Cardiovascular care of pediatric cancer survivors: Mitigating a lifelong risk
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In the long-term surveillance of pediatric cancer survivors, clinicians cannot necessarily be reassured by the appearance of wellness.
“The scenario is quite common now where a patient beats their cancer and then loses to cardiac disease — they develop cardiac disease in their mid-30s, have heart failure by age 40, and an early cardiac death,” Gregory T. Armstrong, MD, MSCE, member of the department of epidemiology and cancer control at St. Jude Children’s Research Hospital and co-leader of St. Jude’s Cancer Control and Survivorship Program, said in a presentation at the American College of Cardiology’s (ACC) Advancing the Cardiovascular Care of the Oncology Patient virtual course. “In your practice, you are going to see survivors who come to you and look well, but we need to talk about surveillance and screening based on their risk.”
‘A tremendous risk’
Armstrong discussed data on cardiotoxicity in cancer survivors from large cohort studies. He cited data from the SEER database, which reported that 5-year survivorship for childhood cancers has improved steadily across the decades, with 85% of children attaining this milestone.
“We know from SEER that as of 2018, there were 483,000 survivors of childhood cancer in the United States,” Armstrong said. “It is estimated that by 2020, we’d have half a million —we’ll find out in a year or 2 whether that’s correct. Nevertheless, this is a growing population, a prevalent population. It’s also an aging population.”
Armstrong also discussed cause-specific mortality among aging cancer survivors. In a study published in 2009 in Journal of Clinical Oncology, Armstrong and colleagues assessed cumulative mortality in 5-year cancer survivors and identified specific treatment-related risk factors for late mortality.
“Even after 5 years, we lose children to late recurrence [of their primary cancer] and progression,” Armstrong said. “We also lose children to external causes such as accidents and injuries, trauma and suicide but, by far, the biggest concern is that of nonrecurrence, nonexternal causes. These are medical causes of death that are usually treatment related.”
after diagnosis surpasses that of death from the primary cancer.
“Our survivors have a 15-fold greater risk for dying of cancer than the general population has of dying from cancer, but they have a sevenfold greater risk for dying of cardiac disease,” Armstrong said. “This is a tremendous risk across their lifetime and underlying that risk for cardiac mortality is risk for cardiac disease.”
‘No safe dose’
Increasingly, evidence suggests that these cardiac risks directly relate to anticancer treatments used and their dosage.
Pointing to data published in 2013 in Journal of Clinical Oncology from the Childhood Cancer Survivors’ Study (CCSS), of which he is the principal investigator, Armstrong noted an increased risk for clinical heart failure in childhood cancer survivors aged 45 years.
“When we look at severe and life-threatening clinical heart failure, we see that by the time survivors are 45 years of age, 11.8% who received radiation plus anthracycline have developed clinical heart failure,” Armstrong said. “In patients who received anthracycline alone, the number is lower at 6.8%, and in those who received radiation alone, it was 5%.”
In comparison, only 0.3% of healthy siblings developed clinical heart failure at age 45 years (P < .001).
The same was true for coronary artery disease, Armstrong said. By age 45 years, 9% of a population previously treated with chest-directed radiation had developed coronary artery disease compared with 1% of those treated without radiation and 0.3% of healthy siblings (P < .001).
Armstrong noted that in terms of heart failure associated with anthracycline use, the risk is dose dependent.
“Looking at data from the United States and also from the Netherlands, it’s very clear that with increasing doses of anthracyclines, there’s an increasing risk ratio for developing heart failure,” he said. “In fact, this risk is seen at doses you might consider very low.”
mg/m2 of anthracyclines and not consider it cause for concern. However, even this amount confers a threefold increased risk for heart failure within that patient’s lifetime.
“One thing I like to say is that there is no safe dose of anthracyclines,” he said.
Radiation also is known to contribute to heart disease risk in pediatric cancer survivors. Armstrong discussed a 2019 study in Journal of Clinical Oncology, in which Bates and colleagues reported that high doses of radiation, even to small volumes of the heart, increase the risk for heart disease.
“The researchers looked at patients who received 20 Gy or more of radiation but to a small volume of the heart, between 0.1% to 29%, less than a third of the heart,” he said. “Yet the 30-year cumulative increased risk was 6.4% compared to 3.4% for those without radiation, which is a 2.5-fold increased risk.”
“So, I think when we look at these data, we can also say there’s likely no safe dose of chest-directed radiation,” he said.
