'First Signal' of Reduced Toxicity From Childhood Cancer Tx

Pam Harrison

January 16, 2020

Efforts to reduce long-term cardiac toxicity from radiotherapy and chemotherapy in the treatment of childhood cancer appear to be bearing fruit. A new analysis of data from the Childhood Cancer Survivor Study shows a decrease in coronary artery disease (CAD).

The study was published online January 15 in the BMJ.

"Survivors of childhood cancer have been found to have a very high prevalence of chronic health conditions — not just cardiac conditions, but chronic health conditions in general — and it's important to remember that we are finding them in 20- and 30-year-olds, not in the seventh, eighth, or ninth decade of life, where you might expect to find them," explained lead author Daniel Mulrooney, MD, St. Jude Children's Research Hospital, Memphis, Tennessee.

"With this study, we're seeing the first signal that there is a decrease in some [treatment-related] cardiac toxicity, particularly in CAD, and not at the expense of overall survival, so the efforts that oncologists have made to minimize toxicity in the past have now been successful," he told Medscape Medical News.

Evidence That CAD Has Declined

This study has provided, for the first time, statistically significant evidence that the risk for CAD has declined among childhood cancer survivors who underwent treatment in more recent decades, comments Mike Hawkins, DPhil, University of Birmingham, United Kingdom, and colleagues in an accompanying editorial.

"This was principally due to a strong decline among survivors of Hodgkin lymphoma," they emphasize.

They agree with the study's authors that this decline in CAD can be attributed to a reduction in exposure to radiotherapy during the decades analyzed.

The editorialists also note that issues regarding survivorship are "extremely important" to all players involved in childhood cancer, including patients and their families.

Thus, "clear and consistent guidance about clinic follow-up after childhood cancer is...required," they emphasize.

With this in mind, the International Late Effects of Childhood Cancer Guideline Harmonization Group has now been established to inform international practice. Led by key European and US investigators, the group has already produced several guidelines to inform practice internationally, the editorialists comment.

Long-Running Study of Survivors

The Childhood Cancer Survivor Study (CCSS) is a multi-institutional retrospective cohort study involving 23,462 survivors of the most common childhood cancers treated in the United States and Canada from the 1970s through the 1990s.

A little more than one quarter (26.4%) of the cohort were treated in the 1970s; 39.9% were treated in the 1980s; and 33.7% were treated in the 1990s.

The median age at diagnosis was 6.1 years, and the median age at last follow-up was 27.7 years.

"For this analysis, we included all reported cardiac conditions of grades 3–5, including heart failure, coronary artery disease (including myocardial infarction or coronary revascularization), heart valve replacement, pericardial disease, and arrhythmias requiring pacemakers or cardioversion, or death from any one of these five conditions," the researchers note.

Outcomes of cancer survivors were compared to those of 5057 siblings of the cancer survivors.

"Compared with survivors with a diagnosis in the 1970s, the risk of heart failure, coronary artery disease, and valvular heart disease decreased in the 1980s and 1990s but only significantly [so] for coronary artery disease," the study team report.

The incidence of CAD declined by 47% between the 1970s and the 1990s; it declined by 35% between the 1970s and the 1980s.

"This was primarily attributable to decreases in the rate of coronary artery disease among survivors of Hodgkin lymphoma," they add. In this group of patients, historical reductions in exposure to cardiac radiation have been particularly pronounced.

Mulrooney noted that the highest risk factor for CAD is radiation exposure.

"Not only have fewer children been exposed to radiation over the decades, but the doses used were more moderate, and radiation techniques have changed over time, too — both the source of radiation and the fields of radiation are more moderate than they used to be," he explained. This is why lower radiation exposure has had such an appreciable impact on the prevalence of CAD in adult survivors, Mulrooney added.

The largest decline in heart failure, though not statistically significant, was also observed from the 1980s to the 1990s, when it dropped by 27%.

"The higher the anthracycline dose, the higher the risk of heart failure," Mulrooney explained.

In an attempt to minimize cardiac toxicity, "investigators have brought the dose down over time, so while exposure to anthracyclines has gone up overall, it was in a lower dose range, which is less likely to cause heart failure," he added.

Similarly, although again not statistically significant, a decline in other cardiac toxicities was observed across the decades, with the exception of arrhythmias.

On the other hand, after adjusting for confounders, the decline in other cardiac outcomes remained relatively unchanged over the decades.

The risk for heart failure increased fivefold among survivors of neuroblastoma who were treated in the 1990s, even though these patients are now more likely to live into adulthood.

The authors note that this increase corresponds with the intensification of treatment for neuroblastoma patients during recent decades.

Risk Factors for Outcomes

Among the risk factors associated with each cardiac outcome, the investigators found a dose-response relationship between CAD risk and increasing mean exposure to heart radiation. The risk increased more than twofold for patients who received 15 to 35 Gy during treatment of their cancer and by almost sixfold for those who received 35 Gy or more.

High-dose cardiac radiation increased the risk for valvular heart disease almost 14-fold. The risk for hypertension was also increased, although to a much lesser degree.

Traditional cardiovascular risk factors were also "strongly associated" with an increased risk for nearly all cardiac outcomes that were assessed, the researchers note.

For example, both dyslipidemia and hypertension were associated with a significantly greater risk for CAD, although, somewhat surprisingly, diabetes was not.

Hypertension increased the risk for pericardial disease more than sixfold. High-dose heart radiation, high-dose anthracyclines, dyslipidemia, and hypertension all significantly increased the risk for arrhythmias.

Mulrooney suggested that the fact that modifiable CV risk factors still play an important role in cardiac outcomes for adult survivors of childhood cancer is a signal that physicians should intervene where they can to reduce the risk for toxicity.

The authors and editorialists have disclosed no relevant financial relationships.

BMJ. Published online January 15, 2020. Full text, Editorial

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