Increased Risk for CVD in Some Cancer Survivors

Roxanne Nelson, RN, BSN

February 27, 2018

ORLANDO — Cancer survivors are now living for so long that other health concerns become important, including cardiovascular disease (CVD).

Two new studies looking at CVD in survivors of colorectal cancer (CRC), and also as a consequence of treatment for Hodgkin's lymphoma, were presented here at the recent Cancer Survivorship Symposium (CSS) 2018: Advancing Care and Research.

Discussing both studies, Julia H Rowland, PhD, from the Smith Center for Healing and the Arts, Washington, DC, said, "The good news is that cancer survivors are living longer."

"The bad news is that they are living long enough to experience consequences of curative treatment," she continued.

"All of those putative risk factors seen in small print on the consent forms — we are now seeing them manifest in the clinic," she said.

CRC and CVD — Common Risk Factors?

One of the studies found a significant increase in the risk for CVD among CRC survivors 10 or more years after their diagnosis, as compared to the general population.

The study was presented by David Baraghoshi, MS, a graduate research assistant from the Huntsman Cancer Center, Salt Lake City, Utah, who explained that few studies have examined the relationship between CRC survivorship and long-term CVD risk.

"Colorectal cancer and cardiovascular disease share common risk factors, such as obesity, lack of physical activity, and smoking," he said. "Therefore, there is a need to explore the long-term risk of cardiovascular disease in this population."

Using the Utah Population Database, Baraghoshi and colleagues identified 1749 CRC survivors and 6480 controls from the general population who had at least 10 years of follow-up. Data on CVD diagnoses came from two of the largest healthcare providers in Utah.

Among 1749 CRC survivors who had survived for at least 10 years, 1001 (57.2%) were diagnosed with CVD 10 or more years after their cancer diagnosis. Compared with the general population, survivors had an increased risk for hypertension (hazard ratio [HR], 2.84; 95% confidence interval [CI],  2.59 - 3.11); diseases of the heart (HR, 2.66; 95% CI, 2.37 - 2.98); diseases of the arteries, arterioles, and capillaries (HR, 3.91; 95% CI, 3.33 - 4.58); diseases of the veins and lymphatics (HR, 2.58; 95% CI, 2.46 - 2.99); and cerebrovascular disease (HR, 2.98; 95% CI, 2.36 - 3.76).

"For both populations, the two most common diagnoses were for hypertension and diseases of the heart," said Baraghoshi.

For the more broadly defined CVDs, they found that the risk for diagnosis was twofold higher among the CRC survivors than the general population (38.5% vs 15%). There was also an increased risk for the more specific definitions, such as acute myocardial infarction (2.63% vs 1.31%) and transient cerebral ischemia (2.25% vs 0.62%).

"We also sought to identify demographic risk factors among CRC survivors," he said.

Risk factors associated with a higher risk for CVD include being male (HR, 1.16 vs female), being age 65 years or older (HR, 1.54), a body mass index of greater than 30 kg/m2 or obesity at baseline (HR, 1.25), being a smoker at baseline (HR, 1.53), and hypertension at baseline (HR, 1.60).

Those with one or more comorbidities at baseline also had a significantly higher risk for CVD (HR, 1.64).

"I would like to see further research in respect to physical activity and how we can help mitigate this risk," Baraghoshi said. 

No Link Between POI and CVD

Another study looked at female survivors of Hodgkin's lymphoma and found that CVD risk was not associated with primary ovarian insufficiency (POI), which can be a treatment-related side effect.

Lead author, Flora van Leeuwen, PhD, from the Netherlands Cancer Institute, Amsterdam, commented: "We've known for a long time that female survivors of Hodgkin lymphoma treated with alkylating chemotherapy and/or pelvic radiotherapy have an increased risk of primary ovarian insufficiency, which is defined as premature menopause before the age of 40 years."

She pointed out that among women with natural menopause, POI has been associated with increased risk for CVD. "Very few studies have examined the long-term effects of POI in cancer survival, and we have only found a few on the protective effect of early menopause against radiation-induced breast cancer," Van Leeuwen said.