Radiation also is known to contribute to heart disease risk in pediatric cancer survivors. Armstrong discussed a 2019 study in Journal of Clinical Oncology, in which Bates and colleagues reported that high doses of radiation, even to small volumes of the heart, increase the risk for heart disease.
“The researchers looked at patients who received 20 Gy or more of radiation but to a small volume of the heart, between 0.1% to 29%, less than a third of the heart,” he said. “Yet the 30-year cumulative increased risk was 6.4% compared to 3.4% for those without radiation, which is a 2.5-fold increased risk.”
Armstrong added that a very low dose of radiation to a large volume of the heart also increases risk.
“So, I think when we look at these data, we can also say there’s likely no safe dose of chest-directed radiation,” he said.
Barriers to care continuity
Because of these risks, continuity of care and surveillance are essential but can be complicated by a plethora of guidelines, knowledge gaps and other challenges.
In another presentation during the ACC course, Kevin C. Oeffinger MD, FASCO, and Rachel Barish, MSN, ANP-BC, AACC, discussed strategies for the long-term management and surveillance of pediatric cancer survivors.
“When we think about survivorship care, there is just a lot of inherent complexity in taking care of these patients,” Barish, a nurse practitioner in the outpatient cardiology clinic at MedStar Georgetown University Hospital, said in the presentation. “When we think about quality care, what does that look like? It is going to look like addressing blood pressure targets or working on smoking cessation. It is going to look like screening for cardiovascular complications. However, I also think it’s important to think about the view from 10,000 feet and how much is really involved in creating quality care for cancer survivors.”
Barish noted the many professional guidelines available for following pediatric cancer survivors and discussed the need to monitor these individuals for recurrent/new cancers, other physical effects, psychosocial effects and chronic conditions. She discussed some of the obstacles preventing survivors from receiving quality long-term care, including lapsed insurance, loss of caregiver support, knowledge gaps, treatment fatigue, transitions along the care continuum, new cancer diagnosis, underrepresentation of a population in the guidelines and lack of communication.
“When these patients come either to the end of their cancer care, or to one of these milestone transition points, such as getting through surgery or completing a phase of chemotherapy, we’re really trying to get them on a road toward coordinated and excellent care,” Barish said. “They will encounter these stumbling points along the way, but I think as long as we keep that destination in mind, we can get there.”
The value of risk calculators
In an interview with Healio, Oeffinger, a family physician and a professor in the department of medicine at Duke Cancer Institute (DCI) and founding director of the DCI Center of Onco-Primary Care, discussed modifiable risk factors in pediatric and adolescent and young adult cancer survivors, noting that the most prevalent modifiable cardiovascular risk factors in these patients are “hypertension, dyslipidemia and diabetes — in that order.
added. “It requires teamwork.”
“Contemporary cancer therapy should include the patient’s primary care provider as part of the team, not merely as a social visit,” he added. “It requires teamwork.”
Oeffinger discussed a case study involving “Mary,” a 40-year-old African American cancer survivor who underwent treatment at age 20 years for stage IIA Hodgkin lymphoma. Her treatment included 21 Gy involved-field radiotherapy, including the neck and mediastinum, as well as five cycles of doxorubicin hydrochloride, bleomycin, vincristine sulfate, etoposide phosphate, prednisone and cyclophosphamide, or the ABVE-PC regimen. Mary had no family history of cancer or premature cardiovascular disease. She had normal BMI and blood pressure, was a never-smoker, nondiabetic and had mild dyslipidemia.
In assessing Mary’s potential cardiovascular risk, Oeffinger noted that she faced other risks as well. He cited a study published in 2014 in the Journal of Clinical Oncology for which he was an author that showed a population of women treated with a similar regimen as Mary.
“By the age of 51, 30% of these women have already been diagnosed with breast cancer,” he said during his presentation. “That’s comparable to what we see in the BRCA1 mutation population (31%). Importantly, if we look at their mortality 15 years after their diagnosis, 50% of these women are dead, and half of those deaths are from their breast cancer.”
Oeffinger said an atherosclerotic cardiovascular disease (ASCVD) risk calculator would place Mary at relatively low (0.5%) 10-year risk for an ASCVD event.
“An ASCVD risk calculator is inappropriate to use for patients treated with mediastinal radiotherapy,” Oeffinger said. “What we see in our studies is that this population actually has a fairly elevated risk for coronary artery disease, akin to someone with diabetes or a longtime smoker.”
He noted Mary’s risk using the CCSS cardiovascular risk calculator, which factors treatment exposures into its calculation. Using this tool, Mary’s 10-year absolute risk is 7%, whereas her risk for heart failure was 6.3% and her stroke risk was 1.3%.
