Influence of Cardiotoxic Risk on Treatment Choice in Adult Cancers

It is a time of unprecedented therapeutic innovation in oncology. While we still rely heavily on our tried and true therapies for cancer care prevention, surgery, radiation, and chemotherapy newer treatments with novel mechanisms of action have expanded our options. In addition, we have better tools to predict risk of recurrence and sequelae of treatment. How we use these tools to treat and cure cancers is the bigger question. Optimal use of the available treatment options to cure disease while facilitating a healthy survival among our patients is our principal goal. Thus, understanding and reducing the risk of long-term sequelae of treatment remains a critical part of treatment planning.

The concept of maximizing efficacy and minimizing toxicity while controlling cost remains fundamental to the triple aim of shifting from volume- to value-based cancer care: improving an individual patient’s care quality, reducing per capita costs of treatment, and improving population health. This serves as the framework for the Value Pathways program, and choice of therapeutic agents should be taken in context with each individual patient when making treatment decisions.¹ Because guideline systems are based in large part on clinical trials, and only a select 3% of US cancer patients enroll in prospective clinical trials, oncologists need to make careful decisions about whether certain guideline-based treatments are appropriate for their patients who may on average be older, have more comorbid illness, and therefore, be more likely to experience toxicities related to their disease and its treatment. In addition, further research needs to be conducted with real-world data to better characterize differential toxicity profiles in populations that are underrepresented in these clinical trials and require treatment: the elderly, minorities, individuals who have survived and received treatment for other cancers, and individuals with a heavier burden of comorbidities.

Many agents have been implicated in causing cardiac toxicity, but quantifying how often this toxicity occurs, identifying which patients are more susceptible, and determining the context of risk versus benefit of treatment are all important considerations when deciding the appropriate treatment for a patient. This consideration is different in patients with potentially curable cancers versus patients undergoing chronic treatment for incurable cancers. What is required is not an extensive review of acute and chronic toxicity of systemic treatments in cancer, but rather of how chronic cardiotoxicity risk in cancer therapy impacts treatment choices for our patient. As we often use pathways, guidelines, and clinical trials to guide us in evidence-based treatment decisions, it is important to recognize that these guidelines are created based on results from clinical trials that enroll, on average, younger and healthier patients compared with the average cancer patient who enrolls in trials. In addition, minorities and patients with a history of other cancers have lower rate of enrollment in clinical trials, and thus are underrepresented in these prospective clinical studies that direct pathway and guideline development.

Cardiac Toxicity and Treatment Change in Patients Treated With Curative Intent

Anthracyline-related cardiac toxicity

Anthracylines remain the greatest concern, as they are a common part of chemotherapy regimens administered for curative intent. Their associated cardiac toxicity can be severe and permanent, often resulting in a clinical presentation of heart failure, pathologic evidence of damage to cardiac muscle, and progression to severe heart failure and even death. Chronic anthracycline-related cardiac toxicity is well described and is a dose-dependent phenomenon.² Doxorubicin is the anthracycline most frequently associated with cardiac disease, though all anthracyclines pose some risk. While cardiac toxicity is relatively infrequent (1.7%) with cumulative doses of doxorubicin of <300 mg/m2, other risk factors can increase the incidence of cardiac toxicity even at lower doses of anthracycline exposure.³ While cumulative dose poses the highest risk for cardiac toxicity, preexisting cardiac disease, hypertension, diabetes, prior chest wall irradiation, older age, and concomitant administration of other potentially cardiotoxic drugs can all increase the possibility of cardiac toxicity.⁴

For patients treated with curative intent, such as in the adjuvant setting for breast cancer, these risk factors may alter chemotherapy regimen choice or dose for the patient. For example, if a patient with early-stage breast cancer requires chemotherapy for risk reduction but has risk factors for chronic anthracycline-related cardiac toxicity, a non-anthracycline choice of chemotherapy may be a more reasonable therapeutic option. The uptake of docetaxel and cyclophosphamide in the adjuvant treatment of breast cancer is an ideal example of the increased utilization of non-anthracycline regimens observed in the last several years.⁵ Sometimes, even if a patient has a higher risk of recurrence, the patient’s age, prior treatments, and comorbidities increase the risk for complications and deter administration of adjuvant chemotherapy. These are challenging decisions for doctor and patient as they carefully weigh the risk versus benefit of using anthracyclines.

