Vascular Injury in Cancer Survivors

Abstract

With an increase in the number of patients surviving many years following succesful cancer treatment has come an improved understanding of the long-term effects of cancer therapy and its implications on future health. Premature cardiovascular disease is a significant cause of early morbidity and the leading non-cancer cause of death in this population. Chemotherapeutic agents and radiation therapy are known to be cardiotoxic. However, numerous vascular related toxicities have also been observed among cancer survivors, such as myocardial ischemia, transient ischemic attacks, and stroke, suggesting a degree of chronic endothelial injury and dysfunction leading to premature atherosclerotic disease. Vascular health in cancer survivors may be further compromised by metabolic abnormalities such as obesity, insulin resistance, and dyslipidemias which have also been reported following cancer therapy. Furthermore, some survivors experience gonadal dysfunction and loss of potentially protective sex steroids or undergo hormonal therapies that induce additional metabolic abnormalities. The effects of cancer therapies upon the endothelial monolayer have not been fully explored. An understanding of potential injury to and dysfunction of the circulatory system among cancer survivors is essential for identifying preventive strategies and therapeutic targets.

Improvements in cancer therapies and supportive care have led to an increasing number of individuals living many years following diagnosis and treatment of a malignancy. While rates vary by histology, clinical staging, and age at diagnosis, five-year overall survival for adults is nearly 65%[1] and even higher in pediatric oncology at 80%. In the United States, over 10 million individuals have previously been treated for a malignancy and are now long-term survivors.[2] With ongoing cancer research, new drug development, and an aging population, this number will continue to climb over the coming decades.

The long-term health effects of cancer treatments are significant. A majority of survivors report a chronic health condition related to their prior therapy and 25% of these are classified as severe and/or life-threatening.[3] Additionally, all-cause mortality is increased compared to the general population [4] and, at least, among childhood cancer survivors death from late adverse events overtakes death from recurrent disease at 30 years from diagnosis.[5]

Cardiac Toxicity

Cardiovascular disease is the leading non-cancer cause of death in this population and is frequently insidious in onset, presenting years following initial therapy. Nearly all chemotherapeutic agents (alkylators, anitmetabolites, vinca alkaloids, and immune modulators) have been reported to have some acute or chronic cardiotoxicity.[6,7] However, the anthracyclines (e.g. doxorubicin, daunorubicin), among the most widely used and effective anti-cancer agents, have been the most studied.[8–10] While directly contributing to improved survival rates, these agents have been associated with significant adverse cardiac outcomes. Among childhood cancer survivors, Steinherz et al. first reported a 23% incidence of echocardiographic abnormalities as late as 20 years following exposure.[11] Sixty-three percent of those treated with over 500 mg/m² had some decrease in fractional shortening 10 years later. These findings, subsequently confirmed by others, appear to be directly related to dose and time from exposure.[12,14] The pathophysiology of this injury is not fully understood but believed to be related to the generation of reactive oxygen free radicals that alter redox cycling on mitochondrial membranes causing uncoupling of the electron transport chain, resulting in myocyte apoptosis.[15]

Similarly, radiation therapy, an effective tool in the treatment of a variety of neoplasms, also has significant late cardiovascular effects. Constrictive pericarditis is a late manifestation of pericardial injury, myocardial fibrosis may lead to dysrhythmias, and endocardial fibrosis results in valvular thickening and calcifications.[16] Hancock et al. described premature coronary artery disease among survivors of adult and childhood Hodgkin lymphoma (HL) treated with mediastinal radiation therapy.[17,18] The relative risk of death from a myocardial infarction was 3.1 (95% CI 2.4–3.7), was not significantly reduced by limiting cardiac radiation exposure with subcarinal blocking, but increased with time from treatment. Specifically among childhood and adolescent cancer survivors (mean age at treatment 15.4 years and mean follow-up 10.3 years) the relative risk of death from myocardial infarction was even higher at 41.5 (95% CI 18.1–82.1).[17] Like anthracyclines, radiation-induced effects may be subclinical and present years following exposure. Risk factors include higher radiation doses, fractions in excess of 2.0 Gy/day, larger heart volumes within the irradiated field, younger age at treatment, and concomitant use of cardiotoxic chemotherapy. [19] Additionally, animal [20] and autopsy [21] studies have confirmed ionizing radiation as a risk factor for the development of coronary plaques, medial fibrosis, and adventitial thickening.

