AJR 2004; 182:1123-1128
© American Roentgen Ray Society
Radiation Injury After Hypofractionated Stereotactic Radiotherapy for Peripheral Small Lung Tumors: Serial Changes on CT
Toshiaki Takeda1,
Atsuya Takeda1,
Etsuo Kunieda1,2,
Akitoshi Ishizaka3,
Kazuhiko Takemasa1,
Kyoko Shimada1,
Seika Yamamoto1,
Naoyuki Shigematsu2,
Osamu Kawaguchi2,
Jun-ichi Fukada1,2,
Toshio Ohashi2,
Sachio Kuribayashi2 and
Atsushi Kubo2
1 Department of Radiology, Tokyo Metropolitan Hiro-o General Hospital, 2-34-10
Ebisu, Shibuya-ku, Tokyo 150-0013, Japan.
2 Department of Radiology, School of Medicine, Keio University, 35 Shinanomachi,
Shinkuku-ku, Tokyo 160-8582, Japan.
3 Department of Medicine, School of Medicine, Keio University, Tokyo 160-8582,
Japan.
Received June 16, 2003;
accepted after revision November 10, 2003.
Address correspondence to T. Takeda
(t-takeda{at}hiroo-hospital.metro.tokyo.jp).
Abstract
OBJECTIVE. We studied the serial changes and CT manifestations of
pulmonary radiation injury after hypofractionated stereotactic radiation
therapy for peripheral small lung tumors.
SUBJECTS AND METHODS. Hypofractionated stereotactic radiation
therapy was applied to 20 patients with proven primary (n = 11) or
metastatic (n = 9) lung cancer, for a total of 22 lesions of 3 cm or
less in diameter located within 3 cm from the parietal pleural surface.
Follow-up CT was scheduled at 1 and 3 months, and every 3 months
thereafter.
RESULTS. Ground-glass opacities were observed around four (18%) of
22 lesions at 3–6 months. The opacities nearly corresponded to the
planned target volume, but half of them were unevenly distributed.
Ground-glass opacities gradually disappeared or evolved into dense
consolidation while shrinking. Dense consolidations developed in 16 (73%) of
22 lesions, including seven in the center of the planned target volume and
nine in the periphery of the planned target volume. Dense consolidations moved
in six of these 16 lesions and gradually shrank, becoming fixed as solid or
linear opacities approximately 12 months later.
CONCLUSION. The pulmonary opacities observed after hypofractionated
stereotactic radiation therapy for peripheral small lung tumors may not
precisely correspond to the planned target volume (unlike those with
conventional radiation therapy) and may change in shape and location
dynamically during the first year. Knowledge of these findings is necessary to
avoid misunderstandings concerning tumor regrowth or new tumors.
Introduction
Currently, surgery is the treatment of choice in the early stages of lung
cancer. Although conventional radiation therapy may be selected as a less
invasive intervention in elderly patients and in those with inoperable
disease, the rate of local control of malignancy after radiation therapy is
approximately 30%, which is lower than for surgical resection
[1]. Stereotactic irradiation
can deliver high radiation doses to localized lesions with great accuracy,
allowing a strong antitumoral effect while lessening radiation injury to
normal tissues [2]; it has been
applied to the treatment of small intracranial tumors with excellent results
[2]. More recently,
hypofractionated stereotactic radiotherapy has been applied to the treatment
of extracranial malignant tumors, with preliminary studies reporting greater
than 90% control rates for small localized lung tumors
[3–5].
In this study, we applied hypofractionated stereotactic radiotherapy to the
treatment of small lung tumors and observed the various radiologic patterns of
change after irradiation. As indicated by previous reports
[6,
7], radiation injuries caused
by conventional coplanar radiotherapy show distinct linear margins on CT that
correspond to the margins of the irradiation field. However, because
hypofractionated stereotactic radiotherapy is delivered in a 3D spherical
volume with a steep gradient between the periphery of the planned target
volume and normal adjacent tissue, the shape of the radiation injury should be
considered three-dimensionally. Hypofractionated high-dose irradiation, with
highly concentrated narrow beams that target small volumes, is associated with
markedly different dose distributions and biologic effects on tissues from
those described for coplanar conventional radiotherapy. The aim of this study
was to describe the CT characteristics of radiation injury after
hypofractionated stereotactic radiotherapy for small lung malignancies.
