Reasons most commonly cited for not referring included lack of patient interest in fertility preservation (38%), lack of time because of emergent need to start therapy (28%), and poor prognosis for future fertility (6%).

Three key factors contribute to a lack of referrals by oncologists, according to Dr. Loren: a lack of time, a lack of access to reproductive endocrinologists in the oncologist’s network/institution, and a lack of baseline knowledge about fertility preservation options.

"Many oncologists don’t know a lot about this; so they worry if they bring this up, patients are going to start asking, ‘What are my options?’ " Dr. Loren said.

"We have studied this issue specifically among clinicians who provide bone marrow transplantation to cancer patients. Lack of knowledge and lack of access to a provider are the biggest reasons that people don’t refer patients for fertility preservation," she added.

Dr. Loren advises gynecology specialists to make networking inroads with oncologists by offering to be their referral source for patients with questions about fertility preservation. This may include speaking at grand rounds and at occasional meetings of oncology faculty and staff – anything to increase awareness of options for patients. "A key to this is good communication," she said.

In a year-long pilot study carried out at the Tampa, Fla.–based Lee Moffitt Cancer Center to develop a referral system for fertility preservation in patients with newly diagnosed cancer, measures that included placement of informational brochures in the waiting room and establishment of a dedicated telephone line for referrals led to a ninefold increase in the number of calls received (J. Natl. Compr. Canc. Netw. 2011;9:1219-25). The researchers concluded that such a referral system "allows oncologists to fulfill their obligation and make informed decisions about fertility preservation, thereby improving the full cancer care continuum."

Dr. Chung, Dr. Loren, Dr. Noyes and Dr. Gracia said that they had no relevant financial disclosures.

Fertility preservation for young women facing cancer therapy has garnered endorsements from leading medical groups in oncology and reproductive medicine, and it isn’t in the experimental stages anymore, interviews with experts suggest.

"There is more literature coming out showing that egg freezing does work," said Dr. Clarisa R. Gracia, director of fertility preservation at the University of Pennsylvania Health System, Philadelphia. "We have more data that we can show patients to say, ‘This is not as experimental as it used to be. It is improving, and it is a real option to offer.’ "

Courtesy Dr. Clarisa R. Gracia

For example, several randomized controlled trials have shown that using frozen eggs is equivalent to using fresh eggs (Hum. Reprod. 2010;25:66-73; Hum. Reprod. 2010;25:2239-46).

The two most common methods of fertility preservation are embryo freezing and egg freezing, according to Dr. Nicole Noyes, a New York City–based reproductive endocrinologist who specializes in infertility, in vitro fertilization (IVF), and egg freezing.

Both procedures involve the use of follicle-stimulating hormone, an injectable medication that causes maturation of multiple eggs in the woman’s ovaries as opposed to a single egg that is naturally ovulated. The stimulated eggs are then gently aspirated from the ovary and placed in a Petri dish.

From this point, either the eggs can be frozen in the unfertilized state or, alternatively, sperm is added, allowing for fertilization and, thus, the creation of embryos prior to freezing. Using either method, eggs or embryos remain cryopreserved until a pregnancy is desired, at which time they are removed from liquid nitrogen for usage. In the case of eggs, fertilization is required post thaw before transfer back to the uterus.

Single girls and women who don’t have a male partner and, thus, don’t have a source of male gamete – other than donor sperm from a bank or "friend" – most often choose egg freezing, whereas women in a committed relationship more often freeze embryos.

"In my patient population, even patients in a committed relationship often choose to freeze some of their gametes unfertilized to increase reproductive autonomy and to lower the relationship pressure – especially given all the stress," she said.

Another fertility preservation option is ovarian tissue freezing, an experimental procedure in which clinicians remove a piece of the ovary via laparoscopy and freeze it. The stored tissue can then be thawed and transplanted back into the pelvis at a later time, in the hope of achieving ovarian function with ovulation and subsequent pregnancy.

"Ovarian tissue freezing is also sometimes offered to prepubertal girls with hopes that it will later function as a source of eggs for that person. To date, there have been no pregnancies or births from tissue transplanted back after being removed at a prepubertal age," Dr. Noyes said.

