Jpn J Clin Oncol 2001;31(2)55–60
© 2001 Foundation for Promotion of Cancer Research
Intra-thoracic Failure Pattern and Survival Status Following 3D
Conformal Radiotherapy for Non-small Cell Lung Cancer: a
Chun-Ru Chien1,2, Shang-Wen Chen1,3, Chang-Yao Hsieh2, Ji-An Liang3, Shin-Neng Yang3, Chao-Yuan Huang2and
1Department of Radiation Therapy and Oncology, Shin Kong Wu Ho-Su Memorial Hospital, Taipei,2Department of
Oncology, National Taiwan University Hospital, Taipei and3Department of Radiation Therapy and Oncology, China
Medical College Hospital, Taichung, Taiwan
For reprints and all correspondence: Fang-Jen Lin, Department of Radiation
Therapy and Oncology, Shin Kong Memorial Hospital, 95 Wen Chang Road,
Shi-Lin, Taipei, Taiwan. E-mail: email@example.com
Abbreviations: 3D, three-dimensional; 3DCRT, 3D conformal radiotherapy;
AC, adenocarcinoma; ATS, American Thoracic Society; BTV, biological target
volume; CCRT, concurrent chemo-radiotherapy; CPE, contralateral malignant
pleural effusion; CT, computed tomography; C/T, chemotherapy; CTV, clinical
target volume; CTV1, tumor site/risky tumor bed, ipsilateral hilum, whole
mediastinum and bilateral SCF when indicated; CTV2, tumor site or risky
tumor bed with/without ENI; CTV-N CTV of risky lymphatics; CTV-T, CTV of
peri-tumor region; CXR, chest X-ray; CW, chest wall relapses; EBRT, external
ipsilateral malignant pleural effusion; LFF, local failure free; LRR-CT, local-
regional failure diagnosed by CT; NS, non-specified; NSCLC, non-small cell
lung cancer; OS, overall survival; OP, operated; PN, pleural nodular relapses;
PTV, plannedtargetvolume;RO,radiationoncologist;RT,radiotherapy; RTOG,
Radiation Therapy Oncology Group; SCC, squamous cell carcinoma; SCF,
supraclavicle fossa; TS, tumor site/bed
Received July 24, 2000; accepted November 24, 2000
Background: To study the intra-thoracic failure pattern, clinical target volume (CTV) and sur-
vival status following 3D conformal radiotherapy (3DCRT) boost for non-small cell lung cancer
Methods: From May 1994 through June 1998, 33 patients (26 male, seven female) with NSCLC
were treated with a complete course of radiotherapy (RT) in our institute. Group A included 10
patients receiving radical operation and adjuvant postoperative RT. The other 23 patients
(groups B and C) received definitive radiotherapy as local treatment. Among them there were
seven cases as group B (stage I–II) and 16 cases as group C (stage III). Fifteen (15/33) patients
received chemotherapy. The radiotherapy strategy constituted conventional AP/PA radiotherapy
(RT) 19.8–45 Gy (median 39.6 Gy) plus 3DCRT boost 6–34.2 Gy (median 20 Gy). The median
total tumor dose was 59.6 Gy (ranging from 39.8 to 64.8 Gy). Patients were followed up regularly
(6/33) or until their death (27/33). Nineteen patients received follow-up chest computed tomog-
raphy (CT). The relationship between intra-thoracic failure found by chest CT and the initial RT
and boost RT fields was analyzed. Local failure was defined as one of the following: clinical dis-
ease progression, CXR progression or relapse noted by CT. The overall survival (OS) and local
failure free survival (LFF) were obtained using the Kaplan–Meier method.
Results: Sixteen intra-thoracic failures were noted in 15 follow-up chest CT examinations,
which included nine in-field relapses, three partial in-field relapses and four out-field relapses.
The 2-year OS and LFF for groups A, B and C were 78.8/59.2, 14.2/16.7 and 6.2/7.1% respec-
tively. RTOG grade III/IV complications included one pneumothorax (RTOG grade III).
