Reports of a Possible Causal Link between Brain, Head, and Neck Tumors and Radiation Exposure during Coronary Interventional Procedures: A Sobering Look at the Data

Ryan R. Reeves, MD and Ehtisham Mahmud, MD

1Division of Cardiovascular Medicine, Sulpizio Cardiovascular Center, University of California, San Diego, La Jolla, CA, USA

Introduction

Radiation exposure is a hazard for patients and physicians during fluoroscopically-guided invasive cardiovascular procedures. Patients are at risk for radiation-induced skin injuries and there are measurable risks of exposure to the primary beam of any imaging modality that uses ionizing radiation. Concerns regarding chronic low dose radiation exposure are supported by large studies that focus on radiation exposure and conclude that an increased risk of malignancies does indeed exist[1]. The Life Span Study followed over 100,000 survivors of the Hiroshima and Nagasaki atomic bombs for nearly four decades starting in 1958;when focusing on nervous system malignancies,7% of the cases were felt to be in excess with an attributable fraction of 13% to exposure of four Gy or less [2]. Although the risk of chronic scatter radiation exposure to procedural operators is recognized as a potential hazard, it has not been well quantified especially as related to the head and neck region [3–5]. Recently, contemporary case reports and well-designed microbiological and biological studies have highlighted the potential risk of radiation effects to the head and neck of operators and the potential for the development of malignant tumors. Despite the lack of definitive evidence proving an association, these concerns have sparked a movement towards further decreasing operator radiation exposure.

Table 1 A Summary of the Occupational Exposure Limits from the 2007 and 2011 Recommendations from the International Commission on Radiological Protection [Refs. 2, 3].

Operator Exposure

Operators of invasive cardiovascular procedures are exposed to some of the highest levels of radiation in the medical field [6, 7]. The median individual doses for seven experienced invasive cardiologists ranged from 0.43 to 2.85 mSv when measured outside of the lead apron over 50 four-week periods[8]. Based on the findings of this four-year study,the potential yearly exposure for unprotected areas is over 37 mSv. During the study period, three of the seven operators exceeded the recommended dose limits established by the International Commission on Radiological Protection (Table 1). These limits are suggested to decrease the risk of both deterministic and stochastic effects related to occupational radiation exposure by using historical and contemporary biological and physical data and are periodically updated [9].

Increasingly complex procedures and higher procedural volumes have further increased patient and operator radiation exposure [10, 11].Measured radiation doses are significantly higher as the complexity of coronary procedures progresses from diagnostic angiography to percutaneous coronary intervention (PCI) and ultimately to complex and higher risk PCI procedures like recanalization of chronic total occlusions from the retrograde approach [12]. Patient preference and a lower risk of bleeding have resulted in an increase in radial access for coronary procedures. A recent meta-analysis concluded that a small but signifi-cant further increase in fluoroscopy time and dose area product exists for the radial approach compared to transfemoral access during diagnostic coronary angiography and PCI procedures [13].Significant operator exposure is not limited to coronary procedures; effective dose, as well as localized eye and hand doses, are significantly higher during peripheral procedures than diagnostic coronary angiography [7]. Contemporary procedures,such as transcatheter aortic valve replacement and endovascular aortic repair, require significant radiation doses and potentially pose the same hazards as invasive coronary angiography [14–16].

Exposure to the head and neck region is not negligible and has been measured during endovascular and cardiac procedures. Ingwersen et al. estimated the average eye dose per procedure to be 19±36 microSv across both cardiac and peripheral procedures [7]. It was estimated that a busy operator performing mostly peripheral procedures has the potential for annual exposure of 26.2 mSv at the eye level. When evaluating endovascular aortic repair, the mean exposure to the head of the primary operator was 53 microSv (range 24–130) per procedure [17]. The mean exposure to the left side of the head of eleven invasive cardiologists in The Brain Radiation Exposure and Attenuation During Invasive Cardiac Procedures (BRAIN) study was 16.5±3.9 microSv per case [18], and significantly higher than at other cranial locations (Figure 1).This was despite the fact that the catheterization laboratories in the BRAIN study included modern exposure reduction technologies including, ceilingsuspended lead shields with flexible lamellae, lead aprons suspended from the table-side, and large viewing monitors.

Figure 1 The Mean Radiation Exposures of Eleven Invasive Cardiologists Measured across the Cranium.Cranial radiation exposure increases when measured at points moving from right to left (outside left vs. outside center,P<0.075; both outside left and outside center vs. outside right, P<0.001) across the forehead and is significantly higher than ambient controls located outside of the catheterization laboratory (the mean of the outside locations vs. Ambient Controls, P=0.006). Reproduced with permission from Reeves et al. JACC Cardiovasc Intv, 2015 [18].

