Long-term results of curative intraluminal high dose rate brachytherapy for endobronchial carcinoma.

Abstract

The treatment strategy of central lung tumors is not established. Intraluminal brachytherapy (ILBT) is widely used for palliative treatment of endobronchial tumors, however, it is also a promising option for curative treatment with limited data. This study evaluates the results after ILBT for endobronchial carcinoma.
Sixteen-endobronchial carcinoma of 13 patients treated with ILBT in curative intent for 2000 to 2008 were retrospectively reviewed. ILBT using high dose rate 192 iridium thin wire system was performed with 5 Gy/fraction at mucosal surface. The patient age ranged from 57 to 82 years old with median 75 years old. The 16 lesions consisted of 13 central endobronchial cancers including 7 roentgenographically occult lung cancers and 3 of tracheal cancers. Of them, 10 lesions were treated with ILBT of median 20 Gy combined with external beam radiation therapy of median 45 Gy and 6 lesions were treated with ILBT alone of median 25 Gy.
Median follow-up time was 32.5 months. Two-year survival rate and local control rate were 92.3% and 86.2%, respectively. Local recurrences were observed in 2 lesions. Three patients died due to lung cancer (1 patient) and intercurrent disease (2 patients). Complications greater than grade 2 were not observed except for one grade 3 dyspnea.
ILBT combined with or without EBRT might be a curative treatment option in inoperable endobronchial carcinoma patients with tolerable complication.

Full text

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RESEARCHOpen Access
Long-term results of curative intraluminal
high dose rate brachytherapy for
endobronchial carcinoma
Hidemasa Kawamura1*, Takeshi Ebara1,2, Hiroyuki Katoh1, Tomoaki Tamaki1, Hitoshi Ishikawa3, Hideyuki Sakurai3
and Takashi Nakano1
Abstract
Background: The treatment strategy of central lung tumors is not established. Intraluminal brachytherapy (ILBT) is
widely used for palliative treatment of endobronchial tumors, however, it is also a promising option for curative
treatment with limited data. This study evaluates the results after ILBT for endobronchial carcinoma.
Method: Sixteen-endobronchial carcinoma of 13 patients treated with ILBT in curative intent for 2000 to 2008 were
retrospectively reviewed. ILBT using high dose rate 192 iridium thin wire system was performed with 5 Gy/fraction
at mucosal surface. The patient age ranged from 57 to 82 years old with median 75 years old. The 16 lesions
consisted of 13 central endobronchial cancers including 7 roentgenographically occult lung cancers and 3 of
tracheal cancers. Of them, 10 lesions were treated with ILBT of median 20 Gy combined with external beam
radiation therapy of median 45 Gy and 6 lesions were treated with ILBT alone of median 25 Gy.
Results: Median follow-up time was 32.5 months. Two-year survival rate and local control rate were 92.3% and
86.2%, respectively. Local recurrences were observed in 2 lesions. Three patients died due to lung cancer (1 patient)
and intercurrent disease (2 patients). Complications greater than grade 2 were not observed except for one
grade 3 dyspnea.
Conclusions: ILBT combined with or without EBRT might be a curative treatment option in inoperable
endobronchial carcinoma patients with tolerable complication.
Keywords: Lung cancer, Radiation therapy, High dose rate, Intraluminal brachytherapy, Curative intent
Background
With the recent advance in diagnostic techniques, in-
creasing number of small lung tumors has been
detected. In particular, widespread use of bronchoscopy
and sputum cytology detects tumors localized in the
bronchial lumen. Surgery is regarded as the first choice
of treatment for endobronchial carcinoma. However,
endobronchial carcinoma is usually detected in high-risk
patient and it is not rare that the patient has poor pul-
monary function. Furthermore, 10% of patients have
synchronous or non-synchronous multiple lesions [1,2].
Because of the poor pulmonary function and multiple
lesions, curative surgery is not always indicated for
endobronchial carcinoma. Thus, treatment strategy for
early endobronchial cancer in medically inoperable
patients should be examined.
Intraluminal brachytherapy (ILBT) is widely performed
in medically inoperable endobronchial carcinoma as a
palliative and second line treatment [3-6]. On the other
hand, some reports showed high response rates and the
potential of curative treatment of ILBT in selected
patients [7-13]. Hence, we speculate that ILBT combined
with external beam radiation therapy (EBRT) may play
an important role as a curative treatment for endobron-
chial carcinoma. Therefore, we analyze clinical result of
our institute to elucidate to curability of ILBT for early
lung cancer.