When patients have curable cancers with fewer treatment options, as is the case with some acute leukemias and lymphomas, the benefit of treatment so far outweighs the risk of treatment that the decision is usually made to pursue aggressive therapy despite the risk of adverse complications. In these situations, choices to embark upon aggressive therapy are often balanced with treatment modifications in an attempt to reduce risk. A review of 7 major studies concluded that the risk of cardiac toxicity with anthracyclines was reduced following longer infusion rather than bolus infusion schedules.⁶

This risk reduction, however, was not demonstrated in the pediatric literature specifically childhood leukemia survivors where cardiotoxicity was not different between patients who received their anthracyclines in a prolonged infusion versus bolus treatment in a prospective trial.⁷ Dexrazoxane has also been used to attempt to prevent cardiotoxicity, but its effectiveness remains unclear, and some studies hint that it could increase the risk of secondary malignancies.⁸

Targeted therapies

Targeted therapies also pose a risk of cardiac toxicity. Trastuzumab is commonly used in the adjuvant setting to treat with curative intent the 20% to 25% of patients with breast cancer who overexpress the epidermal growth factor receptor, Her-2/neu. While trastuzumab is potentially cardiotoxic, it is not a dose-dependent phenomenon, and it often manifests with asymptomatic echocardiogram findings of decreased ejection fraction, does not cause permanent damage to the cardiac myocytes, and is often reversible with treatment.⁹ Frequently, patients can even be re-challenged with trastuzumab and tolerate it without further toxicity when it is administered after the cardiac function has recovered. While prior exposure to anthracyclines and a history of cardiac disease increase the risk of trastuzumab-related cardiac toxicity, elevated body mass index, hypertension, and diabetes mellitus are not recognized as risk factors.¹⁰

Combining trastuzumab with anthracyclines can increase the incidence of cardiac toxicity by nearly 27%, but by a much lower amount (13%) when coadministered with paclitaxel.¹¹ If a patient is at risk for cardiac toxicity and is also at high risk for breast cancer recurrence, a risk-versus-benefit consideration is appropriate prior to choosing a therapeutic regimen. For patients who receive trastuzumab in the adjuvant setting, echocardiography is recommended every 12 weeks so that subclinical cardiac dysfunction can be identified early. In the neoadjuvant setting, pertuzumab is now frequently administered with trastuzamab in early-stage breast cancer to provide a complementary mechanism of Her-2 blockade. A meta-analysis observed a low incidence of cardiac toxicity with pertuzumab—a significant decrease in left ventricular ejection fraction in:

• 6.9% of patients treated with pertuzumab alone
• 3.4% of patients treated with pertuzumab in combination with a nonanthracycline cytotoxic therapy
• 6.5% patients treated with pertuzumab in combination with trastuzumab.¹²

Cardiac Toxicity and Treatment Change in Patients Treated Without Curative Intent

In patients with incurable cancers, the treatment consideration for administration of agents with risk for cardiotoxicity is different. The risk of treatment in these patients may be greater, as the duration of therapy is often prolonged, the patient may have poorer health, there may be a greater choice of therapeutic options, and the benefit in terms of risk reduction is usually less. In older patients, patients with reduced performance status, and patients with a heavier burden of comorbid illness, treatment choice should reflect these heightened risks of complications, and dose reduction should be considered. Other agents used in the metastatic setting do not yet have adjuvant indications; for example in the metastatic setting, alternate drug formulations, such as liposomal doxorubicin, can substantially decrease the risk of cardiotoxicity.

In addition to the targeted therapeutics already mentioned, inhibition of the vascular endothelial growth factor (VEGF) pathway through tyrosine kinase inhibition is associated with cardiotoxicity. As a class, the VEGF-mediated tyrosine kinase inhibitors (TKIs) can have variable effects on cardiac function, and understanding each new agent’s potential for cardiac toxicity demands careful review. A meta-analysis of patients receiving TKIs demonstrated an 8-fold increased risk over patients not receiving TKIs for prolongation of the QTc.¹³ The TKI sunitinib has been associated with a 4% to 8% rate of congestive heart failure.^14,15 Bevacizumab has also been associated with cardiac toxicity, depending on the combination chemotherapy—cardiac issues have been reported only rarely in colon cancer. When bevacizumab was combined with R-CHOP in the MAIN trial, the rates of heart failure increased significantly, from 7% to 16%.¹⁶ In breast cancer, bevacizumab substantially increased the risk of hypertension and congestive heart failure.¹⁷

EBO

In summary, medication-associated risk of cardiotoxicity is an important consideration in determining treatment choice for all patients, especially those at higher risk for complications. These include elderly and patients with significant comorbid illness who are underrepresented in the prospective clinical trials that influence pathway and guideline choices. Given the explosion of new therapies in cancer care, the risk of each new therapy must be clearly understood prior to making treatment decisions with patients. Data from clinical trials alone are insufficient to educate these treatment choices, and real-world evidence from higher-risk populations should be generated to inform these treatment decisions.

Debra Patt, MD, MPH, MBA, is director of public policy, Texas Oncology, and medical director of healthcare informatics and The Pathways Task Force, The US Oncology Network and McKesson Specialty Health.

References

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