Jennifer Levine

Fertility Preservation in Adolescents and Young Adults With Cancer

Preservation of fertility is important to adolescent and young adult (AYA) survivors of cancer. Many survivors will maintain their reproductive potential after the successful completion of treatment for cancer. However total-body irradiation, radiation to the gonads, and chemotherapy regimens containing high-dose alkylators can place women at risk for acute ovarian failure or premature menopause and men at risk for temporary or permanent azoospermia. The most effective and established means of preserving fertility in this population is embryo cryopreservation in women and sperm cryopreservation in men before the initiation of cancer-directed therapy. Cryopreservation of mature oocytes is also becoming more commonplace as methods of thawing become more sophisticated. The use of in vitro fertilization and intracytoplasmic sperm injection has added to the viability of sperm and oocyte cryopreservation. Cryopreservation and transplantation of gonadal tissue in both males and females remains experimental but continues to be evaluated. Hormonal suppression has not been shown to be effective in males but may have promise in females, although larger scale trials are needed to evaluate this. Providing information about risk of infertility and possible interventions to maintain reproductive potential are critical for the AYA population at the time of diagnosis. Given the competing demands of providing complicated and detailed information about cancer treatment, the evolving information related to fertility preservation, and the ethical issues involved, it may be preferable, where possible, to have a specialized team, rather than the primary oncologist, address these issues with AYA patients.

Pregnancy after chemotherapy in male and female survivors of childhood cancer treated between 1970 and 1999: a report from the Childhood Cancer Survivor Study cohort

BACKGROUND The effect of many contemporary chemotherapeutic drugs on pregnancy and livebirth is not well established. We aimed to establish the effects of these drugs on pregnancy in male and female survivors of childhood cancer not exposed to pelvic or cranial radiotherapy. METHODS We used data from a subset of the Childhood Cancer Survivor Study cohort, which followed 5-year survivors of the most common types of childhood cancer who were diagnosed before age 21 years and treated at 27 institutions in the USA and Canada between 1970 and 1999. We extracted doses of 14 alkylating and similar DNA interstrand crosslinking drugs from medical records. We used sex-specific Cox models to establish the independent effects of each drug and the cumulative cyclophosphamide equivalent dose of all drugs in relation to pregnancies and livebirths occurring between ages 15 years and 44 years. We included siblings of survivors as a comparison group. FINDINGS We included 10 938 survivors and 3949 siblings. After a median follow-up of 8 years (IQR 4-12) from cohort entry or at age 15 years, whichever was later, 4149 (38%) survivors reported having or siring a pregnancy, of whom 3453 (83%) individuals reported at least one livebirth. After a median follow-up of 10 years (IQR 6-15), 2445 (62%) siblings reported having or siring a pregnancy, of whom 2201 (90%) individuals reported at least one livebirth. In multivariable analysis, survivors had a decreased likelihood of siring or having a pregnancy versus siblings (male survivors: hazard ratio [HR] 0·63, 95% CI 0·58-0·68; p<0·0001; female survivors: 0·87, 0·81-0·94; p<0·0001) or of having a livebirth (male survivors: 0·63, 0·58-0·69; p<0·0001; female survivors: 0·82, 0·76-0·89; p<0·0001). In male survivors, reduced likelihood of pregnancy was associated with upper tertile doses of cyclophosphamide (HR 0·60, 95% CI 0·51-0·71; p<0·0001), ifosfamide (0·42, 0·23-0·79; p=0·0069), procarbazine (0·30, 0·20-0·46; p<0·0001) and cisplatin (0·56, 0·39-0·82; p=0·0023). Cyclophosphamide equivalent dose in male survivors was significantly associated with a decreased likelihood of siring a pregnancy (per 5000 mg/m(2) increments: HR 0·82, 95% CI 0·79-0·86; p<0·0001). However, in female survivors, only busulfan (<450 mg/m(2) HR 0·22, 95% CI 0·06-0·79; p=0·020; ≥450 mg/m(2) 0·14, 0·03-0·55; p=0·0051) and doses of lomustine equal to or greater than 411 mg/m(2) (0·41, 0·17-0·98; p=0·046) were significantly associated with reduced pregnancy; cyclophosphamide equivalent dose was associated with risk only at the highest doses in analyses categorised by quartile (upper quartile vs no exposure: HR 0·85, 95% CI 0·74-0·98; p=0·023). Results for livebirth were similar to those for pregnancy. INTERPRETATION Greater doses of contemporary alkylating drugs and cisplatin were associated with a decreased likelihood of siring a pregnancy in male survivors of childhood cancer. However, our findings should provide reassurance to most female survivors treated with chemotherapy without radiotherapy to the pelvis or brain, given that chemotherapy-specific effects on pregnancy were generally few. Nevertheless, consideration of fertility preservation before cancer treatment remains important to maximise the reproductive potential of all adolescents newly diagnosed with cancer. FUNDING National Cancer Institute, National Institutes of Health, and the American Lebanese-Syrian Associated Charities.

