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Evaluation of Lung Injury after Three-dimensional Conformal Stereotactic Radiation Therapy for Solitary Lung Tumors: CT Appearance¹

¹ From the Department of Therapeutic Radiology and Oncology, Graduate School of Medicine, Kyoto University, 54 Shogoin Kawahara-cho, Sakyo, Kyoto 606-8507, Japan. Received September 25, 2002; revision requested December 10; final revision received May 17, 2003; accepted June 18. Supported by grants-in-aid no. 09255255, no. 10153231, and no. 13470183 from the Ministry of Education, Culture, Sports, Science, and Technology, and no. 23765293 from the Ministry of Health, Labour, and Welfare in Japan. Address correspondence to Y. Nagata (e-mail: nag@kuhp.kyoto-u.ac.jp).

	ABSTRACT

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PURPOSE: To evaluate the computed tomographic (CT) appearance of tumors and lung injury in patients who have undergone stereotactic radiation therapy (SRT) for solitary lung tumors.

MATERIALS AND METHODS: Twenty-seven patients with primary lung cancer and four with metastatic lung cancer who underwent SRT for solitary lung tumors were enrolled for evaluation. SRT was delivered by using a three-dimensional conformal technique with a stereotactic body frame. A total dose of 48 Gy was administered in four fractions during a period of 2 weeks. After SRT, follow-up CT images were obtained every 2–3 months. Radiation-induced pulmonary injuries were classified into four patterns on CT images. The minimal lung dose to areas demonstrating pulmonary injury at CT was evaluated, and the correlation between the dose and the percentage volume of the whole lung irradiated by more than 20 Gy in total (V20) was assessed by using Spearman rank correlation.

RESULTS: Tumor shrinkage continued for 2–15 months after SRT. Asymptomatic changes in the irradiated lung were noted at CT in all patients within 2–6 months (median, 4 months) after SRT. As the pattern at pulmonary CT changed, patchy consolidation was more predominantly seen as an acute change than were slight homogeneous increase in opacity, discrete consolidation, or solid consolidation; solid consolidation was the more predominantly seen late change. The minimal lung dose to the area demonstrating pulmonary injury in each patient ranged between 16 and 36 Gy (median, 24 Gy). The dose was significantly (P < .001) inversely correlated with the V20 in each patient.

CONCLUSION: The reaction to SRT of the lungs seems similar to the reaction to conventional radiation therapy.

© RSNA, 2003

Index terms: Lung neoplasms, CT, 60.12112 • Lung neoplasms, therapeutic radiology, 60.32, 60.33 • Radiations, injurious effects, complications of therapeutic radiology • Stereotaxis • Therapeutic radiology, three-dimensional

	INTRODUCTION

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The techniques of three-dimensional conformal radiation therapy and patient immobilization have recently been developed, which enables us to focus high doses of irradiation on the target area and relatively less irradiation on normal tissues. In radiation therapy for solitary lung tumors, the local control may be improved safely by using these techniques to deliver a higher dose to only the target volume. The results of several clinical studies on hypofractionated high-dose stereotactic radiation therapy (SRT) with the three-dimensional conformal radiation therapy technique for irradiation of solitary lung tumors have been reported (1–7).

It was considered that the clinical and radiographic appearances of radiation-induced pulmonary change caused by hypofractionated SRT would not be similar to the change induced by conventional radiation therapy because of differences in the total radiationdose, dose per fraction, dose distribution, overall treatment time, and other variables (2–8). Few reports have demonstrated computed tomographic (CT) images associated with hypofractionated SRT of lung tumors, although the CT findings after conventional radiation therapy have been reported previously (9–14). Thus, the purpose of our study was to evaluate the CT appearance of tumors and lung injury in patients who have undergone SRT of solitary lung tumors.

	MATERIALS AND METHODS

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Patients
Since July 1998, three-dimensional conformal SRT with a body frame has been performed in patients with solitary lung tumors at our institution with the approval of our institutional review board and with written informed consent from all patients (4,8). The study reported here comprised 40 patients who were treated with this technique between July 1998 and November 2000.

