Cancer Therapy Vol 2, 469-474, 2004
High dose rate endobronchial brachytherapy for the
management of non-small cell lung cancer with an endobronchial or peribronchial
component
Review Article
Jiade J. Lu1,*,
Yadvindera S. Bains1, Aaron H. Wolfson1, Elio Donna2,
Alfred H. Brandon1, William A. Raub1, Arnold M. Markoe1
1Department of Radiation Oncology, University of Miami
Medical Center/Jackson Memorial Hospital, 1475 N.W. 12th Ave, Miami,
Florida, 33136, USA
2Department
of Pulmonary Medicine, University of Miami Medical Center/Jackson Memorial
Hospital, 1475 N.W. 12th Ave, Miami, Florida, 33136, USA
__________________________________________________________________________________
*Correspondence: Jiade J.
Lu, MD, Department of Radiation Oncology, National University Hospital, 5 Lower
Kent Ridge Road, Singapore, 119074, Singapore; Tel: 011-65-6772-4869; Fax:
011-65-779-6320; Email: jlu@anderson.ucla.edu
Key words: non-small
cell lung cancer, radiation therapy, high dose rate, brachytherapy
Abbreviations:
Complete response, (CR); external beam radiation, (EBRT); high dose rate,
(HDR); high-dose-rate endobronchial brachytherapy, (HDREB); intermediate dose
rate, (IDR); low dose rate, (LDR); non-small cell lung cancer, (NSCLC); partial
response, (PR)
Received: 8 November 2004; Accepted: 22 November 2004;
electronically published: December 2004
Summary
The primary
aim of this study was to determine whether a dose response exists for bronchial
obstruction caused by non-small cell lung cancer (NSCLC) when treated with
increasingly higher radiation doses delivered by a combination of external beam
radiation (EBRT) and high-dose-rate endobronchial brachytherapy (HDREB). The
secondary aim was to document the tolerability of EBRT combined with HDREB.
Thirty patients with medically inoperable or surgically unresectable non-small
cell lung cancer were treated in this phase I/II study with both EBRT and
HDREB. All patients had a peribronchial or endobronchial component with bronchial
obstruction of 50% or more on clinical examination. EBRT was delivered via
megavoltage photons at standard fractionation schedules to a total dose of 66
Gy. The HDREB was delivered using the Nucleotron HDR remote after loading unit
with a 10 Ci Ir-192 source. Each treatment of HDERB was delivered at 1 cm
depth. The first group of 10 patients received 3 treatments of HDREB at 7 Gy
per fraction. The second group of 10 patients received 3 treatments of 8 Gy per
fraction. And the last group of 10 patients received 3 treatments of HDREB of 9
Gy per fraction. HDREB was delivered once weekly. Improvements of obstructions
and acute adverse reactions were evaluated for each group of patients before
escalating to the next higher-level dose level of HDREB. The medium follow-up
time for all 30 patients was 14.5 months. The medium survival for all 30
patients was 13 months (Range 1 month to 38 months). There was no significant
difference of survival among the 3 groups. Complete response or partial
response of bronchial obstruction was seen in 60% of patients in Group 1
compared to 90% of patients in both group 2 and 3 (p=0.05). One patient in
Group 1 and one patient in Group 3 developed grade IV toxicity, and 1 patient
in Group 2 developed grade III toxicity. HDREB of 27 Gy in 3 divided weekly
treatments following 66 Gy of external beam radiation is well tolerated for the
treatment of NSCLC. A statistically significant dose response for bronchial
obstruction from NSCLC is seen when treating with the combination of EBRT and
HDREB beyond 24 Gy.
I. Introduction
Radiation is an effective treatment modality in the
management of locally advanced non-small cell lung cancer (NSCLC), both in
definitive or palliative settings. The dose of external beam radiation is
usually limited to 60-70 Gy due to the surrounding critical normal structures
in the treatment field (Dosoretz et al, 1993; Hernandez et al, 1996; Nguyen et
al, 1999). However, with this dose delivered using conventional fractionation,
the proportion of patients obtaining partial or complete local response ranges
from 20-60% only (Slawson and Scott, 1979; Majid et al, 1986; Chetty et al,
1989). This leaves considerable room for improvement.