Subjects and Methods
The patient population consisted of 17 men and three women (age range,
56–89 years; median, 72.6 years) who were treated with hypofractionated
stereotactic radiotherapy at our institutions between January 1998 and
November 2002. For most patients, surgery was not indicated because of patient
age, the presence of multiple lesions, or poor pulmonary function. Five
patients preferred hypofractionated stereotactic radiotherapy treatment even
though surgery was possible. The study protocol was approved by the
institutional review boards of the institutions, and written informed consent
was obtained from each participant before hypofractionated stereotactic
radiotherapy was performed.
Primary lung cancer was pathologically proven in 11 patients (11 lesions),
and metastases from other primary cancers were diagnosed clinically in nine
patients (11 lesions). Hypofractionated stereotactic radiotherapy was
generally considered if the tumor was 3 cm or smaller in diameter, if it was 3
cm or less from the parietal pleural surface, if craniocaudal
breathing-associated motion of the lesion was 1 cm or less, and if three or
fewer lesions were present at the start of treatment. Because the risk of
atelectasis and reduction of pulmonary function caused by the collapse of
large bronchi was unknown, potential lesions for treatment were limited to
peripheral lesions 3 cm or less from the parietal pleural surface so that the
planned target volume would not contain lobar bronchi. Tumor pathology and
mean tumor volumes are listed in Table
1.
Pretreatment Evaluation and Radiation Treatment
The planned target volume was determined using CT (Xvision, Toshiba)
performed on patients who were breathing at rest. Serial 2-mm-thick scans were
obtained in 2-mm increments at 4–8 sec per slice. Longer scanning
periods were used to define the tumor trajectory associated with breathing.
The planned target volume consisted of the imaged volume, defined as the gross
tumor volume plus an internal margin, plus a 5- to 10-mm setup margin.
Tumor volumes (V) were calculated according to the following
formula:
where R1 (half the maximum diameter),
R2 (half the diameter perpendicular to
R1), and R3 (half the maximum diameter
in the craniocaudal direction) were obtained with calipers on CT. When the
tumor margin was ill defined, the outermost circumference was used. The
diameter in the craniocaudal direction was defined as the product of the
thickness and the number of slices from the top to the bottom of the lesion.
Estimated tumor volumes ranged from 0.5 to 45.5 cm3 (mean, 9.5
cm3).
Treatments were planned using a radiation treatment planning system (FOCUS
version 2.7.0, Computerized Medical Systems). Volumes to be treated were set
so that the planned target volume received an 80% isodose of the maximum dose,
with 80% isodose defined as the therapeutic dose (Figs.
1A,
2A, and
3A). The shape of the field
was adjusted dynamically according to the tumor shape using a multileaf
collimator.
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Fig. 1A. —59-year-old man with lung metastasis from rectal carcinoma.
Typical characteristics of radiation pneumonitis and fibrosis after
hypofractionated stereotactic radiotherapy are seen on serial lung CT scans
after irradiation. Axial unenhanced CT scan obtained before treatment shows
tumor in right upper lobe. PTV = planned target volume.
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Fig. 3A. —70-year-old man with lung metastasis of oropharyngeal
carcinoma. Axial unenhanced CT scan obtained before treatment shows metastatic
tumor in right lower lobe. PTV = planned target volume.
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The irradiation dose generally consisted of 50 Gy in five fractions
administered over 5–7 days. Seventeen lesions in 15 patients were
treated using this dose regimen. When a tumor was adjacent to critical organs
(e.g., spinal cord or esophagus), the fractionated dose was reduced to
5–7 Gy and the total dose was limited to 40–50 Gy.
Radiologic Follow-Up
Patients were interviewed monthly to determine the presence or absence of
symptoms and for chest roentgenographic examination.
