British Journal of Radiology (2003) 76, 891-896
© 2003 British Institute of Radiology
doi: 10.1259/bjr/97164438
Calcification in coronary arteries as quantified by CT scans correlated with tobacco consumption in patients with inoperable non-small cell lung cancer treated with three-dimensional radiotherapy
S Milker-Zabel, MD
1
A Zabel, MD
1,2
C Manegold, MD
3
I Zuna, PhD
2
M Wannenmacher, MD
1 and
J Debus, MD, PhD
1,2
1 Department of Clinical Radiology, Radiation Therapy, University of Heidelberg, 2 Department of Radiotherapy, German Cancer Research Centre, Heidelberg and 3 Department of Internal Medicine/ Medical Oncology, Thoraxklinik, Heidelberg, Germany
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Abstract
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It has been shown that radiological manifestations of coronary artery sclerosis are an indirect measure of co-morbidity and predictive of survival. The aim of the present study is to evaluate the outcome and side effects after three-dimensional (3D) radiotherapy in patients with unresectable non-small cell lung cancer (NSCLC) stage I, II and IIIA, depending on coronary artery calcification, Karnofsky performance index (KI) and co-morbidity. Between 1993 and 1999, 89 patients with unresectable NSCLC were treated with 3D-radiotherapy. The median age was 66.6 years and median KI 80%. All patients had 3D-treatment planning, based on CT scans. The median total dose was 60 Gy in 2 Gy fractions five times a week. The mean follow-up period was 13.2 months and mean survival time 12.2 months. Significant prognostic factors for improved survival were KI and tumour stage. Patients with a KI<90% had a median survival of 6.5 months compared with 14 months, in patients with KI
90% (p<0.001). NSCLC stage I+II showed a significantly longer median survival than patients with NSCLC stage IIIA (16.5 months versus 7 months, p<0.004). A significant correlation was seen between pack-years and coronary artery calcification (p<0.05) and between age and marked coronary artery calcification. The incidence of calcification was 67% in smokers (20 pack-years) and 43/58 in patients >60 years (p<0.007). Side effects, e.g. pneumonitis, did not correlate with coronary artery calcification but correlated with chronic obstructive lung disease in 19/89 patients. Conventional CT scans for 3D-treatment planning are able to detect coronary artery calcification. There is a significant correlation between age, KI, tobacco consumption and vascular calcification. Although there was a trend to worse overall survival, coronary artery calcification was not a significant predictor of progression-free and overall survival.
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Introduction
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Lung cancer is the most frequent malignancy in men and the third in women in industrialized countries [1]. Several studies evaluated survival and the patient's symptomatic status in their measurement of outcome [2]. Several studies have indicated that tobacco is the main cause of lung cancer with latency of 15 to 50 years between the start of smoking and diagnosis of lung cancer [3, 4]. Half of all lung cancers occur in persons aged 65 years and older [5]. Non-small cell lung cancer (NSCLC) in the elderly constitutes 75–80% of all lung cancers [6, 7].
Surgical resection is the treatment of choice for resectable stage I or II NSCLC [8]. Some patients with stage IIIA NSCLC qualify for surgical resection; others should be offered combined modality treatment with radiotherapy and chemotherapy. In older patients co-morbidity at clinical presentation often limits resectability. Nevertheless local control is most important for these patients [9, 10]. Three-dimensional (3D) radiation therapy has heralded a new era in radiation treatment planning in recent years [11, 12]. It is a high precision treatment technique which accurately conforms the required dose to the target, to the anatomic boundaries of the targets and its entire 3D configuration [13]. The application of dose is also limited by pre-existing co-morbidity, e.g. coronary heart disease. It is well known that coronary heart disease is a clinically relevant co-morbidity in the treatment of lung cancer [14, 15]. It is also well known that smokers have a worse tolerance of radiotherapy compared with non-smokers. Large prospective studies provide estimates of the relative and attributable risk associated with cigarette smoking. Smokers have a higher risk of coronary heart disease compared with non-smokers [16, 17]. Kuller showed that smoking is a powerful risk factor for lung cancer and coronary heart disease [18, 19]. Several studies showed a significant correlation between cigarette smoking and atherosclerosis [20, 21].
Görich et al [22] have indicated that aortic calcification is strongly associated with age, smoking habits, hypertension, diabetes and vascular disease. Görich et al developed an assessment scale of calcification. Because of the high X-ray density of calcium, conventional computerized tomography is suitable for detecting vascular calcification. Thus, pre-treatment CT scans allow assessment of coronary artery sclerosis and aortic calcification [23]. Therefore, based on the model of Görich, outcome and side effects were correlated with the degree of coronary artery sclerosis and calcification of the arch of aorta, Karnofsky performance index and co-morbidity in patients with unresectable NSCLC treated with 3D conformal radiotherapy.
