Cardiovascular Side Effects of Cancer Treatment Demand Attention

Improved survivorship rates among cancer patients has brought a growing awareness of a serious latent impact of chemotherapy and radiation: cardiotoxicity. Despite extensive research on the subject, our understanding of the tools for identifying and preventing these complications is limited.

Chemotherapy and radiotherapy are standard treatment regimens in oncology care. As they undergo therapy, patients experience numerous side effects that can drain them both physically and emotionally, and follow-up care for patients in remission is quite focused on determining if the cancer has returned or progressed to a distant site. However, the increasing survivorship rates among cancer patients has brought a growing awareness of a serious latent impact of chemotherapy and radiation: cardiotoxicity (Table 1). Although extensive research has found cardiovascular complications associated with cancer therapy to be responsible for morbidity, and even mortality, among cancer survivors,^1-4 our understanding of the tools for identifying and preventing these complications is limited.

Preventive Measures

Various pharmacologic and nonpharmacologic approaches are being evaluated to prevent or reduce cardiovascular risk in cancer treatment. These include altering the administration strategies for anthracyclines, administering antioxidants like dexrazoxane, and administering cardiovascular drugs such as ACE inhibitors and beta-blockers.⁵ Prophylactic treatment with inhibitors of the renin angiotensin system was recently shown to partially attenuate the cardiotoxicity of doxorubicin and trastuzumab in a mouse model.⁶However, risk stratification using blood-based biomarkers and sophisticated imaging techniques might have the most impact with respect to identifying an appropriate treatment plan to reduce or minimize the cardiovascular effects of these drugs.

Rational drug design—aided by structure activity relationship studies—in the development of newer anticancer agents can also help prevent or reduce cardiovascular side effects. The c-Kit inhibitor imatinib, for example, was redesigned to prevent interaction with Bcr-Abl and JNK proteins, which can limit the agent’s cardiotoxic potential.⁷

Need for Integrated Care

The lessons that have been learned in oncology care, as in all kinds of healthcare, highlight the need for increased communication among the various physicians who contribute along the continuum of care. For a cancer patient, a collaboration between their oncologist and a cardiologist to formulate a multidisciplinary approach to patient care is of the essence—a fact increasingly acknowledged by treating physicians.⁸Management of chemotherapy—related heart failure, prevention of cardiotoxicity by administering cardioprotective agents, cardiac monitoring during chemotherapy, and assessment and prognosis of cardiac risk with respect to a specific chemotherapy regimen are the most commonly observed clinical scenarios that could greatly benefit from an interdisciplinary approach in the management of cancer patients with cardiovascular risk.⁸

Several major cancer centers in the United States (Table 2) now boast a cardio-oncology program that includes a team of cardiologists and oncologists who screen patients prior to receiving chemotherapy, and develop treatment plans that would reduce their risk of cardiac side effects.⁹

Cost-Effectiveness of Screening

The collaboration among oncologists, cardiologists, and other providers who provide care for survivors of pediatric cancer has the potential not just to improve outcomes, but to curtail costs of care in high-risk patients before the disease becomes debilitating.

A study simulating the impact of an interval-based echocardiography assessment on lifetime risk for systolic congestive heart failure (CHF), lifetime costs, quality-adjusted life-years (QALYs), and incremental cost-effectiveness ratios (ICERs) in childhood cancer survivors found a 2.3% to 8.7% reduction in risk for CHF. Further, ICER for assessment every 10 years cost $111,600 per QALY compared with no assessment. Assessment every 5 years yielded an ICER of $117,900 per QALY, while more frequent assessment resulted in ICERs exceeding $165,000 per QALY.¹⁰

The Children’s Oncology Group’s (COG’s) Long-Term Follow-Up Guidelines for Survivors of Childhood, Adolescent, and Young Adult Cancers is a resource for healthcare professionals who provide care to survivors of pediatric malignancies.¹¹COG guidelines recommend lifetime echocardiographic screening for asymptomatic left ventricular dysfunction (ASVLD) in childhood cancer survivors who were treated with anthracyclines. Following the guidelines, researchers found, could extend life expectancy by 6 months, increase QALYs by 1.6 months, reduce cumulative incidence of heart failure by 18% (30 years after cancer diagnosis), and have an ICER of $61,500.¹²

Patient Engagement

The patient can be an active partner in the process, and including the patient in the conversation on long-term care can have a tremendous impact on survival outcomes. The commentary in this issue by Debra Madden, a patient advocate and a 2-time cancer survivor, underscores the importance of an engaged patient.

