The effectiveness of non-pharmacological interventions for the management of cancer treatment-induced cardiotoxicity: a systematic review protocol

Review question What is the effectiveness of non-pharmacological interventions on the management of cancer treatment-induced cardiotoxicity? Background Cardiotoxicity resulting in left ventricular failure is a devastating and most feared outcome of anti-cancer therapy for oncology patients.1 It is possible that a patient may survive cancer only to develop heart failure, which may carry a higher mortality rate than cancer.1 The effects of cardiotoxicity as a result of cancer therapy include myocardial ischemia, hypertension, arrhythmias, thromboembolism, pericarditis and conduction defects which negatively impact on cancer rehabilitation and survivorship require attention.2–7 Of significant concern gaining the attention of cardiologist and oncologists is the development of left ventricular dysfunction (LVD) as a result of singular or concomitant cancer therapies, potentially progressing to heart failure (HF), or even death.2,8,9 Evidence for practice for the management of cardiotoxicity is only just beginning to emerge. To date most studies have examined pharmacological therapies for the management of patients with both cancer and HF. Over the last 50 years, there has been a significant amount of Level 1 evidence (systematic reviews of randomized controlled trails) emerging for the pharmacological and non-pharmacological management of heart failure, and nurses have played a major role in the implementation of non-pharmacological nurse-led strategies. However, to date there is a dearth of literature that looks at the non-pharmacological treatment of cardiotoxicity induced heart failure. Therefore, a good understanding of the potential risk factors and service needs, from early detection and optimal management strategies in the acute and survivor stages could enhance the safety of anti-cancer treatments, and ensure that extended cancer-free survival translates into improved survival and quality of life. Cardiotoxicity is a general term describing “toxicity that affects the heart”.10 International oncological guidelines define cardiotoxicity as “an absolute decrease in left ventricular ejection fraction (LVEF) >10 percent units associated with a decline below its normal limit of 50%”.11(p. 2474) Acute, sub-acute and chronic cardiotoxicity may occur in cancer patients as a direct result of the very treatment which aims to improve survival outcomes and can further compromise the clinical effectiveness, applicability and tolerability of cancer therapy.10,34,35,126 Recent data reports that the risk of developing HF secondary to cardiotoxicity is up to 15 times higher in cancer populations when compared to the general population, which substantially increases with age.2,29,80,125–127 Recent figures further report one in four women treated with trastuzumab eventually develop HF resulting from cardiotoxic insult, with varying statistical data for other chemotherapeutic agents varying from 1–5% incidence rates depending on cardiovascular risk factors, cumulative doses and cardiac tolerability of cancer therapy.2,29,80,125–127 The development of HF can potentially compromise cancer survivorship and quality of life independent of the oncological prognosis.11 Heart failure is correlated with a high incidence of morbidity and mortality.12 Characterized by frequent and recurrent hospital admissions, the economic burden for ongoing management is exponential.4,6,13,14 Risk factors that contribute to the development of HF include coronary artery disease, hyper- or hypotension and arrhythmias, and therefore remain the focus for prevention or treatment.4,6 As a complex progressive clinical syndrome, HF results from structural or functional myocyte damage, compromizing the ability of the ventricles to fill with blood or eject blood.15–18 Toxicity to the ventricles from agents such as chemotherapeutic drugs or radiotherapy results in structural and morphological changes to the left ventricle.16,19–21 This process is well recognized by cardiologists as cardiac remodeling.6 As the chamber morphs in size and structure, the haemodynamic stress may temporarily or permanently depress ventricular function.4,6 Typically, patients present with shortness of breath and fatigue, two common clinical manifestations limiting their functional capacity, exercise tolerance and significantly compromising quality of life.6 The development of cardiac rehabilitation programs have proven effective for the management of heart failure to improve survival, quality of life and reduce cardiovascular risks for cardiac sequale.22,23 However, cardiac rehabilitation programs are yet to determine the effects of a bundle of non-pharmacological interventions on the incidence, management or prevention of cardiotoxicity in cancer patients. Management of heart failure Cardiac rehabilitation and secondary prevention programs are integral to the comprehensive care and management of patients with HF to improve survival, quality of life and reduce cardiovascular risks for cardiac sequale.14,22–24 With approximately 20% of patients dying in the first year after diagnosis, key management strategies require both pharmacotherapy and non-pharmacological approaches to treat this progressive and potentially fatal condition.18,25,16 The fundamental principles of non-pharmacological cardiac rehabilitation focus on implementing interventions such as exercise, dietary modifications, cessation of smoking, improving psychosocial wellbeing, reducing stress and mortality, with evidence-based practice showing improvements to each component, and contributing to an improved quality of life in individuals with HF.14,22,26 Cancer and cardiotoxicity Cancer is estimated to be the