ORIGINAL 
Annals of Nuclear Medicne Vol 3 No. 2, 73-81, 1989 
Gallium-67 citrate imaging for the assessment of radiation pneumonitis 
Masaaki KATAOKA 
Department of Radiology, Ehime University School of Medicine 
In order to evaluate its usefulness in the assessment of radiation pneumonitis, gallium-67 citrate (67Ga) imaging was performed before and after radiation therapy (RT) on 103 patients with lung cancer. In 23 patients with radiation pneumonitis detected radiographically, ab-normal 67Ga uptake in sites other than tumors was found in all pOSt-RT 67Ga lung images. Three patterns of uptake were found : (A), focal uptake corresponding to the RT field (n= 10); (B), diffuse uptake including the RT field (n=4), and (C), diffuse uptake outside the RT field (n=9). The area of 67Ga uptake was consistent with that of interstitial pneumonitis as revealed histopathologically in 7 cases. 67Ga uptake in pattern (C) was an indicator of poor prognosis for the patients with radiation pneumonitis. 67Ga uptake in the patients with reversible pneumonitis disappeared with steroid therapy. Sixteen (20%) of 80 asymptomatic patients, in whose chest radiographs there was no finding of radiation pneumonitis, showed transient 67Ga uptake. These were considered to occur in the subclinical radiation pneumonitis. These data suggest that 67Ga imaging is more sensitive than chest radiography in the detection of radiation pneumonitis and is useful in the assessment of the extent and clinical course of radiation pneumonitis. 
Key words : 
Radiation pneumonitis, Gallium imaging, Radiation injury to the lung. 
INTRODUCTION 
SINCE ITS INTRODUCTION by Edwards and Hayes,1 gallium-67 citrate (67Ga) imaging has been widely used in imaging a variety of neoplasms and inflammatory lesions.2-4 In inflammatory lesions of the lung, including sarcoidosis,5,6 Pneumocystis carinii infection 7 drug-induced pneumonitis,8 and idiopathic interstitial pneumonitis,9,10 67Ga imaging has been reported to be helpful in determining the degree of activity of the disease process and its spatial extent. In patients who received radiation therapy (RT) for lung cancer, radiation injury to the lung is one of the most common complications, and is characterized by an acute and chronic reaction.n An acute reaction called radiation pneumonitis usually begins 
Received September 26, 1988 ; revision accepted December, 12, 1988. * This paper was presented at the 35th Annual Meet-ing of The Society of Nuclear Medicine in San Francisco. Send correspondence and reprint contacts to Masaaki Kataoka, M.D., Department of Radiology, Ehime University School of Medicine, Shitsukawa, Shigenobu-cho, Onsen-gun, Ehime 791-02, JAPAN 
l to 3 months after RT, and may subside leaving no clinical or radiologic residua or may progress to an irreversible chronic pulmonary fibrosis.12-14 Radiation pneumonitis occurs in only a small proportion of treated patients, but sometimes causes severe respiratory distress and even death.15-19 It is, therefore, really important to establish its extent and to estimate the clinical course. In this paper, we have assessed the usefulness of 67Ga imaging in determining the extent and clinical course of radiation pneumonitis by comparing it with clinical symptoms, chest radiographs, and histopathologic findings in the lung. 
MATERIALS AND METHODS 
Between November 1976 and December 1985, 189 patients with non-resected lung cancer were treated with RT at the Department of Radiology, Ehime University Hospital. One hundred and three patients were included in this study according to the follow-ing criteria for patient selection : (a) 67Ga imagings were performed before and after RT ; (b) the tumor dose was over 50 Gy in patients with non-small cell lung cancer (NSCLC), and over 20 Gy in patients with small cell lung cancer (SCLC) ; (c) the clinical course of each patient was known ; (d) no previous RT was received. Of these criteria, (b) was the most important in patient selection, as about 40 % of the 1 89 patients had reached a stage of cancer too advanced to treat with the intention of curing it. Eighty-eight (85.4%) were males and 15 (15.6%) females. Their ages ranged from 33 to 86 years (mean age, 67 years). Each patient was irradiated with X-ray from a 10 MV linear accelerator, using parallel opposing anterior and posterior portals. The target volume included the lung tumor defined by chest radiography or computed tomography, plus 1 to 2 cm margin, plus adjacent hilar and mediastinal structures, even if the tumor did not extend to these structures. The tumor dose was 50 Gy to 90 Gy (mean, 67 Gy) in NSCLC patients, and 20 Gy to 70 Gy (mean, 43 Gy) in SCLC patients in a conventional fractionation schedule (1.8-2.0 Gy/fraction/day). Chemotherapy was combined with RT in about a half of the NSCLC patients, and in all of the patients with SCLC. Regimens of chemotherapy,20-23 which varied from patient to patient, are summarized in Table 1 . According to their clinical symptoms of radiation pneumonitis, the findings of chest radiograph, and their response to steroid therapy, patients were graded into 3 classes as follows : (1) asymptomatic: patients who had no evidence of radiation pneumonitis on the chest radio-graph and no symptoms of radiation pneumonitis; (2) reversible : symptomatic patients who had radiation pneumonitis in the chest radiograph, but whose symptoms disappeared with steroid therapy ; (3) fatal : patients who died of radiation pneumonitis. The diagnosis of radiation pneumonitis was established collectively, from the clinical symptoms, chest radiography, positive C reactive protein, increased erythrocyte sedimentation rate, the refractoriness to antibiotics therapy, and/or, in the cases of 7 patients, from the histopathology of the lung. 67Ga imaging was performed 72 hours after intravenous injection of 111 MBq (3 mCi) of 67Ga, with a large-field-of-view gamma camera with three energy window settings and a medium-energy parallel hole collimator. The first post-RT imaging was performed at a time ranging from O to 8 weeks (mostly within one month) after the completion of RT. The second post-RT imaging was performed within 5 months after the completion of RT, if clinically indicated. All 67Ga images, including those obtained before RT, were retrospectively compared and analyzed for abnormal 67Ga uptake in sites other than the original or recurrent tumors. 67Ga images after RT were classified as positive when the pulmonary uptake in sites other than tumors exceeded the body back-ground, and were classified as negative in the other cases. Routine chest radiography was performed once a week for the first month after the end of RT, at 2-week intervals during the second month, and at 1-month intervals thereafter. Additional radiography was carried out when radiation pneumonitis was suspected, or 67Ga images were positive. We com-pared the findings in 67Ga images with clinical symptoms and with the chest radiograph findings, and in 7 patients with the histopathology of the lung. 