The eligibility criteria for patients with primary lung cancer were as follows: (a) a solitary pulmonary nodule without nodal or distant metastases (T1–3N0M0) was present, (b) tumor size was less than 40 mm in diameter, (c) the patient could remain stable in the body frame for more than 30 minutes, (d) oxygen was not normally required, (e) the histologic findings could be confirmed, (f) surgery was contraindicated or refused, and (g) the spinal cord could be kept out of the high-dose area (5 Gy per fraction). The eligibility criteria for patients with metastatic lung cancer were as follows: (a) one or two pulmonary nodules were present, (b) tumor size was less than 40 mm in diameter, (c) the patient could remain stable in the body frame for more than 30 minutes, (d) oxygen was not normally required, (e) the spinal cord could be kept out of the high-dose area (5 Gy per fraction), and (f) the primary tumor was controlled.

Of the 40 patients, 34 (27 with primary lung cancer and seven with metastatic lung tumor) were irradiated with 48 Gy in total, three were irradiated with 40 Gy in total, and three were irradiated with 60 Gy in total. In this study, of the 34 patients irradiated with 48 Gy, 31 patients (27 with primary lung cancer and four with metastatic lung tumor) treated for single tumors were enrolled for analysis; three patients with metastatic tumors, who were treated for two tumors each, were excluded. Among the 27 patients with primary lung cancer, the histologic diagnosis was confirmed with transbronchial lung biopsy or percutaneous biopsy results in 25 patients. The histologic diagnoses are shown in Table 1. The clinical stages of primary lung cancer were T1N0M0 in 16 patients, T2N0M0 in eight patients, and T3N0M0 in three patients. The primary lesions in the four patients with metastatic lung tumors are shown in Table 2. The pulmonary function and clinical background (presence of chronic obstructive pulmonary disease, quantity of cigarettes smoked, and other factors) of the patients were not closely evaluated in this study.

CT Imaging
Follow-up CT examinations (Xvigor; Toshiba Medical Systems, Tokyo, Japan) were performed regularly every 2–3 months in the 1st year after radiation therapy and every 3–6 months thereafter for the evaluation of tumor response and the detection of radiation-induced pulmonary injury after SRT. CT examinations were performed by using a conventional nonhelical technique at 120 kVp, 200 mAs, 5-mm collimation around the tumor, and 10-mm collimation at other sites. One hundred milliliters of nonionic iodinated contrast agent were administered intravenously at a rate of 1.0 mL/sec (for the initial 40.0 mL) and 0.5 mL/sec (for the remainder) by using an automatic injector, and the scanning delay was 60 seconds.

The tumor response at CT was evaluated by using both lung window (level, -700 HU; width, 900 HU) and soft-tissue window (level, 60 HU; width, 400 HU) settings. Response Evaluation Criteria in Solid Tumors, or RECIST, was used for the evaluation of therapeutic efficacy on CT images (15) (Table 3). The tumor sizes were measured by a board-certified radiologist (T.A.) by using a CT image obtained at the isocenter level. If the tumor location changed because of a change in lung volume at follow-up CT, the tumor size was measured on the section in which the tumor appeared to show the largest size. The National Cancer Institute’s Common Toxicity Criteria (16) (Table 4) were used to evaluate clinical complications of the respiratory tract. Grading was performed by one of the authors (Y. Nagata). The CT appearance of radiation-induced pulmonary injury was classified into four patterns (by T.A.) according to the categories reported by Libshitz and Shuman (10): (a) homogeneous slight increase in opacity that uniformly involves the irradiated portions, (b) patchy consolidation within the irradiated lung that does not conform to the shape of radiation portal, (c) discrete consolidation that conforms to the shape of the radiation portal but does not uniformly outline it, and (d) solid consolidation that conforms to and totally involves the irradiated portions of the lung.