The advantage of ovarian tissue freezing is that it can be performed in a few hours. The disadvantages are that it requires surgery (general anesthesia and laparoscopy or laparotomy), and there are relatively few successes at this time.

"There have been 17 live births reported worldwide from ovarian tissue freezing and transplantation" in patients who had cancer, Dr. Gracia said "While that’s a limited number, it shows that it can work, and it gives ammunition to keep referring patients to reproductive endocrinologists who are involved in fertility preservation and who are aware of what’s available."

Timing and Cancer Type Are Critical

Young women with breast cancer, gynecologic cancer, or a hematologic malignancy are the patients most often seeking fertility preservation, said Dr. Noyes. It takes an average of 17 days from the day of consult with a reproductive endocrinologist to the day of oocyte retrieval, and this can be an obstacle.

"For some malignancies, that’s too long to wait, such as for hematologic malignancies including non-Hodgkin’s lymphoma – the really sick patients who have a full tumor load," she said.

"In breast cancer cases, we generally do oocyte retrieval between surgery and chemotherapy. There’s usually a 4-6 week window there, so that usually is not an issue. The problem is, sometimes the oncologist doesn’t call you until they’re 5 weeks after their surgery to ask if you can do the oocyte retrieval in 7 days."

Bone marrow transplant patients face almost a 100% chance of ovarian failure from the pretreatment for the transplant. "Those patients are great candidates for fertility preservation," Dr. Noyes said. "Any regimen that has an alkylating agent such as cyclophosphamide (Cytoxan), those patients are at high risk. Almost all breast cancer patients get Cytoxan."

Not all female cancer patients opt for fertility preservation, however. For example, the initial treatment for Hodgkin’s lymphoma, ABVD (doxorubicin hydrochloride [Adriamycin], bleomycin, vinblastine, and dacarbazine), is a chemotherapeutic regimen with low toxicity that usually does not cause infertility.

"Many of those patients do not end up doing fertility preservation, because ultimately 90% of women with Hodgkin’s lymphoma get cured and will be able to get pregnant without a problem, as long as they try before the age of 35," Dr. Gracia said.

The problem is that "10% of women who relapse will then require a bone marrow transplant as the subsequent therapy," she continued, and no one knows who they will be. "That treatment causes infertility in over 95% of patients."

Many oncologists do not refer Hodgkin’s lymphoma patients on the assumption that all will be fine after ABVD therapy. "But if the chemotherapy regimen fails and [the patients] come back to see me, at that point the options are more limited in terms of what you can offer them. ... Their ovaries may not respond as well to treatment in order to stimulate the ovaries with injections of gonadotropin, and then retrieve eggs in order to freeze eggs or embryos."

Providing fertility preservation for patients with leukemia can be challenging, Dr. Gracia added, because they sometimes are so sick "that it’s not really safe to put them through procedures like ovarian stimulation, or egg or embryo freezing. Those are patients we are often not able to help."

Cancer prognosis also can be a factor in deciding whether a patient is a good candidate for fertility preservation, although Dr. Noyes urged caution on that issue. "Even if a patient has stage III cancer and the survival rate is 20%, I don’t think it’s my place to judge that. ... If she is in the 20% who survive, she will not be happy if you say, ‘I didn’t do oocyte retrieval because I didn’t figure you would make it,’ " she explained.

In a survey answered by 516 oncologists, slightly less than half of respondents took "a neutral stance" on the advisability of poor-prognosis patients pursuing fertility preservation. While 23% agreed that these patients should not pursue fertility preservation, 32% disagreed; data were missing for 1%. Similarly, 51% had no opinion on posthumous parenting, only 16% expressed support, and 32% were opposed. Again, data were missing for 1%.

"Oncologists’ personal attitudes regarding posthumous reproduction were related to referral of patients with a poor prognosis," the authors wrote, noting that religious beliefs can influence physician attitudes (J. Support. Oncol. 2011 [doi: 10.1016/j.suponc.2011.09.006]).

