Drs. Holly Hoefgen, MD & Karen Burns, MD Cincinnati Children s Hospital Medical Center Cincinnati, OH

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1 Drs. Holly Hoefgen, MD & Karen Burns, MD Cincinnati Children s Hospital Medical Center Cincinnati, OH Dr. Janie Benoit, MD Hôpital Maisonneuve-Rosemont - Université de Montréal Québec, Canada

2 Childhood, Adolescent and Young Adult (CAYA) Cancer & Survivorship Multidisciplinary team approach to survivorship care The role of the Gynecologist

3 Childhood cancer is NOT rare 43 children are diagnosed every single day Over 40,000 children are in treatment every year Average age at diagnosis is 6 Affects all ethnic, gender, and socio-economic groups

5 Survival rates for childhood cancers have increased dramatically Current 5 year survival >83% In 2013, estimated 420,000 survivors of childhood cancer in US Expected to reach 500,000 by 2020 Armstrong et al, 2016

6 Source: Surveillance, Epidemiology, and End Results (SEER) Program (seer.cancer.gov) Based on follow-up of patients into 2012

7 Therapies today aim for cure, not treatment Cancer treatment has life-long side effects These are being addressed with changes in up front therapy Focus on how to minimize or eliminate these side effects while maintaining or improving the cure rates Concept of a total cure Cure alone is not enough Team approach take measures now (at diagnosis/during therapy) that maximize quality of life later Even at diagnosis we plan for the future

8 Risk is dependent upon: Age at diagnosis Therapy received Pre-existing medical conditions and family environment Effects of therapy may be present during or immediately after therapy or present years later Survivorship is an evolving field Influx of new drugs with new mechanisms of action Aging population

Most childhood cancer survivors had photon radiation Induces double-stranded DNA breaks that are not amenable to repair Induces apoptosis Primarily effects dividing cells, however, can cause damage

9 Most childhood cancer survivors had photon radiation Induces double-stranded DNA breaks that are not amenable to repair Induces apoptosis Primarily effects dividing cells, however, can cause damage to cells in growth arrest Effects of radiation are localized to field of interest plus scatter area Fibrosis Loss of elasticity Increased risk of secondary cancers Emerging field of proton radiation

10 Traditional chemotherapy affects cells that are actively dividing Specific for phase of cell cycle, not cell type Act via different mechanisms altering DNA and/or DNA repair mechanics Anthracyclines Alkylating Agents Antimetabolites Vinca alkaloids/plant produces Platinum compounds Miscellaneous New era of targeted therapy Immunotherapy CAR T cell Target is specific to cancer cell Monoclonal antibodies Kinase inhibitors Small molecules Anti-angiogenesis Little information on late effects Bevacizumab Dasatinib

11 Traditional chemotherapy affects cells that are actively dividing Specific for phase of cell cycle, not cell type Act via different mechanisms altering DNA and/or DNA repair mechanics Anthracyclines Alkylating Agents Antimetabolites Vinca alkaloids/plant produces Platinum compounds Miscellaneous New era of targeted therapy Immunotherapy CAR T cell Target is specific to cancer cell Monoclonal antibodies Kinase inhibitors Small molecules Anti-angiogenesis Little information on late effects Bevacizumab Dasatinib

12 Directly inhibit DNA synthesis Interclation DNA strand breaks Free radical formation Cardiac myocytes are affected in dose-dependent manor At risk for cardiomyopathy years later Commonly used in pediatrics Doxorubicin Daunorubicin Idarubicin Mitoxantrone Dactinomycin

13 Directly inhibit DNA synthesis Alkylation Cross-linking of DNA Gonadotoxicity is dose dependent Azoospermia POI Commonly used in pediatrics Cyclophosphamide Ifosfamide Melphalan Lomustine Carmustine Busulfan Dacarbazine Procarbazine Temozolomide

Alkylating Agents Busulfan Carmustine (BCNU) Chlorambucil Cyclophosphamide Ifosfamide Lomustine (CCNU) Mechlorethamine Melphalan Procarbazine Thiotepa Heavy Metals

14 Alkylating Agents Busulfan Carmustine (BCNU) Chlorambucil Cyclophosphamide Ifosfamide Lomustine (CCNU) Mechlorethamine Melphalan Procarbazine Thiotepa Heavy Metals Carboplatin Cisplatin Non-Classical Alkylators Dacarbazine (DTIC) Temozolomide Radiation Therapy TBI Cranial ( 30 Gy) Pelvis, lower spine Prepubertal 10 Gy Pubertal 5 Gy

Childhood cancer survivorship clinics are common in COG affiliated institutions Inclusion criteria vary Five years from diagnosis Two years off therapy Age of patients will vary Followed until

