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Successful cancer treatment may lead to cardiac complications later
Complications affect adult survivors of pediatric and adolescent cancers.
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Anthracycline and radiation doses have been identified as key links to cardiovascular disease later in life among adult survivors of pediatric and adolescent cancers. Although ongoing findings continue to define the effect of these two factors, comprehensive research is being conducted in all aspects of childhood cancer survivorship.
The Childhood Cancer Survivor Study involves thousands of patients diagnosed with cancer between 1970 and 1986 who survived at least 5 years, as well as sibling controls. Hundreds of papers detailing many aspects of the issues and complications of this fragile group have significantly improved physicians’ knowledge of the increased morbidity and mortality risks in this group. Independent research has validated many of the findings published as part of this multi-dimensional cohort.
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Photo courtesy of University of Miami Department of Biomedical Communications |
However, clinical and behavioral questions remain. Beyond anthracycline and radiation use, the effect of other agents on the heart later in life requires further study. Some older adolescent survivors with a perceived shortened lifespan may indulge in high-risk behaviors, whereas others who had a malignancy at a similar age use their second chance to stay healthy and active. Many patients who were diagnosed with cancer at a very young age have no concept of their survivorship one way or the other, but they are still at risk because of treatment exposure or other genetic factors. Moreover, researchers continue to investigate the role of the malignancy itself.
HemOnc Today spoke to a cross-section of experts in myriad fields about childhood cancer survivorship and the risk for cardiovascular disease. Perhaps the most commonly voiced concern was addressed by Roger L. Berkow, MD, professor and vice-chair of pediatrics and pediatric hematology/oncology at the University of Alabama at Birmingham.
“We simply do not know enough about patients who were treated as children and are now in their late 50s or 60s, when many cardiovascular events are happening in the general population,” Berkow said. “Findings indicate that the incidence and risk of cardiovascular and other complications of the disease and treatment may increase throughout the lives of these survivors. Unfortunately, we have not seen any real plateaus in the data. We need longer follow-up because it still is not certain where we are going.”
Anthracyclines and radiation
Steven E. Lipshultz, MD, chair of pediatrics and executive dean for child health at the University of Miami Leonard M. Miller School of Medicine, chief of staff of the Holtz Children’s Hospital and member of the University of Miami Sylvester Comprehensive Cancer Center, recently wrote an editorial in which he catalogued several of the issues surrounding cardiovascular issues related to pediatric cancer survivorship.
Lipshultz focused initial comments on results published by Tukenova and colleagues, who studied 4,122 5-year survivors of childhood cancer diagnosed before 1986 in France and the United Kingdom, totaling 86,453 person-years of follow-up.
A cumulative anthracycline dose of more than 360 mg/m2 was significantly associated with increased risk for cardiac disease-related death (RR=4.4; 95% CI, 1.3-15.3). Children who had received an average radiation dose that exceeded 5 Gy to the heart also were at a significantly greater risk for cardiac death. The RR was 12.5 for patients who had received 5 to 14.9 Gy and 25.1 for patients who had received more than 15 Gy.
Daniel A. Mulrooney, MD, assistant professor of pediatrics in the division of pediatric hematology/oncology/blood and marrow transplantation at the University of Minnesota, and colleagues drew similar conclusions from a cohort of 14,358 5-year survivors who were diagnosed when they were younger than 21 years.
Exposure to 250 mg/m2 or more of anthracyclines was associated with a two- to fivefold increase in risk for congestive heart failure, pericardial disease and valvular abnormalities compared with survivors who had not been exposed to anthracyclines. Cardiac radiation exposure of 1,500 centigray or more was linked to a two- to sixfold increase in risk for congestive heart failure, myocardial infarction, pericardial disease and valvular abnormalities compared with those with no radiation exposure.
“These results give us great insight into the role of cumulative anthracycline and radiation dose,” Lipshultz told HemOnc Today. “They also give further evidence of the synergy between chemotherapy and radiation exposure and the potential impact they can have on the heart.”
Mitchell T. Saltzberg, MD, medical director of the heart failure program at Christiana Care Health System in Newark, Del., provided a clinical perspective on this question. “The impact of radiation on the heart is complicated,” Saltzberg said. “Scar tissue forms at the chest level and in the mediastinum, and it also develops near the coronary arteries. This puts tremendous stress on the heart muscle.”
Elvira C. van Dalen, MD, PhD, of the department of pediatric oncology at Emma Children’s Hospital in Amsterdam, said “children treated with anthracyclines and radiotherapy involving the heart — including the mediastinum, upper abdomen, thorax, thoracic spinal cord and total body irradiation — have the highest risk.”