In areas that demonstrated radiation-induced pulmonary injury at CT, the threshold lung dose was evaluated by one of the authors (T.A.), who compared the dose distribution at the treatment-planning CT examination and the maximal extent of pulmonary changes at the follow-up CT examination. The isodose curve was made for every 4 Gy in total at treatment-planning CT, and an image fusion between the treatment-planning CT images and the follow-up CT images was manually established by referring to the bony structures. Since the extent of pulmonary injury did not always conform to the isodose curve, the minimal dose in the area demonstrating the pulmonary changes was recorded. If the volume of the involved lung changed, surrounding structures on the CT images, such as pulmonary vessels, bronchi, or fissures, were also used for reference. In addition, the correlation between the minimal lung dose and V20 was evaluated to assess whether there was a dose-volume relationship affecting the likelihood of pulmonary injury.

Statistical Analysis
Spearman rank correlation coefficient was used to assess the correlation between the minimal lung dose (when radiation-induced pulmonary injury appeared on CT images) and V20. Statistical significance was defined by P < .05.

	RESULTS

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The planning target volume was 0.5–38.6 cm³ (median, 15.1 cm³). The maximum dose of the planning target volume was 100.4%–105.0% (median, 102.3%), and the minimum dose of the planning target volume was 84.7%–96.9% (median, 92.5%) of the isocenter dose. The V20 was 1.0%–11.6% (median, 4.6%).

Patients underwent follow-up CT examinations for 2–31 months (median, 14 months) after SRT. The maximal responses on CT images were complete response in five patients, partial response in 24 patients, and progressive disease in two patients (Table 5). Thus, the overall response rate (combined complete response and partial response) was 94% (29 of 31). In some cases it was difficult to distinguish the residual tumor from radiation fibrosis, and, therefore, we assessed any suspicious residual irregular density after SRT as a residual tumor.

View larger version (18K): [in this window] [in a new window] [Download PPT slide]   Figure 1. Graph shows the changes in tumor sizes in all patients. The tumor size was measured as the product of the widest diameter and the perpendicular diameter of the target. Measurements were obtained in the CT image showing the greatest tumor size of each image set.

View larger version (66K): [in this window] [in a new window] [Download PPT slide]   Figure 2. Transverse CT images obtained in a 69-year-old man with primary lung cancer (T1N0M0, adenocarcinoma) show a representative case of the clinical course after SRT. The irregularly shaped patchy consolidation and homogeneous slight increase in opacity appeared around the tumor 4 months after SRT; after 6 months, a new patchy consolidation appeared. Afterward, the patchy consolidation diminished and changed to solid consolidation with scarring. Although it can not be accurately distinguished between the residual tumor and the solid consolidation in the image 15 months after SRT, no recurrence was observed, even in the 25- and 31-month images, and the tumor was considered as showing partial response.

View larger version (111K): [in this window] [in a new window] [Download PPT slide]   Figure 3. Transverse CT images show a representative case of patchy consolidation. Left: Image obtained for treatment planning at the isocenter. Right and bottom: Images obtained 5 months after SRT show an irregularly shaped consolidation that does not conform to the dose distribution curve. It is visible with the lung window setting (top right) and can be partially detected with the soft-tissue window setting (bottom).

View larger version (110K): [in this window] [in a new window] [Download PPT slide]   Figure 4. Transverse CT images show a representative case of homogeneous slight increase in opacity. Left: Image obtained for treatment planning at the isocenter. Right and bottom: Images obtained 6 months after SRT. The opacity around the tumor (arrow) was slightly and homogeneously increased with the lung window setting (top right), and there were no abnormal shadows around the tumor with the soft-tissue window setting (bottom).

View larger version (109K): [in this window] [in a new window] [Download PPT slide]   Figure 5. Transverse CT images show a representative case of solid consolidation. Left: Image obtained for treatment planning at the isocenter. Right and bottom: Images obtained 13 months after SRT. Consolidation involving the tumor and surrounding lung tissue in the treatment-planning CT image was observed with the lung window setting (top right), and most of this consolidation was detectable with the soft-tissue window setting (bottom).