* Correspondence: kawa@gunma-u.ac.jp
1Department of Radiation Oncology, Gunma University Graduate School of
Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan
Full list of author information is available at the end of the article
© 2012 Kawamura et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the
Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use,
distribution, and reproduction in any medium, provided the original work is properly cited.
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Methods
The charts of 16 lesions with 13 endobronchial carcin-
oma patients treated with ILBT in 2000 to 2008 were
retrospectively reviewed. The extent of tumor involve-
ment was assessed by bronchoscopy, chest X-ray, chest
computed tomography (CT) using contrast medium.
Distant metastasis was detected by brain CT or mag-
netic resonance imaging, chest and abdomen CT and
bone scintigraphy. Roentgenographically occult early
endbronchial cancer (ROEC) was defined by Japanese
lung cancer society [14]. Namely, ROEC is defined as
follows; The tumor can not be detected with X-ray and
CT scans, located in sub segmental or more proximal
bronchi, size is less than 2 cm, peripheral margin is vis-
ible bronchoscopically, and is identified as squamous cell
carcinoma histologically.
Radiation technique and radiation dose
Radiotherapy consisted of a combination of external
beam radiotherapy and intraluminal brachytherapy in
principle.
Intraluminal brachytherapy (ILBT)
The pretreatment of ILBT was performed according to
the standard procedures for bronchoscopic examination.
The applicator catheter was inserted by the oral inser-
tion method as following. The catheter was guided to
the target bronchus under bronchoscopy. The catheter
has two wings at the tip of the external tube (Create
Medic Co. Ltd., Japan). We used 20 mm catheters for
trachea, and 15 mm catheters for bronchus. After the
tumor was confirmed to lie between the two wings, the
wings open and act as spacers to keep the source placing
at the center of the bronchus, thus the catheter was
fixed [11]. The radiation source tube was inserted to re-
place the inner tube, and ILBT was conducted using the
high dose rate192Ir thin wire remote after loading sys-
tem (Microselectron, Nucletron, The Netherlands). The
dose distribution was calculated with orthogonal X-ray
films. The irradiation dose was measured by taking the
bronchial mucosal surface as the reference point, and a
dose of 5 Gy per fraction was delivered at the point, two
fractions per week. The distances between the radiation
source and the mucosal surface were provisionally stan-
dardized of 10 mm for the trachea, 7 mm for the main
bronchi, 5 mm for the lobar and segmental bronchi and
3 mm for sub-segmental bronchi from the center of the
source. We confirmed the catheter positions carefully
before and after each treatment to check eccentricity of
the catheter by fluoroscopy.
External body radiation therapy (EBRT)
EBRT was performed in 10 lesions. The radiation fields
were encompassed the primary lesion and regional lymph
nodes area and the lesions were irradiated by anterior and
posterior parallel-opposed fields. Either 6- or 10-MV X-rays
were used at a dose of 2 Gy per fraction, 5 times per week.
CT based dosimetric evaluation
CT based dosimetry was performed in the latest 1 patient.
CT was scanned using the same couch of fluoroscopy in
the treatment room and the data were imported into a
brachytherapy planning system (PLATO v13.3, Nucletron,
The Netherlands). The dose distribution and dose volume
histogram were calculated.
Follow up and statistics
Actuarial analysis was used to determine overall survival
and local control by the method of Kaplan-Meier [15]
using jmp version 8.0.1 (SAS Institute Inc. USA). Overall
survival was measured from the first day of radiation ther-
apy on study until death of any cause. Local control was
measured from the first day of radiation therapy until the
date of local and/or regional recurrence. Local control was
assessed by bronchoscopy, chest X-ray and chest CT con-
ducted frequently more than every 6 months. Biopsies
were performed when there were suspicious lesions. Treat-
ment related toxicity was evaluated with Common Ter-
minology Criteria for Adverse Events version 3.0 (National
Cancer Institute).