She also said anthracycline-induced cardiotoxicity is dose-dependent, a point that was placed in clinical terms by Berkow and Mulrooney.
“We are moving toward treatment that is risk-adaptive,” Berkow said. “The therapy should be adapted to the risk of the patient. We are trying to pare back on specific agents to try to limit complications. By doing that in a variety of disorders and then monitoring treatment, we can give more therapy to patients who have a higher risk of recurrence and less to patients with lower risk of recurrence.”
Mulrooney agreed but said such risk assessment and scaling is difficult.
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“This is a tricky thing to do,” he said. “We do not want to lose gains in survivorship associated with these therapeutic modalities. That said, we need to stratify risk and try to understand why child A develops heart failure and child B does not, and then adjust treatment regimens accordingly.”
Van Dalen said it is not only anthracyclines and radiation that are increasing risk.
“Other therapies such as high-dose cyclophosphamide, high-dose ifosfamide and vincristine may also be associated with cardiotoxicity,” she said.
Lipshultz said there are treatment-related risks of cardiac disease, but there are other factors at play.
“If we are pitting one agent against another, we may be missing the point,” he said. “Nobody gets just one agent. It is important to look beyond therapy to see why these survivors are developing cardiovascular complications.”
Stress factors
The experience of having cancer as a child or adolescent has psychological ramifications that can also have a cardiac component. Stuber and colleagues conducted a study to determine the frequency of post-traumatic stress disorder among 6,542 childhood cancer survivors older than 18 years and 368 of their siblings. Eligible participants who had been diagnosed between 1970 and 1986 were asked to complete a comprehensive survey.
The OR for post-traumatic stress disorder among survivors compared with their siblings was 4.14 (95% CI, 2.08-8.25). After controlling for demographic and treatment variables among survivors, educational level of high school or less (OR=1.51; 95% CI, 1.16-1.98); being unmarried (OR=1.99; 95% CI, 1.58-2.50); having an annual income of less than $20,000 (OR=1.63; 95% CI, 1.21-2.20); and being unemployed (OR=2.01; 95% CI, 1.62-2.51) were also linked to increased risk for the stress disorder.
“These individuals are prone to early sexual activity, smoking and drug abuse, most of which is rooted in a perceived shorter life expectancy,” Saltzberg said. “We see teen pregnancy because of the disbelief that they are unable to get pregnant. We see stress-related eating disorders. They grow up more quickly, they make questionable lifestyle decisions, they are less likely to exercise, and they are more likely to engage in self-destructive behavior. All of these things can contribute to cardiovascular disease.”
Furthermore, Lipshultz said these behaviors can become cyclical and lead to a downward spiral that results in even more increased risk.
“Individuals who engage in self-destructive behavior to this degree are not only placing themselves at risk for disease, but they are also less likely to hold a job and, consequently, have health care coverage,” he said.
Although research is being conducted on these behaviors, separating them from treatment, survivorship and normal adolescent or young adult behavior has proved challenging. “Risk factors such as smoking rates, obesity, BMI, anxiety, fatigue and sleep disturbance may play a role in cardiovascular disease among survivors, but their exact role is not yet known,” van Dalen said.
Berkow said despite these concerns, not all of the news is bad.
“About 40% or 45% of patients will have long-term physical complications, but it has been reported that only about 10% say that their quality of life is impacted,” he said. “A 90% positive quality-of-life rate is actually quite good.
“Kids being kids, they often do not understand the seriousness of their underlying disease and that without treatment, it would have been fatal,” Berkow said. “Adolescents who were old enough to understand their situation may realize that they have a new lease on life. Survivors who view their situation this way often avoid the self-destructive behaviors.”
Metabolic, malignancy factors
Meacham and colleagues investigated 8,599 survivors and 2,936 siblings as part of the Childhood Cancer Survivor Study. They prospectively followed 5-year survivors who had been diagnosed from 1970 to 1986. They evaluated participants for BMI of more than 30 kg/m2 based on self-reported data and self-reported use of medications for hypertension, dyslipidemia and impaired glucose metabolism. The presence of three or more of the studied factors indicated cardiovascular risk factor cluster, which they described as a surrogate for metabolic syndrome.
Survivorship was linked to increased likelihood of use of medications for hypertension (OR=1.9; 95% CI, 1.6-2.2), dyslipidemia (OR=1.6; 95% CI, 1.3-2) or diabetes (OR=1.7; 95% CI, 1.2-2.3), according to the results.
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Central nervous system prophylaxis, particularly in patients with leukemia, may increase metabolic risk factors. “Cranial radiation, specifically pituitary radiation, has been linked to increased rates of diabetes and obesity,” Berkow said.
