Estimating Incidence of Organ Cancer Related to PCI Radiation Exposure in Patients Treated For Acute and Chronic Total Occlusions

Abstract: Background. Minimal data exist on the number of additional cancer cases related to radiation exposure following percutaneous coronary intervention (PCI). The aim of this study is to estimate the lifetime attributable risk (LAR) of cancer incidence for individual organs following radiation exposure during PCI in the context of two opposite sides of the angiographic spectrum of coronary occlusive disease: ST-elevation myocardial infarction (STEMI) and chronic coronary total occlusion (CTO). Methods and Results. We identified all consecutive patients treated with PCI for STEMI (n = 555) and for CTO (n = 543) in a tertiary care center in 6 years. The LARs of cancer incidence for 6 organs were estimated using the Biological Effects of Ionizing Radiation (BEIR) VII model. The estimated LAR of cancer incidence for individual organs was found to markedly increase as the age of the patient decreased and was significantly higher for the lung (additional risk up to 18/100,000 persons exposed in CTO and 9/100,000 persons exposed in STEMI patients, respectively; P<.0001) and for the red bone marrow (up to 3.5/100,000 persons exposed and 1.5/100,000 persons exposed, respectively; P<.0001). Conclusions. In PCI procedures, the lung was the organ with the highest radiation absorbed. The number of additional estimated cancer cases for individual organs was on average two times higher in patients treated with PCI for CTO and the highest estimated LARs were for lung and red bone marrow cancers.

J INVASIVE CARDIOL 2013;25(9):441-445

Key words: cancer, chronic total occlusion, STEMI, radiation exposure, lung cancer

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Percutaneous coronary intervention (PCI) is now the most widely used strategy to treat patients with chronic or acute ischemic coronary syndromes and has been tested in multiple clinical scenarios against both medical and surgical therapies. In this context, radiation dose exposure has been related to an additional risk of developing a radiation-induced cancer for medical staff and for patients who are directly exposed.^1-5 The life attributable risk (LAR) of cancer incidence describes an excess of disease cases over a follow-up period with population background rate determined by the experience of unexposed individuals for each of several specific cancer sites at each age of exposure.⁶ There is a great deal of interest in estimating the LAR of cancer incidence related to ionizing diagnostic examinations.^7-10 During an acute myocardial infarction hospitalization, patients are exposed to a median radiation dose of ≈15 mSv and more than 65% of this radiation dose is directly related to coronary angiography and primary PCI for ST-elevation myocardial infarction (STEMI), which is a life-saving procedure enabling restoration of coronary blood flow after abrupt vessel occlusion.¹¹ On the opposite side of the spectrum of coronary ischemic syndromes, PCI for recanalization of coronary chronic total occlusions (CTOs) exists, and is associated with symptom relief and improvement in long-term mortality.^12-15 However, percutaneous recanalization of a hard calcified plaque is generally acknowledged to be a challenging, expensive, and time-consuming procedure with high levels of radiation exposure.^16-19 Currently, minimal data exist on the number of additional cancer cases related to radiation exposure during PCI. We aimed to estimate the patient’s LAR of single-organ cancer incidence associated with radiation exposure in the context of these two opposite sides of the angiographic spectrum of PCI procedures.

Methods

Population. All consecutive patients who underwent elective PCI for single CTO or primary PCI for STEMI in a single tertiary care center (San Raffaele Institute in Milan, Italy) between July 2002 and December 2008 were analyzed. The indications for PCI in CTO patients were symptomatic myocardial ischemia and/or evidence of reversible myocardial ischemia from perfusion or stress testing. CTO was defined as a coronary obstruction with TIMI flow grade 0 (flow grades based on results of the Thrombolysis In Myocardial Infarction trial) with an estimated duration superior to 3 months. The duration of the occlusion was either determined by the interval from the last episode of acute coronary syndrome, or in those with no history of acute coronary syndrome, from the first episode of effort angina consistent with the location of the occlusion or by previous coronary angiography. All STEMI patients underwent primary PCI within 12 hours after symptom onset, including patients with cardiogenic shock. Primary PCI and stenting of the infarct-related artery were performed according to the clinical protocol of American College of Cardiology/American Heart Association Guidelines for the Management of Patients with STEMI.²⁰ All CTO procedures performed in our institution were done by the most expert and dedicated operators for CTO.