View larger version (80K): [in this window] [in a new window] [Download PPT slide]   Figure 6. Transverse CT images show a representative case of discrete consolidation. Left: Image obtained for treatment planning at the isocenter. Right and bottom: Images obtained 10 months after SRT. Consolidation (arrows) involving the high-dose area ( 24 Gy) (not strictly conforming to the 24 Gy isodose line) in the treatment-planning CT image was observed with the lung window setting (top right) and could be partially detected with the soft-tissue window setting (bottom).

View larger version (89K): [in this window] [in a new window] [Download PPT slide]   Figure 7. Transverse CT images show a representative case of wedge-shaped radiation-induced pulmonary injury. Left: Image obtained for treatment planning at the isocenter. Right and bottom: Images obtained 5 months after SRT. Wedge-shaped discrete consolidation involving the hilar and peripheral side of the tumor was observed. This shadow did not conform to any isodose curves.

View larger version (86K): [in this window] [in a new window] [Download PPT slide]   Figure 8. Transverse CT images show a representative case of round-shaped radiation-induced pulmonary injury. Left: Image obtained for treatment planning at the isocenter. Right and bottom: Images obtained 4 months after SRT. Round-shaped patchy consolidation was observed around the tumor (arrows).

View larger version (114K): [in this window] [in a new window] [Download PPT slide]   Figure 9. CT image shows the isodose curve superimposed on radiation-induced pulmonary change 4 months after SRT. In this case, the pulmonary change (contoured with a thick dashed line) appeared on and within the 16-Gy line (thick solid line). The outer thin dashed line indicates the 12-Gy line, and the inner thin solid line indicates the 20-Gy line.

View larger version (12K): [in this window] [in a new window] [Download PPT slide]   Figure 10. Graph shows correlation between the minimal dose at which radiation-induced pulmonary change occurred and the V20. The dose distribution at CT generated by the three-dimensional treatment-planning system and the radiation-induced pulmonary changes at follow-up CT were compared, and the minimal dose for the appearance of pulmonary change was determined. There was a significant inverse correlation between the minimal dose and V20.

	DISCUSSION

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It was sometimes difficult to distinguish radiation-induced pulmonary change from a tumor, presumably because of the difference in the shape of the irradiated lung between SRT and conventional radiation therapy. In SRT, multiple noncoplanar portals with various directions were used. The shape of the dose distribution with a lower dose tended to become large and irregular, while a higher dose could be concentrated uniformly on the tumor. In contrast, in conventional radiation therapy, the shape of the dose distribution of irradiated lungs was simple, and the boundary between the nonirradiated and irradiated lung was usually distinct. In the evaluation of the patients who have undergone SRT, radiologists should not hastily judge volume progression around the tumor to be local recurrence. Of course, it is an essential problem to determine whether viable cells are present in the fibrotic scar after SRT. In this study, autopsies were not performed in any patients. Therefore, we could not confirm the results by using histologic examination, and, at present, close follow-up studies are necessary to make a correct diagnosis. Other modalities, such as positron emission tomography, may also help in evaluating the tumor response and detecting tumor recurrence (17–19).

In this study, tumor shrinkage lasted 2–15 months (median, 6 months) after SRT; that is, even if a higher radiation dose was delivered with hypofractionated SRT in comparison with the radiation dose with conventional radiation therapy, the tumor did not always reduce rapidly.

The CT appearances of pulmonary changes after conventional radiation therapy were classified by Libshitz and Shuman (10) into four patterns, as stated previously. The homogeneous pattern and the patchy pattern correspond to the acute exudative phase of radiation-induced injury, the discrete pattern corresponds to the organizing or proliferative phase, and the solid pattern corresponds to the chronic fibrotic phase (14). In our study, this classification was extended to SRT because the shape of the dose distribution differed from that in conventional radiation therapy. As a result, the patterns could be grouped by using the Libshitz and Shuman classification. In our study, the patchy consolidation pattern was predominantly seen as an acute change, and the solid consolidation pattern, which would reflect radiation fibrosis, was predominantly seen as a late change.