How Old, How Young, and With Whom?

Age cutoffs for fertility preservation vary from practice to practice, but most physicians won’t perform the practice in patients older than age 46. When providing counseling about fertility preservation options, Dr. Noyes makes it a point to ask the patient if she is in a committed relationship with someone with whom she can rear a child.

"Oftentimes rather than just freezing all embryos, I’ll freeze half as unfertilized eggs and half as embryos, even if the woman is in a committed relationship," Dr. Noyes said. "This creates less pressure on the couple, and there is some reproductive autonomy if things don’t work out. The woman could still use those eggs with someone else."

Dr. Gracia once had a 49-year-old cancer patient seek her assistance with fertility preservation. "I told her, ‘You’re close to menopause and unfortunately, fertility preservation technologies will not work at your age.’ Even in situations where a woman’s fertility is already compromised, a cancer diagnosis often makes individuals even more aware of their future fertility, since treatments may take away their ability to have children."

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With IVF, the efficiency is about a 6%-7% live birth rate per egg. With egg freezing, the efficiency stands at about 5% per egg, "so it’s similar to IVF, which is good," Dr. Noyes said. "We know from years and years of IVF that every egg isn’t meant to be a baby. Otherwise, the pregnancy success rate would have gone from about 30%, which it was in 1990, to almost 100% now. It improved from about 30% in 1990 to 50%-60% now."

To date, Dr. Noyes has performed fertility preservation in about 125 cancer patients, and 6 of them have returned to use the frozen eggs or embryos. "On average, they are using their preserved eggs or embryos about 3 years after preserving them," she said. "It depends on their age when they freeze the eggs or embryos. The very young girls aren’t going to be back for a decade or more."

The best candidates for ovarian tissue freezing are children, "because it’s not possible to stimulate the ovaries of a girl who hasn’t gone through puberty yet," Dr. Gracia said. "That’s really the only option they have. We also offer it to patients who are at extremely high risk for going through ovarian failure or infertility, like patients who need to get transplants or those who receive high doses of alkylating agents."

Fears of Recurrence

Some breast cancer patients ask Dr. Karine Chung, director of the Fertility Preservation Program at the University of Southern California, Los Angeles, if fertility treatments or becoming pregnant will increase the risk that the cancer may return. She tells them that "while theoretically it is a concern that becoming pregnant after breast cancer could increase the rate of recurrence, there have been a number of very well-designed, large studies that have shown that that is not the case."

"As far as whether going through IVF or ovarian stimulation increases the risk of recurrence, we don’t think so. There is very limited data looking at that, but if you compare what happens during an IVF cycle and what happens during pregnancy, an IVF cycle is a very short period of time in which a woman is exposed to high levels of estrogen, whereas pregnancy is a relatively long time in which a woman is exposed to high levels of estrogen. If pregnancy has not turned out increased recurrence, we don’t think that IVF will, either," she said.

Dr. Alison W. Loren, fellowship program director in the division of hematology/oncology at the University of Pennsylvania, Philadelphia, tells her hematology patients that there is "really no increased risk of recurrence of blood cancers, if they choose to become pregnant after their cancer treatment."

On the other hand, women who have hormone receptor–positive cancers "are generally counseled to wait at least 5 years after their cancer treatment is complete to become pregnant, but that’s not evidence based. There are concerns in cases where the fertility window is shortened. For example, if you advise a 32-year-old woman to wait 5 years after her last cancer treatment to get pregnant, you could be jeopardizing her ability to get pregnant."

Increased recurrence rates for certain types of cancer following fertility preservation were reported at the March 2102 annual meeting of the Society of Gynecologic Oncology in Austin, Tex. A study from Japan reported a recurrence rate of 24% after use of high-dose medroxyprogesterone acetate in young patients with endometrial cancer. The total number of pregnancies was 42; delivery outcomes were 19 normal deliveries, 11 cesarean sections, 2 premature deliveries, 5 spontaneous abortions, 2 induced abortions, 1 unknown, and 2 ongoing pregnancies (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.006]). A separate, multicenter study in the United States found that the risk of recurrence in patients with serous borderline ovarian tumors was 35% among patients who underwent fertility-sparing surgery, compared with 15% in other patients; at least 7 healthy infants were delivered (Gynecol. Oncol. 2012;125;S5 [doi: 10.1016/j.ygyno.2011.12.007]).