Individual organ doses. The 1990 recommendations of the International Commission on Radiological Protection (ICRP) require the use of effective dose (E; in Sievert units) as the primary dose limiting quantity (ICRP 1991). It is defined as the sum of the weighted equivalent doses in 12 critical tissues and organs of the body plus a remainder composed of some additional organs, as summarized in equation: E = ∑ wT HT. Here, wT is the weighting factor for tissue or organ (T) and HT is the equivalent dose in T (in Sv). Since the recommended value of the radiation weighting factor is 1 for photons of any energy (ICRP 1991), the equivalent dose is the same as the absorbed dose. The determination of equivalent doses deposited in those critical organs is therefore considered as a key component in ICRP’s methodology of risk assessment.²¹ The dose area product (DAP) meter technique (or kerma area product) is the most reliable measure for dynamic examinations such as fluoroscopy, in which the projections, direction, and parameters are continually varying.²² To determinate the effective dose for each available organ (Table 1), we used the ICRP 103 weighting factor for tissue or organ and the conversion equivalent organ dose DAP factor for PCI reported by Compagnone et al.²³ Finally, the mSv dose was further converted in Gy (0.1 Gy = 100 mSv for x-ray) to estimate, according to the BEIR VII 12D-1 risk table, the LAR of cancer incidence for colon, liver, lung, red bone marrow, stomach, and thyroid.⁶ The LAR of cancer incidence was not estimated for heart, skin, esophagus, bone, and breast because the first four are not present in BEIR VII tables and the HT/DAPPCI conversion factor for the breast was not previously reported.²³

Statistical analysis. Continuous variables were reported as mean ± standard deviation (SD) and compared with Student’s t-test or Mann-Whitney or Wilcoxon tests, based on the normality (Kolmogorov-Smirnov goodness-of-fit test) of the data. Categorical variables (as frequencies or percentage) were compared with χ² statistics or Fisher’s exact test when indicated. Two-side P-values <.05 were considered statistically significant. All data were analyzed with the Statistical Package for Social Sciences 18.0.2 (SPSS, Inc). All patients provided written informed consent for the procedures according to the Hospital Ethics Committee. 

Results

Between July 2002 and December 2008, a total of 555 patients underwent primary PCI for STEMI and 543 underwent single PCI for CTO (Table 2). Between STEMI and CTO patients, no significant difference was found in terms of age (61 ± 11.2 years vs 61.5 ± 9.4 years) and body mass index (26.9 ± 3.2 vs 27.2 ± 2.8). Instead, the following characteristics were significantly higher in CTO patients: male sex (90% vs 83%; P<.0001), DAP (250 ± 16 Gycm² vs 136 ± 98 Gycm²; P<.0001), and fluoroscopy time (32 ± 17 minutes vs 14 ± 12.5 minutes; P<.0001). The equivalent doses (HT) and the effective dose applied to individual organs during PCI for CTO and STEMI are illustrated in Figures 1 and 2. In both CTO and STEMI groups, the lung was the organ with the highest HT (125 ± 79 mSv vs 68 ± 49 mSv, respectively; P<.0001), followed (in order) by esophagus, heart, liver, stomach, and red bone marrow. The lowest HT values (mean value below 20 mSv) were observed for the bone, colon, skin, and thyroid. The HT values applied to individual organs were all significantly higher in CTO compared to STEMI patients (P<.0001). The age-dependent estimated LARs of single organ cancer incidence based on BEIR VII model following PCI in CTO and STEMI patients are illustrated in Figure 3. In both CTO and STEMI patients, the estimated LARs of cancer incidence for individual organs were found to markedly increase as the age of the patient decreased, indicating a higher risk for developing cancer in young patients. In patients age 45-49 years, the estimated LAR of cancer incidence was significantly higher for the lung (additional risk of 18/100,000 persons exposed in CTO patients and 9/100,000 persons exposed in STEMI patients) and for the red bone marrow (3.5/100,000 persons exposed and 1.5/100,000 persons exposed, respectively). In both groups, the estimated LAR of cancer incidence for stomach, colon, and liver was very low and trivial for the thyroid. Between the ages of 45 and 64 years, the LAR for lung and red bone marrow cancer incidence was up to 5 and 2 times higher in CTO compared to STEMI patients, respectively (P<.0001). Considering the estimated LARs for colon, liver, and thyroid cancers, no significant difference was found within each age group between CTO and STEMI patients.