Results
Patients’ characteristics
Patients’ characteristics were shown in Table 1. The age
at the treatment was 57 to 82 years old with median
75 years. Of 16 lesions, 13 lesions were central (hilar)
endobronchial cancers including 7 ROEC and 3 lesions
were tracheal cancers. The sizes of all tumors measured
by bronchoscopy were less than 2 cm. X-ray or CT could
not measure the tumors. The histology of all tumors is
Squamous cell carcinoma. Of 13 patients, 8 patients had
multiple cancers and 4 of these patients had multiple
lung cancers. The median follow-up for all patients is
Table 1 Patient Characteristics
Number of Patients13
Age57-82 (median 75) years old
Male/Female13/0
Smoking Yes/No13/0
Brinkman Index200–2400 (median 1620)
Number of tumors16*
Tracheal cancer3
Central end-bronchial cancer13
(ROEC 7)
*3 pts. treated metachronous lung cancers.
ROEC roentgenographically occult lung cancer.
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32.5 months. Chemotherapy was administered to 2 patients
prior to radiation therapy for metachronous lung cancer by
the referred physicians.
Dose of radiation therapy
Treatment’s characteristics were shown in Table 2. Ten of
16 lesions were treated with combination of ILBT and
EBRT. The median dose of ILBT was 20 Gy and the me-
dian dose of EBRT was 45 Gy. Six lesions were treated with
ILBTalone and the median dose of ILBT was 25 Gy.
Local control and overall survival
The 2 year local control rate was 86.2% as shown in
Figure 1. The 2 year local control rates of ROEC and
others were 83.3% and 87.5%, respectively. The 2 year local
control rates of ILBT alone and combination of ILBT
and EBRT were 80.0% and 88.9%, respectively. The local
control was not statistically different whether the lesion
was ROEC or whether radiation therapy included EBRT.
The 2 year overall survival rate calculated from the be-
ginning of first radiation therapy was 92.3%. Three
patients received ILBT twice for different lesions, and
the total Kaplan-Meier survival curve as shown in
Figure 2.
Local recurrences were observed in 2/16 lesions. One
tracheal cancer patient, treated with the combination of
ILBT and EBRT, died of recurrence. In another case, pa-
tient who was treated right upper lobe lesion with ILBT
alone, was received salvage right upper lobe resection
and is still alive without disease. The causes of death
were lung cancer in 1 case and other disease in 2 cases.
Complication
All patients had some mucosal changes (inflammations
and telangiectasia), however, only two (15%) patients
have clinical symptoms (developed Grade 2 or greater
treatment-related complication).
One patient developed Grade 3 dyspnea. He had poor
pulmonary conditions before the ILBT treatment (severe
emphysema and received left upper lobe resection for
atypical carcinoid and temporally received home oxygen
therapy once), and promoted his past disease by treat-
ments. Another patient developed Grade 2 cough in
chronic phase. His tumor was located at the spur of left
upper and lower lobe. The lesion was treated with com-
bination of ILBT and EBRT. Four session of ILBT
was performed. Of them, sources were inserted into
the upper bronchus in 2 sessions and the lower bron-
chus in 2 sessions. EBRT was administered with 45
Gy/21 fractions after ILBT. At 19 months after treat-
ment brochofiber scope showed the stenosis of left main
bronchus.
Case presentation of CT based dosimetric evaluation
Sixty-years-old man without any symptom was diag-
nosed as squamous cell carcinoma of lung detected by
sputum cytology. He had smoked with 1.5 packs for
45 years. Tumor located at the spur of right B6 and
intermediate bronchus. ILBT was performed with 20 Gy
in 4 fractions followed by EBRT of 40 Gy in 18 fractions.
CT based dose distribution showed that 95% of the clin-
ical target volume receives more than 90% of the
Table 2 Treatment characteristics
ILBT alone6 lesions
20-25 Gy(median 25 Gy)
5 Gy/fraction
ILBT+EBRT10 lesions
ILBT5-20 Gy (median 20 Gy)
5 Gy/fraction
EBRT40-61 Gy/18-30 fractions (median 45 Gy)
ILBT intraluminal brachytherapy.
EBRT external body radiation therapy.
Figure 1 Local control rate after the start of radiation therapy.
Kaplan-Meier estimates showing local control rates.
Figure 2 Overall survival rate after the start of first radiation
therapy. Kaplan-Meier estimates showing overall survival rates for
patients received ILBT. Three patients were treated 2 lesions each in
different time point, thus, graph includes overlapping data.