Lesion characteristics were periodically examined on CT (Xvigor or Xvision,
Toshiba) even in the absence of clinical symptoms at follow-up visits
approximately 1 and 3 months after treatment, and in principle every 3 months
thereafter. The interval of CT varied slightly depending on each patient's
clinical status. If dubious opacities were seen on periodic radiography,
additional CT was performed between the scheduled examinations. Single-slice
helical CT of the entire lung without contrast material was performed using
scanning parameters of slice thickness, 10 mm; pitch, 1; tube voltage, 120 kV;
tube current, 200 mA; and 0.75 sec per slice. Images focused on tumors and
associated pneumonitis were obtained by helical scanning with slice thickness,
2 mm; pitch, 1; tube voltage, 120 kV; tube current, 250 mA; and 0.75 sec per
slice. High-resolution CT was reconstructed using a high-spatial-resolution
algorithm. Of 100 total CT series, high-resolution CT scans were obtained
concurrently in 61 studies. An average of 4.5 CT series per lesion were
performed, including an average of 2.8 high-resolution CT series. The mean
follow-up period after high-resolution CT was 17.6 months (range,
4.5–51.6 months). No patients received chemotherapy.
Interpretation of CT Findings
The time of appearance of ground-glass opacities or dense consolidations
(with respect to completion of radiation therapy), location of appearance
(center or periphery of the planned target volume), serial changes (changes in
density, size, and location), and time of appearance of bronchiectasis were
systematically recorded. CT images were independently interpreted by four
diagnostic radiologists who were familiar with the clinical diagnosis and the
development of lung tumors. CT characteristics were determined on the basis of
a consensus among at least three of the four examiners.
Results
Demographic characteristics of the lesions and characteristics of the
radiation injuries are detailed in Table
1.
After hypofractionated stereotactic radiotherapy, ground-glass opacities
and dense consolidations were observed as initial lung CT findings at
3–4 months. Thereafter, the ground-glass opacities either disappeared or
evolved into dense consolidations. Dense consolidations that were seen
initially gradually shrank to become solid or linear opacities consistent with
lesion fixation (Figs. 1A,
1B,
1C,
1D,
1E,
1F,
2A,
2B,
2C,
2D,
2E,
2F,
3A,
3B,
3C,
3D,
3E,
3F). No ground-glass opacities
or dense consolidations were observed at sites remote from the planned target
volume.
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Fig. 1B. —59-year-old man with lung metastasis from rectal carcinoma.
Typical characteristics of radiation pneumonitis and fibrosis after
hypofractionated stereotactic radiotherapy are seen on serial lung CT scans
after irradiation. CT scan at 1 month after irradiation shows decrease in
tumor size.
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Fig. 1C. —59-year-old man with lung metastasis from rectal carcinoma.
Typical characteristics of radiation pneumonitis and fibrosis after
hypofractionated stereotactic radiotherapy are seen on serial lung CT scans
after irradiation. CT scan at 4 months reveals appearance of dense
consolidation and its surrounding ground-glass opacity.
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Fig. 1D. —59-year-old man with lung metastasis from rectal carcinoma.
Typical characteristics of radiation pneumonitis and fibrosis after
hypofractionated stereotactic radiotherapy are seen on serial lung CT scans
after irradiation. CT scan at 8 months shows shrinkage of dense consolidation
and its movement toward hilum.
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Fig. 1E. —59-year-old man with lung metastasis from rectal carcinoma.
Typical characteristics of radiation pneumonitis and fibrosis after
hypofractionated stereotactic radiotherapy are seen on serial lung CT scans
after irradiation. CT scan at 11 months shows presence of dilated bronchi
within opacity.
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Fig. 1F. —59-year-old man with lung metastasis from rectal carcinoma.
Typical characteristics of radiation pneumonitis and fibrosis after
hypofractionated stereotactic radiotherapy are seen on serial lung CT scans
after irradiation. CT scan at 22 months shows fixation of opacity. Subsequent
CT characteristics remained unchanged.
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Fig. 3D. —70-year-old man with lung metastasis of oropharyngeal
carcinoma. CT scan at 6 months shows increase in size of dense consolidation
and onset of movement. Center of tumor is now located more cranially.
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Fig. 3E. —70-year-old man with lung metastasis of oropharyngeal
carcinoma. CT scan at 9 months shows decrease in tumor size, thinning of dense
consolidation, and movement of lesion toward hilum.
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Ground-glass opacities appeared on CT scans in four (18%) of 22 lesions at
3–6 months after completion of radiation therapy. They all corresponded
closely to the planned target volume. In two instances, the ground-glass
opacities were evenly distributed in the planned target volume (Figs.