Female survivors of Hodgkin's lymphoma already have a very high risk for CVD because of mediastinal radiotherapy and anthracycline treatment, she explained. In addition, women with premature natural menopause have been shown to have a 1.6-fold increased risk for overall CVD, a 1.7-fold increased risk for ischemic heart disease, and a possibly elevated risk for heart failure.

"Women with POL due to surgical menopause have shown inconsistent results. That is probably due to small numbers and limited follow-up," she added.

Using a large Dutch cohort of Hodgkin's lymphoma survivors, the researchers identified 918 women who were treated before age 41 years, between 1965 and 2000. Data on cancer treatment, menopausal status, and cardiovascular events were obtained from medical records, general practitioners, and patient questionnaires.

The median age at first Hodgkin's lymphoma treatment was 25 years, and the median follow-up was 24 years. A total of 299 (33%) women had developed POI, and the median age at menopause among women with POI was 34 years (interquartile range, 28 - 37 years).

The authors identified 463 cardiovascular events in 300 women, of whom 85 developed CVD after POI (valvular heart disease, n = 170; ischemic heart disease, n = 76; and heart failure, n = 54).

The median interval to first CVD event was 22 years, and the cumulative incidence was 56% at age 70 years. "It was very high due to the treatment they had received," said Van Leeuwen.

Overall, POI was not associated with subsequent CVD risk (HR, 0.85; 95% CI, 0.62 - 1.16) compared with a menopausal age of 40 years or older.

A short duration of intact ovarian function after cancer treatment (<5 years) did not increase CVD risk vs a long duration (≥25 years).

Within the cohort, 177 women had used hormone replacement therapy (HRT), and within this subgroup, 115 (65%) had POI (median duration of HRT use, 8.3 years). Survivors who used HRT for 5 or more years did not have a higher CVD risk than non-HRT users (HR, 1.02; 95% CI, 0.64 - 1.62).

The results were similar, van Leeuwen noted, for the different categories of CVD.

However, she did emphasize that only 40% of women used HRT. "It is not very popular in the Netherlands, even in this population, and long-term use is very rare," she said.

Van Leeuwen summarized that neither POI nor age at menopause appears to affect CVD risk in this population, implying that ovarian hormone deficiency may not explain increased CVD risk in naturally menopausal women.

"More research is needed to assess the shared risk factors for POI and CVD," she said. "But these results are very reassuring for our survivors."

Assessment, Discussions Needed

In her discussion of the Dutch paper, Rowland noted that the results were "provocative" because they don't explain the increased risk CVD risk in women undergoing natural menopause. "We need more research to understand the real risk," she said.

She also noted that because of cardiotoxic treatments, such as anthracyclines and mediastinal radiation, the population will have an increased risk for CVD. "Even though it was controlled for in this study, but still, could it be washing out the effect of POI?" she asked. "So perhaps it doesn't matter what the secondary hormonal effects may be."

In the study of CRC survivors, however, CVD risk was elevated across the board. "So the question is, What can be done to mitigate it?" Rowland said.

"There are many ways to reduce risk if we pay attention and act, such as if a patients has a high BMI or is a smoker, we can intervene," she said. "And potentially, we can change risk factors if we pay attention to the risk factors when patients come to clinic."

The take-home message is that healthy lifestyle behaviors need to be discussed. "Some data show that these important topics — diet, exercise, smoking assessment — are not being discussed," Rowland emphasized.

With an aging population, more people with comorbidities are going to be diagnosed with cancer. And this may potentially accelerate the problems in this population. "We need surveillance for recurrence and assessment of and care for longer-term/chronic effects of cancer and treatment," she concluded, as well as "evaluation for CVD and other late effects."

Baraghoshi , Rowland, and van Leeuwen have disclosed no relevant financial relationships.

Cancer Survivorship Symposium (CSS) 2018: Advancing Care and Research. Abstracts 113 and 114. Presented February 17, 2018.

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