The use of high dose rate endobronchial brachytherapy
(HDREB) in the treatment of non-small cell lung has been well documented (Macha
et al, 1987; Cotter and Ellingwood, 1988; Lang et al, 1988). Combining external
beam radiation with endobronchial brachytherapy allows for delivery of
significantly higher dose to a limited area. By combining external beam
radiotherapy (EBRT) and HDREB, higher
partial or complete local response rates ranging between 67-99% can be achieved
(Huber et al, 1987; Cotter and Ellingwood, 1988; Chang et al, 1994).
Although HDREB has been frequently used to treat
non-small cell lung cancer with an endobronchial or peribronchial component,
ideal fractionation schemes and dosages have not yet been fully established.
Doses and fractionation schemes are selected empirically because there is
little prospective data on tolerance doses of the human bronchial wall after
HDREB. Furthermore, the complications caused by the various dose and
fractionation schemes using HDREB are not well characterized.
This prospective phase I/II study was conducted for
the following purposes: to determine whether a dose response exists for NSCLC
when treated with a combination of 66 Gy external beam radiation and escalating
doses of HDREB; and to establish a well tolerated dose schema in patients with
NSCLC who undergo high dose rate endobronchial brachytherapy.
II. Patients and methods
A. Patient selection
Thirty
patients with medically inoperable or surgically unresectable stage III NSCLC
were treated in this institutional phase I/II study with both external beam
radiotherapy and high dose rate endobronchial brachytherapy. Tissue diagnosis
of NSCLC was mandatory for enrollment into the study. All patients had a
peribronchial or endobronchial component with bronchial obstruction of 50% or
more on bronchoscopy examination. Pre-radiotherapy evaluations included a
complete history and physical examination, pulmonary function test, complete
blood counts and serum electrolytes, chest X-ray, CT scan of chest, and
bronchoscope. Patients with metastatic disease, malignant pleural effusion,
history of any other malignancy other than skin cancer, poor performance status
(Karnofsky performance status of less than 60), pathology other than non-small
cell carcinoma, surgically treated lesions, prior history of radiotherapy to
the chest, and those who refused to receive brachytherapy were excluded from
the protocol. Written consent was obtained from all patients before starting
the treatment.
B. External beam radiotherapy
External beam radiation
treatment and high-dose-rate endobronchial brachytherapy were delivered in a
sequential manner.
External beam radiotherapy
was administered via megavoltage (6MVx) photons. The planned treatment dose of
EBRT was 66Gy using a conventional fractionation (2 Gy/fraction) delivered 5
days per week over 33 days. The initial treatment portal included primary
tumor, ipsilateral hilar lymph nodes, and mediastinum through opposed parallel
AP and PA fields. Treatment of supraclavicular fossa was not mandatory. After a
total of 40 Gy delivered through the initial fields, patients were treated with
boost field(s) include the tumor and enlarged lymph nodes defined by chest CT
scan. The EBRT boost dose was 26 Gy. Dose to the spinal cord was limited to 45
Gy or less.
C. High-dose-rate brachytherapy
High-dose-rate brachytherapy
was delivered using the Nucleotron HDR remote afterloading unit with a 10 Ci
Ir-192 source. HDREB were delivered prior to the EBRT if the endobronchial or
peribronchial component could be fully covered by the HDR brachytherapy dose
distribution. For patients with larger tumors, or with complete or near
complete bronchial obstruction, HDREB were delivered after the completion of
EBRT.
The length
of bronchus treated included gross tumor visualized on the bronchoscopy with 2
cm margins proximally and distally. Each treatment of HDREB was delivered at 1
cm depth from the central axis of the radiation source regardless of the size
of the tumor at the time of brachytherapy. The first group of 10 patients
received three treatments of HDREB at 7 Gy per fraction (Group1). The second
group of ten patients received three treatments at 8 Gy per fraction (Group 2).
The last group of ten patients received three treatments of HDREB at 9 Gy per
fraction (Group 3). HDREB was delivered once weekly. Bronchoscopy was performed
during placement of the brachytherapy catheters during each HDREB session to
evaluate any acute side effects or complications. Dose escalation and thus the
protocol would be terminated if there was treatment related death or more than
3 Grade 3 or 4 toxicities were observed in any treatment groups. Evaluation of
tumor response was not performed until three months after the completion of the
treatment.