RESULTS 
(1) The relationship between the patterns of 67Ga uptake and the extent and clinical course of radiation pneumonitis 
In 39 out of 103 cases, 67Ga images after RT showed abnormal pulmonary uptake in sites other than the original or recurrent tumors. These cases bore no evidence of bacterial pneumonia, viral infection or of pneumocystis carinii infection from radiographic examination and/or histopathological examination at biopsy or autopsy. Four patterns of 67Ga uptake were found in these cases as shown in Figure 1 : types O, A, B, and C. The relationship between these pat-terns of 67Ga uptake and the previously described clinical gradings of pneumonitis are summarized in Table 2. When type O changed to type A, O to B, O to C, A to B, A to C, or B to C in follow-up 67Ga images, each patient was classified into the latter type. Sixteen (20%) of the asymptomatic cases revealed positive 67Ga images. All of the 23 symptomatic (reversible and fatal) cases showed positive 67Ga images, which were distributed in type A, B, or C. In the non-chemotherapy group, 67Ga uptake outside the RT field (i.e., types B and C) was noted in 6 cases. Seven (78%) out of those who had 67Ga uptake in type C had been treated with chemotherapy combined with RT, and 5 (56 %) had fatal pneumonitis. Six (26 %) of the 23 symptomatic cases were a-symptomatic when their 67Ga images showed positive findings but became symptomatic later. Changes in the pattern of 67Ga uptake in 21 patients on whom 67Ga imagings were performed twice or more within 5 months after RT are shown in Figure 2. In 7 asymptomatic cases, type A or B changed to type O in 1 to 5 months without any therapy. In 6 out of 10 reversible cases, type A, B, or C changed to type O with steroid therapy, and in 4 cases, a third post-RT imaging was not performed. In 4 fatal cases, type O or A changed to type C, and 3 out of 4 cases died of radiation pneumonitis within a month after the 67Ga image showed type C. A fatal case is shown in Figure 3. 
(2) Comparison of 67Ga uptake with pulmonary histopathology 
In 7 cases, histopathological examination of the lung with abnormal 67Ga uptake was performed by trans-bronchial biopsy or autopsy. Biopsies were performed on 2 patients immediately after the 67Ga images had shown positive findings, and autopsies were per-formed on 4 patients with fatal pneumonitis, and on one patient who had active pneumonitis but died of 
another cause. Patient characteristics and the histopathological classification24,25 of the lung in these cases are shown in Table 3. In 4 patients, who were treated with RT alone, the lung outside the RT field with abnormal 67Ga uptake proved to have mild to severe interstitial pneumonitis due to irradiation. In 3 patients who were treated with chemotherapy combined with RT, the lung outside the RT field with abnormal 67Ga uptake proved to have mild to severe interstitial pneumonitis, or pulmonary fibrosis due to chemotherapy and/or irradiation. An asymptomatic case is shown in Figure 4. 