Biological Effects of Chronic Low Dose Exposure

Exposure to ionizing radiation has the potential to cause a myriad of harmful effects. One of the earliest experimenters was Clarence Dally, an assistant to Thomas Edison. He suffered from diffuse skin and vascular injuries resulting in multiple amputations and surgeries, which prompted to Edison to declare,“Don’t talk to me about X-rays. I am afraid of them.I stopped experimenting with them” [19]. The potential for harmful effects of chronic, low dose exposure to the scatter beam of medical radiation is not without consequences (Table 2) and continues to be an area of research. The stochastic effect of radiation exposure suggests that the risk of a DNA mutation resulting in a malignancy increases with dose and may occur with minimal exposure, while the severity of the outcome is not related to dose.

On a microbiological level, exposure to ionizing radiation may result in altered redox pathways and induce DNA double strand breaks that are usually,but not always, repaired [20, 31]. Damaged DNA and chromosomal abnormalities may be detected with micronuclei assays (MN) and are considered a biological dosimeter [32, 33]. By comparing interventional and clinical cardiologists, Andreassi et al.determined that the group performing fluoroscopically guided invasive procedures had higher MN quantities [23]. Furthermore, in the interventional group, years of practice correlated with elevated MN values, while the results for the clinical cardiologists were not associated with duration of practice.Subsequently, using similar cohorts, MN and genetic analysis of common DNA repair genes were performed; comparably, MN values were higher among the interventional cardiologists [24]. Operator exposure for greater than ten years and the presence of high risk alleles in the DNA repair genes were associated with higher MN frequency and determined to significantly influence chromosomal DNA damage.The shortening of leukocyte telomeres is a biological marker of aging and chromosomal volatility and has been demonstrated in workers tasked with the Chernobyl clean up over the last few decades [34,35]. Measuring telomere length in exposed and unexposed medical workers revealed significantlyshorter strands in the exposed group and an inverse correlation was detected based on both effective dose and a radiological risk score [25].

Table 2 Microbiological, Subclinical, and Clinical Effects of Operator Exposure in the Cath Lab.

Subclinical and clinical effects of chronic, lowdose, radiation exposure to the head and neck region have been studied. Carotid intima-media thickness was examined in over 200 cath lab workers and compared to an equal number of control subjects [25]. Relative to low-exposure staff and unexposed subjects, those who were classified as high- exposure had increased carotid intima-media thickness (cIMT) when measured in both the left and right carotid arteries as well as averaged between the two. Left-sided cIMT correlated with lifetime exposure and a radiological risk score. The difference was particularly striking when the groups were stratified by age; the difference in cIMT based on the three exposure groups was graded and significant in the population less than 45 years of age.This contemporary study suggests that the biological effects of exposure to ionizing radiation may start early and persist throughout one’s career.

It is well known that the lens of the eye is radiosensitive and that exposure may lead to the development of posterior subcapsular cataracts. Over 100 interventional cardiologists underwent evaluation for lens opacities and were compared to a similar number of unexposed individuals; the adjusted odds ratio for the presence of posterior subcapsular lens opacities based on exposure was 3.85(95% Confidence Interval [CI] 1.30–11.40) [28].Exposure duration based on years of practice also increased the risk of an abnormal exam. Other studies of interventional operators have arrived at the same conclusion [29, 30]. These studies prove that despite the low energy of scatter radiation, biological effects may occur and be detected in the eye and the vasculature. The effects of exposure are more likely to develop and be detected in radiosensitive tissue relative to less radiosensitive organs.However, if scatter radiation is biologically active at the neck and eye level, the brain may also be at risk, albeit at a lower probability. Studies involving head exposure with higher doses of radiation suggest the brain is not immune to exposure.

