Peripheral Arterial Disease and Cancer

An Overlooked Link

Peripheral arterial disease (PAD) affects >200 million people worldwide with a 12% age-adjusted prevalence, typically due to atherosclerotic disease.¹ The incidence increases with age with <0.4 per 1000 in men aged 35 to 45 with the disease, increasing to 6 per 1000 men aged >65 years of age, with >20% of patients >80 years with the disease.^1,2 The incidence is thought to be rising due to increased life expectancy and increased prevalence in diabetes mellitus (DM), obesity, and sedentary lifestyle.^1,3 The significance of the disease is that it informs of atherosclerosis in other vascular beds and patients are at increased risk of heart attack and stroke, and vascular-related deaths.⁴ In fact, patients with PAD are four times more likely to die within 10 years than patients without PAD.⁵ Moreover, the 15-year accrued survival rate in patients with PAD is 22% vs 78% in patients without PAD.^6,7 Most patients with PAD are asymptomatic; however, 10-20% of patients will have intermittent claudication and 1-2% will have the terminal form of PAD, critical limb ischemia (CLI), with rest pain, and major or minor tissue loss with risk for amputation.⁸ 

Because of landmark trials such as the PARTNERS study (PAD Awareness, Risk, and Treatment: New Resources for Survival) and REACH registry (REduction of Atherothrombosis for Continued Health), and warnings from groups such as the TransAtlantic Inter-Society Consensus (TASC) Group, the American College of Cardiology (ACC), and the Vascular Society of Medicine (VSM), there has been increased awareness of PAD and its consequences.^9,10 This meant improved attention was paid to risk factor modification with smoking cessation programs, DM and hypertension control, and initiation of statin and antiplatelet therapy. 

With clinical awareness and risk factor management, the CAVASIC study (CArdioVAScular disease in Intermittent Claudication) was performed.¹¹ This was a case-control study with prospective follow-up to identify cardiovascular risk.Included were 255 patients with intermittent claudication at two centers in Austria. Patients with malignancy were excluded from the study. The investigators noted that compared with 8 deaths in the first 5 years of follow-up and 13 deaths in the entire follow-up period from vascular causes, there were 10 deaths and 20 deaths from cancer causes, respectively.¹¹ Their conclusion was that given changes in practices with risk factor control, as compared with earlier studies and observations, patients may now be dying more frequently from cancer than from cardiovascular events.

In another study with 6172 prospectively followed patients, patients with vascular disease had a 19% higher incidence of cancer, compared with patients without vascular disease (standardized incidence ratios=1.19; 95% confidence interval, 1.10-1.29).¹² Interestingly, another study with 109 claudicants demonstrated that there was a relative increase in cancer incidence and deaths when secondary prevention (risk factor modification) was introduced.¹³

A case control study with 223 patients with intermittent claudication treated with antiplatelet agents and for all risk factors present, demonstrated not only that the incidence of vascular-related death was higher with PAD patients compared with non-PAD patients (1.50 vs 0.93, 100 patient-yr [P<.05]), but that the incidence of cancer-related death was higher with PAD patients than non-PAD patients (1.74 vs 0.84, 100 patient-yr; [P<.05]).¹⁴ 

The link between PAD and cancer is based on common risk factors.^12–15 Cancers such as lung, head and neck, and bladder cancer have risk factors of smoking and advanced age, and gastroenterology cancers have risk factors of obesity, sedentary lifestyle, hyperlipidemia, smoking, and advanced age.¹⁶ These risk factors are reflected in those of PAD (advanced age, smoking, DM, hypertension, hyperlipidemia, obesity, and sedentary lifestyle). In addition, common genetic mutations such as those seen with clonal hematopoiesis have demonstrated an increased risk of cancer, poorer prognosis with cancer, and increased risk of myocardial infarction (MI), and stroke.  

Therefore, while there is improved awareness of vascular-related events and vascular-related deaths in PAD patients, the link between PAD and cancer should not be overlooked. This link may necessitate heightened awareness and cancer surveillance in the PAD population, given their increased incidence of cancer and cancer-related deaths. Looking ahead, we may wonder how to best care for the PAD patient once they are diagnosed with cancer, as the impact of medically and procedurally optimizing the PAD patient in the cancer setting has yet to be determined. 

Disclosure: Dr. Bryce reports no financial relationships or conflicts of interest regarding the content herein.

Manuscript submitted February 21, 2020, final version accepted February 21, 2020.

Address for correspondence: Yolanda Bryce, MD, Memorial Sloan Kettering Cancer Center, 1275 York Avenue, New York, NY 10065. Email: brycey@mskcc.org

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