Discussion

The main findings of this paper are: (1) the HT values applied to individual organs were all significantly higher during PCI for CTO compared to PCI for STEMI; (2) in both groups, the highest HT was observed for the lung; (3) the estimated LARs of cancer incidence for individual organs were found to markedly increase as the age of the patient decreased; and (4) the estimated LAR was significantly higher for the lung (additional risk up to 18/100,000 persons exposed in CTO patients and 9/100,000 persons exposed in STEMI) and for the red bone marrow (up to 3.5/100,000 persons exposed in CTO patients and 1.5/100,000 persons exposed in STEMI patients).

Equivalent dose (HT) to individual organs during PCI. The largest man-made source of ionizing radiation are diagnostic and interventional examinations (x-ray and nuclear medicine).²⁴ It is therefore important to monitor patient doses from these procedures to enable the referring clinician and/or cardiologist to make an objective assessment of the justification of the procedure. Each year, several billion diagnostic imaging studies and interventions are performed worldwide, of which at least one-third are cardiovascular.²⁵ Moreover, it has been described that the overall radiation doses received by the patient are relatively high during interventional coronary procedures.^16,17,26,27 Moreover, our data confirm the previously reported results regarding higher fluoroscopic times in CTO procedures.^16-19,28

Until now, the radiation doses received per individual organs during interventional coronary procedures were reported in only two other papers.^21,23 In 1991, the ICRP recommended the use of effective dose as a relevant dose parameter in radiological procedures.²⁹ The new ICRP recommendations still maintain effective dose as the central quantity for dose assessments in radiological protection, but also state that its use for assessing the exposure of patients has severe limitations.³⁰ Therefore, it is not clear which parameter could take the place of effective dose as an efficient, powerful, and easy-to-use tool in patient radioprotection. It was suggested that effective dose could be kept as a quantity used for dose comparisons from different diagnostic procedures/different hospitals/different technologies and equivalent dose (HT) deposited in the critical organs could be considered as more appropriate quantities for planning the patient exposure and risk-benefit assessment.^23,30 Recently, Compagnone et al²³ provided conversion factors between DAP and HT for each organ to enable the equivalent doses to be calculated directly from DAP data, avoiding the need to carry out detailed in-the-field analyses for all projections used on each patient. We found that in both CTO and STEMI procedures, the lung, esophagus, and heart are the most exposed organs (mean HT value >50 mSv) because they are situated within the field of view of the beam. On the contrary, the skin, colon, and bone are the organs/tissues with the lower doses of radiation (mean HT value ≤15 mSv). Previously, Compagnone et al²³ reported, in a normal population that underwent PCI procedures, a mean value of HT for lung and esophagus of 59.5 ± 30 mSv and 52 ± 27 mSv, respectively, that was quite similar to that observed in STEMI patients (68 ± 49 mSv and 58 ± 42 mSv, respectively) and definitely lower compared to that observed in CTO patients (125 ± 79 mSv and 107 ± 67 mSv). 