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prescribed dose (Figure 3). No remarkable acute toxicity
and no recurrence were observed for a year.
Discussion
ILBT has mainly been performed to relieve tumor-
related stenosis of the trachea and/or main bronchi.
Palliative-intent endobronchial ILBT has been reported
to have a high response rate, and most patients who
have undergone it have improved rapidly after the begin-
ning of treatment. Many investigators therefore believe
that ILBT is effective in relieving symptoms and is indi-
cated for palliative treatment of endobronchial tumors
[3-6,12,13].
On the other hand ROEC is a good candidate for cura-
tive ILBT. Some investigators used low-dose-rate intra-
luminal brachytherapy (LDR-ILBT) for the curative
treatment of ROEC. Saito et al. evaluated a total of 79
lesions (71 cases) of ROEC, which were treated with
EBRT and LDR-ILBT. The 5-year overall survival, cause
specific survival, and disease-free rates were 72.3%,
96.1% and 87.3%, respectively with acceptable complica-
tions [8]. Fuwa et al. analyzed 39 ROEC patients treated
with LDR-ILBT and EBRT. The therapeutic effect was
complete responses in 38 patients and the 3-year and 5-
year relapse-free survival rates were both 87%. They
concluded that LDR-ILBT is expected to replace surgery
because of less invasiveness [7]. These studies demon-
strated that LDR-ILBT with EBRT could be curative
therapy for ROEC.
There are few reports on high-dose-rate ILBT (HDR-
ILBT) for the endobronchial cancer. Taulellue et al.
adopted HDR-ILBT alone for endobronchial tumors. In
sub group analysis, overall survival of Group A, which
was consisted 22 (12%) patients who were medically in-
operable and presented with small endobronchial tumor
strictly limited to the bronchial lumen and were not
treated before, was 71% at 12 months and 46% at
24 months, respectively (for all patients, 27% at
12 months and 10% at 24 months). Therefore, conclud-
ing ILBT can be tried with curative intent in patients
who had small endobronchial tumors and are not candi-
dates for other forms of therapy [13]. And Hennequin
et al. showed that HDR-ILBT alone achieved a long-term
cause-specific survival rate of 50% of the patients with
localized endobronchial carcinoma and could be consid-
ered curative treatment [9]. According to these results,
the therapeutic effects of ILBT with EBRT may be super-
ior to that of HDR-ILBT alone even though simple com-
parison is difficult because of the differences of patients’
characteristics. The combination of EBRT is essential to
realize tumor characteristics and homogeneities of dose
distribution. There is uncertainty of the source position
due to moving of catheter accompanied by breathing
during the treatment. And ILBT with the rapid dose fall-
off could not be enough to cover the lesion such an
ROEC with a diameter more than 1 cm, which usually
penetrates beyond the bronchial cartilage. Moreover,
management of subclinical tumor spread including
lymph node metastasis is another problem. The possibil-
ity of lymph node metastasis is un-negligible even if
tumor is small. If recurrence of lymph node metastasis
occur near the ILBT treatment area, re-treatment in-
cluding re-irradiation or surgery is difficult. EBRT is
expected a role to sterilize these lymphatic spread.
In another point of view, dosimetric and anatomical
information from plain radiographs is limited. Longitu-
dinal, tumor margins, and axial catheter displacements
may occur. An incidental high dose for normal tissues
could lead to severe complication while an incidental
low dose for a lesion could lead to local failure. In this
Figure 3 CT based dose distribution. A CT based dose distribution of the recent case. Red thick line is a delineated contour of clinical target
volume (CTV) and magenta line indicates 100% of prescribed dose (5 Gy). 95% of the CTV receives more than 90% of the prescribed dose. The
unit is cGy/fraction.
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series, one patient developed bronchial stenosis and
grade 2 cough after treatment of bronchial spur lesion.
This could be a result of unexpected high dose lesion
induced by the off centering of catheters due to tumor
location (spur of upper and lower lobe). Furthermore, it
is difficult to determine an optimal source position to
the target if tumor infiltrated into bronchial spur, like
the case presentation. Thus, it is important to evaluate
accurately anatomical dose distribution in curative treat-
ment. Therefore, CT based dosimetric evaluation is
expected.
