The Danish National Research Foundation s Centre of Inflammation and Metabolism Rigshospitalet and University of Copenhagen

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2 GERM CELL CANCER A MODEL FOR CANCER SURVIVORSHIP 1981: Lawrence Einhorn labels GCC model for curable neoplasm (Cancer Research, 1981) 1984: modern combination introduced (BEP) 1974: Cisplatin introduced in first clinical trial All Cancers Germ Cell Cancer Year of Diagnosis Lung Cancer Colon Cancer Denmark: Age-adjusted 5-year relative survival,

3 GERM CELL CANCER A MODEL FOR CANCER SURVIVORSHIP Lauritsen (2014), Denmark Relative CVD-HR in BEP-treated GCC survivors Disease Smoking, HR (95% CI) BEP, HR (95% CI) CVD (any) 1.6 ( ) 1.4 ( ) Diabetes 1.3 ( ) 1.4 ( ) Death (CVD) 1.6 ( ) 1.7 ( ) Lauritsen et al. 2013, Eur J Cancer

4 GERM CELL CANCER A MODEL FOR CANCER SURVIVORSHIP In summary, Early detection Accurate staging and (accordingly) standardized therapeutic strategies Highly effective primary anti-neoplastic therapy and excellent prognosis However, High level of acute toxicities and organ dysfunction Prolonged recovery/rehabilitation (often) required Considerably increased risk of long-term cardiovascular morbidities and mortality.but the candidate mechanisms remains poorly understood!

5 MUSCLE DYSFUNCTION IN CANCER PATIENTS Wolfe 2006, Am J Clin Nutr Nathan & Fuld 2010, Thorax Christensen et al. 2014, Ann Oncol is muscle dysfunction involved in post-treatment cardiovascular disease sequelae in cancer survivors?

6 PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS Study Design Baseline 30 of 41 (73%) eligible GCC patients included: randomized to resistance training (INT) or usual care control (CON) 19 healthy subjects included (REF) Post treatment 25 of 30 (83%) patients completed the study 16 of 19 healthy subjects completed the study 3 months follow-up 20 of 30 (67%) were assessed for follow-up Baseline test Day 5-0 Treatment start Day 1 2 nd cycle start Day 22 3 rd cycle start Day 43 Post interv.test Day Follow-up test ~ Day 150 Muscle biopsy x x x Blood sample x x x x x DXA scan x x x Isometric strength test Questionnaires (SF 36 & EORTC) Randomization x x x x x x x x x

7 PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS Muscle Biopsy

8 PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS Safety and feasibility of resistance training in GCC patients during BEP Balanced training volume but lower training intensity (progression)

9 PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS Efficacy of resistance training on muscular profile Christensen et al. 2014, Br J Cancer

10 PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS Efficacy of resistance training on muscular profile Christensen et al. 2014, Br J Cancer

11 PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS Efficacy of resistance training on muscular profile Christensen et al. 2014, Br J Cancer

12 PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS Resistance training dose-response relationship 8 REF-Group 2 INT-Group Change lean mass, Kg R = 0.77, p<0.001 Change lean mass, Kg R = 0.19, N.S Number of resistance training sessions Number of resistance training sessions Change in lean mass, Kg R = 0.61, p<0.01 Change in lean mass, Kg R = -0.09, N.S. -2 0,00 0,60 0,65 0,70 0,75 0,80 0,85 0,90 0,95 1,00 Mean intensity, %1RM (4 exercises) -3 0,00 0,60 0,65 0,70 0,75 0,80 0,85 0,90 Mean intensity, %1RM (4 exercises)

13 In summary, PROGRESSIVE RESISTANCE TRAINING AND CANCER TESTIS In GCC patients, BEP was associated with acute (and severe level of) muscle dysfunction Resistance training during BEP was safe and feasible. Intention-to-treat analyses showed only trends (p<.1) toward improved strength, lean mass and fiber size at end-of-therapy, i.e. rescue/reverse muscle breakdown. No impact of resistance training on qualitative muscular features (myofiber phenotypes and cap. supply) and metabolic profile. BEP significantly altered the normal muscular response to resistance training, causing a non-linear dose-response relationship

14 IS GCC TREATMENT CAUSING ACCELERATED PHYSIOLOGICAL AGEING? Lakata 2002, Heart Failure Reviews

15 IS GCC TREATMENT CAUSING ACCELERATED PHYSIOLOGICAL AGEING? 10 years of ageing: ~2kg muscle loss 3 months post BEP-treatment: ~20% patients lost >1kg lean mass Janssen et al 2000, J Appl Phys

16 IS GCC TREATMENT CAUSING ACCELERATED PHYSIOLOGICAL AGEING? +20 years of ageing (25 to 45 years): +0.7mM in T-CHOL 3 months post BEP-treatment: ~20% patients increased 0.7mM T-CHOL Carroll et al 2005, JAMA

17 IS GCC TREATMENT CAUSING ACCELERATED PHYSIOLOGICAL AGEING? +40 years of ageing: ~2-fold increase in plasma IL-6 levels (irrespective of training status) 3 months post BEP-treatment: ~2-fold increase in plasma IL-6 levels vs healthy age-matched individuals IL-6 Mikkelsen et al 2013, Mech Ageing Dev Christensen et al. 2014, J Clin Endocrinol Metab

18 IS GCC TREATMENT CAUSING ACCELERATED PHYSIOLOGICAL AGEING? CHARACTERIZED BY Sub-clinical hypogonadism and low grade inflammation? Pancreatic endocrine cell deficiency? Vascular injury and muscular inflammation? Christensen et al., Acta Oncologica (submitted) MetS: Insulin resistance, hyperlipidemia, obesity, hypertension? CAN STRUCTURED EXERCISE PREVENT/MITIGATE THIS SEQUALAE? OR REVERSE IT? Lakata 2002, Heart Failure Reviews

19 WHY WE DO RESEARCH Indiana University, 1974: A young man, age 22, is diagnosed with testicular germ cell cancer. The disease quickly progressed, and he was told, he would die from his disease within the next year. We ve done all we can do except one other thing we can try. This is a clinical trial. This is investigational. We do not know if this will be helpful. In fact, we have not tried this before. You would be the first Dr. Lawrence Einhorn Lawrence Einhorn, MD What have I got to lose? If it does not help me, it may help someone else. Let's do it..who would become the first testicular cancer patient to be cured by cisplatin-based chemotherapy. John Cleland THANK YOU FOR YOUR ATTENTION! John & Judy Cleland