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

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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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CHAPTER 8

Summary, discussion

and future perspectives

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SUMMARY

The increase in numbers of long-term cancer survivors makes attention for healthy survivorship important. Cancer treatment with potential early and long-term adverse effects can have a major impact on health-related quality of life. The severity of these adverse effects vary from transient, with minor inconvenience, to permanent with sustained impaired health-related quality of life, chronic disease and ultimately increased risk of death. A challenge in oncology is to prevent or alleviate these adverse effects and therefore, the identification of patients with increased risk for developing these adverse effects is important. Identifying patients with an elevated risk for certain toxicity, could lead to an alternative treatment plan. In that respect, the goal is to personalize treatment with a trade-off for optimal efficacy and limited toxicity.

The influence of lifestyle on cancer risk, cancer treatment outcome and cancer survivorship is substantial. Recent data demonstrate that lifestyle interventions during and after cancer treatment could prevent or positively influence the development of adverse effects. 1-3_Therefore

the aim of this thesis was identifying patients that are susceptible to develop long-term adverse effects of cancer treatment and how lifestyle interventions could prevent or alleviate these long-term adverse effects.

Cancer treatment-induced metabolic syndrome (CTIMetS) increases the risk of cardiovascular disease and impairs survival. In chapter 2, we reviewed the literature on the multifactorial development of CTIMetS. Surgery, radiotherapy, chemotherapy and hormonal therapy all contribute to the development of metabolic or cardiovascular changes with CTIMetS as a result. Lifestyle interventions, whether or not provided in a supervised schedule, may play a key role in preventing CTIMetS or alleviating its consequences. Timing of lifestyle interventions, i.e. early during cancer treatment, might have an additional positive effect in preventing CTIMetS. In

chapter 3, the susceptibility of testicular cancer patients for the metabolic syndrome (MetS)

was investigated. In 173 chemotherapy-treated testicular cancer survivors, hormone levels and cardiometabolic status was evaluated in a cross-sectional study and correlated with single-nucleotide polymorphisms (SNP) in the gene encoding steroid 5-α-reductase (SRD5A2). The SNP rs523349 in the SRD5A2 gene was associated with a significant higher prevalence of MetS compared to wild-type (33% vs. 19%, P = 0.032). In patients with decreased serum testosterone levels (< 15 nmol/l) and a variant genotype the prevalence was even higher compared to wild-type and normal serum testosterone levels (66.7% vs. 17.4%). These data suggest that altered androgen metabolism plays a role in increased susceptibility for developing MetS. In these patients, an early intervention to prevent the development of MetS could lead to a decreased cardiovascular risk.

In chapter 4, preliminary results are presented of ‘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’. In this randomized controlled trial we analyzed the effects of a physical exercise intervention during (early) or after completion (late) of chemotherapeutic treatment with curative intent.

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117 From January 2013 to July 2017 217 patients were included and randomized. 134 of 217 included patients were evaluable and available for preliminary analysis. Primary end-point was difference in cardiorespiratory fitness in terms of VO₂ peak one year after intervention between both groups. There was less decline of cardiorespiratory fitness in the early group (n = 73) during chemotherapy compared to the late group (n = 61). Both groups showed recovery of cardiorespiratory fitness during the intervention. In the 84 patients that completed the trial, no difference was found in cardiorespiratory fitness one year after intervention between both groups. When focusing on testicular cancer patients, significant lower levels of vascular damage parameters, i.e. von Willebrand Factor and blood clotting Factor VIII, were seen in patients allocated to the early group (n = 27) compared to the late group (n = 20). This indicates that the used physical exercise intervention with gradually increased training intensity results in decreased endothelial activation.

