Risk factors may identify which patients could benefit most from fertility preservation

Wassim Chemaitilly

Researchers at St. Jude Children’s Research Hospital have identified specific factors that increase the risk for premature ovarian insufficiency among female childhood cancer survivors.

“These findings are important for the counseling of patients, and also when thinking about indications for fertility preservation prior to treating children and adolescents for cancer,” Wassim Chemaitilly, MD, associate member in the department of pediatric medicine and the division of endocrinology at St. Jude Children’s Research Hospital, told HemOnc Today.

Chemaitilly and colleagues assessed the prevalence of premature ovarian insufficiency, the associated risk factors and long-term outcomes among 921 women (median age, 31.7 years) included in the St. Jude Lifetime Cohort Study. Researchers followed survivors for a median 24 years after their cancer diagnosis.

Investigators reported an 11% overall prevalence of premature ovarian insufficiency.

Radiotherapy to the pelvic region at any dose appeared independently associated with ovarian insufficiency. Conversely, a BMI of 30 kg/m2 or higher appeared associated with decreased risk.

“Precision medicine, including identification of possible genetic factors that influence risk, holds the most promise for identifying young cancer patients or survivors who are most likely to benefit from fertility preservation measures,” Chemaitilly said.

HemOnc Today spoke with Chemaitilly about the study, the implications of the results, and whether the clinical community should change how they practice due to these findings.

Question: What prompted this research?

Answer: Fertility issues are areas of intense interest to childhood cancer survivors and their families. Better defining the risk factors and prevalence of premature ovarian insufficiency among female survivors will help better identify patients who are most likely to benefit from fertility preservation. This study is timely, because there are more options for female fertility preservation. We have the availability of mature oocyte cryopreservation, a technique through which women are able to have some of their oocytes harvested and banked for the future. Moreover, in vitro fertilization is no longer considered experimental. The technique has allowed a subset of women who survived cancer and were exposed to treatments that were toxic to the ovaries to still have the ability to have children later in life.

Q: How was the study conducted?

A: This study is a report from the St. Jude Lifetime Cohort, which enrolls participants who received treatment at St. Jude Children’s Research Hospital for a variety of cancers and tumors when they were children. These survivors were invited to return to St. Jude to participate in research. They completed questionnaires that addressed different aspects of their lives, including health care utilization, and they also underwent direct clinical and laboratory assessments. This cohort has grown to include more than 4,000 survivors to date. The extended follow-up time of a median of 25 years allows investigators to assess the health status of participating survivors several years after they leave the pediatric institution. This particular report examines premature ovarian insufficiency or the interruption of normal ovarian activity prior to the age of 40 years, which is known to occur from the toxicity of certain cancer treatments.

Q: What is unique about this study?

A: Not only did we report on how common premature ovarian insufficiency is in a large cohort of more than 900 women, we identified which treatment factors were mostly responsible. We were also able to look at the consequences of premature ovarian insufficiency on long-term health outcomes, such as cardiovascular disease, bone health and frailty.

Q: What did you find?

A: We found premature ovarian insufficiency is a relatively frequent complication among childhood cancer survivors. Nearly 11% of all female childhood cancer survivors in this cohort have premature ovarian insufficiency.

Q: What are the key factors that elevate infertility risk?

A: Exposure of the ovaries to any radiation level or dose to the pelvic region substantially increases the risk that patients will develop premature ovarian insufficiency. We should be concerned with any irradiation potentially affecting these organs. Treatment with high-dose alkylating chemotherapy agents is another risk factor we identified. The risk for ovarian insufficiency was highest when both of these modalities were combined.

Q: Did any of the findings surprise you?

A: We had one finding that was very thought-provoking in this cohort and came as a surprise to us: Women who were obese at the time of participation in this study were less likely to have had a diagnosis of premature ovarian insufficiency than those who were not obese. We decided to study the association with obesity because it might be a confounding factor for which we would need to adjust, especially because obesity causes menstrual cycle irregularities and challenges to fertility in the general population. Body composition parameters seem to influence the vulnerability of the ovaries to cancer treatments. However, this finding will need to be verified and confirmed in other cohorts.

Q: How should the clinical community alter pract ice in light of these findings?