leading cause of burden for disease for Australia, with more diagnosis of cancer attributed to population growth and the aging population.27 Approximately 60% of cancer patients will survive five years from diagnosis due to medical advancements in multi-modal cancer therapies.28 However, anthracyclines, trastuzumab, high-dose cyclophosphamides and radiotherapy treatments commonly cause decline in ventricular function as a result of cardiac toxicity and can lead to HF.29–32 The incidence rates of cardiotoxicity reported in literature linked to these commonly-prescribed chemotherapy agents are reported at 1–26% with anthracycline,33,34 7–28% with high-dose cyclophosphamides,31,33–35 and 8–30% with trastuzumab.1,34,36,37 However, more than half of patients exposed to anthracyclines develop a degree of cardiac dysfunction up to 20 years post cancer therapy, and anthracycline metabolites can still be detected in cardiomyocytes years after cessation of cancer therapy.11,38 Radiotherapy is one of the primary treatment modalities contributing to cure or palliation.39 When used independently thoracic radiation compromises left ventricular function and advances the development of cardiac disease.40 However, when used in conjunction with chemotherapy, literature reports radiotherapy significantly increases the risk of death from myocardial infarction throughout survivorship.36,40 Cardiac toxicity from chest, breast or oesophageal irradiation is associated with a 22% incidence and women are four times more likely to develop cardiotoxicity, hinting at a gender-bias risk.41–43 Whilst the clinical signs of radiation injury may present immediately after exposure, cardiotoxicity is more likely to occur years to decades after exposure.19,43–45 Radiotherapy effects can be categorized as acute, consequential or late, and cancer patients may clinically present with pericarditis, conduction abnormalities and persistent tachycardia.43,45,46 Breast cancer survivors with left sided chest irradiation are at a higher risk of morbidity and mortality from ischemic heart disease than those exposed to right sided chest irradiation.21,47 Childhood cancer survivors have a greater risk of cardiotoxicity and a higher severity of left ventricular failure when compared to adult survivors with recent cohort studies determining the incidence of HF in this demographic accounts in up to half of cases.48,49 Current research suggests cardioprotective interventions, such as reduction in cardiotoxic agents or cessation of cancer therapy; however, these options must consider the severity of the cancer malignancy.4 Few studies have evaluated the use of pharmacotherapies, such as angiotensin converting enzyme inhibitors (ACEIs), beta-blockers (BBs), angiotensin-receptor blockers (ARBs) or even dexrazoxane, and determine the timing of implementing pharmacological management imminent for cardioprotection.37,50–55 Whilst the results of these studies appear beneficial, they are limited in scope and focus, and are predominantly centered on the benefits of pharmacotherapy protection for this demographic, thus creating an opportunity for further research into the effects of additional non-pharmacological interventions on cardiotoxicity. With a potential lapse in time between exposure to cancer therapy and the development of cardiotoxicity, research that determines the effects of non-pharmacological interventions for prevention or management of HF for these patients is yet to exist.125 Cancer survivorship and rehabilitation The term “survivorship” is a dynamic new concept for cancer patients mainly attributed to revolutionary medical advancements and oncological treatments.40 Similarly, the concept of cancer rehabilitation has evolved as a result of increased incidence of cancer patients living beyond their diagnosis and predicted life-expectancy.56 The primary focus of cancer rehabilitation programs is to prolong active life expectancy independently of the oncological diagnosis or prognosis. In European countries, cancer rehabilitation occurs predominantly as out-patient programs for up to three weeks tailored to the specific needs of the patient.56 In Australia, non-pharmacological strategies to improve outcomes in these patients requires investigation into the acute and survivor stages, and could enhance the safety of anticancer treatments and ensure that extended cancer-free survival translates to improved survival and quality of life. Improved survival rates are accompanied by significantly debilitating cancer-related side effects such as cardiotoxicity, fatigue, decreased cardiopulmonary capacity, impaired or reduced physical activity capability, reduction in nutritional intake and overall reduction in quality of life (QOL).57–59 As these aspects have significantly an adverse impact on the functional capacity of cancer survivors, they clearly illustrate that cancer rehabilitation programs which target the holistic and individual needs of cancer survivors are an integrated and contributory concept in survivorship, for which further research is necessary. Management of cardiotoxicity There is a magnitude of literature which consistently identifies the link between cancer therapy and cardiotoxicity and further demonstrates comparable mortality rates between HF and cancer.60,61 Currently, the National Heart Foundation recommends screening, treatment and follow-up of cardiac disease in cancer patients; however, universally accepted guidelines for short and long term care of cancer cardiotoxicity are currently lacking.121 Considering the exponential expansion of the incidence of cancer and cancer survivorship, the development of universally accepted evidence-based practice guidelines is integral for the management of cardiotoxic cancer survivors. For heart failure patients, cardiac rehabilitation