DISCUSSION 
67Ga uptake in the irradiated lung was first described by Schoot, et al in 1972.26 They reported that transient 67Ga uptake in the irradiated field was seen in 5 patients out of 6 who were restudied 2 months after the completion of RT. Gupta, et al27 described diffuse 67Ga uptake in radiation pneumonitis after focal irradiation of the lung. There have been few reports on the correlation between 67Ga imaging findings and clinical and radiologic findings.28 This study demonstrates that 67Ga imaging showed transient 67Ga uptake in 20 % (16 cases) of the asymptomatic patients, who had no clinical evidence of radiation pneumonitis. Histopathological examination of the lung at biopsy in one patient proved that the lung with such transient 67Ga uptake had mild interstitial pneumonitis, which was considered to be subclinical radiation damage (Fig. 4). The 67Ga imaging depicted subclinical and silent radiation pneumonitis which could not be detected on chest radiography. These findings suggest that 67Ga imaging is more sensitive than chest radiography in the detection of radiation pneumonitis. Detecting an asymptomatic patient may seem to have no clinical significance, because the asymptomatic cases do not need any therapy. However, 23 (59 %) of the patients with positive 67Ga images already had clinical radiation pneumonitis at that time (17 cases) or later (6 cases). It is, therefore, considered important to give pause to adding more chemotherapy and irradiation in asymptomatic patients with positive 67Ga images and to search for the cause of 67Ga uptake or follow those patients carefully. One of the roles of 67Ga imaging in radiation pneumonitis is believed to detect patients who are susceptible to radiation pneumonitis. Pulmonary 67Ga uptake after RT would be a risk factor for radiation pneumonitis. It is believedthat 67Ga imaging should be performed in cases wherein the occurrence of radiation pneumonitis is suspected or in cases who have risk factors for radiation pneumonitis, such as a large irradiated lung volume, a large radiation dosage, a preexisting chronic lung disease, a chemotherapy combined with irradiation, old age, etc. In symptomatic cases, all 67Ga images were positive. These were classified into three types. Type A showed the direct effect of irradiation on the lung, which might have occurred in the rapidly proliferating connective tissue cells present after RT.29 Type B in the non-chemotherapy group suggested that radiation pneumonitis had spread beyond the irradiated lung, as proved histopathologically in selected cases treated with RT alone. Such diffuse 67Ga up-take, of course, should be carefully differentiated from bacterial pneumonia, viral infection, pneumocystis carinii infection, and tumor extension. Al-though it is controversial whether radiation pneumonitis extends over the irradiated lung or not, a few cases with radiation pneumonitis extending out-side the RT field radiographically or histopathologically have been reported (15-19, 30). The present study supports the possibility that radiation pneumonitis sometimes extends beyond the irradiated lung. Two theories may be considered to account for this extension : (1) mediastinal lymphatic blockadel5 and (2) hypersensitivity immune reaction.16,31 The third pattern of 67Ga uptake for radiation pneumonitis was designated type C. The clinical implications of type C in non-chemotherapy groups were still only slightly understood at the time of the present study, for want of histopathological specimens. Prato et al32 emphasized that an early decrease in regional blood flow was significant in the irradiated lung. It is possible that decreased regional blood flow may lead to decreased 67Ga uptake. It is also likely that radiation pneumonitis spreading outside the RT field in these patients occurred in the same manner as in type B. In the chemotherapy group, the effects of both drug and irradiation on the lung contributed to the findings in 67Ga images. Several chemotherapeutic agents have been reported to interact with irradiation33-35 and cause pulmonary damage them-selves.36-38 In addition 67Ga uptake in drug-induced pneumonitis is well known.8 Type C in the chemotherapy group consisted of a 67Ga negative area in the RT field and a positive area outside the RT field, and the findings in the chest radiograph and the microscopic findings in the lung suggested that the former was radiation fibrosis and the latter drug-induced and/or radiation-induced pneumonitis. The patients whose 67Ga image was type C in both the non-chemotherapy and chemotherapy groups suffered from reversible (in 4 cases) or fatal (in 5 cases) radiation pneumonitis. It is likely that the 67Ga up-take of type C would be an indicator of poor prognosis for the patients with radiation- and/or drug-induced pneumonitis. 67Ga uptake of type B, however, would not be an indicator of poor prognosis, as most of the patients with type B had asymptomatic (55.6%) or reversible (33.3%) pneumonitis (Table 2). The close relationship between radiation pneumonitis and 67Ga uptake is evident in our study of the reversible cases (Fig. 2), where 6 cases out of 10 showed negative images after steroid therapy (follow-up imaging was not performed in 4 cases). This observation corresponds to the reported results in sarcoidosis 2,5,6 tuberculosis 2 and in idiopathic pulmonary fibrosis.9,10 The follow-up 67Ga imaging is a sensitive indicator of the assessment of the response to steroid therapy in patients with radiation pneumonitis. In conclusion, 67Ga imaging is a sensitive tool for the detection of radiation pneumonitis and a useful indicator both for the assessment of the extent of radiation pneumonitis and for the estimation of the prognosis of the patients suffering from radiation pneumonitis. Follow-up 67Ga imaging is also fundamental for the assessment of the response to steroid therapy. 
ACKNOWLEDGMENTS 
The author is grateful to Professor K. Hamamoto, M.D., Department of Radiology, Ehime University School of Medicine, and Professor WN. Tauxe, M.D., Department of Nuclear Medicine, University of Pittsburgh Hospital for a lot of useful advice in carrying out this study. The author wishes to thank Associate Professor N. Ueda, M.D., First Department of Pathology, Ehime University School of Medicine, for his assistance in re-viewing the pathologic materials. This study was in part supported by a grant from the Ehime Health Foundation. 
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