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Expert Critique

FROM THE ASCO Reading Room

Elizabeth May Nichols, MD Assistant Professor, Clinical Director University of Maryland School of Medicine, Department of Radiation Oncology

A recent publication by Strongman, et al. in The Lancet provides additional support for the long-term cardiovascular risks experienced by cancer patients, including those with ovarian cancers. In this population-based cohort study, survivors of the 20 most common cancers in the U.K. were compared with age-matched controls without a cancer diagnosis. Patients were eligible for inclusion if they were 18 years or older and alive 12 months following their diagnosis of cancer (including ovarian, cervix, and uterine cancers). There were roughly 108,000 cancer patients matched to about 523,000 controls. Data from primary care practices, hospitals, and cancer registries were retrieved from the U.K. Clinical Practice Research Datalink system. Cardiovascular conditions analyzed included venous thromboembolism, heart failure, cardiomyopathy, arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease.

Risks of cardiovascular conditions were increased in cancer patients. Venous thromboembolism risks were elevated in 18 of 20 cancers analyzed, with an HR of 5.77 (4.51-7.38) for ovarian cancer. These risks persisted for more than 5 years after diagnosis. Risks of heart failure and cardiomyopathy were increased in 10 of 20 cancers, with an HR of 1.59 (1.19-2.12) for ovarian cancer. Increased risks of arrhythmia, with an HR of 1.13 (0.93-1.36); pericarditis, HR of 3.91 (1.87-8.19); coronary artery disease, HR of 1.25 (0.94-1.67); stroke, HR of 1.28 (0.98-1.68); and valvular heart disease, HR of 1.15 (0.78-1.69) were also seen in ovarian cancer.

The hazard ratios for both venous thromboembolism and heart failure were significantly higher in younger patients (younger than age 60) or patients with pre-existing cardiovascular conditions, although in general, increasing age was also correlated with long-term risk of cardiovascular conditions. When stratifying by treatment variables, receipt of chemotherapy for all 20 cancers tested (inclusive of ovarian cancer) seemed to have the most pronounced effect on risks of venous thromboembolism and heart failure/cardiomyopathy. Data also showed continued support for long-term risks seen up to 12 years following diagnosis.

These data continue to support the long-term health effects of cancer therapies with a particular focus on chemotherapy including those that are generally not felt to be "cardiotoxic." These data provide continued support for the importance of aggressive cardiovascular care of cancer patients and support the notion of cancer and/or chemotherapy as a "risk factor" for heart disease with strong consideration for this variable being integrated into risk algorithms. Prevention and early aggressive intervention continue to be key and provide a strong basis for the growing field of cardio-oncology.

Full Critique

One of the largest population-based cohort studies of its kind to date shows that adults who survive the most common site-specific cancers, including ovarian cancer, have a substantially increased medium- to long-term risk of one or more cardiovascular diseases.

Analysis of electronic health records from linked databases in the U.K. showed that 1 year after diagnosis, the risk of cardiovascular disease in 108,215 survivors increased by 50% or more following treatment for hematological, esophageal, lung, kidney, and ovarian cancers.

When compared with 523,541 matched controls without cancer from the general population, the incidence rate of venous thromboembolism per 1,000 patient-years (IR) was significantly increased (P<0.01) in 18 of the 20 most common cancer types.

As Krishnan Bhaskaran, PhD, of the London School of Hygiene & Tropical Medicine in the U.K., and colleagues note in their study online in , these represent more than 90% of all cancer diagnoses. In ovarian cancer survivors, the IR for venous thromboembolism was almost six times higher than in controls (16.7 vs 3.5; adjusted HR 5.77).

"Our findings show that more tailored strategies to minimize and manage cardiovascular risk are needed for people who survive cancer," the team wrote. "Prevention at early stages is a priority because the prognosis for cancer survivors diagnosed with cardiovascular disease is particularly poor."

Although 50% of cancer patients in high-income settings are expected to survive for at least 10 years, there is still concern about the risk of cardiovascular disease as a result of the of cancer treatment and shared risk factors, the researchers noted.

Following an exploratory analysis of survivor data by treatment type, they found that the elevated risk for cardiovascular disease in cancer patients was independent of treatment. The greatest risk, however, was observed in cancer survivors who had undergone chemotherapy -- indicating that chemotherapy may be the primary driver of cardiovascular disease in cancer survivors rather than shared risk factors such as body mass index and smoking.

The study also revealed an increased risk of heart failure or cardiomyopathy in 10 of 20 cancers. The adjusted hazard ratios (HRs) ranged from 1.72 in survivors of prostate cancer to 9.72 in those with pancreatic cancer.

In ovarian cancer survivors, the IR for heart failure or cardiomyopathy risk was 8.6 compared with 6.1 in matched controls (HR 1.67).

There was also an increased risk of arrhythmia, pericarditis, coronary artery disease, stroke, and valvular heart disease for multiple other cancers that persisted for 5 or more years. Once again, the analysis showed that ovarian cancer survivors were also at increased risk.

The risk of pericarditis was nearly four times higher in patients with ovarian cancer than in matched controls without cancer (3.91). Ovarian cancer survivors also had an increased risk for arrhythmia (HR 1.13), coronary artery disease (1.25), stroke (1.28), and valvular heart disease (1.15).

The HRs for heart failure or cardiomyopathy and venous thromboembolism were greater in younger patients and in those without previous cardiovascular disease. Still, absolute excess risks tended to increase along with patient age (2.1% per year in those 80 and older).

These findings are consistent with those from a in the U.S. of 36,232 cancer survivors in the Kaiser Permanente Southern California registry, the investigators noted.

The U.S. study showed a significantly increased risk of cardiovascular disease in survivors of breast and lung cancers, malignant melanoma, and non-Hodgkin lymphoma. No significant difference was found in survivors of nine other cancers, including ovarian cancer. Unexpectedly, a reduction in cardiovascular disease risk was seen in survivors of prostate cancer, the team said, adding that more staffed with oncologists, cardiologists, and specialist nurses will help to address this growing clinical problem.

Bhaskaran, et al. also emphasized the need to increase awareness among primary care physicians about the cardiovascular disease risks faced by many cancer survivors. For example, results from a in England showed that only one-fifth considered cancer in relation to cardiovascular health.

In an accompanying , Anne H. Blaes, MD, and Chetan Shenoy, MBBS, both of the University of Minnesota in Minneapolis, agreed that points to an increased risk of cardiovascular disease and death in the growing number of cancer survivors.

Although it has been known "for decades" that cancer treatments can elevate risk, newer therapies that cause can also contribute to cardiovascular outcomes, Blaes and Shenoy pointed out. In addition, cancer patients with underlying such as hypertension, advanced age, tobacco use, and diabetes have an increased risk for cardiovascular disease before they even begin cancer treatment.

Cardiovascular risk prediction tools that include cancer need to be developed, the commentators emphasized, adding that the study "clearly demonstrates" that clinical risk-assessment tools such as the Framingham risk score and Pooled Cohort Equations are not useful in the setting of cancer survival.

"The inclusion of cancer in these risk prediction tools, beyond the traditional risk factors for the prediction of cardiovascular disease risk, would add incremental value in the general population," Blaes and Shenoy wrote. "In the meantime, clinicians should account for cancer, and especially chemotherapy, as a risk factor for cardiovascular disease when discerning individual patient risks to guide preventive interventions."