Conclusion: Our retrospective study showed that selective omission of contralateral medias-
tinal lymph node station irradiation may be appropriate in RT for NSCLC. Chest wall and pleural
relapses may not be a negligible cause of intra-thoracic failure after RT for NSCLC.
Key words: non-small cell lung carcinoma – conformal radiotherapy – neoplasm local recurrence
Radiotherapy (RT) is an important modality in the treatment of
non-small cell lung cancer (NSCLC) (1–3). In the era of 3D
conformal radiotherapy (3DCRT) and intensity modulated
radiotherapy (IMRT), clear delineation of the clinical target
volume (CTV) (4) on computed tomography (CT) is an impor-
tant step in the practice of modern radiotherapy (1,5–7).
Local failure pattern and survival rate in 3DCRT for NSCLC
Analysis of failure patterns is helpful in delineation of CTV.
However, there have been few studies focusing on the relation-
ship of intra-thoracic failure with the initial irradiated volume
(8–10) and it was not clearly mentioned that they were all
based on chest CT studies. Therefore, we performed this retro-
spective analysis to review the survival status and the local
failure pattern of 33 patients with NSCLC treated with a com-
plete course of RT with 3DCRT boost in our institute from
1994 to 1998.
MATERIALS AND METHODS
From May 1994 through June 1998, a total of 33 patients (26
male, seven female) with non-metastatic NSCLC were treated
with complete courses of radiotherapy in our institute. The
median age at the initiation of radiotherapy was 68.8 years
(range 44.4–82.9 years). No specific occupation history was
noted. Patients’ characteristics are shown in Table 1. All
patients were uniformly staged by complete medical history
and imaging finding. Pathological TNM (pTNM) staging was
based on the operative finding and pathological records in 11
patients. Clinical TNM (cTNM) staging was based mainly on
chest CT for the other 22 patients. Mediastinum lymph node
was considered to be pathologically significant only when the
diameter of the short axis of a lymph node was more than 1 cm
(11). Bronchoscopy, bone scan, abdominal sonography and
brain CT were performed when they were indicated clinically.
The TNM staging was obtained according to the American
Joint Committee on Cancer (AJCC), 5th edition, 1997 (12). All
patients were classified into three groups. Group A included
those patients who received radical operation. Group B
included stage I–II patients who received definitive radiation
therapy alone as local treatment. Group C included stage III
patients who received definitive RT as local treatment (Table
Ten patients received radical operations (tumor excision and
mediastinum lymph node dissection) and adjuvant postopera-
tive RT. One patient received partial open-and-close surgery
for advanced disease (stage IIIB). Twenty-three patients
received RT as definitive local treatment.
The radiotherapy strategy constituted external beam RT
(EBRT) via AP/PA two portals (13), 19.8–45 Gy (median 39.6
Gy) as first-stage RT, followed by 3DCRT boost 6–34.2 Gy
(median 20 Gy) as second-stage RT. The median total tumor
dose was 59.6 Gy (range 39.8–64.8 Gy). The CTV1 in first-
stage RT included tumor site (in non-operated cases) or risky
tumor bed (in operated cases), ipsilateral hilum, whole medi-
astinum and bilateral supraclavicular fossa (SCF) lymphatics
when indicated (such as upper lobe tumor or enlarged SCF
lymph node). The CTV2 in second-stage RT generally
included the tumor site or risky tumor bed with/without
elective nodal irradiation (ENI). For ENI, American Thoracic
Society (ATS) station 6 (anterior mediastinum nodes) were
generally excluded and ATS station 5 (aortopulmonary nodes)
were generally excluded for right lung cancer (12). The margin
between planned target volume (PTV) and CTV is generally
about 1–2 cm. For 3DCRT, a plastic immobilizer with metallic
wire marker was used for each patient. Chest CT was then
performed in the same position with a 5–8 mm slice thickness.
After CTV contouring slice by slice made by radiation oncolo-
gists (S. W. Chen, J. A. Liang, S. N. Yang), treatment planning
was carried out by physicists with Nulceatron PLATO 2.0.