Cerebrovascular Toxicity

Cancer therapy also may significantly affect the cerebrovascular system and increase the incidence and risk of stroke. Two studies from the Childhood Cancer Survivor Study (CCSS) described the risk of stroke among survivors of HL, leukemia, and brain tumors. [22,23] Survivors of HL treated with mantle field radiation had a stroke rate of 109 per 100,000 person-years (95% CI 70.8–161 per 100,000 person-years) a median of 17.5 years from cancer diagnosis; over a 5-fold (95% CI 2.6–12.3) increased risk compared to a sibling control group. Mean age of stroke was 33 years (21–45 years). Similar rates and risks were identified among survivors of leukemia and brain tumors treated with cranial radiation. De Bruin et al. evaluated 2201 five-year HL survivors treated before age 51, also a median of 17.5 years from exposure. The cumulative incidence of stroke or transient ischemic attack (TIA) at 30 years was 7% (95% CI 5–8%) and 2.5 (95% CI 1.7–2.8) and 3.1 (95% 2.2–4.2) times higher, respectively, compared to the general population.[24] Most were from large-artery atherosclerosis (54%) or cardioembolic (24%) and 18% were fatal. On multivariate analysis mediastinal and neck radiation were significant risk factors as was hypertension, however, no significant association with hyperlipidemia, diabetes, smoking, or body weight was identified. Similar risks have been reported among survivors of head and neck cancers. Plummer et al. reviewed thirty years of prior controlled studies of patients treated for head and neck cancer and found the risk of stroke or TIA to be at least double in those previously treated with head and neck radiation.[25,26] Others have reported hazard ratios for ischemic stroke ranging from 1.5 to 1.7 among those treated with neck radiation compared to those not exposed to neck radiation, with a particular increase for those treated between the ages 35–54 years.[26,27] Interestingly, similar risks have not been identified among breast cancer survivors treated with radiation to the supraclavicular region and/or internal mammary nodes.[28–30] Jagsi et al. analyzed the records of 820 breast cancer patients of whom 222 underwent supraclavicular radiation (median follow up 6.8 years) and did not find any association between cerebrovascular events and neck radiation therapy.[28] A similar analysis performed by Hooning et al. compared 4836 breast cancer survivors (> 10 years from therapy) with a matched population and also found no increased risk of stroke.[29]

Radiation to the carotid arteries is a significant contributing factor to premature cerbrovascular disease. In the de Bruin study 17% of survivors had greater than 50% carotid artery stenosis and among survivors treated in childhood, carotid artery intimamedia thickness (IMT) was significantly increased compared to healthy controls following radiation doses as low as 1,800 cGY (p<0.001). [31] Eighteen percent of survivors (mean age 27.5 years, range 14–47) had evidence of carotid plaque compared to 2% of controls. In a focused screening assessment of patients treated with cervical radiation at doses > 5500 cGy (n=40, mean age 68 years) for a head and neck cancer, 40% had >50% stenosis by carotid artery duplex imaging.[32] Similarly, in a study of survivors of nasopharyngeal carcinoma 30% had a > 50% stenosis following radiation exposure. Carotid and/or cerebral vascular plaques are a contributing factor to premature cerebral vascular accidents among cancer survivors.

Circulatory System

While cancer survivors are clearly at risk for a variety of vascular-related abnormalities, the direct effects upon the circulatory system and vascular structures are not well understood. Research has focused on the end-organ toxicity associated with cancer therapy but few have investigated the vascular effects that may present sub-acutely prior to organ dysfunction and clinical presentation. Table 1 includes a brief summary of recent studies of vascular function in cancer survivors.