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Methods and material
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Between 1993 and 1999, 203 patients with unresectable NSCLC received primary conventional or 3D conformal radiotherapy at the University of Heidelberg, Germany. All 89 consecutive patients with unresectable NSCLC stage I (T1-2N0M0), II (T1-2N1M0, T3N0M0) and IIIA (T1-3N2M0, T3N1M0) who received 3D conformal radiotherapy were included in this evaluation.
11 patients had stage I, 29 stage II, and 49 patients stage IIIA. In 44 patients the tumour was located in the upper lobe of the lung. All patients had histologically proven NSCLC and were considered unresectable by thoracic surgeons owing to disease extension or co-morbidity. Co-morbidity mostly consisted of obstructive pulmonary disease (47.8%), hypertension (24.7%), diabetes mellitus (18.9%), coronary artery disease (33.3%). 70% of patients had more than one chronic co-morbid condition. 54 patients (61.1%) had squamous cell carcinoma, 33 (36.7%) adenocarcinoma, and two had anaplastic carcinoma. Before radiotherapy each patient underwent a complete physical examination and a medical history of co-morbid conditions. The median age of all 89 patients was 66.6 years (range, 44–84 years) with a male/female ratio 71/18. The median number of pack years was 45 (range 0–110 pack years), and median Karnofsky performance index was 80% (range, 60–90%).
Radiotherapy was delivered with a 23 MV linear accelerator. All patients included in this analysis received 3D treatment planning. Using a HELAX, TMS planning system (MDS Nordion, Sweden), based on conventional CT scans. At the beginning of 3D treatment planning CT scans with a slice thickness of 4 mm and an 8 mm gap between slices without respiratory gating were used. Planning now uses contiguous 5 mm CT slices, without respiratory gating. The patient was supine with the arms crossed above the head for planning and treatment. Skin marks and laser beams were used to make sure that patient positioning was reproducible every day. The target volume included the primary tumour as well as regional involved lymph nodes according to Kirikutta [24]. 84 patients (94.4%) received primary thoracic radiotherapy and five patients (5.6%) had local relapse after initial surgical resection of early stage lung cancer. Five of 49 patients with NSCLC stage IIIA had combined radiotherapy and chemotherapy and three received adjuvant chemotherapy after radiotherapy. The median total dose was 60 Gy (range, 52.5–60 Gy) in 2 Gy fractions five times a week. No dose reduction was made in patients with coronary artery disease. The mean follow-up for the entire group was 13.2 months. Side effects were documented using common toxicity criteria (CTC) developed by the National Cancer Institute. Acute toxicities (<90 days after beginning of therapy) was considered separately from chronic toxicity (>90 days after the beginning of therapy).
The pre-treatment CT scans for 3D treatment planning were evaluated for calcification in the thoracic aorta (arch of aorta) and coronary arteries. The reader did not have information about the age or smoking habits of the patients. The assessment scale of the calcification is shown in Table 1
[22] and Table 2. All patients were followed until death or until March, 2001. Survival rates were calculated according to the Kaplan-Meier method, and the level of significance of differences in survival curves was calculated by the Log-rank scale. Seven patients were excluded from this evaluation because their CT scans were not available for detailed examination.
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Results
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Vascular calcification
82 of 89 patients were included in the evaluation of vascular calcification. 65 of 82 patients (79.3%) were smokers with more than 20 pack years, 9 (11%) 
20 pack years and 8 (9.7%) non-smokers. Marked calcification (II°) of the aortic arch was seen in 68 patients (82.9%), marked coronary artery sclerosis (II°) in 53 patients (64.6%). An example of the marked calcification of the arch of aorta and coronary artery is shown in Figures 1 and 2. Calcification stage 0° or I° was seen in 15 (arch of thoracic aorta) and 31 (coronary arteries) in pre-treatment CT scans.
A significant correlation was seen between the patients age at the time of radiotherapy and vascular calcification. 43 of 58 patients older than 60 years (74.1%) showed marked calcification (II°) of coronary arteries (p<0.007) compared with 8 of 22 patients 60 years (36.4%). Patients older than 60 years also showed a significant correlation with marked calcification in the arch of aorta (p<0.01). 51 of 58 patients older than 60 years (87.9%) had marked calcification (II°) of the arch of aorta in pre-treatment CT scans. In multivariate analysis a significant correlation was seen between a patient's age at radiotherapy and vascular calcification in the arch of aorta and in coronary artery (p<0.001). The multivariate analysis showed a significant correlation between KI and marked calcification in coronary arteries (p<0.03), but correlation between KI and calcification of the arch of aorta was not significant.
