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Original Report |
1 Division of Diagnostic Imaging, Department of Diagnostic Radiology, The
University of Texas M.D. Anderson Cancer Center, Box 57, 1515 Holcombe Blvd.,
Houston, TX 77030.
2 Department of Surgery, The Texas A & M University System, Health Science
Center, Temple, TX 76508.
3 Division of Radiation Oncology, The University of Texas M. D. Anderson Cancer
Center, Houston, TX 77030.
Received April 12, 2004;
accepted after revision July 28, 2004.
Address correspondence to R. F. Munden.
Abstract
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CONCLUSION. Abnormal hepatic enhancement after extrapleural pneumonectomy and IMRT is common in patients with mesothelioma. Knowledge of the early occurrence and typical location and appearance of IMRT-induced injury can be useful in preventing misinterpretation as metastatic disease or recurrent tumor.
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IMRT is a new technique of conformal radiation therapy that is useful in treating irregularly shaped tumors while limiting injury to adjacent organs. It is based on the use of optimized non-uniform radiation beam intensities [4]. IMRT treatment plans are often generated with inverse planning or automated optimization that use computer optimization techniques to help determine the distribution of beamlet intensities across the target volume. The beamlets are distributed by computer-controlled multileaf collimators. IMRT can reduce toxicity in normal tissue, such as the parotid gland in head and neck neoplasms [5] and the rectum in prostate cancer [6], compared with standard techniques. In other disease sites with complex target volumes, IMRT generally results in superior dose distributions compared with more traditional 3D conformal techniques.
Preliminary survival results at our institution suggest that IMRT has the potential to increase cure rates for mesothelioma. In this study of 50 patients, there has only been one local (in-field) failure [3]. However, because of the close proximity of the liver to the pleural space, radiation injury to the liver from treatment for mesothelioma cannot be completely avoided. We report the appearance of radiation injury to the liver in patients with mesothelioma who underwent IMRT treatment after right extrapleural pneumonectomy.
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Twenty patients at our institution underwent IMRT after right extrapleural pneumonectomy for histologically confirmed mesothelioma: two women and 18 men with an average age of 59 years (range, 46-76 years). Nineteen patients had chest CT scans (n = 34) and one patient had abdominal CT scans (n = 3). Of the 34 chest CT scans, 31 were obtained with a LightSpeed Plus MDCT scanner (GE Healthcare) using a 3.8-mm slice thickness and three were obtained with a CTi single-slice helical CT scanner (GE Healthcare) using a slice thickness of 7 mm. The abdominal CT scans were obtained with an MDCT scanner using a 7-mm slice thickness. All examinations were performed with IV contrast injection of 150 mL of iohexol (Omnipaque 350, Nycomed Amersham) at a rate of 3.0-5.0 mL/sec. For chest CT, a delay of 25 sec was used and the liver was therefore imaged approximately 45 sec after contrast administration. Abdominal CT was performed with a delay of 60 sec. Two board-certified radiologists reviewed pre- and posttreatment CT scans, and findings were made by consensus. Images were reviewed on a PACS workstation (iSite, Stentor) using mediastinal (window level, 40 H; window width, 400 H) and liver (window level, 20-40 H; window width, 100-140 H) window settings. CT scans were correlated with radiation dosimetric treatment curves. IMRT was contoured according to intraoperative placement of radiopaque markers, and target volumes included the ipsilateral chest wall, the mediastinum, the anteromedial pleural reflection, and the area of insertion of the diaphragm and crus. Medical records were reviewed with regard to hepatic symptomatology and function.
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Review of the radiation dosimetric treatment curves for each patient showed that the bandlike hepatic abnormality correlated with the radiation treatment portals. The abnormal hepatic enhancement in all patients corresponded with the region of highest radiation dose (> 45 Gy). The average time from completion of IMRT to the CT examination for all patients was 16 weeks (range, 3-116 weeks). In those patients with an unusual pattern of enhancement of the liver, the average time between IMRT completion and CT examination was 8 weeks (range, 5-11 weeks). In the group with a normal-appearing liver, the average time between IMRT completion and CT examination was 21 weeks (range, 3-116 weeks); however, if the one patient with 116-week follow-up is excluded, the average time between IMRT completion and CT examination was 12.5 weeks (range, 3-32 weeks). All patients with an IMRT-induced hepatic abnormality were asymptomatic and had normal results on liver function tests.