Infertility in reproductive-age female cancer survivors

Improved survival rates among reproductive‐age females diagnosed with cancer have increased the focus on long‐term quality of life, including maintenance of the ability to conceive biological children. Cancer‐directed therapies such as high‐dose alkylating agents and radiation to the pelvis, which deplete ovarian reserve, radiation to the brain, which affects the hypothalamic‐pituitary‐gonadal axis, and surgical resection of reproductive structures can decrease the likelihood of having biological children. Standard fertility preservation strategies such as embryo and oocyte cryopreservation before the onset of therapy offer the opportunity to conserve fertility, but they may not be feasible because of the urgency to start cancer therapy, financial limitations, and a lack of access to reproductive endocrinologists. Ovarian tissue freezing is considered experimental, with limited data related to pregnancies, but it minimizes treatment delay. Studies evaluating gonadotropin‐releasing hormone analogues have had mixed results, although a recent randomized, prospective study in women with breast cancer demonstrated a protective effect. Fertility preservation programs are increasingly being developed within cancer programs. In this article, we describe risks to infertility and options for preservation, raise psychosocial and ethical issues, and propose elements for establishing an effective fertility preservation program. Cancer 2015;121:1532–1539.

Evidence-Based Recommendations for Fertility Preservation Options for Inclusion in Treatment Protocols for Pediatric and Adolescent Patients Diagnosed With Cancer:

As survival rates improve for pediatric cancers, increased attention has been paid to late effects of cancer therapy, in particular, infertility. Fertility preservation options are available for pre- and postpubertal cancer patients; however, many providers lack knowledge regarding options. The aim of this article is to provide a comprehensive synthesis of current evidence and recommendations regarding fertility preservation options for children, adolescents, and young adults undergoing cancer treatment. A systematic search was performed to identify fertility preservation evidence. Fifty-three studies and 4 clinical guidelines were used for the review. Final recommendations consisted of 2 strong and 1 weak recommendation for both female and male fertility preservation options. The treatment team should be knowledgeable about fertility preservation so that they can educate patients and families about available fertility preservation options. It is important to consider and discuss all available fertility options with patients at the time of diagnosis.

Outcomes of adults and children with primary mediastinal B-cell lymphoma treated with dose-adjusted EPOCH-R

Treatment with dose‐adjusted EPOCH (etoposide, doxorubicin, cyclophosphamide, vincristine, prednisone) chemotherapy and rituximab (DA‐EPOCH‐R) has become the standard of care for primary mediastinal B‐cell lymphoma (PMBCL) at many institutions despite limited data in the multi‐centre setting. We report a large, multi‐centre retrospective analysis of children and adults with PMBCL treated with DA‐EPOCH‐R to characterize outcomes and evaluate prognostic factors. We assessed 156 patients with PMBCL treated with DA‐EPOCH‐R across 24 academic centres, including 38 children and 118 adults. All patients received at least one cycle of DA‐EPOCH‐R. Radiation therapy was administered in 14·9% of patients. With median follow‐up of 22·6 months, the estimated 3‐year event‐free survival (EFS) was 85·9% [95% confidence interval (CI) 80·3–91·5] and overall survival was 95·4% (95% CI 91·8–99·0). Outcomes were not statistically different between paediatric and adult patients. Thrombotic complications were reported in 28·2% of patients and were more common in paediatric patients (45·9% vs. 22·9%, P = 0·011). Seventy‐five per cent of patients had a negative fluorodeoxyglucose positron emission tomography (FDG‐PET) scan at the completion of DA‐EPOCH‐R, defined as Deauville score 1–3. Negative FDG‐PET at end‐of‐therapy was associated with improved EFS (95·4% vs. 54·9%, P < 0·001). Our data support the use of DA‐EPOCH‐R for the treatment of PMBCL in children and adults. Patients with a positive end‐of‐therapy FDG‐PET scan have an inferior outcome.

Fertility preservation in children, adolescents, and young adults with cancer: Quality of clinical practice guidelines and variations in recommendations

Fertility preservation care for children, adolescents, and young adults (CAYAs) with cancer is not uniform among practitioners. To ensure high‐quality care, evidence‐based clinical practice guidelines (CPGs) are essential. The authors identified existing CPGs for fertility preservation in CAYAs with cancer, evaluated their quality, and explored differences in recommendations.