The actual dose delivery was calculated without lung density
correction. The portal number in 3DCRT was 2.9 on average
(range 2–4). In most cases three coplanar portals were used. An
Table 1. Patients’ characteristics
SCC, squamous cell carcinoma; AC, adenocarcinoma; NS, non-specified non-
small cell lung cancer; RUL, right upper lobe; RML, right middle lobe; RLL,
right low lobe; LUL, left upper lobe; LLL, left low lobe.
CharacteristicNo. of patients (%)
Total No. of patients33 (100)
Male 26 (79)
Smokers 23 (70)
SCC 20 (61)
AC 12 (36)
NS 1 (4)
RUL 6 (18)
RLL 9 (28)
LLL 6 (18)
Table 2. Patient grouping and staging (patient number)
Group A, 10 patients receiving radical operation; group B, seven stage I/II
patients receiving definitive radiotherapy (RT) as local therapy; group C, 16
stage III patients receiving definitive radiotherapy (RT) as local therapy; IA–
IIIB, TNM staging.
Group A Group B Group CTotal
Total107 16 33
Jpn J Clin Oncol 2001;31(2)
example is shown in Fig. 1. Wedges were used to improve the
dose homogeneity as necessary. The main constraint was to
keep the cumulative spinal dose <50 Gy. The irradiated lung
volume was to be kept as small as possible. The EBRT was
generated from linear accelerators (Siemens, MEVATRON
KDS-2) and shaped by custom-fabricated blocks. Radiother-
apy was given in a period of 37–84 days (median 57 days)
except for one case in 136 days.
Fifteen patients also received chemotherapy(C/T). Gener-
ally, C/T was applied to those with a relatively good general
condition and patient acceptance. The time sequence of C/T
included pre-definitive RT C/T in two cases, adjuvant concur-
rent chemo-radiation therapy (CCRT) in two operated cases,
definitive CCRT in four non-operated cases, adjuvant C/T
following radical operation and RT in five cases and adjuvant
C/T following definitive RT in six cases. Before mid-1997,
MFL (Mitomycin C + Ftoral + Leucovorin) was the main C/T
regimen. After mid-1997, the C/T regiment was Taxotel- and
Gemzar-based C/T(two patients) or Cisplatin-based C/T(three
After completion of treatment, all patients were followed up
until their death. Three of them died of early clinical disease
progression before follow-up CXR was done. Follow-up chest
CT had been performed in 19 cases. Since it is often difficult to
differentiate post-radiation and/or post-operative change from
disease progression, CXR were used to evaluate disease pro-
gression only. CXR progression was defined as a progressive
change in follow-up CXR. Intra-thoracic failure was defined as
obviously enhancing soft tissue mass or progressive change
noted in follow-up chest CT. When there were one or more
intra-thoracic failures noted in the chest CT, local regional
relapse chest CT (LRR-CT) was recorded. The location of the
failure and its geographic relationship with CTV1 and CTV2
were documented. Relapse in CTV2 was defined as ‘in-field’
relapse, while relapse only in CTV1 was defined as ‘partial in-
field’ relapse and relapse outside the CTV1 was defined as
‘out-field’ relapse. The lymph node location was documented
according to AJCC, 5th edition, 1997 (12,14). ‘Local failure’
was defined as one of the following: clinical disease progres-
sion, CXR progression or LRR-CT. Brain CT, bone scan and
abdominal sonography were performed only when distant
metastasis was suspected.
The Kaplan–Meier method was used in the calculation of over-
all survival (OS) and local failure free (LFF). The period of
LFF was from the first day of RT to the first day of local failure
or the last day of imaging study with stationary finding. The
period of OS was from the first day of RT to the day of the last
follow-up, the day of a telephone visit or death. The log rank
test and Cox regression method were used for univariate and
For group A patients, there were four patients living without
disease, three patients died of local failure, two patients died of
both local failure and distant metastasis and one patient died of
distant metastasis. The 1 and 2 year OS/LFF were 80/80 and
For group B patients, there was one patient living without
disease, five patients died of local failure and one patient died
of both local failure and distant metastasis. The 1 and 2 year
OS/LFF were 57.4/50 and 14.2/16.7%, respectively.