Table 1:

Reported Vascular Studies Among Cancer Survivors

Vascular Function Studies	Study type	Study population	Pertinent vascular findings
Impaired vascular function in asymptomatic young adult survivors of Hodgkin lymphoma following mediastinal radiation[64]	Cross-sectional	N=26 Hodgkin lymphoma survivors Mean age=23.3 +/− 5.0 50% male	Impaired endothelial function, decreased peripheral arterial tonometry hyperemia ratios (PAT-HR) 1.67 +/− 0.39 VS 2.03 +/− 0.37 (P<0.01), among survivors treated with RT compared to controls
Long-term causespecific mortality among survivors of childhood cancer[65]	Retrospective cohort British Childhood Cancer Survivor Study	N=17,981 5-year survivors of childhood cancer diagnosed 1940–1991	Increased death from all causes SMR for circulatory disease death 10.7 (95% CI 7.8–14.6). Increasing AER with time from diagnosis. 25% of all excess deaths beyond 45 years attributed to circulatory causes
Acute arterial hemorrhage following radiotherapy of oropharyngeal squamous cell carcinoma[66]	Case series	N=10 Squamous cell carcinoma survivors Mean age 56.5 +/− 3.3 months from primary or adjuvant treatment, chemotherapy and/or radiation 90% male	Acute carotid (common, internal, and external) artery hemorrhage Fatal in 4 of 10
Relation of coronary artery calcium score to premature coronary artery disease in survivors >15 years of Hodgkin’s lymphoma[67]	Cross-sectional	N=47 Survivors of Hodgkin lymphoma, treated with mediastinal radiation Mean age 50 +/− 7 34% male	Total coronary artery calcium volume score higher in survivors with verified coronary disease compared to those without (439 vs. 68, p=0.022). Ten survivors with scores >200.
Cerebrovascular disease in childhood cancer survivors: A Children’s Oncology Group Report[68]	Critical review of the literature	Irradiated childhood cancer survivors (acute lymphoblastic leukemia, Hodgkin lymphoma, head & neck tumors, brain tumors.	Radiation-induced cerebrovascular disease: steno-occlusive disease, moyamoya, aneurysm, mineralizing microangiopathy, vascular malformations, stroke-like migraines.
Stoke as a late treatment effect of Hodgkin’s Disease: a report from the Childhood Cancer Survivor Study[23]	Retrospective cohort Childhood Cancer Survivor Study	N=1,926 Hodgkin lymphoma survivors Mean age=33.8 +/− 7.1 54.3% male	Relative risk of stroke 4.3 (95% CI 2.0–9.3) among survivors and an incidence of 109.8 per 100,000 personyears (95% CI 70.8161.1 per 100,000 person-years).
Late-occurring stroke among long-term survivors of childhood leukemia and brain tumor: a report from the Childhood Cancer Survivor Study[22]	Retrospective cohort Childhood Cancer Survivor Study	N=4,828 Survivors of childhood leukemia N=1,871 Survivors of childhood brain tumors Mean age=24.3 +/− 7.2 years (leukemia); 25.8 +/−7.9 years (brain tumor) 52.8% male (leukemia) 55.2% male (brain)	Relative risk of stroke among leukemia survivors 6.4 (95% CI 3.0–13.8) and 29.0 (95% CI 13.8–60.6) among brain tumor survivors, compared to a sibling control group. Direct dose response with cranial radiation exposure
Premature carotid artery disease in pediatric cancer survivors treated with neck irradiation[31]	Cross-sectional	N=30 History of neck irradiation Mean age=27.5 +/− 10.7 63% male	Carotid plaque present in 18% of survivors vs. 2% of controls (p<0.001) Intima-media thickness (IMT) 0.46mm +/−0.12 in survivors vs. 0.41mm +/−0.06 in controls (p<0.001)
Cardiovascular risk in long-term survivors of testicular cancer[69]	Cross-sectional	N=24 Cisplatin-based chemotherapy treated (CBCT) testicular cancer survivors compared to chemotherapy naïve (CN) (N=15) testicular cancer survivors Mean age=41.4 +/− 10.0 years	Brachial artery flow mediated dilation decreased in CBCT survivors (5.6% vs. 8.8%, p=0.05). Increased soluble ICAM in CBCT survivors compared to CN (234.8 vs. 198.9, p=0.04)
Endothelial function in young adult survivors of childhood acute lymphoblastic leukemia[49]	Cross-sectional	N=75 Survivors of childhood acute lymphoblastic leukemia (ALL) Mean age=30.2+/7.1 years 41.3% male	Decreased brachial artery flow mediated dilation among ALL survivors treated with chemotherapy only (6.5+/−2.6%) and chemotherapy+ cranial radiation (7.1 +/−2.6%) compared to healthy controls (9.5 +/−2.9%).
Long-term complications of platinum-based chemotherapy in testicular cancer survivors[70]	Cross-sectional	N=143 Testicular cancer survivors Mean age=41.2 (17–74)	Rate of hyperlipidemia in both platinum and non-platinum treated survivors higher than national estimates (p=0.05 and 0.03, respectively). Rate of coronary artery disease 11.1% in platinum + radiation treated, 4.3% in platinum only.