1C and
3C), and in the other two
instances the opacities remained unevenly distributed at 4 months, thereafter
evolving into dense consolidations consistent with the planned target
volume.
Dense consolidations appeared in 16 (73%) of 22 lesions on CT scans
obtained at 3- to 8-months' follow-up. Of these, seven exhibited dense
peritumoral consolidations corresponding to the planned target volume (Figs.
1C and
2D), and the remaining nine
showed consolidation limited to the margin of the planned target volume, a
short distance from the isocenter (Figs.
3C and
3D). Although dense
consolidations shrank in seven (44%) of these 16 lesions, the consolidations
did not disappear completely but persisted as solid or linear opacities (Figs.
1F,
2E, and
3F). This shrinkage occurred
within 6–11 months after radiotherapy. In six of 10 lesions followed up
for at least 12 months, the pulmonary opacities became fixed on CT scans,
consistent with the development of fibrosis. Movement of the opacity was
observed in six (37.5%) of the 16 densely consolidated lesions. This movement
was detected simultaneously with shrinkage in five of the six lesions, with
movement toward the hilum in five (Figs.
1A,
1B,
1C,
1D,
1E,
1F and
2A,
2B,
2C,
2D), and with movement away
from the hilum in one.
Bronchiectasis was present in 10 (45.5%) of 22 lesions and developed almost
contemporaneously with dense consolidations that contained dilated or
thickened bronchi. Bronchial thickening and lumen irregularities caused by
traction (i.e., traction bronchiectasis) became apparent along with movement
of the opacities (Figs. 2D and
3E).
Discussion
Hypofractionated stereotactic radiotherapy, a new treatment method for
small lung malignancies, differs considerably from conventional coplanar
radiation therapy because it consists of delivering a single high dose of
radiation with hypofractionation to small irradiation fields. Although
hypofractionated stereotactic radiotherapy is expected to be highly effective
in the control of localized lesions, its acceptance and indications will
expand only if its use is not complicated by high rates of adverse reactions.
Therefore, before considering increased radiation doses in the hope of
achieving improved local therapeutic effects, a thorough clinical and
radiologic evaluation of pulmonary parenchymal injuries caused by irradiation
is needed to verify that hypofractionated stereotactic radiotherapy is a safe
and effective treatment for small lung malignancies.
Classic radiation pneumonitis induced by conventional radiation therapy is
characterized by a linear margin demarcating the treatment port and is
uncommon with exposures of less than 30 Gy but inevitable for exposures
greater than 40 Gy [8].
However, the reported incidence of clinical manifestations associated with
radiation pneumonitis is 7–8%, and the symptoms are usually mild,
despite imaging findings that may appear more prominent
[9,
10]. In our study, only three
patients reported a mild cough associated with radiation injury, and all were
successfully treated with simple therapy. In contrast, sporadic radiation
pneumonitis is an immune-mediated process resulting in lymphocytic alveolitis
that leads to a response remote from the localized pulmonary irradiation and
that is usually associated with severe symptoms and high mortality in the
absence of a "threshold" dose
[11]. Classic radiation
pneumonitis can be classified as either early (1–3 months after
irradiation) or late (3–6 months after irradiation), depending on the
time of appearance of the pulmonary reaction to the radiation. In our study,
hypofractionated stereotactic radiotherapy-induced lung injuries did not
systematically develop in the center of treated volumes, but often began at
the periphery. However, injuries eventually conformed to and remained in the
planned target volume. These findings suggested that a threshold dose was
required to develop pneumonitis, and that hypofractionated stereotactic
radiotherapy-induced lung injuries were classifiable as classic radiation
pneumonitis.
Evolution from ground-glass opacity to dense consolidation to fibrosis was
observed on CT in a relatively small subset of our patients. In contrast, in a
study of 3D conformal radiation therapy, Koenig et al.
