University of Groningen Long-term adverse effects of cancer treatment Westerink, Nico-Derk Lodewijk

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University of Groningen

Long-term adverse effects of cancer treatment

Westerink, Nico-Derk Lodewijk

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Publication date: 2018

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Westerink, N-D. L. (2018). Long-term adverse effects of cancer treatment: Susceptibility and intervention strategies. Rijksuniversiteit Groningen.

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BACKGROUND

In The Netherlands, cancer incidence has almost doubled from 1989 to 2016 to approximately 108,000 cases per year.1_{The outcome of patients with cancer has improved steadily due to earlier}

diagnosis and better treatment protocols. Cancer treatment can result in numerous adverse effects which can be divided into early and late or long-term adverse effects. Early adverse effects like hair loss, nausea, vomiting and bone marrow toxicity occur during treatment. These persist until a few months after treatment and, in most cases, will resolve spontaneously. Long-term or late adverse effects like cardiovascular morbidity, endocrine disturbances, pulmonary morbidity and fatigue can influence quality of life and impair survival for several years or longer.2

These long-term adverse effects can develop years or decades after the initial cancer treatment and often do not resolve spontaneously. Moreover, serious comorbidity can develop which ultimately will impair health-related quality of life and impair or shorten survival.

Cancer treatment can induce the metabolic syndrome. This syndrome can contribute to the development of cardiovascular and metabolic diseases. The metabolic syndrome includes pro-thrombotic features and is characterized by a combination of several cardiovascular risk factors: insulin resistance, dyslipidemia, visceral obesity and high blood pressure.3,4_Furthermore,

it may contribute to the increased risk of developing cardiovascular disease in cancer patients by complex and multifactorial mechanisms.5_{Hormonal changes, like testosterone or estrogen}

disturbances, can play an additional role in its development. Moreover, direct endothelial damage induced by radiotherapy or chemotherapy causes a pro-thrombotic state with an increased risk of thromboembolic events.2_{Unraveling the process of the development of the}

metabolic syndrome can help to develop strategies for prevention.

Factors that influence the development or severity of long-term adverse effects in cancer patients are the type of systemic treatment patients receive, total individual dosage or combination treatment, genetic susceptibility and lifestyle factors.2,6,7_{Higher dosage of for}

example anthracycline-containing chemotherapy or higher dosage of radiotherapy results in more toxicity and an increased risk for developing adverse effects.8,9_{Furthermore, genetic}

susceptibility seems to play a role in the development of long-term adverse effects. For example, certain genes that are involved in the metabolism or clearance of chemotherapy can be altered which may result in more serious adverse effects.10,11_{Also, several lifestyle factors might play a role}

in the development of long-term adverse effects of cancer treatment. For example, decreased physical activity or increased sedentary time cause weight gain resulting in obesity, which is probably the major driving force of the metabolic syndrome.4_{Identifying patients that are at}

risk for long-term toxicity and adverse effects is important. Treatment protocols can be altered and an early intervention with lifestyle improvement can be initiated in order to prevent long-term adverse effects. When effective, this strategy will ultimately result in a more personalized treatment plan.

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Some long-term adverse effects, like the development of metabolic syndrome, can be influenced by lifestyle interventions.4_{A healthy and balanced diet and sufficient physical exercise can lead}

to less fatigue, reduced cardiovascular risk, with decreased lipid levels and blood pressure and less decline or improvement in cardiorespiratory fitness. Lifestyle interventions can possibly results in permanent lifestyle changes and therefore prevent or treat these adverse effects at an early stage. Evidence for positive effects of lifestyle interventions on cancer survivorship and cancer outcome is expanding.12,13_{Especially weight gain after cancer treatment is a substantial}

medical and social problem.14_{In most cancer types, data supports that weight gain is associated}

with an increased all-cause mortality in cancer patients, however little is known about direct causality.15_{Lifestyle interventions to counteract obesity in breast cancer patients seem effective}

for weight loss16-18_{, but more and larger clinical trials with prolonged follow up are needed to}

examine the results on prolonged and healthier survivorship. Furthermore, physical exercise is an easily accessible, low cost and low risk opportunity to decrease several cancer treatment induced problems like fatigue, cardiovascular risk and weight gain.17,19-21_{Physical exercise increases}

cardiorespiratory fitness and assists in maintaining or achieving a healthy body composition.22