A: A surprising finding of this study was that only 31% of women with premature ovarian insufficiency were actually receiving hormone replacement therapy. We need to know why hormone therapy is being withheld from these patients. The barriers to hormone replacement therapy in this population deserve further study, especially since premature ovarian insufficiency is potentially associated with worse long-term health outcomes, such as low bone mineral density and frail health. Frailty has been shown in previous work to be associated with an increased risk for early mortality among childhood cancer survivors. The other implication of these findings is trying to use the information on risk factors associated with premature ovarian insufficiency to better predict occurrence and offer fertility preservation to those patients who are most likely to benefit.

Q: How important it is for members of the cancer care team to have early conversations with their patients about fertility p reservation?

A: It really has been transformative for female childhood cancer survivors to have options for fertility preservation. It is, however, important to better understand which individuals are most likely to benefit from these potentially invasive procedures that may come at a substantial cost. It is possible to predict premature ovarian insufficiency among patients who receive high-risk treatments, such as pelvic irradiation. However, it is more challenging to predict it among survivors who received cancer treatments that were less intense and who may resume puberty/menstrual activity after they are cured from cancer but could still experience menopause at a young age and before they are ready to start a family. Accurately identifying these patients and giving them access to fertility preservation before menopause happens is a substantial challenge in this field.

Q: Do you have plans for additional research?

A: Additional research is being conducted to investigate the potential contribution of genetic factors that could explain some of the interindividual variability we see with certain patients being more vulnerable than others to the adverse effects of cancer treatments.

Q: Is there anything else that you would like to mention?

A: I am hopeful that a better understanding of host factors — variables related to each particular individual, such as genetic predisposition — will, in time, allow a better prediction of premature ovarian insufficiency so that childhood cancer survivors can receive the care that they need with regard to family and life planning. – by Jennifer Southall

Reference:

Chemaitilly W, et al. J Clin Endocrinol Metab. 2017;doi:10.1210/jc.2016-3723.

For more information:

Wassim Chemaitilly, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email: wassim.chemaitilly@stjude.org.

Disclosure: Chemaitilly reports no relevant financial disclosures.

Wassim Chemaitilly

Researchers at St. Jude Children’s Research Hospital have identified specific factors that increase the risk for premature ovarian insufficiency among female childhood cancer survivors.

“These findings are important for the counseling of patients, and also when thinking about indications for fertility preservation prior to treating children and adolescents for cancer,” Wassim Chemaitilly, MD, associate member in the department of pediatric medicine and the division of endocrinology at St. Jude Children’s Research Hospital, told HemOnc Today.

Chemaitilly and colleagues assessed the prevalence of premature ovarian insufficiency, the associated risk factors and long-term outcomes among 921 women (median age, 31.7 years) included in the St. Jude Lifetime Cohort Study. Researchers followed survivors for a median 24 years after their cancer diagnosis.

Investigators reported an 11% overall prevalence of premature ovarian insufficiency.

Radiotherapy to the pelvic region at any dose appeared independently associated with ovarian insufficiency. Conversely, a BMI of 30 kg/m2 or higher appeared associated with decreased risk.

“Precision medicine, including identification of possible genetic factors that influence risk, holds the most promise for identifying young cancer patients or survivors who are most likely to benefit from fertility preservation measures,” Chemaitilly said.

HemOnc Today spoke with Chemaitilly about the study, the implications of the results, and whether the clinical community should change how they practice due to these findings.

Question: What prompted this research?

Answer: Fertility issues are areas of intense interest to childhood cancer survivors and their families. Better defining the risk factors and prevalence of premature ovarian insufficiency among female survivors will help better identify patients who are most likely to benefit from fertility preservation. This study is timely, because there are more options for female fertility preservation. We have the availability of mature oocyte cryopreservation, a technique through which women are able to have some of their oocytes harvested and banked for the future. Moreover, in vitro fertilization is no longer considered experimental. The technique has allowed a subset of women who survived cancer and were exposed to treatments that were toxic to the ovaries to still have the ability to have children later in life.

Q: How was the study conducted?