Long-term risk of cardiovascular disease in 10-year survivors of breast cancer[29]	Retrospective cohort Dutch Late Effects Breast Cancer cohort	N=4,414 10-year breast cancer survivors treated between 1970–1986	Radiation to left or right internal mammary chain, 1970–1979, significantly associated with myocardial infarction (MI) and congestive heart failure (CHF) compared to no radiation. Among patients receiving radiation after 1979, risk for MI declined, risk of CHF and valvular disease increased.
Decreased risk of stroke among 10-year survivors of breast cancer[71]	Retrospective cohort Dutch Late Effects Breast Cancer cohort	N=4,414 10-year breast cancer survivors treated between 1970–1986	Standardized incidence ratio (SIR) for stroke 0.8 (95% CI 0.6–0.9) and transient ischemic attack 0.8 (95% CI 0.7–1.0). Significantly increased risk of stroke among women treated with hormonal therapy 1.9 (95% CI 1.3–2.8).
Stroke rates and risk factors in patient’s treated with radiation therapy for early-stage breast cancer[28]	Cross-sectional	N=820 Early-stage breast cancer survivors	Standardize incidence ratio of stroke/CVA 1.7 (95% CI 1.003–2.06). Supraclavicular radiation exposure significant on univariate analysis, not on multivariate. Tamoxifen exposure not significant alone (p=0.19) but combined with baseline hypertension (p<0.0001).
Utero-ovarian ultrasonographic and Doppler flow analyses in female childhood cancer survivors with regular menstruation and normal circulating follicle-stimulating hormone levels[72]	Cross-sectional	Survivors: Hodgkin lymphoma (N=9) Non-Hodgkin lymphoma (N=5) ALL (n=11) Wilm’s Tumor (N=3) Mean age=19.2 +/−2.7	Increased resistance in uterine and intraovarian arteries in nonovulatory survivors compared to healthy controls (p<0.001)
Cumulative incidence of radiation-induced cavernomas in longterm survivors of medulloblastoma[73]	Retrospective cohort	N=59 Survivors of childhood medulloblastoma	26 cavernomas in 18 survivors (31%). Cumulative incidence 5.6, 14, and 43% at 3, 5, and 10 years.
Valvular dysfunction and carotid, subclavian, and coronary artery disease in survivors of Hodgkin lymphoma treated with radiation therapy[16]	Retrospective cohort	N=415 Hodgkin lymphoma survivors 60% male	7.4% developed carotid and/or subclavian artery disease at a median of 17 years from treatment. Observed-to-expected ratio for coronary bypass surgery or percutaneous intervention 1.6 (95% CI 0.98–2.3).
Long-term survivors of childhood brain cancer have an increased risk for cardiovascular disease[74]	Cross-sectional	N=26 Survivors of childhood brain cancer Mean age 25.8 +/− 4.6 54% male	IMT increased in carotid bulb of cancer survivors compared to healthy controls (0.63 mm +/− 1.6 vs. 0.53 mm +/− 1.1, p=0.02).
Radiation therapy impairs endotheliumdependent vasodilation in humans[75]	Cross-sectional	N=16 Irradiated breast cancer survivors Mean age 58 +/− 10 years	Significantly impaired endothelium-dependent vasodilatation compared to contralateral, nonirradiated arteries (−0.4 +/− 0.4% vs. 3.2 +/− 0.8%) and compared to healthy controls (0.4 +/− 0.4 vs. 2.5 +/− 0.6%), p<0.001.
Preferential impairment of nitric oxide-mediated endotheliumdependent relaxation in human cervical arteries after irradiation[76]	Cross-sectional	N=17 Irradiated head & neck cancer survivors Mean age=60.5 +/− 2.2 years	Impaired endotheliumdependent relaxation to acetylcholine (33 +/− 6% vs. 100 +/− 4%, p<0.001) and A23187 (65 +/− 8% vs. 98 +/− 4%, p<0.01) compared to non-irradiated arteries. No expression of endothelial nitric oxide synthase on irradiated arteries.
Late cranial MRI after cranial irradiation in survivors of childhood cancer[77]	Cross-sectional	N=43 Survivors of childhood cancer	White matter changes, low intensity foci (calcifications or old hemorrhage), and heterogeneous intensity foci of old hemorrhages observed only among irradiated survivors.
Micoralbuminuria, decreased fibrinolysis, and fat inflammation as early signs of atherosclerosis in long-term survivors of disseminated testicular cancer[78]	Cross-sectional	N=90 Chemotherapy treated testicular cancer survivors Mean age 37 (20–65)	Statistically higher levels of fibrinogen, high-sensitivity C-reactive protein, von Willebrand factor, plasminogen activator inhibitor type 1, and tissue plasminogen activator compared to healthy male controls.
Are Hodgkin and nonHodgkin patients at a greater risk of atherosclerosis? A follow-up of 3 years[79]	Prospective cohort	N=96 Hodgkin and nonHodgkin lymphoma survivors Mean age=59.3 +/− 6.5 50% male	Decreased intimamedia thickness over three years (common carotid 1.14 +/−0.17 to 0.8 +/− 0.20, p<0.05). FMD at follow-up 2.56 +/− 1.7.
Is radiation a risk factor for atherosclerosis? An echo-color Doppler study on Hodgkin and non-Hodgkin patients[80]	Cross-sectional	N=42 20 Hodgkin; 22 non-Hodgkin survivors Mean age=58.1 +/− 7 52% male	Increased intima-media thickness in irradiated carotid vessels compared to nonirradiated controls.