Survival rates
The mean survival of the 89 patients with unresectable NSCLC, treated with 3D conformal radiotherapy was 12.2 months (range, 1–76 months). The survival for all patients after 1 year was 38.2% and 16.8% after 2 years.
Patients with a Karnofsky performance index 90% had a median survival of 14 months, those with KI<90% of 6.5 months (p<0.001). Although, the multivariate analysis shows a significant correlation between KI and marked calcification in coronary artery (p<0.03), there was no significant correlation between marked calcification in coronary arteries and survival, calculated according to the Kaplan-Meier method (Figure 3). The median survival of patients with NSCLC staged I and II was 16.5 months, significantly longer than in patients with NSCLC stage IIIA at 7 months (p<0.003).
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Figure 3. Kaplan-Meier plot for survival in 89 patients with unresectable non-small cell lung cancer in dependency of Karnofsky performance index (KI).
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Patients older than 66 years had a median survival of 7 months and patients 65 years had a median survival of 8 months (p>0.417). There was also no significant difference between survival rates for patients with adenocarcinoma and those with squamous cell carcinoma (p>0.89). No difference in survival was seen in different tumour locations.
87 patients (97.7%) died during follow-up. 17 patients (19.5%) treated with 3D conformal radiotherapy died due to local progression of disease. 39 patients (44.8%) died because of respiratory insufficiency. These patients had underlying chronic obstructive pulmonary disease. 29 patients (33.3%) died because of systemic metastases and two patients because of pulmonary embolus.
Side effects
Toxicity was evaluated according to the CTC scale. Early toxicity mostly consisted of grade I-II local erythema of the skin in 21/89 patients (23.6%) and grade I-II° oesophagitis in 23/89 patients (25.8%). No grade III or IV toxicity was observed. The most common late toxicity was pneumonitis in 19/89 patients (21.3%) which required steroid medication. Three of 89 (3.3%) patients developed clinically significant lung fibrosis.
Correlation between vascular calcification and tobacco consumption
A significant correlation was found between consumption of tobacco in patients with more than 20 pack years and coronary artery calcification (p<0.05). 55 of 74 smokers (74.3%) with more than 20 pack years had a marked coronary artery calcification I° and II°. Three of eight non-smokers had also marked (II°) calcification in coronary arteries. The median age of these patients was 65 years (range, 54 to 84 years). No significant correlation was seen between calcification of the arch of aorta and tobacco consumption. 51 of 82 patients (62.2%) with more than 20 pack years had marked calcification (II°) of the aortic arch compared with 15/82 (18.3%) non-smokers.
Correlation between vascular calcification and outcome
Patients with marked coronary artery sclerosis (II°) had a median survival of 7 months (range, 2–63 months), while patients with no coronary artery calcification (0°) had a median survival of 11 months (range, 2–39 months). Patients with calcification I° had a median survival of 8 months (range, 2–76 months) (p>0.39). No significant correlation between calcification in the arch of aorta and survival was seen after 3D conformal radiotherapy independent of tumour stage. The average survival of patients with calcification I° of the arch of aorta was between 8 months and 12 months and in patients with calcification II° of the arch of aorta between 7 months and 9 months (Figures 4 and 5), with a median survival of 6 months (p>0.68). In multivariate analysis a significant correlation between outcome and KI (p<0.001) was found as well as between patients outcome and tumour stage (p<0.03).
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Figure 4. Kaplan-Meier plot for survival in 89 patients with unresectable non-small cell lung cancer in dependency of calcification of the arch of aorta.
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Figure 5. Kaplan-Meier plot for survival in 89 patients with unresectable non-small cell lung cancer in dependency of calcification of coronary arteries.
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Discussion
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In elderly patients co-morbidity at clinical presentation often limits functional resectability of lung cancer. Therefore, elderly patients or patients with many co-morbid conditions have often been treated with primary 3D conformal radiotherapy. One of the most common co-morbid conditions in patients with lung cancer is coronary heart disease. Several studies showed that smoking is a powerful risk factor for lung cancer and atherosclerosis as well as for coronary heart disease and pulmonary disease [18–20]. Strong and Richards [21], found in a study of men at autopsy that atherosclerotic lesions were more extensive in heavy smokers of cigarettes than in non-smokers. These findings agree also with the results of preliminary reports [25, 26].