has been an additional intervention in the management of symptoms and hospital admission rates to improve the quality of life and longevity for these patients. The implementation of heart failure-based non-pharmacological interventions in cancer therapy care and rehabilitation for the management of cardiotoxicity may reduce the incidence of cardiotoxic heart failure, cancer tumor recurrence, hospital admissions, thus improving quality of life and survival rates for cancer patients with cardiotoxicity. Non-pharmacological lifestyle interventions Evidence-based practice guidelines currently exist for after discharge management for both heart failure and cancer.9,62–64 Many of these guidelines currently target the management of disease-related fatigue, depression and anxiety.65 These guidelines are aimed at older cancer survivors, failing to target childhood cancer survivors potentially facing a compromised quality of life as a result of cardiotoxicity.65 Many of the key messages for healthy eating, activity and wellbeing are the same for preventing heart failure and cancer.9,66–68 Evidence-based practice guidelines currently exist for the after discharge management for both heart failure and cancer patients, with many of these key messages targeting healthy eating, increasing physical activity and improving wellbeing. As the combination of a poor diet, lack of exercise, smoking and excessive alcohol consumption increases the risk of cancer and cardiovascular disease, lifestyle interventions focused on these aspects may potentially counteract the adverse effects of cancer therapy, disease progression or relapse, and may reduce the risk cardiovascular disease.9,67,69,70 A diagnosis of cancer may provide multidisciplinary teams with a window of opportunity for “teachable moments” to guide cancer survivors towards reduced rates of remission, progression of cardiotoxicity and improved overall health and wellbeing as the aim of cardiac rehabilitation programs.71–75 Cardiac rehabilitation For HF patients, cardiac rehabilitation has been an additional intervention in the management of signs, symptoms and hospital admission rates to improve the quality of life and longevity for these patients. The implementation of heart failure-based non-pharmacological interventions in cancer therapy care and rehabilitation for the management of cardiotoxicity may reduce the incidence of cardiotoxic heart failure, cancer tumor recurrence, hospital admissions, thereby improving quality of life and survival rates for cancer patients with cardiotoxicity. Exercise For heart failure patients, the inclusion of physical and dietary modifications with pharmacological management has improved cardiac symptoms, exercise capacity (VO2) and left ventricular function.22,76,77 For cancer survivors, research demonstrates the abundance of positive benefits of exercise such as increasing muscle strength and cardiovascular fitness, lowering blood pressure and reducing fatigue.78–82 Furthermore, the six-minute walk test has been integrated into clinical practice as an additional measure to assess exercise tolerance, functional exercise capacity, and global and integrated responses from all body systems.129 Whilst such interventions are recommended for recovery from cancer care and cardiac rehabilitation, exercise rehabilitation is inconsistently incorporated for the management and/or prevention of cardiotoxicity.74,83 Through a basic scoping search, studies appear to focus predominantly on the impact of exercise on quality of life for cancer survivors, and whilst these are significantly important in this population, there is limited research on the impact of exercise on cardiotoxicity.57,84–86 Dietary modifications Obesity is an increasingly prevalent metabolic disorder and with an increased link to cancer, obesity remains a modifiable risk factor for both cardiovascular disease and cancer.130,131 Diet and exercise are interventions which are commonly combined and known for preventing of cardiovascular disease and some cancers, and improving general health, wellbeing and cancer survivorship.7,67,73,87 Several cohort studies have alluded to the positive outcomes of dietary modification clinical trials in reducing cholesterol and blood pressure in HF patients.89 Of significant interest is whether the implementation of nutritional guidelines from the Australian Heart Foundation can reduce the risk of cardiotoxicity by targeting cardiovascular risk factors, such as hypertension and high cholesterol.89,90,122 To the knowledge of the authors, studies on nutritional interventions and cancer are present from low level evidence; therefore current practice lacks evidence-based nutritional guidelines on the management or prevention of cardiotoxicity in humans.92–94 Alcohol modifications For adults, moderate alcohol intake has shown a cardioprotective effect in secondary prevention of heart disease; however, alcohol has been identified as an independent risk factor in cancers of the head and neck.96–98,123 In childhood or adolescent cancer patients, excessive alcohol consumption has the ability to interfere with cell membranes and compromise cell integrity, with a negative impact on survival.97 With up to 75% of head and neck cancers attributed to the combination of alcohol consumption and smoking, clinical practice guidelines for the role of cardioprotection by alcohol are yet to be developed, warranting further research.98,100,101 Cessation of smoking Cigarette smoking is considered an independent risk factor for the development of HF and accounts for up to 30% of all cancer deaths in the general population.5,20,103,104,124 Associated with a significantly advanced tumor grade at diagnosis and a higher recurrence rate of relapse from primary or secondary tumors, smoking is notably a modifiable