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Oncology Times:
doi: 10.1097/01.COT.0000352491.20661.d5
Articles

Oncologists & Cardiologists Joining Together to Tackle Cardiotoxicity

Keller, Daniel M. PHD

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Oncologists worry about chemotherapy-related heart failure, and cardiologists treat it. Efforts are under way to bring the two camps together to better understand the mechanisms of cardiotoxicity, monitor cardiac function in cancer patients, treat heart failure when it occurs, and develop prevention strategies.

Anthracycline drugs have long been known to put patients at risk for permanent cardiotoxicity. More recently, the use of trastuzumab has been associated with possibly reversible cardiotoxicity, and most recently, sunitinib has given strong toxicity signals in small studies. In addition, chest radiation can damage the heart.

At this year's American College of Cardiology Annual Meeting, cardiologists from leading cancer centers discussed what can be done to minimize cardiac damage from cancer treatments. Douglas B. Sawyer, MD, Chief of Cardiovascular Medicine at Vanderbilt University, divided agents into Types I and II:

* Type I agents cause myocardial damage and secondary dysfunction, as exemplified by anthracyclines.

* Type II agents, such as trastuzumab, cause dysfunction.

Dr. Sawyer used doxorubicin as an example of how anthracyclines work. It intercalates into nucleic acids to prevent DNA replication as well as protein translation from RNA in tumor cells. But in the heart it inhibits myofilament protein synthesis, disrupting myocardial sarcomere assembly and leading to systolic dysfunction and decreased diastolic restoring force as well as increased calcium sensitivity.

Calcium activates calpain, an enzyme that degrades the large protein titin that is part of the sarcomere. “If we block calpain [in vitro], we can block the doxorubicin induced titin degradation,” resulting in preservation of the sarcomeres in the presence of doxorubicin, Dr. Sawyer said.

The risk of anthracycline cardiac toxicity increases with cumulative exposure, rising fairly gradually up to a cumulative dose of about 400 mg/m2 and then more sharply with further exposure.

Figure. MING CHEN, M...
Figure. MING CHEN, M...
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“With every dose, independent of when and how patients received it, there is an independent risk, so with each dose it is reasonable to think that there is a certain amount of myocardial injury.” Some heart failure clinics estimate that about one percent of the cases of heart failure are related to prior anthracycline use, he noted.

Regarding trastuzumab, “left ventricular ejection fraction…bounces back” with standard heart failure therapy in people who develop cardiac dysfunction, suggesting “that this is a different form of cytotoxicity.”

Trastuzumab is an anti-erbB2 (HER2) monoclonal antibody, and erbB2 is well expressed on ventricular myocytes and is essential for normal function. Inhibiting its function results in downstream effects that serve to mechanically and electrically decouple the myocytes, he noted.

Finally, Dr. Sawyer questioned whether dysfunction from Type II agents is completely reversible, and he proposed that these agents may limit normal compensatory homeostatic mechanisms, for example, in the setting of hypertension. So he said he would be leery of reinstituting them if a patient had had a problem.

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TKIs

Tyrosine kinase inhibitors (TKIs) are increasingly associated with cardiac toxicity, an effect that was originally unanticipated.

Ming Chen, MD, MMSc, of Dana-Farber Cancer Institute/Brigham and Women's Hospital and Director of the Stress Echocardiography Program at Children's Hospital Boston, referred to the cardiotoxicity of trastuzumab as an “on-target” effect, meaning that the molecule targeted by the drug is also important for cardiac myocyte health.

In contrast, TKIs, which are often relatively nonselective, may inhibit kinase pathways important for cardiomyocytes but which are not the primary oncologic targets.

The TKIs that inhibit vascular endothelial growth factor (VEGF) are associated with hypertension, and this is true of sorafenib and sunitinib, Dr. Chen continued. “Hypertension is the most common type of cardiotoxicity that tyrosine kinase inhibitors cause.” It is an on-target effect and may be mediated through nitric oxide or vascular stiffening.

In addition, lapatinib, imatinib, and dasatinib have been associated with congestive heart failure (CHF), and nilotinib may cause QT prolongation, and rarely, sudden death.

Using sunitinib as an example, Dr. Chen discussed heart failure and cardiac dysfunction. Preclinical data and initial clinical trials in oncology showed no cardiovascular effects of this multi-targeted TKI. But she said that early on she saw a patient who had complained of atypical chest pain, and although all findings were normal, her suspicions were raised enough to do a study of cardiac endpoints.

Among 75 patients with imatinib-resistant gastrointestinal stromal tumor treated with sunitinib and who had normal cardiac function at baseline, by 33 weeks 11% developed a cardiac event, with 8% in New York Heart Association Class III heart failure. Twenty percent had a left ventricular ejection fraction (LVEF) less than 50% at some point.

