Long term toxicity of treatment. Laurence Brugieres Children and Adolescent Oncologic department

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1 Long term toxicity of treatment Laurence Brugieres Children and Adolescent Oncologic department

2 Most TYA with cancer are cured from their malignancy TRAMA

3 What are the consequences of cancer treatment? Many studies have shown an excess of morbidity and mortality in survivors of cancers especially after a cancer in children and adolescents 75% of survivors after childhood cancer have a least one chronic condition in adulthood Mortality risk is increased mostly by > Second malignancies > Cardiovascular complications > Lung disease Hudson, JAMA, 2013 Reulen, JAMA,

4 Long-term consequences of cancer treatment Second malignancies Cardiotoxicity Strokes Nephrotoxicity Fertility impairement Metabolic syndrome and endocrine disorders Neurotoxicity Ototoxicity Fatigue Cognitive impairment Psychosocial issues 25/05/2018 Long term follow-up 4

5 Second malignancies 5

6 patients treated between for selected malignancies > primary acute leukemia (lymphoblastic, myelogenous, or unspecified), > lymphoma (Hodgkin and non-hodgkin), > germ cell tumors (ovarian or testicular), > thyroid cancer, > melanoma, > breast cancer, > sarcomas (soft tissue sarcomas or malignant bone tumors) 25/05/2018 Long term follow-up 6

7 30 year after the 1 st cancer, 13.9% pts with 2 nd cancer Cumulative incidence survivors at 5 years Treated between 1970 et 2011 Age < 15 y y > 40 y Lee, Cancer, may 2018 Median time to second malignancies 16 y in children. 15 y in TYA 10 y in older adults 7

8 Second malignancies : role of treatment 17% 12% Lee et al 25/05/2018 Long term follow-up 8

9 Impact of radiotherapy effect of high-dose irradiation : linear dose-response for most organs but important organ- and host-specific differences 25/05/2018 Long term follow-up 9

10 Cranial irradiation and secondary meningioma and glioma Relative risks at Gy Meningioma ( ): 96.3 Glioma ( ): 21 Neglia, JNCI, /05/2016 Long-term follow-up of childhood cancer survivors with brain tumors 10

11 Seconds maligancies : impact of the dose of radiotherapy Risk of thyroid cancer Risk x15 à Gy Veiga, Radiat Res,

12 Second cancer : impact of radiotherapy Breast cancer Risk x6 à 20 Gy Risk x12 à 40 Gy Inskip, JCO, mars 2017 EFEC - Clinique de Suivi à Long Terme en Oncologie Pédiatrique 12

13 Second malignancies after Hodgkin s lymphoma Risk of cancer increased by 2.39 Cumulative incidence of 13.9 % in males and 24% in females pts treated in Sweeden between 1966 and 2012 Median FU : 12.6 y 1121 second malignancies Sud, JCO 2017

14 Second malignancies after Hodgkin in patients < 35 y at diagnosis males Females Colon lung breast skin NHL leukemia Colon Lung Breast Skin NHL leukemai Cumulative risk at 30 y : 13.9% Cumulative risk at 30 y : 24.5 % for all cancers 13.8% for breast Sud JCO /05/2018 Long term follow-up 14

15 Role of familial history of cancer Risk of second malignancy significantly higher in patients with familial history of cancer

16 Cancer predisposition and subsequent neoplasms in CNS survivors 2779 childhood CNS tumor survivors from St Jude ( ) 81 survivors had 97 subsequent neoplasms SN (64 malignant) 22% had a cancer predisposition syndrome > 3 children with Gorlin syndrome 11 SNs > 9 children with neurofibromatosis type 1 11 SNs > 2 children with Li Fraumeni syndrome 1 SN each > 1 child with neurofibromatosis type 2 1 SN > 1 child with Lynch syndrome 1 SN > 1 child with familial adenomatous polyposis 1 SN > 1 child with Fanconi anemia 1 SN Tsui, Neuro Onco, /05/

17 Guidelines for screening after the end of oncologic follow-up Brain irradiation : brain MRI/ 5 y Cervical irradiation : thyroid ultrasound/5 y Breast irradiation > Gy : > annual screnning beginning at 25 and 8 y after the end of radiotherapy > palpation, ultrasound, MRI and mammo after 35 y In all patients after radiation annual dermatologic examination These guidelines should be adapted to genetic background 17

18 5- Fertility impairement 12 mai

19 Fertility imparirement Concerns both men and women Related to anti cancer treatment > Chemotherapy : ALKYLATING agent > Radiotherapy (ovary, testis, hypophyse) > Surgery 28 mars 2017 EFEC - Clinique de Suivi à Long Terme en Oncologie Pédiatrique 19

20 10938 survivors and 3948 siblings Median follow-up 10 years Decreased likelihood of having lifebirth in survivors vs siblings > male survivors: hazard ratio HR 0 63, ; p< > female survivors HR 0 82, ; p< Risk factors > Males : Cyclophosphamide, ifosfamide, procarbazine, cisplatinum > Females : Busulfan, lomustine > 411 mg/m 2, cyclophosphamide > 7,4 g/m 2 25/05/2018 Long term follow-up 20

21 Cyclophosphamide and male fertility 10.8 g/m² 8.5 g/m² 6.6 g/m² Normospermia 89% si Cyclo < 4 g/m² Green, Lancet onco,

22 Risk of ovarian failure according to age 25/05/2018 Long term follow-up 22

23 Cumulative incidence of premature menopause after Hodgkin lymphoma Risk of premature menopause at 5 y : - 52% after RT 5 gy to ovary - 51% after BEAM - 24% after 6 cycles including AA - Increased in older patients Cumulative risk of premature menopause before 40 y - 81% after > 5 Gy on ovary - 75% after BEAM - 49% after > 6 cycles including AA - 1.4% after ABVD - 3% after susdiaphragmatic RT Swerdlow 2014

24 Ovary radiosensiitivity Dose delivered to ovary leading to infertility Anderson, Lancet diab endoc, mars 2017 EFEC - Clinique de Suivi à Long Terme en Oncologie Pédiatrique 24

25 Organization of long term follow-up 25/05/2018 Long term follow-up 25

26 Long term follow-up of adults survivors of cancer in childhood aiming to Give information on long-term side effects of cancer treatment Propose individualized guidelines for screening for complications according to previous treatment and individual risk factors Improve early detection of complications Set up a network of experts adapted to the patients needs especially for patienst requiring sevral specialists (such as cardiologists, nephrologists, orthopedic surgeons, ) 26

27 Long term follow-up clinic Gustave Roussy 27

28 How can we organize such a follow-up in adults? 28