Therapeutic cranial radiation has been administered for conditions as diverse as tinea capitis and acute lymphoblastic leukemia. The administered doses for intracranial tumors is often greater than 20 Gy while treatment for tinea capitis is typically between 3 and 8 Gy. High dose radiotherapy for brain cancer has been linked with the development of secondary brain tumors [36, 37]; however,studies evaluating short term exposure to moderate doses are more relevant to the risks of chronic exposure to lower intensity scatter radiation. Cranial radiation was a common treatment for tinea capitis starting in the early 1900’s and was the therapy of choice until the development of effective antifungal medication in 1959 [38]. In 1988, Ron et al. used the Israelicentral Population Registry to evaluate the cause of death of over 10,000 people treated with moderate intensity radiotherapy for tinea capitis [39]. Comparisons were performed between the subjects and matched controls as well as between subjects and siblings. The relative risk of mortality from head and neck neoplasms in the irradiated subjects was 2.9 (95% CI 1.2–7.2), and when limited to the comparison of siblings, the relative risk was 6.0(95% CI 1.5–39.5). Patients who were treated for tinea capitis between 1940 and 1959 at New York University, Bellevue Hospital were followed for a median of 39 years with questionnaire mailings and telephone calls with over an 80% follow-up rate[38]. The patients who received radiotherapy (average brain dose of 1.4 Gy; n=2224) were compared with controls (n=1380) receiving only topical medications. There were seven brain malignancies in the exposed group compared to zero in the controls and the rate ratio for any intracranial tumor was 9.5(95% CI 1.7–202) while the standardized incidence ratio for brain cancer was 3.0 (95% CI 1.3–5.9).

The aforementioned studies involved short-term exposure of moderate doses of radiation to children and adolescents. This population is uniquely different than invasive cardiologists and may be at increased risk for radiation-induced malignancies based on developmental stage. However, in a relatively small number of patients, an increased risk of a rare, but serious, event was detected. In 2012, Roguin, et al.published a case report regarding the diagnosis of brain cancer in nine interventional cardiologists and radiologists [40]. Within a few months, information regarding 22 additional cases was communicated to the authors, and an expanded report was published on all 31 cases [27]. The causal relation to occupational exposure was postulated given that the majority of the tumors were left-sided (85%), corresponding to the side of the brain closest to the radiation source in the majority of fluoroscopy-guided procedures [27,41]. The theory that radiation exposure in the cath lab contributed to the predominance in left-sided malignancies is supported by real-world dosimeter data that cranial radiation exposure increases when measured at points moving from right to left across the forehead [18]. The aggressive nature of the tumors is also alarming and lends credence to the heightened awareness in the interventional community. Based on the numbers of interventional operators, differences in practice patterns, and the rarity of the event, it would be extremely difficult to establish causality between chronic exposure to scatter radiation and malignancy, but compared to the general population, statistical data suggest the risk is not insignificant [42].

Table 3 Protective Measures to Decrease Operator Exposure.

Protective and Dose Reduction Methods

Figure 2 The Total Exposure at each Location Relative to the Ambient Control Dosimeters.Comparison of the mean exposures between each pair of dosimeters across the cap controlling for ambient exposure by subtracting the mean of the ambient dosimeters. Exposure inside the cap was 16 and 11 times lower at the left and center locations, respectively. Reproduced with permission from Reeves et al. JACC Cardiovasc Intv 2015 [18].

Radiation safety is of paramount importance for operators performing interventional cardiovascular procedures (Table 3). While as ‘low as reasonably achievable,’ otherwise known as ALARA, should be standard practice whenever medical radiation is administered, baseline and periodic, supplemental training courses that focus on this principle have been shown to decrease exposure [43, 44]. Modern technology related to imaging systems, including large monitors and dose reduction software settings also reduce radiation dose [45–47]. The use of real-time radiation dosimeters, enhanced shielding systems, and tolerable personal protective equipment can incrementally reduce operator exposure[18, 48–51]. Tolerable non-lead caps are readily available that can reduce operator cranial exposure to near-ambient levels (Figure 2) [18]. A potential major step in reducing the incidence of hazards related to working in the cath lab is robotic-assisted PCI. By increasing the operator’s distance from the source and safely performing PCI from within a console protected by leaded barriers, operator exposure may be reduced and the orthopedic issues that result from chronic use of leaded aprons may be avoided[52]. Many of these interventions are very feasible and can be implemented in every cath lab at little cost. Further, routine updates to current cath labs or the construction of new facilities may implement many of these protective measures to provide longterm dose reduction to both patients and operators.

Conclusion

There remains no definitive causal link between exposure to scatter radiation in the catheterization suite and the development of brain cancer. A study providing undisputable evidence is unlikely to be completed given the many years that would be required to study these chronic low doses, the relative rarity of the event, and the low density of operators over large geographic areas. However,evidence already exists that chronic exposure may lead to microbiological and subclinical effects to the head and neck region and vasculature. The rarity of the development of brain cancer is not a strong argument against taking protective measures and ignoring the potential hazard. All operators should be aware of the known harmful effects of chronic moderate dose radiation, the proven biological effects of cath lab exposure, the case reports of malignant left-sided brain tumors, and the feasible interventions that may significantly reduce both patient and operator exposure.

Conflict of Interest

The authors declare no conflict of interest.

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