[12] observed the development
of ground-glass opacity around tumors on CT scans at 3 months after radiation
therapy in 19 of 19 patients treated with total doses between 69.6 and 90.3 Gy
in 33–58 fractions. Three-dimensional conformal radiation therapy used
in that study differs considerably from the hypofractionated stereotactic
radiotherapy used in our study, particularly from the standpoint of the single
dose. The incidence and severity of radiation pneumonitis can depend on the
extent of irradiation, the total dose, and the number of fractions, and may
also be influenced by concurrent chemotherapy
[9]. Thus, the differences
between the two studies with regard to CT patterns are probably attributable
to researchers for the previous study using a higher radiation dose delivered
as a single fraction. Therefore, we hypothesize that on CT, early or mild
radiation injuries appear as ground-glass opacities, whereas severe radiation
injuries appear as dense consolidations.
Movement of dense consolidations often occurred. Movement toward the hilum
was seen in all but one case. Because shrinkage of the opacity and traction
bronchiectasis were usually seen concurrently, the mechanism of these
phenomena seems attributable to fibrosis. Therefore, we think that the
apparent movement of the opacity is largely attributable to the deformity of
the lung caused by fibrosis. Takahashi et al.
[13] observed that the
ground-glass opacities corresponded to thickened interlobular walls because of
fibroblastic cells and collagen fibers in a pig model of radiation
pneumonitis.
Takahashi et al. [13] also
found that the ground-glass opacities were not evenly distributed but at
pathology were predominant near the interstitium. In a dog model, the same
radiation dose caused a more severe reaction when delivered to the periphery
of the right lower lobe than to the right hilum
[14]. These findings indicate
that variable local sensitivity to radiation, depending on the amount of
interstitium, causes nonuniform distribution of ground-glass opacities and
dense consolidations.
We acknowledge several limitations in our study. Although we differentiated
radiation injury patterns as ground-glass opacity, dense consolidation, and
fibrosis, we had no pathologic proof. As with other studies examining
radiation pneumonitis, we found it difficult to obtain specimens from
otherwise asymptomatic patients. Another limitation was the relatively small
number of patients in our study. Although it is fortunate that only a few
patients complained of mild cough and recovered without resorting to steroids
or hospital admission, the number of patients was too small to allow analysis
of the relationship among symptomatic pneumonitis, patient background factors,
and radiation treatment.
In assessing radiologic findings, residual tumor regrowth, lymphatic
spread, and infection should be differentiated from radiation pneumonitis.
Local recurrences especially are sometimes difficult to diagnose in the early
phase because they are often asymptomatic, as is radiation pneumonitis. Four
cases recurred after hypofractionated stereotactic radiotherapy, of which two
had no radiation pneumonitis–induced opacities and one had minimal
ground-glass opacity. In these three cases, the initial radiation effect was
minimal or could not be evaluated and tumors gradually enlarged without a
dramatic change in shape. Therefore, regrowth of the tumors was readily
diagnosed. In the last case, the tumor had almost disappeared shortly after
hypofractionated stereotactic radiotherapy. Dense consolidation surrounding
the initial tumor appeared 6 months later, followed by overtly solid tumor on
its periphery. Needle biopsy confirmed the presence of adenocarcinoma. We
suppose that this may be a typical case of recurrence after hypofractionated
stereotactic radiotherapy. However, we have experienced too few cases to draw
a clear-cut distinction between recurrence and radiation pneumonitis. It is
important to be especially careful during the early assessment of radiation
pneumonitis on CT because the CT pattern evolves serially, and pulmonary
opacity can move. We should be aware that the CT appearance reflects only one
phase of the spectrum.
In conclusion, a size decrease in small lung tumors was generally
observable on CT scans 1–3 months after completion of irradiation by
hypofractionated stereotactic radiotherapy. This decrease in tumor size was
accompanied by reduced areas of dense consolidation and surrounding
ground-glass opacity at 3–6 months. Although ground-glass opacities
generally resolved, the dense consolidations assumed typical CT patterns,
including movement toward the hilum, shrinkage, and fixation at approximately
1 year after treatment. The incidence of ground-glass opacities was relatively
low, and neither ground-glass opacities nor dense consolidations coincided
exactly with dose distribution, occasionally developing away from the
isocenter or remaining heterogeneous. Dynamic changes in ground-glass
opacities and dense consolidations were observed over time. Our results
indicate that assessment of lesions should be done with knowledge of these
changes of radiation pneumonitis on CT during the first year after treatment,
before fixation, to avoid misunderstandings about CT findings resembling tumor
regrowth or the appearance of new lesions.
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Abstract
Introduction
