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Journal of Clinical Oncology, Vol 26, No 19 (July 1), 2008: pp. 3122-3124 © 2008 American Society of Clinical Oncology. DOI: 10.1200/JCO.2008.16.5274
Doxorubicin Cardiotoxicity in the Elderly: Old Drugs and New OpportunitiesAbramson Cancer Center, University of Pennsylvania, Philadelphia, PA Non-Hodgkin's lymphoma is a frequent disease in older patients, and at least half of non-Hodgkin's lymphoma diagnoses occur in patients older than 65 years.1 This diagnosis presents special challenges in the older population because of pre-existing comorbidities, changes in drug pharmacokinetics, and poorer response rates and other outcomes. In addition, the lack of enrollment of older patients with existing comorbidities, such as cardiac disease, onto clinical trials has limited the accumulation of evidence-based clinical knowledge.2 Anthracycline-based chemotherapy improves survival in multiple solid and hematologic malignancies. Doxorubicin is the anthracycline used most frequently in the treatment of diffuse large B-cell lymphoma as part of the cyclophosphamide, doxorubicin, vincristine, and prednisone (CHOP) regimen, with or without rituximab (R-CHOP). The use of doxorubicin is associated with, and often limited by, a risk of cardiotoxicity manifested by left ventricular dysfunction. Multiple risk factors for doxorubicin-associated cardiotoxicity have enabled clinicians to define a high-risk population for cardiotoxicity. The paradox is that some low-risk patients develop cardiotoxicity and not all high-risk patients develop cardiotoxicity.3 The constant increase in cancer incidence and the projected explosive growth of the older population over the next 25 years are compelling forces driving us to answer critical questions of cancer care delivery for the future. These include, but are not limited to, the following: Can we accurately predict who will develop chemotherapy-related cardiotoxicity? Can patients with underlying heart disease receive doxorubicin chemotherapy? How should we look for and manage patients with cardiotoxicity?
In the current issue, Hershman et al4 have taken another step to help answer the first question. They used the Surveillance, Epidemiology, and End Results–Medicare database to identify 6,388 patients This is the third Surveillance, Epidemiology, and End Results–based observational study of anthracycline cardiotoxicity in the elderly and the first to include males and patients with lymphoma. Previously, Doyle et al5 approached the data using a breast cancer population; in their model, they found that those treated with doxorubicin were 2.5 times more likely to experience cardiotoxicity than untreated patients. Similar to the Hershman et al4 study, they also found that women with pre-existing cardiac disease were more likely not to receive anthracycline-based therapy. Pinder et al6 also looked at data for elderly women with breast cancer and also found a higher rate of cardiotoxicity in doxorubicin-treated patients, with the incidence increasing through more than 10 years. Their adjusted hazard ratio for cardiotoxicity was 1.26 (95% CI, 1.12 to 1.42) for women 66 to 80 years old. In their population, baseline predictors for doxorubicin cardiotoxicity were advancing age, black race, hypertension, diabetes, and pre-existing coronary artery disease. All of these studies are observational, and all suffer from the limitations inherent in querying an administrative data set. All clearly underestimate the magnitude of the problem by missing subclinical reductions in systolic and diastolic function: the probable first sign of cardiac myofibril injury in the asymptomatic doxorubicin recipient. Therefore, it is well accepted that cardiotoxicity is an ongoing concern in the older population exposed to anthracyclines. Although there are currently no strict evidence-based guidelines from any group, our approach—and we stress that this is not the current standard of care outside of our institution—is based on the following observations. First, acute toxicity is usually transient and managed clinically. Second, asymptomatic toxicity is common and may progress over time to symptomatic CHF; diastolic dysfunction may be the first clinical manifestation. Third, symptomatic CHF occurs because of a loss of myofibrils. The risk has been classically associated in all populations with the high-risk factors as described in the literature3,7 and can occur with any exposure to anthracycline regardless of formulation and total dosing. Fourth, risk of cardiotoxicity tends to be highest in the first year. Subsequently, there is a latent period with prevalence increasing