AJR 2005; 184:1091-1095
© American Roentgen Ray Society
Radiation Injury to the Liver After Intensity-Modulated Radiation Therapy in Patients with Mesothelioma: An Unusual CT Appearance
Reginald F. Munden1,
Jeremy J. Erasmus1,
William R. Smythe2,
John E. Madewell1,
Kenneth M. Forster3 and
Craig W. Stevens3
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
OBJECTIVE. We sought to report the unusual distribution of
radiation-induced injury to the liver in patients with mesothelioma after
extrapleural pneumonectomy and intensity-modulated radiation therapy
(IMRT).
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.
Introduction
Malignant pleural mesothelioma is an uncommon tumor that arises from
mesothelial cells of the pleura. The prognosis is poor with a median length of
survival in untreated patients of 4 to 12 months
[1]. Local control is thought
to be the most important factor for improved survival but has been difficult
to accomplish. Single-technique therapies of surgery, chemotherapy, or
radiation therapy to accomplish local control have not shown a significant
increase in survival. However, results from recent studies have suggested that
extrapleural pneumonectomy and postoperative radiation offer the best local
control [1]. Because
conventional radiation therapy to the entire hemithorax must be limited
because of potential injury to adjacent organs
[2], intensity-modulated
radiation therapy (IMRT) is being used more frequently after pneumonectomy
[3].
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.
Materials and Methods
From November 2000 to November 2002, all CT scans of the chest and abdomen
of patients with right-sided mesothelioma who underwent extrapleural
pneumonectomy and IMRT were retrospectively reviewed under an institutional
review board-approved protocol. The goal in radiation therapy was to deliver
45 or 50 Gy to the target volume, with a boost to small areas of close or
positive margins up to a maximum of 60 Gy. All treatment was delivered in 25
fractions over 5 weeks. The target volume included the entire ipsilateral
hemithorax. Radiopaque clips placed during the extrapleural pneumonectomy
defined the inferior and anteromedial extent. The volume extended from the
thoracic inlet to the posterior diaphragmatic recess and included the
ipsilateral mediastinum and retrosternal pleura.
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.
Results
The liver was normal in all patients on the pretreatment CT scans. Eight
patients (40%) had an IMRT-induced abnormal enhancement pattern of the liver
that manifested as a focal bandlike region of low attenuation at the periphery
of the liver. One patient had an area of low attenuation in the upper aspect
of the liver and homogeneous high attenuation in the lower aspect. In all
these patients, the abnormality at the periphery of the liver was 1-3 cm in
the transverse dimension. Because of the unusual CT appearance of the liver,
one patient underwent MRI of the abdomen for evaluation of possible tumor
recurrence adjacent to the liver or metastatic disease. Similar to the CT
manifestations, T1-weighted images showed a bandlike area of decreased signal
in the periphery of the liver. This abnormality had regions of low and high
signal compared with the normal liver, and after IV administration of
gadolinium, contrast enhancement of this region was heterogeneous.
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.
Discussion
Malignant pleural mesothelioma is a rare tumor, with approximately 2,000
new cases diagnosed in the United States each year. Treatment options depend
on the stage at presentation. There is an increasing tendency to perform
surgical resection in cases of limited disease and to follow surgery with
radiation therapy [7]. However,
in those patients undergoing pleurectomy, the amount of radiation that can be
delivered is limited because of toxicity to the remaining lung. Recent studies
have suggested that combinations of extrapleural pneumonectomy and
postoperative radiation offer the best local control
[2]. Use of conventional
radiation therapy in the hemithorax after extrapleural pneumonectomy is
limited because of the large volume of tissue to be irradiated and because of
potential radiation injury to adjacent critical organs such as the heart,
spinal cord, kidney, and liver.
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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Fig. 1. —55-year-old man with mesothelioma who underwent extrapleural
pneumonectomy and intensity-modulated radiation therapy (IMRT).
Contrast-enhanced CT scan obtained 7 weeks after completion of IMRT shows
peripheral zone (arrows) of radiation injury to liver.
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Fig. 2A. —63-year-old man with epithelial mesothelioma who underwent
extrapleural pneumonectomy and intensity-modulated radiation therapy (IMRT).
On IMRT isodose image, green line indicates prescription line within which
minimum dose of 45 Gy of radiation was delivered. Zone correlates identically
with abnormal liver findings on CT.
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Fig. 2B. —63-year-old man with epithelial mesothelioma who underwent
extrapleural pneumonectomy and intensity-modulated radiation therapy (IMRT).
Contrast-enhanced CT scan obtained at same level as A shows zone of low
attenuation (arrows) that correlates with dosimetric distribution of
maximum radiation. The blue line indicates lower dosage of 30 Gy, and the red
line indicates areas of dosage boost to 50 Gy.
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Fig. 2C. —63-year-old man with epithelial mesothelioma who underwent
extrapleural pneumonectomy and intensity-modulated radiation therapy (IMRT).
Axial T2-weighted image of liver shows high and low signal within area of
radiation injury (arrows) to liver.
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Fig. 2D. —63-year-old man with epithelial mesothelioma who underwent
extrapleural pneumonectomy and intensity-modulated radiation therapy (IMRT).
Contrast-enhanced T1-weighted image shows enhancement (arrows) of
radiation injury.
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Fig. 3A. —58-year-old woman with epithelial mesothelioma 11 weeks after
intensity-modulated radiation therapy. Contrast-enhanced CT scans of upper
liver show peripheral zone of low attenuation (arrows, A) in
upper aspect of liver and, more caudally, high attenuation (arrows,
B) indicating radiation injury to liver.
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Fig. 3B. —58-year-old woman with epithelial mesothelioma 11 weeks after
intensity-modulated radiation therapy. Contrast-enhanced CT scans of upper
liver show peripheral zone of low attenuation (arrows, A) in
upper aspect of liver and, more caudally, high attenuation (arrows,
B) indicating radiation injury to liver.
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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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Abstract
Introduction