Advising cancer patients about healthy lifestyle during and after treatment is often unremarked, whereas in other patient groups such as patients undergoing a revascularization intervention for coronary artery disease physical exercise during and after this intervention is standard of care.23

In order to understand and to prevent or treat cancer treatment-induced adverse effects, the aims of this thesis are the following. To investigate the development of cancer treatment-induced adverse effects; to examine individual susceptibility for developing long-term adverse effects; and to investigate the effects of physical exercise lifestyle interventions on cancer treatment-induced adverse effects.

OUTLINE OF THE THESIS

In chapter 2 the role of lifestyle intervention programs on cancer treatment-induced metabolic syndrome (CTIMetS) is analyzed. The etiology of CTIMetS differs from the metabolic syndrome in the non-cancer population, but prevention and treatment methods are probably comparable. We reviewed how several treatment types are associated with the development of CTIMetS and analyzed how lifestyle interventions can influence CTIMetS or its individual components. In addition, timing of lifestyle interventions is discussed. The development of the metabolic syndrome can also be accelerated by genetic susceptibility. Identifying these patients may ultimately lead to prevention or early intervention strategies for the metabolic syndrome. Therefore, we analyzed in chapter 3 if altered androgen metabolism contributes to the development of the metabolic syndrome in testicular cancer patients. We evaluated single-nucleotide polymorphisms in the gene encoding steroid 5-α-reductase type II and correlated these with the prevalence of the metabolic syndrome in testicular cancer survivors.

A low-cost and promising strategy to prevent or treat CTIMetS, i.e. lifestyle intervention,

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is investigated in chapter 4. A preliminary report is presented of the trial ‘Optimal timing of a tailored physical exercise program during cancer chemotherapy to reduce long-term cardiovascular morbidity - ACT trial: design and a preliminary report on cardiorespiratory fitness and vascular markers’. Specific timing of lifestyle interventions, i.e. during or after completion of cytotoxic treatment, might be of influence on the outcome. In this randomized trial, the effect of timing of a physical exercise intervention on cancer treatment-induced adverse effects during cancer treatment is investigated. The primary endpoint of this study is cardiorespiratory fitness in terms of difference in volume oxygen at peak effort (VO₂ peak) one year after completion of the intervention. Because decreased cardiorespiratory fitness is often present in cancer patients and is a predictor of increased mortality, investigating intervention strategies to prevent or treat this appears to be relevant and of clinical importance.24

To identify patients that are susceptible for developing cardiotoxicity after cancer treatment, we evaluated in chapter 5 whether a genetic predisposition for dilated cardiomyopathy (DCM) in patients who are treated with anthracycline-containing combination chemotherapy, are more prone to develop a cardiomyopathy. Anthracyclines are still often and successfully used in cancer treatment, but their use is limited because of their cardiotoxic adverse effects. We identified childhood and adult cancer survivors who were treated with anthracycline combination chemotherapy from 1976 to 1999 and 1987 to 2008 respectively at the departments of pediatric oncology and medical oncology of the University Medical Center Groningen. Next, we screened medical records of these patients for clues of decreased left ventricular systolic function. Signs for a possible genetic predisposition were observed through screening of the patients family history, for example when a family member was suffering from heart failure or deceased due to heart failure or when a family member was deceased at young age or due to a non-atherosclerotic cardiac cause. In potentially positive cases, cardiac function with DNA analysis for DCM-related genes was performed.