D. Chemotherapy
All
patients in this study had locally advanced disease and received systemic
chemotherapy in addition to external beam radiation and brachytherapy. All 30
patients received cisplatin or carboplatin based chemotherapy concurrently
during external beam radiation but not during HDREB.
Two
patients in Group 1 also received a short course of neoadjuvant chemotherapy
before entering this protocol. The pre-radiation baseline CT scan and
bronchoscopy evaluations were performed for both patients after the completion
of their neoadjuvant chemotherapy but within one week before the starting of
radiation. Both patients had more than 50% obstruction at the primary sites in
their baseline evaluations before the starting of radiation treatment.
E. Post-treatment Evaluation
All patients were followed up
by their radiation oncologists and pulmonologists after the completion of the
treatment. All patients were required to receive monthly fiberoptic
bronchoscopy for toxicity and response evaluation starting at two to four weeks
after the treatment for at least 4 months. CT scan of the chest were required
for all patients at 3 months time after the completion of treatment. After
that, follow up clinical examinations were performed every three months in
either the radiation oncology or pulmonology clinics.
Response to
treatment was graded by objective findings include both bronchoscopic and
radiological studies at 3 months after the completion of radiotherapy.
Subjective findings, including symptomatic changes, were not used to define the
response to therapy. Complete response (CR) was defined as the complete
disappearance of all clinical and radiological evidence of bronchial
obstruction at the primary site; partial response (PR) as a 50% or greater
decrease in the bronchial obstruction on both CT of the chest and bronchoscopy
examination; stable disease as a response less than 50% decrease but not more
than 25% increase of the bronchial obstruction on either chest CT or
bronchoscopy examination; and progressive disease as more than 25% increase in
the size of the obstruction in either examination.
Acute and
late toxicities from treatments were graded according to the Radiation Therapy
Oncology Group criteria. Late toxicities were defined as symptoms first
occurring 90 days after treatment or lasting beyond 90 days after the
completion of treatment. Toxicities were evaluated weekly during the radiation
treatment and at each follow-up after the completion of treatment (Cox et al,
1995).
III. Results
A. Patient characteristics
The median age of all 30 patients was 65 (range
50-72). Twenty-six patients were male and 4 were female. All patients have
either AJCC stage IIIa or IIIb non-small cell lung cancer with endobronchial or
peribronchial components. Twenty-nine
patients received both external beam radiotherapy and brachytherapy according
to the protocol. One patient in Group 2 received three applications of HDR
brachytherapy (total brachytherapy dose was 24 Gy) followed by external beam
radiation but stopped external beam radiation at 60 Gy for non-medical reasons.
Two patients in Group 1, 2 patients in Group 2, and 1 patient in Group 3
received HDREB prior to the starting of EBRT.
PatientsÕ characteristics are listed in Table 1.
B. Follow up
The median follow up time for all 30 patients was 14.5
months (range 1 to 38 months). One
patient in Group 1 died of local disease progression approximately 5 weeks
after treatment. All other patients had more than 3 months follow-up and
received examinations according to the requirement of the protocol including a
CT scan of the chest at 3 months after the completion of treatment.
C. Response and survival
Complete or partial response at the primary site was
obtained in 6 cases (60%), 9 cases (90%), and 9 cases (90%) in the three groups
of patients, respectively (Table 2).
We compared the response data of patients in Group 1 with the response of
patients in Group 2 and 3 combined because of the identical response rates (CR
and PR combined), and found the difference reached statistical significance
(p=0.05).
The medial survival for all 30 patients was 13 months
(range 1 to 36 months). Significant difference of survival among the three
groups was not expected for this small group of patients with locally advanced
disease.
D. Toxicity
Documentation of severe acute and
late toxicities (defined as Grade 3 and Grade 4 toxicities according to RTOG toxicity
criteria) was mandatory for all patients. Although documentation of Grade 1 and
Grade 2 toxicities was required by our radiation oncology department policy, it
was not required by this research protocol.