as the time after treatment completion increases. Fifth, there may be some cardioprotective effect from blocking the renin-angiotensin system with either angiotensin-converting enzyme inhibitors (ACE-Is) or angiotensin receptor blockers (ARBs). Sixth, CHF, when it occurs, is not clinically different from CHF caused by nonanthracycline causes. Finally, current evidence-based guidelines for the management of CHF can be applied to patients with anthracycline cardiotoxicity. We approach the cardiovascular management from the following three perspectives: first, primary prevention to give the oncologist every opportunity to optimally treat the underlying lymphoma; second, a proactive approach to early detection to attenuate the potential of left ventricular (LV) dysfunction; and third, modern treatment of heart failure when there is any change in LV function, with or without symptoms. Primary Prevention Because of the prevalence of high-risk risk factors, patients are screened for traditional cardiac risk factors and evidence of pre-existing cardiac disease. Nothing can replace a thorough history and physical examination. Care providers should be vigilant in asking about any subtle change in performance status, the presence of breathlessness, and subjective awareness of chest pain and/or palpitation. Examination clues include resting tachycardia, neck vein distention, palpable cardiomegaly, new murmurs or gallop sounds, and signs of fluid overload (eg, unexpected weight gain, rales, edema). Because lymphoma is often an aggressive disease in the elderly, our cardiologists work closely with our oncologists and see all new patients emergently and expedite the completion of all required cardiac staging studies within 24 to 48 hours. We aggressively treat hypertension, diabetes, and hyperlipidemia. Whenever it is clinically appropriate, we make sure that ACE-Is or ARBs and β-blockers are part of the therapeutic regimen, and we readily switch from other drug classes to these agents before the start of chemotherapy. We have a low threshold to add statins in light of the possible protective effect of this drug class on anthracycline cardiotoxicity.8 For patients with pre-existing coronary artery disease, in the absence of acute coronary syndromes, we do not pursue an invasive strategy with percutaneous revascularization but aggressively maximize their medical therapy. We recommend baseline echocardiography with Doppler and tissue Doppler components and mandate that the echocardiographer measures the left ventricular ejection fraction (LVEF) by planimetry rather than estimating a range. We are also vigilant about documenting surrogates for preload and afterload (blood pressure and heart rate) to help with serial comparisons. We also recommend measurement of a baseline B-type natriuretic peptide level. With these data, we are able to proceed with anthracycline-based chemotherapy in all patients except those with unstable angina and critical valve disease. Proactive Approach to Early Detection: How Should We Look for Cardiotoxicity? We are biased and favor echocardiography over nuclear angiography (multiple-gated acquisition scan). The echocardiogram gives additional information beyond LVEF that may signal cardiotoxicity before an actual decrease in LVEF without any radiation exposure for the patient. We always serially follow the patient with the same cardiac testing modality in the same laboratory whenever possible. In the absence of symptoms or a change in physical examination, we generally perform serial echocardiograms at two-cycle intervals in the elderly population. Recently, we began to use biomarkers to look for early cardiotoxicity. We measure troponin levels 5 to 7 days after each cycle of chemotherapy. Although the approach described by Cardinale et al9 involved troponin measurement at earlier and more frequent intervals, the slow clearance and persistence of elevation justifies our approach. We are currently prospectively assessing the value of this simplified schedule. Before each chemotherapy cycle in this population, we also measure B-type natriuretic peptide levels as a marker of LV dysfunction. Any biomarker elevation or change in echocardiogram findings is a trigger to reassess all therapy. After treatment completion, we continue to be vigilant using history and physical examination to detect cardiotoxicity. We currently repeat echocardiograms at 6, 12, and 24 months after treatment, and then, similar to our protocol for long-term follow-up of asymptomatic survivors, we repeat studies every 5 years in the absence of new findings.7 Can Cardiotoxicity Be Prevented Without Diminishing the Efficacy of Chemotherapy?