Chemotherapy-induced cardiotoxicity is one of the most threatening adverse effects of anthracycline chemotherapy. Although a dose dependent relation is found, no safe dose is defined and cardiotoxicity is still an adverse effect with severe and potentially fatal consequences. Susceptibility for anthracycline associated cardiomyopathy (AACM) is examined in chapter 5. We hypothesized that the presence of genes associated with dilated cardiomyopathy (DCM) is a risk factor for developing AACM. We identified five DCM families with each one patient with AACM, and one patient with AACM with a family member with previously unrecognized, possible early sign of mild DCM. In two of these families, pathogenic mutations were identified in the gene that is involved in cardiac myosin synthesis (MYH7), which confirms the genetic character of DCM in these families. According to this observation, we emphasize the importance of evaluation of cardiac function before administration of cardiotoxic chemotherapy in patients with a family history of DCM or heart failure. Cardiotoxic cancer treatment in patients with DCM or patients with families of DCM, might result in severe cardiac toxicity. Intensive cardiac monitoring or an alternative treatment regimen is recommended in this situation.

Ten year survival rates of metastatic testicular cancer patients treated with bleomycin, etoposide and cisplatin (BEP) chemotherapy are excellent in the range of 80-90%. However, 10% of these patients develop bleomycin-induced pulmonary toxicity which can be fatal in 1-3%. So far, it is unknown why some patients develop severe pulmonary toxicity. In chapter

6, we investigated whether fibrosis markers transforming growth factor-β1 (TGF-β1), growth

differentiation factor-15 (GDF-15) and inflammation marker high sensitivity C-reactive protein (hs-CRP) could predict bleomycin-induced pulmonary changes on computed tomography (CT) scans. We found mild or moderate signs of pulmonary fibrosis on CT scans in 68% of bleomycin-treated patients. In 63% of patients, these changes resolved completely and in 37% they diminished during follow up (median follow-up duration with CT scan of 175 days). TGF-β1, GDF-15 and hs-CRP serum levels were not different in patients with and without pulmonary changes on CT scans and are therefore not suitable as predictive markers. In chapter 7, we focused on susceptibility of bleomycin-induced pulmonary toxicity and the role of iron metabolism. In 369 patients with metastatic testicular cancer treated with bleomycin and cisplatin combination chemotherapy, summary, discussionandfutureperspectives

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we analyzed DNA for variants in the hemochromatosis gene (HFE). We investigated whether variants H63D and C282Y in the HFE gene, which is involved in iron metabolism, are associated with the development of pulmonary toxicity. Compared to 11% of the wild-type patients, 21% heterozygote (n = 16) and 50% homozygote patients (n = 2) for H63D variant developed bleomycin-induced pulmonary toxicity (P = 0.012). When confirmed, this strategy may help to identify patients at risk for developing bleomycin-induced pulmonary toxicity.

DISCUSSION AND FUTURE PERSPECTIVES

Increasing knowledge of adverse effects of cancer treatment and early recognition will lead to improved cancer survivorship. Cancer treatment-induced adverse effects include pulmonary toxicity, neuropathy, increased cardiovascular risk and an increased susceptibility to metabolic disorders. In this thesis, we investigated susceptibility and treatment strategies for these adverse effects. Lifestyle intervention is an important strategy to avoid, prevent and treat cancer treatment-induced adverse effects. Evidence shows that adequate physical activity has beneficial effects in the prevention of cardiovascular and metabolic chronic diseases in the non-cancer population.4-8_{Trials with combined diet and exercise or dietary education alone}

can prevent MetS, diabetes mellitus type 2 and cardiovascular disease.9,10_{A recent study of}

63 testicular cancer survivors showed an improvement of VO₂ peak with 3.7 ml/min/kg (95% confidence interval [CI] 2.4-5.1, P < 0.001) in patients randomized to a supervised 12-week high intensity interval training compared to usual care. Moreover, the intervention group showed increased reduction in Framingham 10-year CVD risk score of mean -0.6 (95% CI -1.0 to -0.1, P = 0.011).11_{In a retrospective questionnaire-based study of 1,187 childhood cancer survivors, it was}

demonstrated that increased and vigorous exercise (i.e. ≥ 9 metabolic equivalent task (MET) hours per week) was associated with significant lower cardiovascular events compared to no exercise (adjusted rate ratio of 0.45, 95% CI 0.26-0.80).12_{Furthermore, in breast cancer survivors}

physical exercise might reduce cancer-related fatigue. In a meta-analysis of nine studies (n = 1,156), supervised aerobic exercise was more effective in improving cancer-related fatigue than conventional care (standardized mean difference of -0.51, 95% CI -0.81 to -0.21, P = 0.001).13