The response-to-injury hypothesis of atherosclerosis proposed by Ross [33] would suggest that an acute inflammatory response progresses to a chronic inflammatory state and atherosclerotic plaque formation. Chemotherapy and/or radiation therapy in the course of cancer treatment may initiate a vascular injury, induce an inflammatory response, stimulate a hemostatic vascular surface, and lead to endothelial dysfunction, atherogenesis, and eventual progression to overt vascular and end organ dysfunction. (Figure 1) In addition to this endothelial process, radiation may also initiate perivascular fibrosis within the vascular adventitial layer, potentially leading to reduced vessel compliance with or without the concurrent development of atherosclerosis.[34] This review focuses on the endothelial effects of cancer therapy. Many of the end-organ toxicities described in this population may be the result of atherosclerotic disease with sub-clinical progression over many years. Additionally, the loss of potentially protective sex steroids, poor physical function, and metabolic abnormalities induced by prior cancer therapy may further impair vascular health in this population.

Figure 1:

Vascular Toxicity Model in Cancer Survivors

Endothelium

Simultaneous with improvements in cancer survival rates and an understanding of the long-term effects of cancer therapy, there have been considerable advances in vascular biology and recognition of the role of the endothelium to vascular health. Previously believed to be an inert cellular layer, this “organ” is now appreciated to be highly metabolic and physiologically active. A well regulated monocellular layer covering an area of 4,000–7,000 m² and accounting for 1kg of average adult human weight [35], the endothelium plays a central role in the tightly regulated balance between vasodilation and constriction, anticoagulation and thrombosis, and angiogenesis and cellular inhibition. Sheer stress induces release of endothelial nitric oxide synthase (eNOS) which catalyzes the oxidation of L-arginine to nitric oxide (NO) and citrulline. NO, the most potent known endogenous vasodilator, stimulates smooth muscle guanylate cyclase to produce cyclic guanosine 5’-monophosphate (cGMP) resulting in vasodilation. [36] It also acts synergistically with prostacyclin to inhibit platelet aggregation and adherence to the endothelium. Finally, NO inhibits myointimal hyperplasia by preventing smooth muscle cell migration into the intimal layer. [37] Injury to this system may occur from a variety of insults and ultimately lead to endothelial dysfunction, atherogenesis, and vascular disease.