Follow-up CT scans were available for five of the eight patients with radiation injury to the liver. One patient died from unrelated illnesses, and another died from diffuse metastatic disease. One patient was lost to follow-up. For the five patients with follow-up CT examinations, the average time between the discovery of abnormal CT findings and follow-up was 27.2 weeks (range, 6-54 weeks). In four of the patients, the appearance of the liver returned to normal, and in the other patient, an area of increased attenuation developed.
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IMRT is a new technique of conformal radiation therapy that is useful in treating irregularly shaped tumors while limiting injury to adjacent organs. Traditional conformal radiation therapy uses radiation that is delivered through multiple photon beams of uniform intensity that may be modified by a wedge or in other simple unidimensional manners. In IMRT, each photon beam is subdivided into small beamlets with the intensity of each beamlet varied by computer-controlled dynamic multileaf collimators. Therefore, the dose distributions of radiation can be shaped to conform to irregular tumor margins and also to avoid critical normal tissue of the target organ or surrounding organs. Because of the ability to use IMRT techniques to treat irregularly shaped tumors and spare nearby normal organ parenchyma, IMRT has been adapted to treat cancers of the breast, head and neck, prostate, and pleura (mesothelioma) [8]. Recently, IMRT has been adapted to treat patients with malignant mesothelioma who have undergone extrapleural pneumonectomy [9]. Adaptation of IMRT in these patients is especially valuable because of the large and irregular tumor bed that needs to be treated and because of the ability to limit radiation injury to the adjacent organs. IMRT in these patients results in a concave distribution of radiation dose to the outer edge of the liver, thus keeping the dose to the inner two thirds of the liver below 30 Gy. Even so, the peripheral 5-10 mm of the liver is exposed to radiation doses above 30 Gy and thus is susceptible to radiation injury.
Clinical radiation injury of the liver has been reported to occur in 6-66% of patients whose livers are irradiated [10-12]. Factors that are more likely to result in hepatic toxicity include whole-liver irradiation and doses greater than 30 Gy. Acute radiation hepatitis usually occurs within 2-6 weeks after completion of radiation therapy and presents with right upper quadrant discomfort. Liver function is also often abnormal but usually returns to normal [13]. The radiologic appearance of radiation injury to the liver has been well described [10, 14, 15]. Conventional radiation treatment ports of the liver are usually in the anteroposterior or oblique orientation, and liver injury typically corresponds to these ports. Radiation injury to the liver usually presents in the acute phase as an area of sharply demarcated low attenuation. On histologic evaluation, the low attenuation is from edema and variable amounts of fatty infiltration and lipofuscin-laden macrophages [16]; the low attenuation most often resolves. MRI of the acute injury reveals high signal on T2-weighted imaging that is thought to be related to increased water content [17].