Testicular cancer patients are frequently treated with a combination of bleomycin, etoposide and cisplatin (BEP) chemotherapy resulting in a 5-year overall survival of 80-90%.25_{Unfortunately,}

bleomycin can cause pulmonary toxicity in about 10% of the patients and in 1-3% this toxicity can be fatal.26_{Identification of patients prone to develop this pulmonary toxicity is extremely}

important to individually modify treatment regimens. In chapter 6 we analyzed the prevalence of bleomycin-induced pulmonary changes on computer tomography (CT) scans in patients treated for metastatic testicular cancer and tested if several fibrosis markers were predictive factors. CT scans were analyzed for lesions suspect for bleomycin-induced changes. Plasma samples were collected before, during and after treatment and quantified for fibrosis and inflammation markers. The levels of these markers were correlated with the frequency of the bleomycin-induced pulmonary changes.

In chapter 7 we analyzed the link between iron metabolism and bleomycin- or cisplatin-induced toxicity. Previously, it was demonstrated that iron homeostasis may play a role in idiopathic pulmonary fibrosis and cisplatin-induced nephrotoxicity.27,28_{Iron homeostasis can be}

altered in patients with hereditary hemochromatosis, a genetic disorder resulting in altered iron

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metabolism caused by variants of the hemochromatosis (HFE) gene. In idiopathic pulmonary fibrosis, carriage of variants in the HFE gene leads to excessive accumulation of extracellular iron in lungs. We hypothesize that altered iron metabolism plays a role in the development of pulmonary toxicity by bleomycin or in renal toxicity by cisplatin. Therefore, we investigated whether there was an association between variants in the HFE gene and the development bleomycin-induced pulmonary toxicity or cisplatin-induced nephrotoxicity.

In chapter 8 we summarize the main findings of this thesis, followed by a discussion, including the clinical implications of the results and directions for future perspectives and research. In chapter 9 a Dutch summary is provided.

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REFERENCES

1. Integraal Kankercentrum Nederland. Nederlandse kankerregistratie, 1989 tot 2015. www.cijfersoverkanker.nl. 2. de Haas EC, Oosting SF, Lefrandt JD, Wolffenbuttel BH, Sleijfer DT, Gietema JA. The metabolic syndrome in cancer

survivors. Lancet Oncol. 2010;11:193-203.

3. Expert Panel on Detection, Evaluation, and Treatment of High Blood Cholesterol in Adults. Executive summary of the third report of the national cholesterol education program (NCEP) expert panel on detection, evaluation, and treatment of high blood cholesterol in adults (adult treatment panel III). JAMA. 2001;285:2486-2497.

4. Grundy SM, Cleeman JI, Daniels SR, et al. Diagnosis and management of the metabolic syndrome: An american heart association/national heart, lung, and blood institute scientific statement. Circulation. 2005;112:2735-2752.

5. Van Gaal LF, Mertens IL, De Block CE. Mechanisms linking obesity with cardiovascular disease. Nature. 2006;444:875-880. 6. Altena R, Hummel YM, Nuver J, et al. Longitudinal changes in cardiac function after cisplatin-based chemotherapy for

testicular cancer. Ann Oncol. 2011;22:2286-2293.

7. Boer H, Proost JH, Nuver J, et al. Long-term exposure to circulating platinum is associated with late effects of treatment in testicular cancer survivors. Ann Oncol. 2015;26:2305-2310.

8. Ewer MS, Von Hoff DD, Benjamin RS. A historical perspective of anthracycline cardiotoxicity. Heart Fail Clin. 2011;7:363-372.

9. Darby SC, Ewertz M, McGale P, et al. Risk of ischemic heart disease in women after radiotherapy for breast cancer. N Engl J Med. 2013;368:987-998.

10. Nuver J, Lutke Holzik MF, van Zweeden M, et al. Genetic variation in the bleomycin hydrolase gene and bleomycin-induced pulmonary toxicity in germ cell cancer patients. Pharmacogenet Genomics. 2005;15:399-405.

11. Boer H, Westerink NL, Altena R, et al. Single-nucleotide polymorphism in the 5-alpha-reductase gene (SRD5A2) is associated with increased prevalence of metabolic syndrome in chemotherapy-treated testicular cancer survivors. Eur J Cancer. 2016;54:104-111.