In conventional radiation therapy, acute pulmonary changes usually occur about 1–8 months after the completion of radiation therapy (10,12,14,20,21). In this study, the initial pulmonary changes at CT appeared 2–6 months after the completion of radiation therapy, which is similar to the results in conventional radiation therapy. If a new pulmonary opacity coinciding with the high-dose area (16 Gy) appears within 6 months after SRT, radiologists should consider the appearance of radiation-induced pulmonary change.

Chronic fibrous changes were also evaluated in our study. The solid consolidation pattern, which was regarded as chronic fibrous change, was seen 6–15 months after SRT, and no solid consolidation was seen as the predominant pattern until more than 6 months after SRT in this study. The solid consolidation pattern was usually observed 6–24 months after conventional radiation therapy (12,14,20).

It is important to note that none of the patients with pulmonary changes on transverse CT images had clinically severe (grade 2 or more) symptoms in this study. The reason is assumed to be that the lung volume irradiated with a very high dose was relatively small, and there was sufficient nonirradiated lung tissue since the lung is regarded as the parallel organ. Graham et al (22,23) reported the correlation between radiation pneumonitis and the dose-volume relationship in three-dimensional conformal radiation therapy with conventional fractionation. In the study by Graham et al (22), the V20 was significantly (P = .001) correlated with the presence of grade 2 or higher radiation pneumonitis, and if the V20 was less than 25%, 25%–37%, or more than 37%, the incidence of radiation pneumonitis would be estimated at 0%–4%, 2%–12%, or 19%–30%, respectively. In our study, the V20 in all patients was less than 25%; therefore, it is consistent that none of our patients developed clinically important pneumonitis from the point of the dose-volume relationship. However, further investigation will be needed as to whether applying the results of Graham et al directly to our own is appropriate, because the fraction size and overall treatment time were different between conventional radiation therapy and SRT.

In our study, the pulmonary function and clinical background of the patients were not closely evaluated. Therefore, further evaluation that includes the change in pulmonary function is desirable.

In this study, the minimal dose for which pulmonary injury appeared on CT images of each patient was 16–36 Gy. These doses were substantially lower in patients with a higher V20. That is, the minimal dose to the injured lung was related to the percentage volume that received more than 20 Gy. Although a dose-volume relationship has been reported for the occurrence of radiation injury in the rectum after prostate cancer treatment (24,25), to our knowledge ours is a new finding not previously reported for lung injury. The cells for repair may migrate in the injured lung from the normal tissue that received a low dose, and the further that low-dose region is from the region of injury, the less likely it is that the injured cell can be repaired. This explanation is only speculative, and our follow-up period was not very long. Therefore, further follow-up studies are necessary.

In conclusion, the CT appearance of radiation-induced pulmonary injury from SRT of the lung seems similar to that from conventional radiation therapy. However, the extension of the change on CT images should be interpreted by considering the shape of dose distribution peculiar to SRT.

	ACKNOWLEDGMENTS

 
The authors gratefully acknowledge Daniel Mrozek, BS, for helping with the English translation.

	FOOTNOTES

 
Abbreviations: SRT = stereotactic radiation therapy, V20 = percentage volume of the whole lung irradiated by more than 20 Gy in total

Author contributions: Guarantor of integrity of entire study, Y. Nagata; study concepts, T.A.; study design, Y. Nagata; literature research, T.A.; clinical studies, all authors; data acquisition, T.A.; data analysis/interpretation, T.A., Y. Nagata; statistical analysis, T.A.; manuscript preparation, T.A., Y. Nagata; manuscript definition of intellectual content and editing, Y. Nagata; manuscript revision/review and final version approval, T.A., Y. Nagata, M.H.

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This Article Abstract Figures Only Full Text (PDF) All Versions of this Article: 2301021226v1 230/1/101    most recent Submit a response Alert me when this article is cited Alert me when eLetters are posted Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Citing Articles Citing Articles via HighWire Citing Articles via Google Scholar Google Scholar Articles by Aoki, T. Articles by Hiraoka, M. Search for Related Content PubMed PubMed Citation Articles by Aoki, T. Articles by Hiraoka, M.