Görich et al [22] found a significant correlation between aortic calcification in CT scans and age, smoking habits, hypertension and diabetes. Included in their analyses were 2130 patients, half of them with lung cancer. The most significant risk factor for aortic calcification was patient age. Smoking as a predictive factor for vascular calcification was especially important in younger patients. Hypertension as co-morbidity showed a significant correlation with calcification of the aorta. Several studies have indicated that vascular calcification is a strong predictive factor of outcome in patients [27].
In our analysis, conventional CT scans used for 3D treatment planning were analysed to detect coronary artery calcification and calcification of the arch of aorta. We showed that coronary artery calcification can be detected with regular CT scans used for 3D treatment planning, without additional diagnostic imaging. However, there are more sophisticated CT-techniques available to examine the coronary arteries. Becker et al [28] compared electron beam CT and prospectively cardiac cycle gated conventional CT for detection and quantification of coronary artery calcifications. They concluded that both methods are equivalent for quantification of coronary artery calcifications. In contrast to angiography of the coronary arteries, conventional CT can not detect soft plaques. Masuda et al [29] described coronary artery calcifications in 90% of 108 patients who had significant coronary artery stenosis angiographically, while 80% of 121 patients with significant stenosis of coronary arteries showed calcification in conventional CT. For detection of coronary artery stenosis with conventional CT, the sensitivity is 65% and specificity 87% [29]. We demonstrate in this evaluation that conventional CT scans are sensitive enough to detect calcification and to differentiate between three grades of calcification. Furthermore, we were able to correlate tobacco consumption with the grade of vascular calcification in the coronary arteries and the arch of aorta.
In our analysis a significant correlation between patients age at radiotherapy and vascular calcification as well as between smoking habits and vascular calcification was shown. A strong correlation with vascular calcification was seen in patients older than 60 years and a smoking history of more than 20 pack years. However, no significant correlation was seen between calcification of coronary arteries or arch of aorta and the clinical outcome of patients. This may be different in patients with longer follow-up.
Glanzmann et al [30] analysed the risk of myocardial infarction in 339 patients treated with radiotherapy because of lymphogranulomatosis. In patients without coronary heart disease the risk of myocardial infarction was lower than in patients with a coronary heart disease. In our evaluation there was no significant correlation between calcification of the arch of thoracic aorta or coronary artery sclerosis and survival. This may be attributed to the low patient number of 89 patients and short follow-up of 13.2 months mean. It is well known that Karnofsky performance index and tumour stage are prognostic factors in patients with NSCLC [31, 32], which is consistent with our data.
In the evaluation of Inoue et al [33], 69 of 191 patients (36%) had a mild radiation pneumonitis and 25 patients (13%) a severe radiation pneumonitis. They found no correlation between baseline patient characteristic and radiation pneumonitis. In our analysis, we found a significant correlation between patients without chronic obstructive pulmonary disease as co-morbid condition and pneumonitis after radiation therapy, independent of coronary artery calcification.
In the literature several studies showed an association between vascular calcification and a higher risk of radiation induced side effects. We found that marked calcification in the coronary arteries was associated with a higher risk of radiation induced pneumonitis but this did not reach significance. However, it is not clear if this is an underlying cause mechanism because of the low number of patients in our analysis.
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Conclusion
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Conventional CT scans for 3D treatment planning are sensitive enough to detect coronary artery calcification without requiring additional time or examinations. We conclude that there is a correlation between patients age and vascular calcification as well as between tobacco consumption of patients and vascular calcification. The small vessels such as the coronary arteries are particularly affected in patients older than 60 years and/or with more than 20 pack years. Although, KI90% correlated significantly with longer survival and low coronary calcification in univariate analysis no significant correlation was seen in patients without coronary calcification in multivariate analysis. Thus, vascular calcification, especially marked calcification in the coronary arteries, does not seem to be an independent prognostic factor for survival after 3D conformal radiotherapy in patients with unresectable NSCLC stage I, II or IIIA.
Finally, it would be interesting to compare the prognosis of patients with ischaemic heart disease and coronary artery calcification who do not have lung cancer with this series. If their survival is longer than the patients with lung cancer, even after treatment, that may be an explanation of why there was no correlation between coronary artery calcification and survival. Patients would need to survive the lung cancer in order to develop the complications of ischaemic heart disease. If the radiotherapy was more effective then the result may have been different.
Received for publication March 31, 2003.
Revision received July 8, 2003.
Accepted for publication July 29, 2003.
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Abstract
Introduction