Studies using CT have provided valuable dosimetric
information in ILBT of gynecological tumors [16], so
that some institutes reports on CT based endbronchial
ILBT [12, 17-19]. They pointed out that CT based dos-
imetry is promising, however, faster on-line treatment
planning is needed for the routine clinical application of
this technique. Furthermore, the rapid dose fall-off in
ILBT mucosal dose prescription should be used with
caution in curative treatments where ILBT, without add-
itional external radiotherapy, is used as the sole treat-
ment modality. The toxicity of ILBT, in particular fatal
haemoptysis and bronchial wall necrosis, has been corre-
lated with the total dose, fraction size, volume encom-
passed by the 100% isodose, and a proximal tumor
location. Therefore CT based dosimetry is promising to
evaluate these parameters. Lagerwaard et al. suggested
about mucosal dose prescription, which should only be
used in combination with centered applicators [18].
Because of these reasons, we have performed ILBT
combined with EBRT for ROEC. Although there is no
significant difference of local control and survival be-
tween ILBT alone and ILBT combined with EBRT in this
study, we recommend ILBT combined with EBRT for
ROEC as the reasons mentioned above. Accurate diag-
nosis of tumor spread with fluorescent endoscopy and
endoscopic ultrasound and accurate dosimetry with CT
assisted ILBT would make ILBT sophisticated and may
omit of combination EBRT for particular tumors.
Recently, peripheral small lung cancers in medically
inoperable patients have been well controlled with hypo-
fractionated schedules by stereo-tactic radiotherapy
(SRT). However, central lesions are not indicated of SRT
because of the normal tissue complications [20]. ILBT is
a promising alternative method for curative treatment of
central small lesions. Furthermore, the candidate for
good indication of ILBT may be increase. With the re-
cent advance in diagnostic techniques, increasing num-
ber of small lung tumors has been detected. Moreover, it
is not rare that patients possess several intrinsic pro-
blems including a high incidence of multiple cancers (in
lungs and other organs), and a high frequency of poor
pulmonary function because it commonly occurs in
heavysmokers. Furthermore,elderly lungcancer
patients and patients having co-morbidity are increasing
and required appropriate treatment approach. Thus,
medically inoperable patients are increasing and alterna-
tive approach should be investigated. The importance of
ILBT as a curative intent should be re-examined because
of its less invasiveness.
Conclusions
HDR-ILBT with or without EBRT might be a curative
treatment option in inoperable endobronchial carcinoma
patients with tolerable toxicity.
Abbreviations
ILBT: Intraluminal brachytherapy; EBRT: External beam radiation therapy;
CT: Computed tomography; ROEC: Roentgenographically occult early
endbronchial cancer; LDR: Low-dose-rate; HDR: High-dose-rate.
Competing interests
The authors have no financial disclosures or conflicts of interest to report.
Acknowledgement
Some part of this manuscript was presented at the 51st Annual Meeting of
American society for Radiation Oncology, November 1–5, 2009.
Author details
1Department of Radiation Oncology, Gunma University Graduate School of
Medicine, 3-39-22 Showa-machi, Maebashi, Gunma 371-8511, Japan.
2Department of Radiation Oncology, Saitama Medical University International
Medical Center, 1397-1 yamane Hidaka-shi, Saitama, Japan.3Department of
Radiation Oncology and Proton Medical Research Center, Tsukuba University,
Tennodai 1-1-1, Tsukuba, Ibaraki, Japan.
Authors’ contribution
HK: Reviewed charts, collected data, and drafted the manuscript. TE:
Reviewed charts, collected data, aided in the design of the study, reviewed
the manuscript. HK: Aided in the design of the study, reviewed the
manuscript. TT: Aided in the design of the study, reviewed the manuscript.
HI: Aided in the design of the study, reviewed the manuscript. HS: Aided in
the design of the study, reviewed the manuscript. TN: Aided in the design of
the study, edited the manuscript. All authors read and approved the final
manuscript.
Received: 6 April 2012 Accepted: 23 July 2012
Published: 23 July 2012
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doi:10.1186/1748-717X-7-112
Cite this article as: Kawamura et al.: Long-term results of curative
intraluminal high dose rate brachytherapy for endobronchial carcinoma.
Radiation Oncology 2012 7:112.
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