One patient in Group 1 developed
Grade 4 toxicity (hemorrhage from the bronchus at the HDR treatment site), 1
patient in Group 2 and 1 patient in Group 3 developed radiation bronchitis. All
3 patients developed toxicities within 90 days after the completion of their
brachytherapy (Table 3). Although
Grade 1 or 2 radiation induced toxicity of esophagus and bronchus was observed
during follow-up examinations in multiple cases, no other substantial acute or
late toxicities were observed and reported. There were no treatment-related
deaths.
The planned treatment with external
beam radiation therapy with HDR boost was well tolerated in the majority of the
patients.
IV. Discussion
Patients with locally advanced non-small cell lung
cancer are generally treated with external beam radiotherapy combined with
chemotherapy; however, previous experience has confirmed that this combined
treatment can only achieve limited clearance of the disease because the dose of
the treatment is generally limited by other critical structures in the chest.
Endobronchial brachytherapy for NSCLC has been well studied extensively
previously. Palliative effects ranging from 50-100% for different types of
symptoms have been reported.
Endobronchial brachytherapy can be delivered at low
dose rate (LDR), intermediate dose rate (IDR), or high dose rate (HDR). HDR brachytherapy units, which deliver radiation at
more than 12 Gy per hour, are now widely available in most cancer treatment
centers. Because the radioactive sources are more precisely controlled and
safety of the treatment delivery is improved, it is the more commonly utilized
brachytherapy modality for lung cancer treatment.
Even though HDREB is widely used to treat locally
advanced NSCLC, no specific clinical guidelines have been established. The most
commonly accepted dosage of HDREB used with external beam radiotherapy has been
3-5 fractions of 5 Gy HDR brachytherapy, but other HDR brachytherapy schedules
have also been used. The brachytherapy dose and schedule are chosen mostly
empirically. Theoretically, higher dose per fraction may increase the rate of
complications, but it may also improve the rate of local control and/or
palliation.
Because of the rapid fall of dose
with distance, the complication rates from brachytherapy treatments are
generally tolerable given the relatively high doses delivered. Rates of severe
complications from the HDREB are reported to be 3-11% (Burt et al, 1990;
Aliberti, 1995; Langendijk et al, 1998; Kotsianos et al, 2000). Common complications
from HDREB include hemoptysis, radiation bronchitis, and esophagitis. Fatal
hemoptysis and tracheoesophageal fistula caused by HDREB have been reported but
the occurrence is relative rare. Burt et al. retrospectively reported that
patients tolerated well with a single fraction of 15-20 Gy prescribed to 1 cm
from the center of the source (Burt et al, 1990). Aliberti analyzed 9 series in
the literature and reported 11.3% hemoptysis in 576 cases (Aliberti, 1995). In
a retrospective study reported by Langendijk et al, external beam radiotherapy
combined with endobronchial brachytherapy as primary treatment for NSCLC did
not lead to a higher risk of massive hemoptysis as compared to EBRT alone when
fraction sizes for brachytherapy of 7.5 or 10 Gy were used (Langendijk et al,
1998). Kotsianos et al, (2000) analyzed 48 biopsy specimens of
three-dimensional miniorgans of the human bronchial wall histologically after
high-dose-rate brachytherapy with escalating dosage. The range of the
high-dose-rate irradiation was around 75 Gy. The authors found that there was
no histologically apparent tissue damage regardless of the irradiation dose and
concluded that normal bronchial epithelium has a high tolerance to early
epithelial damage by irradiation (Kotsianos et al, 2000). Several other
clinical studies attempted to define the optimum doses and fractionation
schemes in brachytherapy for lung cancers (Huber et al, 1987; Speiser and
Spratling, 1993; Gollins et al, 1994). These trials confirmed a high tolerance
of bronchial epithelium to brachytherapy; however, the maximal tolerance dose
has not been defined in any prospective studies.
In our series, only 3 patients (one
patient from each group) developed Grade 3 or Grade 4 toxicities. All patients
developed treatment induced esophagitis with mild to moderate severity (Grade 1
to 3) during or shortly after the completion of external beam radiotherapy.