Mechanisms of physical exercise on improved cancer outcome are complex and multifactorial. Ashcraft et al. reviewed 53 articles and summarized intratumoral and systemic effects of exercise in cancer patients. These include influence on angiogenesis and vessel maturity, apoptosis, DNA synthesis and repair, immune cell infiltration, oxidative balance and enhanced immune response and metabolic processes, like glucose and lipid regulation.14_{Therefore, physical}

exercise could play a major role in cancer prevention, tumor progression and development of metastasis. Timing and intensity of physical exercise during cancer treatment is subject of currently conducted research. Furthermore, lifestyle interventions should focus on how intensity of physical exercise during cancer treatment influences cardiorespiratory and cardiovascular outcomes in different cancer patient groups. The differences in cardiovascular outcome and

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119 intensity is investigated in chapter 4 and appeal for this. Furthermore, future research should not only be conducted in curative treatment setting or survivors, but also in the non-curable or palliative cancer population. Promising effects on progression-free survival or development of metastasis make this justifiable.14,15

Adherence to lifestyle intervention during cancer treatment depends largely on intrinsic motivation. When patients are confronted with cancer diagnosis and treatment, their main focus is cancer cure. Changing lifestyle to obtain healthy survivorship after treatment is of minor importance. However, thoughts about patient’s own influence on survival and a healthy lifestyle often develop just after being diagnosed with cancer. Evidence shows that this teachable moment is an excellent opportunity to discuss and implement lifestyle change.16_Improvements

for lifestyle interventions during or after cancer treatment include group-based training as well as tailoring training sessions, preferably in the patient’s own environment. Unfortunately, these two may conflict. Data on supervised vs. unsupervised lifestyle interventions show that results of unsupervised interventions are in general moderate compared to supervised interventions in terms of adherence and improvement of cardiorespiratory fitness.1,2,17_{In the ACT trial, we}

did experience that supervised physical exercise in a rehabilitation center is important in terms of monitoring of safety and adjustment of exercises. Especially in the case of complex multidimensional problems which require a multidisciplinary approach. Moreover, group-based training might have a motivational benefit compared to individual-based training.18

Group-based training also leads to beneficial effects probably similar to a peer support group with the possibility to exchange information, experiences, and emotions which might result in less anxiety and depression.19_{However, major barriers in physical exercise interventions are the}

frequency of the training sessions, traveling and the time consuming aspect. The frequency of the training sessions in the ACT trial, i.e. 36 training sessions in total with three training sessions per week, was experienced as high by many patients and resulted in an attendance of median 26 and 31 training sessions for the early and the late group respectively. Difficulties with traveling or traveling alone was often a hurdle for patients. Facilitating a physical exercise intervention in the patient’s own environment, at a familiar training facility and with a familiar physiotherapist or lifestyle coach could overcome these hurdles. Especially with one-dimensional problems like improving physical fitness. To our knowledge, there is no data on difference in efficacy between supervised physical exercise at a training facility located in a rehabilitation center vs. a patient’s own training facility. Future research might provide more insights on the adherence and the effects and safety of physical exercise interventions in respect to this topic.