“This is an 18-fold increased risk for coronary artery disease compared to a similarly aged and gender individual without cancer,” Oeffinger said.
‘Aggressive’ surveillance, risk mitigation
Oeffinger said for survivors of pediatric cancers such as Hodgkin lymphoma, he recommends comprehensive and regular testing for cardiovascular issues.
“The Hodgkin lymphoma survivor population is a high-risk population, higher risk than a diabetic,” he said. “We need to think aggressively about their risk reduction, blood pressure management, statin therapy, exercise and screening.”
For these patients, Oeffinger recommended a resting echocardiogram to assess for heart failure and left ventricular function every 2 years.
“I typically do a stress echocardiogram or radionucleotide stress test about every 3 to 5 years, depending upon what we see, and we work closely with a cardiologist,” he said, adding that it’s important to adjust for baseline tachycardia and make sure patients are exercised above the minimal threshold to get a maximal effort.
Armstrong emphasized the importance of exercise as a preventive measure for survivors of pediatric cancers.
“Another area where we need to think about mitigating disease is exercise. In the CCSS, we looked at activity and broke it down based on the number of net hours per week of activity,” he said. “We saw that those with no activity compared to those who have high activity segregate out quite nicely. When you look at health-related, late mortality, higher activity is associated with decreased mortality, and this held true in multivariable models as well.
Care across a lifetime
In discussing a case study of a young woman who had undergone stem cell transplantation for a recurrence of her cancer, Barish cited the value of telemedicine in maintaining continuity of care.
“There is a lot of research about how challenging it is for an individual patient to move from pediatric to adult models of care,” she said. “These patients might have parents who had been very heavily involved, and maybe they want to launch themselves and be a bit more independent in their engagement,” she said. “This is our moment to make telehealth work for us. This patient lives 45 miles from my clinic, but she is a patient who we want to remain engaged and stay connected with us via telehealth from anywhere she is, and throughout the years of her survivorship care.”
Armstrong discussed the potential use of biomarkers in predicting cardiovascular effects of pediatric cancer treatments.
“We are going to show some very interesting data at ASCO that may suggest that in longitudinal studies, the use of global longitudinal strain and B-type natriuretic peptide as biomarkers may allow us to identify who may develop future cardiomyopathy,” he said.
Armstrong emphasized that there is definite cause for optimism for the future of childhood cancer survivors. He discussed reductions in the intensity of treatment for patients with acute lymphocytic leukemia, Hodgkin lymphoma and Wilms tumor.
“We, as a population of pediatric oncologists have, over time, identified populations who didn’t need the intensity of therapy that we gave them in the 1970s,” he said. “So, in the 1980s and 1990s we reduced that. As early as 15 years, we are seeing lower risks for cardiac deaths. This is a very encouraging finding — our efforts to reduce therapy in survivors decades ago are now extending the lives of survivors of childhood cancer.”
References:
- Armstrong GT. Cardiovascular concerns in AYA and adult survivors of childhood cancer. Presented at: American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient virtual course; Feb. 11-12, 2022.
- Armstrong GT, et al. J Clin Oncol. 2009;doi:10.1200/JCO.2008.21.1425.
- Armstrong GT, et al. J Clin Oncol. 2013;doi:10.1200/JCO.2013.49.3205.
- Barish R, Oeffinger KC. Adult and pediatric cancer survivorship: Management of modifiable CV risk factors. Presented at: American College of Cardiology’s Advancing the Cardiovascular Care of the Oncology Patient virtual course; Feb. 11-12, 2022.
- Bates JE, et al. J Clin Oncol. 2019;doi:10.1200/JCO.18.01764.
- Blanco JG, et al. J Clin Oncol. 2012;doi:10.1200/JCO.2011.34.8987.
- Moskowitz CS, et al. J Clin Oncol. 2014;doi:10.1200/JCO.2013.54.4601.
- SEER Cancer Statistics Review, 1975-2012. https://seer.cancer.gov/archive/csr/1975_2012/. Updated Nov. 18, 2015. Accessed March 16, 2022.
- Van der Pal HJ, et al. J Clin Oncol. 2012;doi:10.1200/JCO.2010.33.4730.
For more information:
Gregory T. Armstrong, MD, MSCE, can be reached at greg.armstrong@stjude.org.
Rachel M. Barish, MSN, ANP-BC, AACC, can be reached at rachel.m.barish@gunet.georgetown.edu.
Kevin C. Oeffinger, MD, FASCO, can be reached at kevin.oeffinger@duke.edu.
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