Estimated LARs of cancer incidence for individual organs after PCI. The LARs of cancer incidence for several solid tumors have been tabulated as a function of patient age at the time of exposure by the National Research Council and represent the number of additional cancer cases per 100,000 persons exposed (over a lifetime) to a single dose of 0.1 Gy.⁶ Previous estimates of LAR of cancer incidence were derived in any case from a theoretical simulation model and related to an association between ionizing radiation from computed tomographic coronary angiography and/or other therapeutic procedures.^7,8 Considering all these data, we believe that the potential increase in cancer-related deaths associated with exposure to radiation during cardiac imaging and/or therapeutic procedures should be weighed against the potential risk related to the underling cardiovascular disease. The majority of diagnostic radiological procedures in symptomatic patients, including coronary catheterization, confer an extremely low risk of cancer, which is justified by the medical necessity. In contrast, it is not yet clear which of the various applications of PCI in the context of the wide spectrum of coronary ischemic syndromes (coronary stable angina, unstable angina, acute myocardial infarction) outweigh the risk of radiation exposure. This study estimated the LAR of cancer incidence for individual organs related to radiation exposure during PCI in the context of two opposite sides of the spectrum of PCI procedures (STEMI and CTO). We showed that in a target population of patients with STEMI (age 45-80 years), the number of additional cancer cases of lung cancer is low, ranging from 5/100,000 persons exposed to 9.5/100,000 persons exposed for an average x-ray exposure of 136 ± 98 Gycm² and is lower for the red bone marrow, ranging from 1/100,000 persons exposed to 1.5/100,000 persons exposed. Therefore, in these patients, the risk of cancer after PCI for STEMI is absolutely low and irrelevant compared to the benefits of PCI for STEMI. On the other side of the spectrum, in patients with CTO, the LAR of lung and red bone marrow cancer is higher, ranging from 7.5/100,000 persons exposed to 18/100,000 persons exposed and 1.5/100,000 persons exposed to 3.5/100,000 persons exposed, respectively (average x-ray exposure of 250 ± 158 Gycm²). Thus, our results do question whether our current enthusiasm for some therapeutic procedures, such as PCI for CTO, should be tempered. Since the present study was not designed as a cost-benefit study, at the moment we cannot conclude that attempts to recanalize CTOs are not worthwhile. On the contrary, we believe that recanalization of coronary CTO can be associated with favorable long-term outcomes and can reduce the necessity for coronary artery bypass surgery.¹² However, as in many areas of medicine, one size does not fit all, and in each case we should balance the real clinical benefit that such complex procedures provide with the risk associated with ionizing radiation. Thus, we should try to limit patient radiation exposure as much as possible and perhaps for a complex CTO in young patients (<60 years old), especially females, we should reconsider the indication for PCI in favor of coronary artery bypass surgery. Moreover, it should also be emphasized that in the present study the estimation of the LARs referred to a single PCI procedure; in contrast, in daily practice, some patients with a CTO may have had multiple procedures. The substantial reduction of LAR for any single cancer in the aged population compared with the young population is easily explained by reduced biological cellular turnover and shorter life expectancy in the aged population and is consistent with other previous reports.^7-9,31 Finally, we can suggest that interventional radiological procedures must be done under the subsequent dose level as recommended by the ICRP report 120,³² namely, peak skin dose of 3 Gy, kerma area product of 500 Gycm², air kerma at the patient entrance reference point of 5 Gy, and fluoroscopy time of <60 minutes, even if these cut-offs are directly related to a deterministic risk. In addition, prior to a CTO PCI attempt, it would be more appropriate to identify the subgroups of patients who would most benefit from the recanalization as patients with chronic renal failure, low left ventricular ejection fraction, and insulin-dependent diabetes mellitus.¹⁵

Study limitations. The estimates are not based on epidemiological data of actual malignancies in populations of patients receiving PCI; such data are not available and will not be available for the foreseeable future. The LAR of cancer estimates using BEIR VII are subject to several sources of uncertainty due to inherent limitations in epidemiological data and in the general understanding of how radiation exposure increases the risk of cancer.⁶ Despite these uncertainties, the BEIR VII phase 2 model used in this study, and in others on computed tomographic coronary angiography,^7,8,31 remains the most comprehensive and updated assessment of individual additive risk of cancer after single PCI x-ray exposure.

Conclusion

In this study, we observed that the estimated equivalent doses (HT) applied to individual organs during PCI for CTO were considerably higher than those applied during PCI for STEMI. According to the BEIR-VII model, the number of estimated additional cancer cases for individual organs was on average two times higher in patients treated with PCI for CTO and the highest lifetime attributable risks were for lung and red bone marrow cancers. 

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*Joint first authors.

From the ¹Cardio-Thoracic-Vascular Department, San Raffaele Institute, Milan, Italy, ²AITRI (Italian Association of Interventional Radiographers), Milan, Italy, and 3EMO-GVM Centro Cuore Columbus, Milan, Italy.

Disclosure: The authors have completed and returned the ICMJE Form for Disclosure of Potential Conflicts of Interest. The authors report no conflicts of interest regarding the content herein.

Manuscript submitted April 21, 2013, provisional acceptance given May 15, 2013, final version accepted June 18, 2013.

Address for correspondence: Cosmo Godino, MD, Cardiology Unit, San Raffaele Scientific Institute, Via Olgettina 60, 20132 Milan, Italy. Email: cosmogodino@gmail.com