“Most importantly, LVEF declines were at least in part reversible, and symptoms were generally responsive to withholding drug therapy and [providing] medical management of heart failure,” Dr. Chen said. She also found that sunitinib, as a VEGF inhibitor, increased hypertension from 6% of subjects at baseline to 47% after four cycles of drug (24 weeks)—“So blood pressure increase can be rapid and profound.”

The risk factors for cardiac events were a history of coronary artery disease (CAD) or hypertension, and CAD also raised the risk of CHF. While some clinical trials in oncology may exclude patients with hypertension, other cardiac risks, or prior cancer therapies, in actual practice patients often present with these additional risk factors for cardiac dysfunction.

“For clinicians, increased vigilance for early signs of cardiotoxicity in those with comorbidities or extensive treatment history is very important,” Dr. Chen emphasized.

Experiments with mice showed that cardiac cell apoptosis occurred in the presence of sunitinib only when the animals were made hypertensive. So to be particularly cautious, Dr. Chen advised that “early identification and treatment of hypertension may prevent apoptosis which is induced by sunitinib.”

Finally, she discussed her unpublished data that sunitinib cardiotoxicity is reversible by withdrawing the drug and adding an angiotensin-converting enzyme inhibitor (ACEI) and a beta-blocker. LVEF often largely recovers, and histologic changes in the heart (e.g., mitochondrial swelling and loss of christae) normalize. Reinstituting sunitinib for some patients with metastatic cancer, Dr. Chen found that “they were actually able to tolerate a re-challenge with ACE [inhibitor] and beta-blocker therapy.”

She summarized by saying that TKIs can be associated with hypertension, heart failure, myocardial infarction, and cardiac dysfunction, as well as thromboembolic events. Each agent, depending on its molecular targets, can have its own profile of potential cardiotoxicity, but not all TKIs are cardiotoxic. If identified early, cardiac effects may be partially reversible, indicating the need for vigilance.

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Radiation-Induced Heart Disease

Figure. JAE OH, MD, ...
Figure. JAE OH, MD, ...
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Chest irradiation is a risk factor for cardiac disease, and Jae Oh, MD, Co-Director of the Echocardiography Laboratory and Director of the Pericardial Clinic at Mayo Clinic College of Medicine, illustrated the point by showing a study of a large series of patients (1,261) treated for Hodgkin disease before age 41. With a mean follow up of 17.8 years, 55% of patients in that 2003 study had died, with a relative risk of death of 6.8, cardiovascular death of 6.3, and 13.6 if the patient was treated before age 21.

The cause of death in the first five years is mainly from Hodgkin; at years five to 15, from solid tumors; and cardiac disease starts to rise as a cause at 15 to 20 years.

Similarly, death from MI increases at about year 10 in women receiving adjuvant left chest radiation for breast cancer compared with radiation of the right side. There was no significant difference in death rates from MI for left- vs right-sided disease if women did not receive radiation.

Besides MI, radiation can affect heart valves and cause pericarditis and effusion early on and constrictive pericarditis later. “It is a most challenging and difficult patient to take care of because they do not do well even with pericardectomy, which is a cure for most other patients with constrictive pericarditis,” Dr. Oh said.

Heart transplant is now under consideration in lieu of pericardectomy. And he added that Mayo does prophylactic pericardectomy for patients with prior mediastinal irradiation if they are in for bypass grafting or other heart surgery not related to pericardial disease. Screening echocardiography should be considered for any patients who received chest radiation, he said.

After mediastinal radiation there is also a high prevalence of asymptomatic heart disease in general, and specifically, aortic valvular disease. Moderate to severe left ventricular diastolic dysfunction raises the risk of death five to 10 times compared with normal function, he said.

He summarized by saying that radiation can damage any cardiac structures, including coronary arteries, valves, myocardium, and pericardium. The injury occurs 10 to 15 years after radiation treatment, and the incidence of cardiac tumors is frequent.

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Awards for 2 OT Writers!

Two OT writers have won awards from the most recent competition of the American Society of Healthcare Publication Editors.

Contributing Writer Lola Butcher received a Bronze Award in the category of “Regular Department” for her Practice Matters columns, specifically for these:

* “Demand for Oncology Pharmacists Growing as Key Role is Increasingly Valued” (8/25/08 issue).

* “In Wake of Economic Downturn, Dire Predictions, at Least in Short-term, for Future of Biotech Discoveries” (11/25/08 issue).

* “Are Financial Worries Prompting Patients to Skip Needed Health Care?” (12/10/08 issue).

And OT Special Correspondent Eric T. Rosenthal received a Bronze Award in the category of “Case History” for his article “Nick Petrelli & Colleagues Challenge Non-Accruing Clinical Trial Investigators to Live Up to Designation or Lose It (7/25/08 issue).

All the articles are available online at www.oncology-times.com

Next Time: The second part of this article will cover monitoring chemotherapy-induced heart failure and treating late doxorubicinrelated congestive heart failure.

© 2009 Lippincott Williams & Wilkins, Inc.

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