16 Childhood cancer survivorship clinics are common in COG affiliated institutions Inclusion criteria vary Five years from diagnosis Two years off therapy Age of patients will vary Followed until age 21 Followed until age 18 OR 10 years from therapy Followed without an age limit Multiple models of care Consultation service Multidisciplinary vs referral Assume care Transition to adult center

19 Etc. Oncology Gynecology Cardiology Endocrinology Genetics l Rehab Care manager/nurse Nutritionist Surgeon Pediatrician Psychologist

Periodic evaluation starting at about 10-13 years old History Puberty (onset and tempo) Menstrual cycle Symptoms of POI Coitarche and sexual

21 Periodic evaluation starting at about years old History Puberty (onset and tempo) Menstrual cycle Symptoms of POI Coitarche and sexual function On Physical Exam Tanner stage breast Gynecologic exam: signs of estrogenized hymen, vaginal dryness Screening labs FSH/LH Estradiol +/- AMH

22 Causes Treatment Primary ovarian insufficiency (Chemo, Radiation) Surgery (Bilateral oophorectomy) Gonadotropin deficiency (2ndary Neurosurgery, Radiation) Hypothalamic dysfunction (Malnutrition, stress, ) Others Hormone replacement therapy: estrogen and progesterone Treatment must start early Maintain healthy bones and heart For overall well-being Prevention of psychosocial stress

23 Signs of puberty before 7 or 8 years Evaluation FSH/LH Estradiol +/- GnRH Stim test Bone age Etiologies Cranial Radiation (Risk factors 20 Gy) Idiopathic Others Armstrong GT, Whitton JA, Gajjar A, Kun LE, Chow EJ, Stovall M, et al. Abnormal timing of menarche in survivors of central nervous system tumors: A report from the Childhood Cancer Survivor Study. Cancer. 2009;115(11):

24 Normal menstrual cycle is days Menstruation flow Length 7 days Flow: about 3 to 6 full pads or tampons per day or less than 80 ml Menstrual dysfunctions Oligomenorrhea Amenorrhea Menorrhagia Metrorrhagia ACOG Committee Opinion No. 651: Menstruation in Girls and Adolescents: Using the Menstrual Cycle as a Vital Sign. Obstetrics and gynecology. 2015;126(6):e143-6.

25 Specific Etiologies Temporary changes due to chemo/radiation treatment Dysthyroidism (hypo or hypert4) Chemo Radiation to thyroid ( 10 Gy: hypot4, 40 Gy: hypert4) Hyperprolactinemia Cranial Radiation ( 40 Gy) Gonadotropin deficiency Cranial radiation ( 30 Gy) Others (Thrombocytopenia, R/O Pregnancy) Appelman-Dijkstra NM, Kokshoorn NE, Dekkers OM, Neelis KJ, Biermasz NR, Romijn JA, et al. Pituitary dysfunction in adult patients after cranial radiotherapy: systematic review and meta-analysis. The Journal of clinical endocrinology and metabolism. 2011;96(8):

27 General Recommendation Those treated with 1+ gonadotoxic treatments should be made aware of POI (level A & C) Who Needs Surveillance Counseling regarding risk of POI and fertility implications recommended for survivors treated with: Alkylating agents in general (level A evidence) Cylcophospamind & procarbazine (level C evidence) Radiotherapy potentially exposing the ovaries (level A evidence) Surveillance Modalities for pre- and peri-pubertal survivors Monitoring of growth, pubertal development & progression (Tanner staging) is recommended for pre-pubertal survivors* (EO) FSH & E are recommended for evaluation of POI in pre-pubertal survivors* who fail to initiate or progress through puberty. (EO) Surveillance Modalities for post-pubertal survivors FSH & E are recommended for evaluation of POI in post-pubertal survivors* with menstrual dysfunction or who desire fertility assessment. (EO) HRT should be stopped prior to lab evaluation AMH is NOT recommended as primary surveillance for evaluation of POI in survivors* who desire assessment about potential future fertility (EO) AMH maybe be reasonable in conjunction with FSH and estradiol in survivors* 25 yo (EO)

28 When should pre- and peri-pubertal survivors be referred? Referral to peds endocrinology / gynecology is recommended for any survivor who has No signs of puberty by 13 yo Primary amenorrhea by 16 yo Failure of pubertal progression (EO) When should post-pubertal survivors be referred? Referral to Gyn/Endocrionology is recommended for post-pubertal survivors* with menstrual dysfunction suggesting POI (EO) What should be done when abnormalities are identified? Consideration of HRT is recommended for pre-, peri-, post-pubertal survivors diagnosed with POI by referral to Gyn/Endocrinology (EO) What should be done when potential future fertility is questioned? Referral to Gyn/REI/Endocrinology is recommended for post-pubertal female survivors* without signs/symptoms of POI, who desire assessment of potential future fertility (EO)