Moving beyond the clinic, Lipshultz said adult survivors of pediatric and adolescent cancers are more likely to be sedentary, which, in turn, increases metabolic risk.
Meacham and colleagues also conducted an evaluation of BMI in 7,195 adult survivors of pediatric or adolescent cancers diagnosed from 1970 to 1986 and demographically matched controls. Low BMI was defined as less than 18.5 kg/m2, and obesity was described as BMI of at least 30 kg/m2.
Obesity was observed most frequently in women who survived leukemia (OR=1.5; 95% CI, 1.2-1.8) and men who survived leukemia (OR=1.2; 95% CI, 1-1.5). Hodgkin’s disease was linked to being underweight in men (OR=1.7; 95% CI, 1.3-2.3) and women (OR=3.5; 95% CI, 2.3-5.3). Other survivors who tended to be underweight included:
- Wilms’ tumor (OR=1.8; 95% CI, 1.2-2.8 for men, and OR=5.5; 95% CI, 3.1-9.7 for women);
- Women who survived bone cancer without amputation (OR=1.9; 95% CI, 1.2-2.9);
- Men who survived leukemia (OR=2.4; 95% CI, 1.6-3.6);
- Men who survived brain tumors (OR=2.7; 95% CI, 1.6-4.4);
- Men who survived non-Hodgkin’s lymphoma (OR-3.1; 95% CI, 1.9-5.2);
- Men who survived neuroblastoma (OR=4.9; 95% CI, 2.48-10);
- Men who survived soft tissue sarcoma (OR=3.5; 95% CI, 2-6).
“Underweight survivors were more likely to report adverse health and major medical conditions,” the researchers wrote.
Despite these results, most clinicians agree that more robust data are needed to determine the extent to which each particular malignancy is associated with later cardiovascular disease.
“It is not possible to state which childhood cancers are associated with the highest risk of cardiac problems,” van Dalen said. “This depends on the exact treatment patients received — which, in turn, depends on the type of cancer, the stage of disease, etc. — and on the presence of other risk factors, including younger age at diagnosis.”
Saltzberg said leukemia and lymphoma affect the fluid surrounding the heart, and an active tumor can affect the heart tissue.
“The heart disease we see among cancer survivors is distinct from naturally occurring disease,” he said. “The research indicates that this is largely treatment-related, but further investigation is required for specific malignancies.”
Follow-up and care
Despite uncertainty about the role of treatment, malignancy and behavior in driving heart disease in these survivors, the data are clear that survivors are at an increased risk for cardiovascular complications.
Other results from Tukenova and colleagues indicated that the overall standardized mortality ratio was 8.3-fold higher (95% CI, 7.6-9) in cancer survivors compared with the general population of France and the United Kingdom. The mortality rate caused by cardiovascular diseases was fivefold higher (95% CI, 3.3-6.7) among survivors compared with the general population.
Other results from Mulrooney and colleagues indicated that survivors of cancer were significantly more likely than siblings to report congestive heart failure (HR=5.9; 95% CI, 3.4-9.6), myocardial infarction (HR=5; 95% CI, 2.3-10.4), pericardial disease (HR=6.3; 95% CI, 3.3-11.9) or valvular abnormalities (HR=4.8; 95% CI, 3-7.6).
With so many associations with serious complications, it is also generally recognized that this population should have access to health care coverage and receive careful follow-up.
Nathan and colleagues conducted a cross-sectional survey of health care use in 8,522 participants in the Childhood Cancer Survivor Study. They assessed the frequency and type of health care visits in the preceding 2 years and whether those visits involved screening tests or information on reducing long-term risks for complications that may be related to cancer.
Patients at high risk for cardiomyopathy or breast cancer were evaluated for completion of echocardiograms and mammograms. Demographics, treatment, health status, chronic medical conditions and health care use were evaluated.
Some involvement in the health care system was reported by 88.8% of participants. However, only 31.5% received survivor-focused care, and only 17.8% reported survivor-focused care that involved advice or discussion about risk reduction or the ordering of screening tests, according to the results.
Participants who were black, older at the time of interview or did not have health insurance were less likely to receive survivor-focused care that emphasized risk reduction.
A recommended echocardiogram was administered to 28.2% of those at risk for cardiomyopathy, and a recommended mammogram was administered to 40.8% of women at risk for breast cancer.
“Survivors with cardiovascular disease tend to present 10 to 15 years after therapy,” Saltzberg said. “They have coronary artery disease and proximal lesions that may require bypass. Although these complications are remote or delayed in terms of when they had the malignancy, they often happen at a much younger age than they do in the general population. We need to make sure they are still in the system when these problems arise.”