Early autopsy studies identified histologic changes suggestive of early atherosclerosis in the coronary arteries of irradiated survivors of HL who experienced a myocardial infarction. The intimal layer was thickened by large fibroblasts, collagen deposition, endothelial cells, and histiocytes resulting in luminal narrowing and media thickening with adventitial scarring. [38,39] Pathologic changes vary by size and type of vessel involved with the microvasculature being more radiosensitive than the larger vessels. Endothelial injury following radiation has been observed by electron microscopy with swelling of the cytoplasm, formation of pseudopodia leading to luminal narrowing, and detachment of the endothelial cells from the basal lamina. [40] Loss of the capillary network may lead to eventual tissue ischemia and contribute to the cardiac fibrosis, arrhythmias, and myopathies seen later in life.[41] Smaller sized arteries (< 100 μm) are prone to adventitial fibrosis, medium sized vessels (100 – 500 μm) develop intimal fibrosis with collagen and fibroblast deposition, and the larger vessels (>500 μm) may be somewhat protected by a thicker wall and wider lumen but also show evidence of myointimal proliferation and, rarely, spontaneous rupture.[40] Lipid laden macrophages (foam cells) have been observed in each of these three vessel sizes. Spontaneous agerelated atherosclerotic plaques might be expected in larger vessels, but their presence in small and medium sized vessels is suggestive of radiation injury. Additionally, the anatomical location of coronary plaques following chest radiation is clearly influenced by the prior radiation field, with lesions preferentially affecting the coronary ostia and, potentially more lethal, proximal coronary tree while sparing the distal distribution frequently outside the therapeutic window. [21] The circulatory system is particularly vulnerable to radiation injury.

Acute release of endogenous prostaglandins and thromboxanes generates an inflammatory state with altered vascular dilatation and permeability. Macrophage and monocyte activation leads to cytokine release, such as tumor necrosis factor (TNF), interleukins (IL-1, IL-6, IL-8), and moncyte chemotactic factor.[42] The interaction of these chemokines leads to ongoing inflammation, fibroblast proliferation, and eventual adventitial fibrosis. Similar effects have been reported within the myocardium with acute neutrophil infiltration leading to pericardial and myocardial fibrosis.[42] In addition to cytokine release, gene expression of procollagen I and III was found to be upregulated in a mouse model 12 and 3 months, respectively, following radiation exposure with release of TGF-β1 and IL-1β preceding procollagen mRNA expression.[43]

This inflamed state may lead to hemostatic dysfunction, thrombus formation, and growth of artheromatous plaques. Von Willebrand factor is released from injured endothelial cells and production of thrombomodulin and adenosine diphophatase is decreased leading to a pro-thrombotic state on the vessel wall.[34] Once initiated selectin and adhesion molecule expression is increased on the endothelial surface, inducing leukocyte trafficking, migration, and atheromatous plaque progression. Expression of vascular cell adhesion molecule −1 (VCAM-1), a major molecule responsible for atherosclerosis [44], is elevated on the endothelial surface overlying growing atheromas and is responsible for monocyte and T-lymphocyte recruitment into the vessel intima and growing plaque.[45]

Endothelial activation following radiation exposure leads to activation of the nuclear factor-kappa B (NF-_KB) transcription signaling pathway. Studying gene expression networks related to cardiovascular disease Halle et al. compared arterial biopsies from irradiated vessels to non-irradiated vessels within the same patient.[46] Thirteen genes were synchronously expressed in all patients with a majority activated in the NF-kB pathway, suggesting chronic inflammation years following radiation exposure. Activation was further confirmed by immunhistochemistry and immunofluorescence studies.

Early endothelial dysfunction manifested by chronic inflammation and decreased vascular compliance has been measured in a number of diverse populations and found to be predictive of subsequent atherosclerosis.[47,48] However, few studies have conducted vascular functional measures in cancer survivors. Studying 75 survivors of acute lymphoblastic leukemia, Dengel et al. found significantly decreased endothelialdependent flow mediated dilation (FMD) among survivors treated with chemotherapy only (6.5%) and those treated with chemotherapy plus cranial radiation (7.1%) compared to controls (9.5%) (p<0.001).[49] In a pilot study, Chow et al. also found decreased arterial reactivity among a heterogeneous group of childhood cancer survivors exposed to ≥ 300 mg/m2 of anthracyclines.[50] In ongoing studies, our data also suggest chronic vascular inflammation and endothelial activation. We identified increased high sensitivity C-reactive protein (hsCRP), total cholesterol, lipoprotein (a), and fibrinogen levels among survivors of HL (median 12.3 years from diagnosis) compared to participants in the Coronary Artery Risk Development in Young Adults (CARDIA) study, as well as an elevation in circulating endothelial cells (CECs) compared to healthy controls, suggestive of chronic inflammation.[51] The previously overlooked effects of cancer therapy on the pervasive endothelial layer may hold a key to better understanding the pathophysiology of adverse vascular outcomes in cancer survivors.