75% of cancer survivors without children stated they wanted to

Many patients report that infertility significantly limits their

social/emotional wellbeing Both male & female survivors desired

more satisfaction and less regret following fertility

29 75% of cancer survivors without children stated they wanted to have children in the future. Many patients report that infertility significantly limits their quality of life by jeopardizing their self-esteem and social/emotional wellbeing Both male & female survivors desired knowledge about fertility effects of their treatments and showed more satisfaction and less regret following fertility preservation counseling, even if no option was pursued. A third of survivors who already had at least one child wanted another

Discuss risk of infertility according to treatment received www.livestrong.

org Evaluate fertility potential AMH Antral follicular count FSH/LH/Estradiol Refer to

30 Discuss risk of infertility according to treatment received Oncofertility consortium Savemyfertility.org Evaluate fertility potential AMH Antral follicular count FSH/LH/Estradiol Refer to fertility specialist if appropriate Oocyte Cryopreservation Embryo Cryopreservation Could consider ovarian tissue cryopreservation But also discuss risk of pregnancy

Chapter about Contraception and special considerations in cancer survivors. Effficiency is key in young girls. Discussion about contraception should start before sexual debut.

32 Chapter about Contraception and special considerations in cancer survivors. Effficiency is key in young girls. Discussion about contraception should start before sexual debut. IUD are safe options Contra-indications to estrogen include active cancer. Some survivors are already at risk of decreased bone mineral density, therefore depo-provera might not be the best choice.

33 Etiologies Delayed puberty Primary ovarian insufficiency Vaginal dryness Vaginal stenosis Dyspareunia Vulvovaginitis: radiation, GVHD, etc. Psychosexual dysfunction Poor self-esteem Depression Fear Guilt Fatigue

34 Enquire about it Possible Treatments Psychologist Treatment of psychiatric disorder such as depression Physical therapist (Perineal physiotherapy) Vaginal dilation Sex therapist HRT Vaginal lubrication Support Etc.

Should wait until remission or ok from oncologist At least 6 months Also depends on risk of relapse Check for recommended delay in pregnancy after chemo 3 to 6 months after methotrexate 6 months for

35 Should wait until remission or ok from oncologist At least 6 months Also depends on risk of relapse Check for recommended delay in pregnancy after chemo 3 to 6 months after methotrexate 6 months for most chemo: time to get rid of damaged oocytes Uterine vascular insufficiency with pelvic radiation Risk of miscarriage Risk of IUGR Risk of preterm labor Cardiomyopathies From anthracycline chemo (doxorubicin or danorubicin) Radiation to chest Other considerations Prior abdominal surgery Hip replacement AVN

vulva Isolated genital GVHD rare, but possible When: 7-10 months s/p HSCT (can occur > 1-2 yrs later)

36 What: Systemic immune disorder Most common late effect of allogeneic hematopoietic stem cell transplant (HSCT) Incidence: Unknown (newer literature suggests 25-49%) 68% vulva, 28% vaginal + vulva Isolated genital GVHD rare, but possible When: 7-10 months s/p HSCT (can occur > 1-2 yrs later) Who: PBSC > BM No impact: conditioning type, parity, age, GVHD prophylaxis, vaginal infection hx Recurrence: Unknown

37 Clinical Symptoms: NIH vs Stratton scoring systems Diagnosis: Clinical vs Biopsy

38 Treatment Vulvovaginal Care Measures Topical Estrogen Topical Immunosuppressive Agents Topical corticosteroids Topical calcineurin inhibitors Prevention of Vaginal Stenosis / Narrowing GYN Monitoring of patient s post-hsct Consider early & extended routine evaluation of all allo-hsct recipients Regular monitoring for HPV related disease (risk s/p GVHD) HPV Vaccination Elevated breast cancer risk after a HSCT increased w/ TBI or local chest radiation Monitor for high risk of POI and infertility <5% recover ovarian function for limiter period of prior to POI Overall conception rate after HSCT < 1%

39 High risk of vaginal stenosis if 25 Gy in prepubertal girls 50 Gy in pubertal girls/women Consideration of prophylactic vaginal dilation Vaginoplasty might be needed Consider buccal graft

Female Health Issues after Treatment for Childhood Cancer

Female Health Issues after Treatment for Childhood Cancer The effects of childhood cancer therapy on female reproductive function depend on many factors, including the girl s age at the time of cancer