Eight of our cases presented with an area of low attenuation at the periphery of the liver, indicating acute radiation injury (Fig. 1). Although the appearance was typical for acute radiation injury, the distribution was not typical. When the area of low attenuation of the liver on CT was compared with the IMRT dose distributions (Figs. 2A, 2B, 2C, and 2D), there was correlation of the high-dose regions (> 45 Gy) with liver changes on CT. Follow-up CT scans were available for five of the eight patients with radiation injury to the liver. For these five patients, the average time between the discovery of abnormal CT findings and follow-up was 27.2 weeks (range, 6-54 weeks). In one of these patients, the area of acute injury visualized on the initial CT scan developed a region of high attenuation seen on the follow-up CT scan. This appearance of chronic injury of the liver has been reported to occur when there is fatty infiltration of the normal liver but sparing of infiltration into the irradiated liver because of radiation injury [16]. In the other four patients, the appearance of the liver returned to normal. Interestingly, in one of these four patients, areas of high and low attenuation were seen on the first follow-up CT scan obtained at 11 weeks (Figs. 3A, and 3B). On subsequent follow-up CT scans obtained at 15 and 27 weeks, the liver exhibited increased attenuation but then was found to have returned to normal at the 1-year follow-up. One patient underwent MRI 11 weeks after IMRT because of the abnormal CT findings (Figs. 2A, 2B, 2C, and 2D). The MR images revealed nodular areas of increased signal on T2-weighted imaging and enhancement of the nodular areas on T1 imaging after administration of contrast material. The nodular areas were within a band of low signal that correlated with the IMRT radiation field. Unfortunately, longer follow-up was not available, but at the time that the scan was obtained, the results of the patient's liver function test were normal (alanine aminotransferase, 39 IU/L; aspartate aminotransferase, 24 IU/L).
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The reason that some patients developed radiographic changes in the liver and others did not is not clear. Because radiation injury to tissue is a stochastic event and this was not a prospective study with required CT at regular intervals, some cases of liver injury may have been missed. Other patients may have been more resistant to radiation-induced cell death because of differences in intrinsic radiation sensitivity. Abnormal results of liver function tests were uncommon probably because only a small portion of the liver showed radiographic changes, so the changes in liver function test values may have been so small that they did not exceed the normal range. Alternatively, the changes may have been rather sudden and so were missed by sampling times. Now that these changes have been identified, it will be important to prospectively evaluate the significance of these events.
Limitations of our study are due to the inherent limitations of a retrospective study including variability in imaging intervals. The variation in the timing of the CT examinations prevents assessment of the temporal sequence of CT findings of liver changes. When reviewing the average time interval between IMRT completion and CT examination in the patients with abnormal and normal livers, we found a significant difference between these two groups. However, for one patient in the group with normal livers, the interval between IMRT completion and CT examination was 116 weeks, which altered the overall average. When this patient is removed from the calculations, the average interval for the patients with normal livers was 12.5 weeks, compared with 8 weeks for the patients with abnormal livers. More important, the interval for those patients with CT manifestations of IMRT-induced injury averaged 8 weeks, with a range between 5 and 11 weeks; there were five patients with normal livers with intervals within this range and a total of nine patients with intervals within 15 weeks. Therefore, it is unlikely that the timing of the CT examination had an impact on the detection of abnormal liver changes. To understand the temporal sequence of liver changes would require completion of a study with standardized time intervals for CT after IMRT therapy. A further potential limitation of the study is the lack of biopsy confirmation that the hepatic abnormalities were a manifestation of radiation-induced injury. However, the radiologic appearance on CT and MRI in the acute phase and the return to a normal appearance of the liver in four patients at follow-up is consistent with historic reports of radiation-induced injury to the liver. In fact, the appearance of IMRT-induced injury is typical and can be diagnosed with a high degree of certainty if the history of IMRT is known. Knowledge of the IMRT treatment field in these patients can be useful if radiologic manifestations of the hepatic injury are not typical. If needed, correlation with dose distributions can confirm the distribution of radiation therapy to the chest and abdomen in patients who have undergone extrapleural pneumonectomy for mesothelioma.
In summary, therapeutic doses of conventional radiation to the liver result in characteristic changes of the liver on radiologic images that are well described. IMRT, a unique form of radiation therapy that is being increasingly used in patients with mesothelioma, results in an unusual pattern of liver radiation injury. Awareness of IMRT-induced hepatic injury and the typical location and appearance can be useful in preventing misinterpretation as metastatic disease or recurrent tumor.
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This article has been cited by other articles:
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S. W. Anderson, J. B. Kruskal, and R. A. Kane Benign Hepatic Tumors and Iatrogenic Pseudotumors1 RadioGraphics, January 1, 2009; 29(1): 211 - 229. [Abstract] [Full Text] [PDF] |
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