However, no new symptoms of esophagitis were observed and no existing
esophagitis worsened during the HDREB. We have confirmed that the total dose of
up to 27 Gy in 3 weekly fractions of HDR endobronchial brachytherapy after a
definitive course of external beam radiation treatment to the lung is well
tolerated. Further dose escalation may be possible in light of our results.
Most studies reported significant symptomatic
improvement after HDREB (Burt et al, 1990; Chang et al, 1994; Gollins et al,
1994; Kelly et al, 2000). In a
retrospective review reported by Kelly et al, significant and slight
improvement of HDREB were reported in 32% and 34% patients, respectively (Kelly
et al, 2000). However, repeated
bronchoscopy after HDREB demonstrated that overall objective response rate
correlated with subjective response and symptomatic relief in less than 80% of
the cases. The response rates of our
study were measured by both CT scan of the chest and follow up bronchoscopy
examinations. All study results were confirmed by the treating pulmonologist
and radiation oncologist. Subjective
response information such as dyspnea, cough, amount of hemoptysis or other
symptoms reported by patients, was not used to measure the response rate.
Patients treated with higher dose HDREB (24 Gy or more) achieved significantly
higher response rates compared to patients received 21 Gy of HDREB.
Many patients with locally advanced
NSCLC have relatively bulky primary disease; however, the therapeutic range of
HDREB is limited and may not cover the primary tumor completely. Therefore,
HDREB should be used after EBRT for the majority of patients unless the initial
primary tumor volume can be covered by HDREB. In our study, only a few patients
with small primary tumors were treated with HDREB first. Comparison between
patients treated with HDREB before or after EBRT was not done because of the
limited number of patients in each group.
The response rate of patients in groups 2 and 3 is
identical (90%). We do not know whether further increase of HDREB dose will
further improve the local response or not. It was originally planned to
escalate the HDREB dose to 30 Gy delivered in 3 weekly fractions; however, to
detect any significant but small improvement of response over 90% would require
a substantially larger sample size, and such study may not be feasible in a
single institution.
Patients with unresectable and locally advanced
non-small cell lung cancer are generally treated with definitive radiotherapy
with chemotherapy, either sequentially or concurrently (Perez et al, 1987;
Dillman et al, 1990; Le Chevalier et al, 1991). All patients in this protocol
received concurrent chemotherapy according to our institutional chemotherapy
regimen. Two patients in Group 1 also received a short course of neoadjuvant
chemotherapy. Both patients received brachytherapy after EBRT and had partial
response after the completion of radiotherapy. The post-treatment evaluations
for these 2 patients were compared to the chest CT scan and bronchoscopic
findings after the completion of neoadjuvant chemotherapy. It is unlikely that
this slight deviation from chemotherapy schedule would have any substantial
effect on our overall conclusion.
The prognosis of patients with
locally advanced non-small-cell lung carcinoma is generally poor. The overall
2-year survival rate is less than 25% (Perez et al, 1987; Hazuka and Turrisi,
1993), and the median survival is around 12 months with external beam radiation
and concurrent chemotherapy (Sause et al, 1995). Distant metastasis is common
in this group of patients and is the most common cause of death. The median
survival time for our patients was 13 months, which is comparable to the
historical data. Because the end points of this study are the overall response
rates and the rate of Grade 3 and 4 complications at different dose regimens,
follow up for patientsÕ survival data was not required by this prospective
protocol. Nevertheless, our clinical chart review data showed that the majority
of patients deceased developed distant metastasis. Thus, improvements in
survival will also depend on better systemic control.
V. Conclusion
High-dose-rate brachytherapy
of 27 Gy in three divided weekly treatments, plus 66 Gy of external beam
radiation is well tolerated and effective for the treatment of obstruction from
non-small cell lung cancer with endobronchial or peribronchial component. A
statistically significant dose response for NSCLC is seen when treating with a
combination of external beam radiation and high dose rate endobronchial
brachytherapy with a dose of 24 Gy or higher in 3 weekly fractions. EBRT followed by fractionated adjuvant
HDREB is a strategy that deserves to be optimized and then tested in a larger
scale prospective trial to learn if it can improve outcome.
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Jiade J. Lu