12. Jiralerspong S, Kim ES, Dong W, Feng L, Hortobagyi GN, Giordano SH. Obesity, diabetes, and survival outcomes in a large cohort of early-stage breast cancer patients. Ann Oncol. 2013;24:2506-2514.

13. Ewertz M, Jensen MB, Gunnarsdottir KA, et al. Effect of obesity on prognosis after early-stage breast cancer. J Clin Oncol. 2011;29:25-31.

14. Vance V, Mourtzakis M, McCargar L, Hanning R. Weight gain in breast cancer survivors: Prevalence, pattern and health consequences. Obes Rev. 2011;12:282-294.

15. Playdon MC, Bracken MB, Sanft TB, Ligibel JA, Harrigan M, Irwin ML. Weight gain after breast cancer diagnosis and all-cause mortality: Systematic review and meta-analysis. J Natl Cancer Inst. 2015;107:djv275.

16. Goodwin PJ, Segal RJ, Vallis M, et al. Randomized trial of a telephone-based weight loss intervention in postmenopausal women with breast cancer receiving letrozole: The LISA trial. J Clin Oncol. 2014;32:2231-2239.

17. Rock CL, Flatt SW, Byers TE, et al. Results of the exercise and nutrition to enhance recovery and good health for you (ENERGY) trial: A behavioral weight loss intervention in overweight or obese breast cancer survivors. J Clin Oncol. 2015;33:3169-3176.

18. Reeves MM, Terranova CO, Eakin EG, Demark-Wahnefried W. Weight loss intervention trials in women with breast cancer: A systematic review. Obes Rev. 2014;15:749-768.

19. Gardner JR, Livingston PM, Fraser SF. Effects of exercise on treatment-related adverse effects for patients with prostate cancer receiving androgen-deprivation therapy: A systematic review. J Clin Oncol. 2014;32:335-346.

20. van Waart H, Stuiver MM, van Harten WH, et al. Effect of low-intensity physical activity and moderate- to high-intensity physical exercise during adjuvant chemotherapy on physical fitness, fatigue, and chemotherapy completion rates: Results of the PACES randomized clinical trial. J Clin Oncol. 2015;33:1918-1927.

21. Bergenthal N, Will A, Streckmann F, et al. Aerobic physical exercise for adult patients with haematological malignancies. Cochrane Database Syst Rev. 2014;11:CD009075.

22. Courneya KS, McKenzie DC, Mackey JR, et al. Effects of exercise dose and type during breast cancer chemotherapy: Multicenter randomized trial. J Natl Cancer Inst. 2013;105:1821-1832.

23. Heran BS, Chen JM, Ebrahim S, et al. Exercise-based cardiac rehabilitation for coronary heart disease. Cochrane Database Syst Rev. 2011;(7):CD001800. doi:CD001800.

24. Schmid D, Leitzmann MF. Cardiorespiratory fitness as predictor of cancer mortality: A systematic review and meta-analysis. Ann Oncol. 2015;26:272-278.

25. Loehrer PJ S, Johnson D, Elson P, Einhorn LH, Trump D. Importance of bleomycin in favorable-prognosis disseminated germ cell tumors: An eastern cooperative oncology group trial. J Clin Oncol. 1995;13:470-476.

26. Simpson AB, Paul J, Graham J, Kaye SB. Fatal bleomycin pulmonary toxicity in the west of scotland 1991-95: A review of patients with germ cell tumours. Br J Cancer. 1998;78:1061-1066.

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27. Sangiuolo F, Puxeddu E, Pezzuto G, et al. HFE gene variants and iron-induced oxygen radical generation in idiopathic pulmonary fibrosis. Eur Respir J. 2015;45:483-490.

28. Baliga R, Zhang Z, Baliga M, Ueda N, Shah SV. In vitro and in vivo evidence suggesting a role for iron in cisplatin-induced

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