Cardiovascular disease – The risk in treatment of prostate cancer

Prof James Ker expands on the risk of cardiovascular disease when treating prostate cancer.

Global burden of cancer

The Global Burden of Disease Cancer Collaboration described the cancer burden for 29 cancers in 195 countries¹. In 2017, there were 24,5 million incident cancer cases worldwide of which prostate cancer (PC) contributed 1,3 million incident cases. 

There has been improvement in cancer survival which has created a large and growing population of cancer survivors. About half of patients diagnosed with cancer will survive 10 years or longer². 

There are serious concerns that these cancer survivors could have increased medium-term to long-term risks for developing cardiovascular diseases (CVD) which are driven by cardio-toxic therapies for cancer, shared risk factors between cancer and cardiovascular diseases, and mechanisms related to cancer biology.

An UK electronic data-based study identified 108 215 cancer survivors compared to 523 541 matched controls without cancer². The results showed an increased risk of thromboembolism (obstruction of a blood vessel by a blood clot that has dislodged from another site in the circulation), heart failure and cardiomyopathy (disease of the heart muscle that makes it harder to pump blood to the rest of body), increasing in risk with advancing age and more pronounced in patients who received chemotherapy. These results were also seen in patients with PC.

Androgen-deprivation therapy (ADT)

ADT, also known as hormone therapy, is widely used for the treatment of PC because it can alleviate symptoms in patients with metastatic PC and it may have a survival benefit in some. 

Though, it does cause dyslipidaemia (abnormal level of blood lipids), insulin resistance with the metabolic syndrome, sarcopenic obesity (low muscle mass and high fat mass) and osteoporosis (porous bones)³. 

The risk of cardiovascular disease

The undesirable changes in lipid and glucose metabolism increase the risk of cardiovascular diseases. This risk seems to be the highest in elderly patients who had recent cardiovascular events.

In a large prospective cohort of more than 7 000 patients with localised PC, it was demonstrated that those without pre-existing cardiovascular disease had an increased risk to develop heart failure with a hazard ratio of 1,80 with time. This result implies a relative risk increase of 80% which can be as low as 40%, but can be as high as 132%. 

Those patients with pre-existing cardiovascular disease had an increased risk of arrhythmias (rate or rhythm problem of heartbeat)⁴. 

In a retrospective study from Australia, ADT was associated with an increased risk of CVD as well as increased risk of depression, diabetes mellitus and hyperlipidaemia (high cholesterol)⁵. 

In contrast, a population-based retrospective cohort study of 20 651 men with non-metastatic PC didn’t show any difference in any CVD or mortality between those receiving ADT and those men not receiving ADT⁶. 

Despite these discrepant observational reports, the overall clinical problem reflects an increase in cardiovascular risk factors and CVD in ADT. 

Which ADT is best?

GnRH agonists and antagonists are also used as ADT with the assumption that there could be less cardiovascular risks.

A post-hoc study of pooled data from six phase three studies on more than 2 000 PC men with pre-existing CVD, showed that the GnRH antagonist had the least cardiovascular deaths as compared to a GnRH agonist⁷.

A small phase two study comparing a GnRH agonist and antagonist in a randomised trial in 80 patients with advanced PC, showed less major cardiovascular and cerebrovascular events (strokes) as a secondary outcome when the GnRH antagonist was used⁸.

Certainly, many more studies of this nature need to be done to answer the question of which ADT is best.

SUMMARY AND SUGGESTIONS

1. Observational data has led to the concept that ADT used in PC therapy carries the risk of increased cardiovascular risk factors and CVD.
2. Increased risk of heart failure seems to be a particular problem.
3. Regular measurement of cardiovascular risk factors, such as lipid levels, glucose, blood pressure and weight in men with PC seems warranted.
4. Therapy to reduce the risk of CVD is important, including statin therapy, blood pressure therapy, metformin for metabolic syndrome, cessation of smoking and regular exercise, etc.
5. Depression needs therapy as well as its presence increases the risk of cardiovascular mortality by nature of its effect on systemic inflammation.
6. Individualising approach to patients with PC, weighing the advantages versus the possible harms of ADT and active measures to combat cardiovascular diseases is imperative.

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