Overcoming Challenges to Meaningful Informed Consent for Whole Genome Sequencing in Pediatric Cancer Research

Introducing whole genome sequencing (WGS) into pediatric cancer research at diagnosis poses unique challenges related to informed consent. WGS requires tissue obtained prior to initiating treatment, when families may be overwhelmed with uncertainty and fear. Motivation to participate may be high without fully understanding the range of possible results, including secondary findings. Little is known about parental knowledge, attitudes, and beliefs about this type of research.

Gonadotoxicity of Cancer Therapies in Pediatric and Reproductive-Age Females

The natural depletion of the finite number of follicles present in the ovaries can be accelerated by cancer treatment, leading to acute ovarian failure or premature menopause. The negative impact of cancer therapy on ovarian follicular reserve, hypothalamic-pituitary-ovarian axis function, uterine function, and cardiac function can impact the ability of female cancer survivors to conceive or carry a biologic pregnancy to term. Chemotherapeutic agents that affect the cell cycle interfere with growing follicles, whereas alkylating agents have a non-cycle-specific mechanism of action leading to single- and double-strand DNA breaks, thereby potentially affecting both quiescent and dividing cells in the ovary. Chemotherapy can also lead to cortical fibrosis, blood vessel damage, and stromal damage in the ovary. The impact of cancer treatment on reproductive potential depends on the age of the patient, the chemotherapeutic agents used, the duration of treatment, the total cumulative dose administered, and patient-specific factors. Current efforts are focusing on determining the gonadotoxicity of specific chemotherapeutic regimens rather than single agents. Irradiation of the ovaries (in total body radiation; direct pelvic, abdominal, or spinal irradiation; or scatter irradiation) of 1–2 Gy in girls and 4–6 Gy in adults depletes the follicle population and permanently impacts ovarian function. Posttreatment, reproductive capacity should be monitored through the measurement of gonadotropins and markers of follicle health, such as anti-Mullerian hormone (AMH).

Preserving Fertility in Children and Adolescents with Cancer

In the face of excellent survival rates for pediatric and adolescent cancer, preserving the opportunity to have biological children is an important component of long term quality of life. Yet, modern chemotherapeutic regimens continue to pose a threat to fertility. The only fertility preservation methods available to pre-pubertal children of both genders is cryopreservation of gonadal tissue, a highly experimental intervention, or shielding/re-location of reproductive tissue in the setting of radiation. These techniques are available in the post pubertal population as well, but post pubertal patients also have the option for cryopreservation of gametes, a process that is much simpler in males than females. For this reason, prior to the initiation of therapy, sperm banking should be considered standard of care for males, while consideration of embryo or oocyte cryopreservation should be limited to those females at risk of developing ovarian failure. Attention to reproductive health and fertility preservation should continue after the completion of therapy. Establishing programs that streamline access to current fertility preservation techniques will assist in ensuring that all eligible patients can avail themselves of current options.

Reproductive Function and Outcomes in Female Survivors of Childhood, Adolescent, and Young Adult Cancer: A Review

Some survivors of childhood, adolescent, and young adult cancer are at increased risk of gonadal dysfunction and adverse pregnancy outcomes. We reviewed currently available literature that evaluated reproductive function and pregnancy outcomes of female cancer survivors diagnosed before the age of 25 years. High-dose alkylating agent chemotherapy and abdominal/pelvic radiotherapy adversely affect gonadal function in a dose-related fashion, with older age at exposure conferring greater risk as a result of the age-related decline in ovarian reserve. Gonadal injury clinically manifests as ovarian hormone insufficiency (delayed or arrested puberty, premature ovarian insufficiency, or premature menopause) and infertility. The effect of molecular-targeted agents on ovarian function has not been established. For female cancer survivors who maintain fertility, overall pregnancy (relative risk, 0.67 to 0.81) and live birth rates (hazard ratio, 0.79 to 0.82) are lower than those in the general public. Pregnancy in cancer survivors also may be associated with risks to both the mother and the fetus related to miscarriage; preterm birth; and, rarely, cardiomyopathy. Women at risk for these complications require preconception assessment and counseling from both obstetricians and oncology providers. The risk for inherited genetic disease in offspring conceived after cancer treatment exposure is not increased. The optimization of reproductive outcomes and minimization of risks of pregnancy complications in survivors requires informed, risk-based assessment and monitoring.