Early Identification and Management of Pediatric Patients with Malignancy at Increased Cardiovascular Risk

In November 2018, an 18-year-old male was transferred to Cleveland Clinic Children’s in respiratory failure. He was found to have a large mediastinal mass in his chest eroding his trachea. He subsequently had cardiac arrest requiring placement on extracorporeal membrane oxygenation (ECMO).

After 40 days on ECMO, the patient had recovered and was successfully weaned off ECMO support. Pediatric oncologist Seth Rotz, MD, initiated aggressive treatment for his malignancy with anthracyclines and radiotherapy. The tumor responded, but after receiving 225 mg/m2 of anthracyclines, the patient developed biventricular dysfunction.

Dr. Rotz enlisted the help of cardiologist Shahnawaz Amdani, MD, a specialist in pediatric heart failure with special interest in cardio-oncology. Dr. Amdani started the patient on an Angiotensin Converting Enzyme Inhibitor for cardioprotection. The patient subsequently received an additional 150mg/m2 of anthracycline (raising the cumulative anthracycline dose to 375mg/m2) without worsening heart failure. The mass was contained, and by June, the patient’s heart function had returned to normal. “His latest Troponin T is normal suggesting no ongoing myocardial damage and NT-pro BNP is normal suggesting no ongoing ventricular wall stress, both of which are very reassuring,” says Dr. Amdani.

The cost of survival

Chemotherapy with anthracyclines and radiation therapy have significantly improved survival outcomes for children with many forms of cancer. Yet the effectiveness of these treatments can come at a high cost to the heart.

“Cardiovascular disease is a leading cause of morbidity and mortality in cancer survivors,” says Dr. Amdani.

At Cleveland Clinic Children’s, a standardized protocol involving early assessment of cardiac risk provides for identification of patients early on that will need to be monitored closely from a cardiovascular standpoint and, if needed, started on cardioprotective medications. Availability of the full compliment of medical and surgical therapies to attenuate risk and lifelong follow-up helps ensure optimal outcomes for these patients.

“Pediatric cancer patients are generally fairly healthy except for their malignancies. We want them to survive their cancer and live long and healthy lives,” says Dr. Amdani.

Known risks

The effects of radiotherapy to the chest are cumulative with repeated exposure, and can result in valve dysfunction and premature coronary artery disease. Risk begins to increase after receipt of 15 Gy and becomes significant at 35 Gy.

Anthracycline therapy reduces heart function in a dose-dependent fashion indexed to body surface area. “The lifetime risk of heart failure in cancer survivors is significant and can be as high as approximately 25 times that of the general population in someone who had received around 250 mg/m2 of anthracyclines. The bottom line is, there is really no safe dose of anthracyclines,” says Dr. Amdani. “Acute decline in cardiac function can occur during the first infusion,” he says.

In light of these risks, pediatric oncologists may opt to use dexrazoxone for cardioprotection some patients receiving anthracyclines. The agent counteracts free radicals produced by the chemotherapy. “Dexrazoxone used to be controversial, but recent data have shown it to be safe, and it prevents problems very well,” says Dr. Rotz.

Screening protocol

Currently, with no available evidence-based guidelines for cardiac screening and management during cancer therapy in pediatric patients, Cleveland Clinic Children’s heart failure team has devised their own protocol.

Among high risk patients, each time a patient receives anthracycline chemotherapy, a combination of screening tests is performed within 48 hours to capture any early side effects. These include blood test to evaluate cardiac makers of ventricular wall stress (NT-pro BNP) and myocardial injury (Troponin T); an electrocardiogram (to assess for any heart rhythm abnormalities); and an echocardiogram (to evaluate for changes in cardiac dimensions, valvular regurgitation and ventricular function).

“It is important to have a cardiologist on your team who is passionate about these patients. They will understand that even when a patient is at high risk for cardiac complications, lifesaving cancer treatment takes priority,” says Dr. Rotz.

Dr. Amdani agrees. “The cancer is more concerning. Sometimes we have to deal with the cancer now and worry about cardiac implications later.”

Handling complications

At Cleveland Clinic Children’s, a full complement of cardiac treatments is available to help pediatric cancer patients survive any cardiac complications that may occur.

Patients experiencing an acute decline in heart function, can be supported with intravenous medicines to help strengthen their heart in the short term. “For patients with end-stage heart failure we do have the option of implanting a left and/or right ventricular assist device in order to bridge them safely to heart transplantation if need be,” says Dr. Amdani. “Here at the Cleveland Clinic Children’s we are a part of a large multi-center trial to evaluate the efficacy of new heart failure medications that may change outcomes for pediatric patients with heart failure. As a top-notch institution, we are always a part of such amazing trials that ultimately allow us to help our patients in the best possible way,” says Dr. Amdani.

Long-term care

Dr.Rotz currently follows cancer survivors in a designated Cancer Survivor Clinic. Regular follow-up alongside Dr.Rotz enables Dr. Amdani to monitor patients for changes in heart function that may appear several years after cancer treatment ends. These patients receive the same screening tests used during their cancer treatment, along with tests for arrhythmia, ischemia and vascular disease. It is also important for these cancer survivors to understand that they are at an increased risk for obesity, diabetes and atherosclerotic cardiovascular disease and hence they are screened for these at every cardiology visit by Dr. Amdani.

Hoping for answers

Although their screening protocol works well, the physicians have a “wish list” of changes that would improve safe risk prediction.

“Screening with imaging tests can facilitate risk prediction, but in young kids, a good quality cardiac MRI requires sedation and children often get anxious, thus not allowing for adequate use of this technology. Hopefully, these issues will be solved with rapid-sequence MRI imaging,” says Dr. Amdani.

Because the amount of blood drawn from very young patients must be limited, Dr. Amdani hopes to participate in clinical trials of urinary tests designed to replace blood tests for NT-proBNP and Troponin to help cardiac assessment.

One of the most hopeful advances is the potential to limit cardiac complications by using lower doses of anthracyclines. “We are currently conducting trials to see whether we can obtain the same cure rates with less anthracyclines,” says Dr. Rotz.

Dr. Rotz hopes someday to have a simple genetic test that will predict how patients’ hearts will respond to cancer treatment. He also believes it will be crucial to determine if clonal hematopoiesis of indeterminate potential (CHIP) mutations is an important issue in pediatric cancer survivors, and how this may affect long-term cardiac risk.

Until these dreams are realized, Drs. Rotz and Amdani will continue to use the tools at their disposal to help ensure their young patients survive and live normal, fulfilling lives free from cancer and heart disease.