Lipshultz said: “There needs to be greater follow-up on cohorts, since this has major public health and health resource implications as one of the largest emerging groups at risk for prematurelty-expressed symptomatic cardiovascular disease. We also need to develop and validate both cardioprotective strategies during active cancer therapy and also the tools to assess global cardiac risk for these survivors to identify those at greatest risk to allow for early validated interventions that can reduce the risk of subsequent clinically significant cardiovascular disease.”
Berkow brought the issue back to basic terms. “This is about surveillance,” he said. “This is about meeting basic health care needs. If we do not meet the needs of this high-risk population of survivors, it is going to place a severe burden on the system as they get older, and we will all be dealing with the consequences.” – by Rob Volansky
For more information:
- Lipshultz SE. J Clin Oncol. 2010;28:1276-1281.
- Meacham LR. Cancer. 2005;103:1730-1739.
- Meacham LR. Cancer Epidemiol Biomarkers Prev. 2010;19:170-181.
- Mulrooney DA. BMJ. 2009;339:b4606.
- Nathan PC. J Clin Oncol. 2008;26:4401-4409.
- Stuber ML. Pediatrics. 2010;125;e1124-1134.
- Tukenova M. J Clin Oncol. 2010;28:1308-1315.
Disclosures: The sources interviewed for this story reported no relevant financial disclosures.
What should clinicians do to combat cardiovascular complications in pediatric and adolescent cancer survivors?
Our research focused on the risk factors that precede cardiovascular events in these populations. We looked at classic metabolic syndrome, obesity, hypertension, dyslipidemia and diabetes. Patients who had any three of those were at greater risk for stroke or myocardial infarction down the road.
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We thought that obesity would be the driver, but it was not the case. Obesity is obviously such an evil and pervasive problem that surely it would put these survivors at risk for high cholesterol and other more direct factors. It was interesting that, as a whole group, cancer survivors did not carry higher rates of obesity than the general population. Survivors are getting more obese, and their siblings are getting more obese, but survivors are not getting more obese than their siblings.
It was also interesting that high blood pressure, lipids and diabetes were all very comparable in their increased risk. Relative risk for high blood pressure was slightly higher in the survivor cohort compared with relative risk for dyslipidemia or diabetes but not strikingly different.
The important point here is that we have to start thinking about these cardiovascular risk factors at a much earlier age in cancer survivors. We should not wait until they are in their 40s before we check blood pressure and cholesterol. Even in their 20s and 30s, we need to start paying attention to these risk factors, whereas in the general population, we do not focus on these things so early.
The good news is that there is often heightened surveillance. These individuals are likely to be receiving counseling and close follow-up as part of a survivorship program. The typical 25-year-old is not going to the doctor regularly, but these survivors are. If they have access and are in the health care system, we need to make sure they understand these risk factors.
Lillian R. Meacham, MD, is a medical director of the Cancer Survivor Program of the Aflac Cancer Center and Blood Disorders Service for Children’s Healthcare of Atlanta.
Disclosure: Dr. Meacham reports no relevant financial disclosures.
Obesity is obviously a problem in the general population, and we see it more frequently in two populations of childhood cancer survivors: those who had leukemia and brain tumors. This is particularly true in women. The obesity is largely linked to cranial radiation at a young age.
However, the pathophysiology of what is happening in the brain is still not known. Data are emerging but questions remain. It may be linked to a sedentary lifestyle or fatigue, but those are likely not the only explanations.
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What can be said definitively is that we need follow-up interventions in which we encourage basic health practices such as eating healthy and maintaining physical activity levels. Of course, it is possible that neurologic or physical impairment may keep these patients from being active, but we have to capitalize on their care as much as possible.
A survivorship follow-up visit is a teachable moment. We can’t take away that exposure to anthracycline, doxorubicin, platinum agent or radiation, but we can emphasize the importance of health promotion. If they already have a baseline risk, we should do what we can to prevent it from getting worse.
Survivors of pediatric cancers are accessing care and getting in to see a doctor in fairly strong numbers. They are visiting a general medical contact, but when it comes to risk-based screening, they are not being asked whether they have had radiation exposure or exposure to the agents that may put them at risk for cardiovascular disease. It is critical to get them into survivorship-focused long-term follow-up. They need to be checked for BMI, dyslipidemia and hypertension. Targeted interventions need to be in place to determine if they need an echocardiogram or EKG. Heart disease hits this population earlier than it hits the general population, so we need to do everything we can to reduce associated morbidity and mortality curves.
Jacqueline Casillas, MD, is an associate director, Jonsson Comprehensive Cancer Center, Patients and Survivors Program Area, the University of California Los Angeles.
Disclosure: Dr. Castillas reports no relevant financial disclosures.