A collaborative study published in 2013 evaluated whether an educational intervention—in the form of a newsletter—could improve medical follow-up in pediatric cancer survivors who were at increased risk of treatment complications. The study population included survivors—at least 25 years of age—who had participated in the Childhood Cancer Survivor Study and were at an increased risk of cardiovascular disease, breast cancer, or osteoporosis related to previous cancer treatment. The study authors designed a newsletter that included either brief health risk information or an insert with more comprehensive risk information. A survey, conducted 2 years following the distribution of the newsletter, evaluated the impact of the intervention on medical follow-up by the survivors.¹³

While the study found no advantage to including detailed information on health risks that the survivors faced, the newsletter increased patient awareness of the risk factors of developing cardiac problems and osteoporosis. This led to an increase in discussions on cancer-related risks with physicians and significantly influenced participation in health screening.¹³

EBO

The importance of patient engagement and self-care is being appreciated, not just during the care process, but much earlier during drug development. Drug developers, regulators, providers, and health plans are increasingly paying attention to patient-reported symptoms. Organizations have developed strategies to measure and validate patient-reported outcomes, with the aim of improving both the quality of care delivered and health outcomes. As awareness of cardio-oncology issues increases, measures being adopted on multiple fronts can be expected to reduce the cardiac impact of oncology treatment regimens.

References

1. Oeffinger KC, Mertens AC, Sklar CA, et al. Chronic health conditions in adult survivors of childhood cancer. N Engl J Med. 2006;355:1572-1582.

2. Reulen RC, Winter DL, Frobisher C, et al. Long-term cause-specific mortality among survivors of childhood cancer. JAMA. 2010;304:172-179.

3. Meinardi MT, Gietema JA, van der Graaf WT, et al. Cardiovascular morbidity in long-term survivors of metastatic testicular cancer. J Clin Oncol. 2000;18:1725-1732.

4. Heidenreich PA, Hancock SL, Lee BK, et al. Asymptomatic cardiac disease following mediastinal irradiation. J Am Coll Cardiol. 2003;42:743-749.

5. Magnano LC, Martínez Cibrian N, Andrade González X, Bosch X. Cardiac complications of chemotherapy: role of prevention. Curr Treat Options Cardiovasc Med. 2014;16(6):312.

6. Akolkar G, Bhullar N, Bews H, et al. The role of renin angiotensin system antagonists in the prevention of doxorubicin and trastuzumab induced cardiotoxicity. Cardiovasc Ultrasound. 2015;13(1):18.

7. Fernández A, Sanguino A, Peng Z, et al. An anticancer C-Kit kinase inhibitor is reengineered to make it more active and less cardiotoxic. J Clin Invest. 2007;117(12):4044-4054.

8. Hofstatter E, Saadati H, Russell K, Russell R 3rd. Clinical vignettes: integrated care of cancer patients by oncologists and cardiologists. Curr Cardiol Rev. 2011;7(4):258-261.

9. Hresko A. How (and why) to develop a cardio-oncology partnership. The Advisory Board Company website. http://www.advisory.com/research/cardiovascular-roundtable/cardiovascular-rounds/2014/01/how-and-why-to-develop-a-cardio-oncology-partnership. Published January 10, 2014. Accessed May 11, 2015.

10. Yeh JM, Nohria A, Diller L. Routine echocardiography screening for asymptomatic left ventricular dysfunction in childhood cancer survivors: a model-based estimation of the clinical and economic effects. Ann Intern Med. 2014;160:661-671.

11. Long-term follow-up guidelines for survivors of childhood, adolescent, and young adult cancers. Children’s Oncology Group website. http://survivorshipguidelines.org/. Accessed May 11, 2015.

12. Wong FL, Bhatia S, Landier W, et al. Cost-effectiveness of the children's oncology group long-term follow-up screening guidelines for childhood cancer survivors at risk for treatment-related heart failure. Ann Intern Med. 2014;160(10):672-683.

13. Steele JR, Wall M, Salkowski N, et al. Predictors of risk-based medical follow-up: a report from the Childhood Cancer Survivor Study. J Cancer Surviv. 2013;7(3):379-391.