Patients that are already active in sports or have affinity with healthy lifestyle are more easy to be motivated. Most challenging are patients without affinity with healthy lifestyle, like obese or smoking patients who are possibly less familiar with physical activity and healthy lifestyle. In Northern parts of the Netherlands, 25% of the population smokes and approximately 50% is overweighed with a BMI > 25.20_{Strategies to motivate these patients include financial rewarding.}

In a randomized study of 2,538 participants investigating financial incentives for smoking cessation, it was demonstrated that sustained abstinence, i.e. more than six months, was higher

summary, discussionandfutureperspectives

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in incentive programs compared to usual care (9.4-16% vs. 6.0% respectively, P < 0.05).21_In

contrast to a recent randomized clinical trial which showed no differences in time to vascular re-hospitalization or death in 1,509 patients diagnosed with acute myocardial infarction receiving financial incentives combined with electronic reminders and social support for medication adherence compared to usual care (hazard ratio of 1.04, 95% CI 0.71-1.52, P = 0.84).22_Future

studies could include financial incentives or a loyalty program for healthy behavior in cancer patients. The effect of rewarding can be investigated with lower insurance fees for patients that succeed in weight loss, weight stability or smoking cessation while facilitating them with a physical exercise or lifestyle intervention.

Accumulation of unrepaired DNA damage, induced by genotoxic agents, and telomere shortening are potent inducers of cellular senescence. Senescence is a cellular state of irreversible growth arrest which plays an essential role to prevent expansion of pools of damaged cells. The stable arrest of unstable cells represents an important tumor suppressor mechanism and guarantees tissue homeostasis.23_{The number of senescent cells increases and accumulates with}

age in different organisms including humans and mice. The presence of an excessive number of senescent cells has been associated with age-related diseases like atherosclerosis, chronic obstructive pulmonary disease and Alzheimer’s disease.24-26_{More recently, different studies in}

mice have reported that elimination of senescent cells alleviates a wide range of age-related symptoms, including cardiovascular and renal dysfunction, sarcopenia, osteoporosis, frailty and hypercholesterolemia.27-29_{Furthermore, cytotoxic treatment in cancer patients possibly enhances}

cellular senescence in healthy tissue and is therefore probably involved in the development of long-term adverse effects.30_{Exercise was demonstrated to prevent cellular senescence}

in circulating leukocytes in the vessel wall and regulates telomere-stabilizing proteins.31

Furthermore, in 20 healthy males the effect of aerobic exercise was investigated on telomeric genes. Compared to pre-exercise blood samples, significant regulation of key telomeric genes was seen post-exercise.32_{These findings provide new insights on the effect of exercise on cellular}

aging and telomere length and subsequently adverse effects in cancer treatment.

In some studies, caloric restriction seem to increase efficacy of cancer treatment.33,34

Furthermore, dietary measures in cancer survivors results in significant changes in waist circumference, weight and fasting insulin levels.35_{CTIMetS, with its obesity driven background, is}

probably very suitable for lifestyle interventions with dietary measures. Guidance and education for these patients can help to obtain a healthy weight and energy balance. Testicular cancer patients treated with chemotherapy are prone to develop the metabolic syndrome.36_During

treatment, corticosteroid therapy as anti-emetic drugs are administered with side effects of increased appetite and weight gain. Dietary measures during cancer treatment might prevent weight gain and consequently the metabolic syndrome. Studies are needed to further investigate how and in what way diet can influence weight gain and the development of the metabolic syndrome in this specific population of cancer patients.

In the past years, the incidence of testicular cancer has increased from 5 in 100,000 in 1990 to 8 in 100,000 in 2016.37_{In metastatic testicular cancer patients receiving bleomycin as a}