Metabolic Abnormalities

In addition to the direct vascular toxicity of cancer therapy, interactions with chronic metabolic conditions experienced by cancer survivors may further contribute to premature circulatory disease. Recent studies have suggested an increased prevalence of and risk for the metabolic syndrome – defined by hypertension, obesity, insulin resistance, and dyslipidemias – among cancer survivors, adding to the underlying cardiovascular risk in this population.[52] Contributing factors likely include hormonal deficiencies such as hypothyroidism, growth hormone deficiency, and gonadal failure.[53] Childhood cancer survivors treated with total body and/or abdominal radiation are at particularly high risk [54] as are survivors of hematopoietic stem cell transplant (HSCT).[55,56] Analyzing leukemia survivors, Chow et al.[57] recently compared 48 off-therapy patients in remission with 26 survivors treated with total body irradiation and HSCT. Twenty-three percent of HSCT survivors met the criteria for metabolic syndrome compared to 4.2% of the non-transplanted survivors (p=0.02). Additionally, HSCT survivors had increased levels of hsCRP and leptin levels and decreased adiponectin, suggestive of underlying inflammation and increased visceral fat. However, among 118 survivors of childhood hematologic malignancies not treated with transplant and only 11% exposed to cranial radiation, we found evidence of significantly increased insulin resistance and decreased vascular compliance, mean age of evaluation 14.8 years (9.8–18.0), even after adjustment for body mass index.[58,59] Dyslipidemias and insulin resistance may be present independent of increased body mass index, suggesting the metabolic phenotype may be unique in this population.[60] Hormonal effects of cancer therapy will likely increase the number of survivors with vascular abnormalities given that the treatment of breast and prostate cancers often involve hormone-modifying agents that have been linked to features of the metabolic syndrome. Androgen suppression in prostate cancer is associated with dyslipidemia and an increased risk of cardiovascular disease and insulin resistance. Anti-estrogen therapy, particularly aromotase inhibitors, used in breast cancer therapy can also significantly alter lipid profiles and cardiovascular risk. Furthermore, among ovarian cancer survivors the risk for developing the metabolic syndrome is 1.7 (95% CI 1.1–2.8) fold higher compared to the general population.[61] The long-term vascular effects of hormone modifying cancer therapies will require further investigation.

Conclusion

Cancer therapies have significant long-term health consequences beyond merely cure of the underlying malignancy, and while many of the end-organ toxicities have been broadly investigated, the mechanisms of these adverse late outcomes have yet to be fully understood. Chemotherapy and radiation therapy induce vascular inflammation and endothelial injury that may be the unifying factor to explain many of the cardiac and cerebral toxicities experienced by cancer survivors. Inflammatory states have been associated with atherosclerotic disease; however, it is unclear if the current cardiovascular risk stratification scores (i.e. Framingham) used in other populations can also be applied to cancer survivors, particularly those treated at a young age. Cardiovascular risk measures should be specifically studied in cancer survivors and/or new scores developed which account for the chemotherapy and radiation exposures in this unique population.

Advances in both cardiovascular and cancer research have suggested that the two disease processes may be more alike than previously assumed. In fact, toxic metabolites such as tobacco and dietary exposures, clonal proliferation, cellular dysregulation, and chronic inflammation are just some of the common pathways that have been implicated in the pathogenesis of both atherosclerosis and cancer.[62,63] It may not be as uncommon as once thought that survivors of a malignancy are prone to development of vascular disease. Future research should investigate these common mechanisms with the goal of changing treatment regimens to prevent the initial injury and developing therapeutic interventions to treat late vascular toxicity and guide patient counseling.