Hershman et al4 suggest fewer cycles of chemotherapy in octogenarians to minimize cardiovascular and hematologic adverse effects. We have developed a different approach at the Abramson Cancer Center of the University of Pennsylvania using a modified chemotherapy schedule. In deciding about treatment, we divide patients into the following two age groups: 65 to 74 years of age and
To date, we have used this modified approach in more than 15 patients over the age of 75 years without compromising lymphoma treatment efficacy and without cardiotoxicity or cardiac deaths. For the patients with an absolute contraindication to anthracycline use, we use nonanthracycline regimens with curative potential, such as cyclophosphamide, etoposide, procarbazine, and prednisone ± bleomycin.11 Modern Treatment of Cardiotoxicity In patients at high risk of cardiotoxicity or who develop cardiotoxicity, we aggressively titrate doses of ACE-Is, ARBs, β-blockers, and spironolactone to maximally tolerated doses. We use diuretics when there are documented signs of congestion and then, on an as-needed basis, using daily weight as a guide to diuretic need. In conclusion, we are fortunate to care for patients in an era of cure-directed chemotherapy applicable to a progressively aging population with cancer whose age or comorbidity in the past would have excluded them from aggressive treatment. We have an effective lymphoma chemotherapeutic armamentarium, and we move closer each day, with contributions like the study by Hershman et al4 to guide us, to more accurate risk stratification to ameliorate chemotherapy-associated cardiotoxicity. We have the diagnostic methods available for early detection of heart failure and the evidence-based cardiology guidelines to treat it. We have reached a point when aggressive lymphomas have become curable diseases, even in the older population. AUTHORS’ DISCLOSURES OF POTENTIAL CONFLICTS OF INTEREST The author(s) indicated no potential conflicts of interest. AUTHOR CONTRIBUTIONS Conception and design: Joseph R. Carver Data analysis and interpretation: Joseph R. Carver, Stephen J. Schuster Manuscript writing: Joseph R. Carver, Stephen J. Schuster, John H. Glick Final approval of manuscript: Joseph R. Carver, Stephen J. Schuster, John H. Glick
REFERENCES
1. Thieblemont C, Coiffier B: Lymphoma in older patients. J Clin Oncol 25:1916-1923, 2007 2. Lichtman S, Wildiers H, Chatelut E, et al: International Society of Geriatric Oncology Chemotherapy Taskforce: Evaluation of chemotherapy in older patients-an analysis of the medical literature. J Clin Oncol 25:1832-1843, 2007 3. Carver J, Shapiro C, Ng A, et al: American Society of Clinical Oncology clinical evidence review on the ongoing care of adult cancer survivors: Cardiac and pulmonary late effects. J Clin Oncol 25:3991-4008, 2007 4. Hershman DL, McBride RB, Eisenberger A, et al: Doxorubicin, cardiac risk factors, and cardiac toxicity in elderly patients with diffuse B-cell non-Hodgkin's lymphoma. J Clin Oncol 26:3159-3165, 2008 5. Doyle JJ, Neugut AI, Jacobson JS, et al: Chemotherapy and cardiotoxicity in older breast cancer patients: A population-based study. J Clin Oncol 23:8597-8605, 2005 6. Pinder MC, Duan Z, Goodwin J, et al: Congestive heart failure in older women treated with adjuvant anthracycline chemotherapy for breast cancer. J Clin Oncol 25:3808-3815, 2007 7. Carver JR, Ng A, Meadows AT, et al: Cardiovascular late effects and the ongoing care of adult cancer survivors. Dis Manag 11:1-6, 2008[CrossRef][Medline] 8. Haendeler J, Hoffmann J, Zeiher AM, et al: Antioxidant effects of statins via S-nitrosylation and activation of thioredoxin in endothelial cell: A novel vasculoprotective function of statins. Circulation 111:856-861, 2004 9. Cardinale D, Sandri MT, Colombo A, et al: Prognostic value of troponin I in cardiac risk stratification of cancer patients undergoing high-dose chemotherapy. Circulation 109:2749-2754, 2004 10. Mato AR, Morgans AK, Roullet MR, et al: Primary cardiac lymphoma: Utility of multimodality imaging in diagnosis and management. Cancer Biol Ther 6:12:1-4, 2007[Medline] 11. Chao NJ, Rosenberg SA, Horning SJ: CEPP(B): An effective and well-tolerated regimen in poor-risk, aggressive non-Hodgkin's lymphoma. Blood 76:1293-1298, 1990
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Copyright © 2008 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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65 years old with diffuse large B-cell lymphoma who met their inclusion criteria. The cardiac risk profile was typical of the Medicare population, with a high prevalence of diabetes (31.9%), hypertension (73.1%), and hypercholesterolemia (53.6%). The authors were meticulous in defining pretreatment disease in exquisite detail and used strict rules to minimize the limitations associated with a retrospective review of an administrative database. Of interest, only 42.4% of eligible patients received doxorubicin-based chemotherapy, which was associated with a 29% increase in risk of cardiotoxicity. Not surprisingly, they found that doxorubicin increased the risk of subsequent cardiotoxicity, with a hazard ratio of 1.29 (95% CI, 1.02 to 1.62). They reconfirmed previously known information that this risk was associated with increasing doxorubicin dose (using a surrogate of number of claims for total dose), increasing age, prior heart disease, and risk factors for heart disease (diabetes and hypertension). The 8-year adjusted congestive heart failure (CHF)–free survival rate was 74% in patients receiving doxorubicin compared with 79% in patients not receiving doxorubicin; the occurrence of CHF was unusually high in both groups but was higher in patients treated with doxorubicin. In a separate multivariate model, the interaction of doxorubicin and hypertension was the only variable that was statistically significant. 