8

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121 component of BEP chemotherapy, approximately 10% develops bleomycin-induced pulmonary toxicity and in 1-3% this may be fatal.38,39_{To identify patients at risk for developing}

bleomycin-induced pulmonary toxicity, it is important to find early predicting markers or risk factors. If such markers or risk factors are available before or early after start of chemotherapy, treatment can be adjusted to avert pulmonary toxicity. Strategies that we investigated in chapter 6, i.e. fibrosis biomarkers TGF-β1, GDF-15 and hs-CRP and CT scans, were not suitable to early detect development of bleomycin-induced pulmonary toxicity. Furthermore, pulmonary changes on CT scan in BEP combination chemotherapy treatment are very common (68%) and most of these changes resolve spontaneously. This indicates that identification of patients where pulmonary toxicity reaches a point beyond self-limiting and develops into bleomycin-induced pneumonitis is challenging. The pathophysiology of idiopathic pulmonary fibrosis (IPF), a chronic, progressive fibrosing interstitial pneumonitis of unknown cause, might be similar to bleomycin-induced pneumonitis. A combination of selected features were used that were helpful as predictor of increased risk of mortality.40_{These features included increased level of dyspnea, decreased}

forced vital capacity by ≥ 10% absolute value, decreased diffusion capacity for carbon monoxide by ≥ 15% absolute value and worsening of fibrosis on high-resolution CT scan. Furthermore, in a study of 34 patients with IPF, declines of 10% or more in saturation during a 6-minute walk test was associated with increased mortality (hazard ratio of 23.3, 95% CI 1.5-365, P = 0.025).41

Possibly, these features can be investigated in patients with bleomycin-induced pulmonary toxicity and used in a composite scoring system to predict development of bleomycin-induced pneumonitis. In chapter 7 we found that a variant in the HFE gene is associated with a higher prevalence in bleomycin-induced pulmonary toxicity. The protein which HFE gene encodes facilitates iron transportation across the cell and prevents accumulation. An altered HFE gene possibly results in accumulation of iron in serum and combined with bleomycin this might lead to formation of free radicals with toxicity and cell death.42_{In future research, determination of}

serum levels of iron, transferrin and ferritin might provide more insight on iron accumulation and bleomycin-induced pneumonitis in testicular cancer patients.

Long-term adverse effects of cancer treatment are health care issues that should not solely concern the medical specialist. A lot of long-term adverse effects are also of the general practitioner’s (GP) concern, like management of cardiovascular risk, diabetes and fatigue. The majority of GP’s are probably not sufficiently involved and unaware of the risks and problems that cancer survivors cope with. In contrast with palliative cancer care, GP’s are insufficiently trained in long-term survival care but their role is important. Information about intensive treatment that patients receive can be of vital importance for the GP. Screening and treatment of adverse effects like a high cardiovascular risk profile in patients treated with chemotherapy and or radiotherapy, screening for the metabolic syndrome, hormonal disturbances, sexual problems, psychosocial problems are aspects that also a GP could provide. In a study of Lang et al. patients prefer an active role of their GP in cancer treatment and follow-up to discuss these issues.43_In

the Netherlands, GP’s use very accurate and reliable guidelines in their daily practice formed by the Dutch College of General Practitioners.44_{A guideline about possible health issues that}

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cancer survivors experience could be very helpful. Future research should focus on developing such a guideline to facilitate the GP in cancer care and long-term survivorship care. Furthermore, the role of GP’s in lifestyle education should not be underestimated. Optimizing lifestyle should be implemented throughout the healthcare system, starting before the time of diagnosis. With an estimated 42% of cancer incidents caused by a modifiable risk factor, prevention is of major importance.45_{An active role of the GP in prevention is mandatory.}

In conclusion, increasing numbers of cancer survivors require specific and dedicated care for long-term adverse effects of cancer treatment. Early markers or susceptibility profiles to identify patients at risk to prevent severe adverse effects could be of great value. Future studies should focus on the pathogenesis of adverse effects and how to intervene at an early stage. Lifestyle advice should be implemented throughout the healthcare system. Future lifestyle research in cancer patients should focus on adherence, intensity of physical exercise, dietary measures and optimal organization, with the use of a simple survivorship care plan which puts patients in control. GP’s should be increasingly involved in cancer survivorship care, management of long-term adverse effects of cancer treatment and cancer prevention. Practical guidelines could be of assistance and should be drafted in the coming years.

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