A: This study is a report from the St. Jude Lifetime Cohort, which enrolls participants who received treatment at St. Jude Children’s Research Hospital for a variety of cancers and tumors when they were children. These survivors were invited to return to St. Jude to participate in research. They completed questionnaires that addressed different aspects of their lives, including health care utilization, and they also underwent direct clinical and laboratory assessments. This cohort has grown to include more than 4,000 survivors to date. The extended follow-up time of a median of 25 years allows investigators to assess the health status of participating survivors several years after they leave the pediatric institution. This particular report examines premature ovarian insufficiency or the interruption of normal ovarian activity prior to the age of 40 years, which is known to occur from the toxicity of certain cancer treatments.

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Q: What is unique about this study?

A: Not only did we report on how common premature ovarian insufficiency is in a large cohort of more than 900 women, we identified which treatment factors were mostly responsible. We were also able to look at the consequences of premature ovarian insufficiency on long-term health outcomes, such as cardiovascular disease, bone health and frailty.

Q: What did you find?

A: We found premature ovarian insufficiency is a relatively frequent complication among childhood cancer survivors. Nearly 11% of all female childhood cancer survivors in this cohort have premature ovarian insufficiency.

Q: What are the key factors that elevate infertility risk?

A: Exposure of the ovaries to any radiation level or dose to the pelvic region substantially increases the risk that patients will develop premature ovarian insufficiency. We should be concerned with any irradiation potentially affecting these organs. Treatment with high-dose alkylating chemotherapy agents is another risk factor we identified. The risk for ovarian insufficiency was highest when both of these modalities were combined.

Q: Did any of the findings surprise you?

A: We had one finding that was very thought-provoking in this cohort and came as a surprise to us: Women who were obese at the time of participation in this study were less likely to have had a diagnosis of premature ovarian insufficiency than those who were not obese. We decided to study the association with obesity because it might be a confounding factor for which we would need to adjust, especially because obesity causes menstrual cycle irregularities and challenges to fertility in the general population. Body composition parameters seem to influence the vulnerability of the ovaries to cancer treatments. However, this finding will need to be verified and confirmed in other cohorts.

Q: How should the clinical community alter pract ice in light of these findings?

A: A surprising finding of this study was that only 31% of women with premature ovarian insufficiency were actually receiving hormone replacement therapy. We need to know why hormone therapy is being withheld from these patients. The barriers to hormone replacement therapy in this population deserve further study, especially since premature ovarian insufficiency is potentially associated with worse long-term health outcomes, such as low bone mineral density and frail health. Frailty has been shown in previous work to be associated with an increased risk for early mortality among childhood cancer survivors. The other implication of these findings is trying to use the information on risk factors associated with premature ovarian insufficiency to better predict occurrence and offer fertility preservation to those patients who are most likely to benefit.

PAGE BREAK

Q: How important it is for members of the cancer care team to have early conversations with their patients about fertility p reservation?

A: It really has been transformative for female childhood cancer survivors to have options for fertility preservation. It is, however, important to better understand which individuals are most likely to benefit from these potentially invasive procedures that may come at a substantial cost. It is possible to predict premature ovarian insufficiency among patients who receive high-risk treatments, such as pelvic irradiation. However, it is more challenging to predict it among survivors who received cancer treatments that were less intense and who may resume puberty/menstrual activity after they are cured from cancer but could still experience menopause at a young age and before they are ready to start a family. Accurately identifying these patients and giving them access to fertility preservation before menopause happens is a substantial challenge in this field.

Q: Do you have plans for additional research?

A: Additional research is being conducted to investigate the potential contribution of genetic factors that could explain some of the interindividual variability we see with certain patients being more vulnerable than others to the adverse effects of cancer treatments.

Q: Is there anything else that you would like to mention?

A: I am hopeful that a better understanding of host factors — variables related to each particular individual, such as genetic predisposition — will, in time, allow a better prediction of premature ovarian insufficiency so that childhood cancer survivors can receive the care that they need with regard to family and life planning. – by Jennifer Southall

Reference:

Chemaitilly W, et al. J Clin Endocrinol Metab. 2017;doi:10.1210/jc.2016-3723.

For more information:

Wassim Chemaitilly, MD, can be reached at St. Jude Children’s Research Hospital, 262 Danny Thomas Place, Memphis, TN 38105; email: wassim.chemaitilly@stjude.org.

Disclosure: Chemaitilly reports no relevant financial disclosures.