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The data have not yet been published in a medical journal except as meeting abstracts, however, and Dr. Loren was reluctant to comment until more information becomes available.

Cost Can Be an Obstacle

Insurance rarely covers the cost of fertility preservation for cancer patients, and the costs can reach $20,000. Fertile Hope’s Sharing Hope Program for Women, an initiative of the Lance Armstrong Foundation, invites cancer patients to apply for discounted services and donated medications (www.fertilehope.org). Eligibility requirements include being a U.S. citizen or permanent resident with an annual household income of less than $75,000 (single) or $100,000 (married), and having not yet started fertility-damaging cancer treatments.

Other resources for patients include Fertile Action (http://fertileaction.org), which was founded by a breast cancer survivor, and MyOncofertility.org (http://myoncofertility.org), an education resource provided by the Oncofertility Consortium.

Who Has Expertise in Fertility Preservation?

New guidelines from the National Comprehensive Cancer Network establish young adult and adolescent cancer patients as a distinct group whom oncologists should routinely send for fertility counseling. Will they?

Oncologists are not necessarily knowledgeable about the options or in the habit of referring patients to reproductive endocrinologists or other clinicians who specialize in fertility, according to Dr. Chung.

"Because [the oncologists’] knowledge of fertility and ovarian function in general is somewhat limited, to have a meaningful discussion about fertility preservation options with these patients is difficult," she said.

The American Society of Clinical Oncology (J. Clin. Oncol 2006:24:2917-31). and the American Society for Reproductive Medicine (Fertil. Steril. 2005;83:1622-8) have previously recommended that all women be offered counseling and an opportunity to preserve their fertility before cancer therapy, but implementation appears to be mixed.

According to a 2009 survey of 249 oncologists who practice at academic medical centers, 95% reported routinely discussing a cancer treatment’s impact on fertility (Fertil. Steril. 2010;94:1652-6). Only 39% said they routinely referred female cancer patients to a reproductive endocrinologist or ob.gyn. who specializes in fertility, however, while 18% said they never refer their patients. Reasons most commonly cited for not referring included lack of patient interest in fertility preservation (38%), lack of time because of emergent need to start therapy (28%), and poor prognosis for future fertility (6%).

Three key factors contribute to a lack of referrals by oncologists, according to Dr. Loren: a lack of time, a lack of access to reproductive endocrinologists in the oncologist’s network/institution, and a lack of baseline knowledge about fertility preservation options.

"Many oncologists don’t know a lot about this; so they worry if they bring this up, patients are going to start asking, ‘What are my options?’ " Dr. Loren said.

"We have studied this issue specifically among clinicians who provide bone marrow transplantation to cancer patients. Lack of knowledge and lack of access to a provider are the biggest reasons that people don’t refer patients for fertility preservation," she added.

Dr. Loren advises gynecology specialists to make networking inroads with oncologists by offering to be their referral source for patients with questions about fertility preservation. This may include speaking at grand rounds and at occasional meetings of oncology faculty and staff – anything to increase awareness of options for patients. "A key to this is good communication," she said.

In a year-long pilot study carried out at the Tampa, Fla.–based Lee Moffitt Cancer Center to develop a referral system for fertility preservation in patients with newly diagnosed cancer, measures that included placement of informational brochures in the waiting room and establishment of a dedicated telephone line for referrals led to a ninefold increase in the number of calls received (J. Natl. Compr. Canc. Netw. 2011;9:1219-25). The researchers concluded that such a referral system "allows oncologists to fulfill their obligation and make informed decisions about fertility preservation, thereby improving the full cancer care continuum."

Dr. Chung, Dr. Loren, Dr. Noyes and Dr. Gracia said that they had no relevant financial disclosures.