Prevention and screening of long term side effects. Lena Specht MD DMSc Professor of Oncology Rigshospitalet, University of Copenhagen Denmark

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1 Prevention and screening of long term side effects Lena Specht MD DMSc Professor of Oncology Rigshospitalet, University of Copenhagen Denmark

2 Disclosures Member of Advisory Board and Principal Investigator, Takeda Member of Advisory Board, Merck Research Agreement, Varian Medical Systems Principal Investigator, Nanovi

3 Incidence and mortality of lymphoma in Europe Age standardized rates and absolute numbers

4 Absolute excess risk of death from different causes in a Hodgkin lymphoma cohort study (Aleman et al. 2003)

5 Long-term complications of Hodgkin lymphoma treatment Second malignancies and cardiovascular disease are the most common serious long term complications Cohort studies (typically registry data): Information on treatment of the individual patients is very limited Case-control studies: Matched controls may be difficult to find, there is no untreated control group Large number of studies have been published, but because of the long latency they analyze outdated treatments (higher radiation doses, larger irradiated volumes, outdated chemotherapy regimens) We have analyzed long-term complications of RT much more extensively than of CT

6 We need Studies of the treatments of the past with in depth analyses of dose-response relationships Extrapolations to modern treatments Quantitative estimates of the risk of serious longterm side effects of modern treatments Development of mathematical tools to combine the estimates to provide an overall risk of serious longterm side effects from different treatment strategies

7 Radiation dose-response relationship for risk of coronary heart disease in Hodgkin lymphoma survivors ISRT Mantle RT van Nimwegen FA et al. JCO 2016

8 Radiation dose-response relationship for risk of valvular heart disease in Hodgkin lymphoma survivors ISRT (aortic valve) Mantle RT Cutter DJ et al. JNCI 2015

9 Radiation dose-response relationship for risk of heart failure in Hodgkin lymphoma survivors Not an issue Van Nimwegen et al. Blood 2017 e-pub

10 Quantitative estimate of the excess risk of cardiac event as a function of specific doses of anthracyclines and radiation to the heart Example: An increase in mean heart dose of 5 Gy yields the same excess risk of cardiac event as an increase in cumulative anthracycline dose of 50 mg/m² ( 1 cycle of ABVD) Maraldo MV et al. Lancet Haematol 2015

11 Second malignancies in 3905 Dutch pts. treated for Hodgkin lymphoma in three different time periods (decreasing radiotherapy and increasing chemotherapy) Schaapveld et al. NEJM 2015; 373:

12 Why is there no difference in second cancers when RT is decreased and CT is increased? CT may be more cancerogenic than we thought Only now are large cohorts of patients with years follow-up appearing We have perhaps shown less interest in analyzing long-term consequences of CT The mechanism behind secondary cancerogenesis may be more complicated than the direct induction of DNA damage leading to somatic mutations Genetic susceptibility, DNA-repair defects Immune system (suppression, systemic chronic inflammation)

13 Guidelines (interventions have rarely been tested in randomized trials) After radiotherapy including breast in women < 30: start mammography (MRI?) 8-10 years after treatment After alkylating agents and radiotherapy including lung: Stop smoking Annual chest imaging for patients at increased risk of lung cancer Immune compromised patients: Sun-safety practice Regular self-examination and annual skin examination by dermatologist After radiotherapy to the abdomen: Selected patients (e.g. family history) colonoscopy screening every 5 years starting 10 years after treatment

14 Cardiovascular disease, how to avoid it Radiotherapy: Limit dose and volume to the heart Highly conformal treatment to involved site only Treatment in deep inspiration breath hold Chemotherapy: Limit cumulative doses of cardiotoxic drugs Free-radical scavenging cardioprotectant (Dexrazoxane), but concern about possible interference with antiacancer activity Some indications of possible benefit from ACE-inhibitors and beta-blockers (no evidence yet)

15 Guidelines for cardiac follow-up Annual blood pressure, serum glucose, lipid screening Baseline echocardiogram at 5-10 years, then periodic. Stress echocardiogram recommended after chest radiotherapy Possible screening tools (evidence for use as standard is still lacking): Serial endocardial biopsy Serial BNP and troponin level testing Serial MUGA or radionucleide angiography Exercise testing Echocardiogram Carver JR et al. ASCO guidelines. JCO 2007; 25: Bovelli D et al. ESMO guidelines. Ann Oncol 2010; 21(Suppl.5):

16 De Haas EC. Lancet Oncol 2010; 11:

17 Endocrine function Chemotherapy (alkylating agents), radiotherapy to pelvic area: Options for preserving fertility prior to treatment initiation Sperm banking Ovarian or egg freezing Effect of hormonal suppression during chemotherapy uncertain, recent randomized trial negative (Demeestere et al. JCO 2016; 34: ) Radiotherapy to the neck: Annual TSH

18 Peripheral neuropathy Overall incidence in patients treated with multiple agents around 38 % Higher incidence with treatments including platinum drugs, vinca alkaloids, brentuximab vedotin, bortezomib Partially reversible in 80%, resolves in around 40 % after 6-8 months.

19 Peripheral neuropathy Hershman DL et al. ASCO guidelines. JCO 2014; 32:

20 Peripheral neuropathy

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22 Cognitive, emotional and psychosocial function Counseling on health habits and psychosocial issues Psychoactive drugs have been tested, e.g., Methylphenidate (stimulant), not for routine practice Rehabilitation Survivorship clinics

23 Thank you for your attention