risk health behavior linked to negative outcomes in cancer survivorship.5,7,66 Despite the known damaging effects of smoking, 17 to 30% of childhood cancer survivors smoke throughout the survivorship stages.105 While cessation of smoking should be encouraged in patients facing potential cardiotoxic cancer therapies, further research is required to ascertain the effects of smoking on the development of cardiotoxicity and to provide rigorous and supportive strategies to maintain tobacco abstinence.104 Complementary and alternative medicine Complementary and alternative medicine (CAM) is becoming increasingly popular among cancer patients in conjunction with conventional medical management.106–109 Defined as therapies not regarded as conventional medicine, such as yoga, meditation and massage, up to 90% of hospitalized cancer patients seek CAM to enhance wellbeing, quality of life and chances of survival, and to reduce the risk of cancer recurrence and cancer treatment associated side effects.106,108–116,119 For HF patients, the ability for these alternative therapies to positively impact on reducing distress, blood pressure and cardiac mortality has been well-established; however, these are limited to cardiac rehabilitation programs for unknown reasons.111,115 Furthermore the combination of these alternative approaches may in turn decrease depression, stress and anxiety, inadvertently targeting cardiac risk factors.22,32,110–117 Currently, literature does provide evidence of the improvements in quality of life for both cancer and cardiac patients; however the effects of mindfulness-based stress reduction techniques, such as yoga, massage and meditation, are yet to be determined in the management of cardiotoxicity when incorporated with other lifestyle changes. An initial review of the literature suggests there is substantial evidence on the incidence of cardiotoxicity amongst cancer patients as a result from cancer therapies. However, there is developing research which justifies the implementation of non-pharmacological interventions in the care of cancer patients to improve patient outcomes; however gaps remain within research and evidence-based practice strategies for the aftercare of patients who have developed cardiotoxicity after cancer treatment. Therefore, this systematic review will investigate the evidence on the management of cardiotoxicity and the role of non-pharmacological interventions. Inclusion criteria Types of participants This review will consider any studies that include patients, irrespective of age or gender, diagnosed with any type of cancer, who are treated with chemotherapy and/or radiotherapy, with or without an additional surgical intervention, and diagnosed with a cardiac complication as a result of that treatment. Studies will be included regardless of active or previous cancer therapy undertaken by participants prior to involvement with the study intervention(s). Non-English language studies will be assessed by scientific translation services if required and included, based on inclusion criteria. Types of intervention(s) The types of interventions to be eplored in this review are non-pharmacological interventions for cardiac function and may include but are not limited to: Cardiac rehabilitation Exercise Cessation of smoking Dietary modifications Meditation Yoga Massage Comparator Participants who were offered standard care for the ongoing management cancer and/or heart failure. Types of outcomes This review will consider studies that include the following outcome measures Primary outcomes (changes to cardiac function): Primary signs of heart failure such as shortness of breath and changes in resting heart rate measured by beats per minute VO2MAX measured by peak expiratory volume (ml/kg/min or L/min) during exercise test on cycle ergometer or treadmill Six-minute walk test measuring the total distance in steps or meters walked in six minutes measuring aerobic capacity Body Mass Index as measured by approved body composition analyzer or manual calculation (height [kg]/weight [cms]2). Secondary outcomes: Quality of life measured by any of the following; European Organisation for Research and Treatment of Cancer Quality of Life Questionnaire of Cancer of Cancer of Cancer of Cancer Body Mass by or by the following body to a by measuring the of the at the level of the Body measured by approved Types of studies This review will consider study randomized controlled controlled trials and which the effectiveness of non-pharmacological interventions on cancer treatment induced cardiotoxicity. The aims to both and studies in A process will be used only from up to An initial limited of and will be undertaken by an of the in the and of as well as their A all identified and will be undertaken all included as well as the will for literature the and by for within the of the of all identified will be for additional studies and prevalent to additional The to be of The for studies will of and National for and National of Studies to be used will cardiotoxicity, heart failure, cardiac rehabilitation, cardiotoxic cancer, cancer chemotherapy, radiotherapy, chest diet, dietary exercise, smoking yoga, massage, meditation of quality for will be assessed by two independent for prior to inclusion in the review from the of and Review that between the will be or with a will be from included in the review the data from The data will include specific the interventions, study and outcomes of to the review question and specific data possible be in statistical results will be to data as and their will be for will be assessed the standard and based on the study included in this statistical is not possible the will be in and figures to in data of interest The that there is of is in this This systematic review will contribute to the primary degree at