For group C patients, there was one patient living without
disease, 11 patients died of local failure, three patients died of
both local failure and distant metastasis and one patient died of
distant metastasis. The 1 and 2 year OS/LFF were 43.7/7.1 and
The 2 year OS of all patients for smoker/non-smoker,
operated (OP)/non-operated (nonOP) and chemotherapy/non-
chemotherapy were 21.7/20, 50/8.7 and 20/22.2%, respec-
tively. In univariate analysis, the only statistical significance
was found in OP/nonOP (p = 0.006). The same was found in
multivariate analysis (p = 0.021). The 2 year LFF of patients
receiving an RT dose of >60 Gy was inferior to those receiving
an RT dose of <60 Gy (8/17%) without statistical significance.
Seven patients in group A received follow-up chest CT; five
LRR-CT were found in four of the seven patients (follow-up
CT in one patient showed two local regional relapses). The
relapse pattern included three ‘in-field’ relapses, one ‘partial
in-field’ relapse and one ‘out-field’ relapse. Twelve patients in
groups B and C received follow-up CT; 11 LRR-CT were
found in 11 of the 12 patients. The relapse pattern included six
‘in-field’ relapses, two ‘partial in-field’ relapses and three
Figure 1. Representative diagram of the beam arrangement in RT for NSCLC.
Anterior superior left oblique view of beam arrangement in one case with right
low lobe tumor and 4R mediastinum lymph node. G (brown), gross tumor
volume; pinkish, spinal cord; R (yellowish), right lung; L (yellowish), left
lung; green, beam arrangement.
Local failure pattern and survival rate in 3DCRT for NSCLC
‘out-field’ relapses (Table 3). For the nine cases of ‘in-field
relapse’, the median total RT dose was 60 Gy (range 46–64.6
Gy). For the three cases of ‘partial in-field relapse’, the RT
dose to relapse site was 45, 49.6 and 53.1 Gy, respectively. All
the sixteen LRR-CT were first failure site except in one case
in which LRR-CT was found 1 month later after distant
metastasis was found. A representative diagram showing the
distribution of the LRR-CT is shown in Fig. 2.
Extra-thoracic metastases were noted in eight cases (bone
metastases in four cases, liver metastases in two cases and
brain metastases in two cases). Isolated extra-thoracic metasta-
sis was noted in two cases (brain and bone). Three extra-
thoracic metastases were found within 2 months after the
evidence of local failure and the other three extra-thoracic
metastases were found within 2 months before evidence of
local failure. The only RTOG grade III/IV complication was
one pneumothorax (RTOG grade III), which was noted in one
case in group C during the course of RT.
The optimum area of CTV for NSCLC is still not well estab-
lished (15–17). The ratio of the largest to smallest contoured
volume had been reported to be within the range 1.6–2 among
different radiation oncologists (RO), independent of the ex-
perience of the RO (17). According to ICRU Report 62 (4),
CTV included CTV-T and CTV-N. So it is better to have infor-
mation about the lymphatic drainage of the lung and the
relapse pattern to assess what should be included in CTV-N
With regard to CTV-N, the lymphatic drainage of lung
cancer is mainly ipsilateral and cephalad irrespective of the
primary site (18). It seems that there is a tendency to reduce the
volume of CTV, although skip metastasis was found in 20–
80% of pN2 patients (19,20). Emami et al. suggested a strategy
to include high-risk area, ipsilateral hilum, mediastinum and
selective ipsilateral supraclavicular fossa for post-operative
RT to NSCLC (21). Armstrong and Ginbey suggested that it
may be appropriate to ignore subclinical extensions when
designing CTV (5,22). McGibney et al. suggests omission of
ENI and 3DCRT to achieve dose escalation (23). Armstrong et
al. suggested a strategy to exclude ENI after 50 Gy for dose
escalation (median dose 70.2 Gy) for a better survival rate
(32% 2 year OS for inoperable NSCLC) (24). For clinical
stage I cases, only 13% pathological N2 metastasis had been
reported (25) and Hayakawa et al. reported similar results
Figure 2. Representative diagram of numbers and locations of intra-thoracic
failures. CW-3, three chest wall relapses; PN-3, three pleural nodular relapses;
TS-6, six recurrences at tumor site/bed; ILN-2, two ipsilateral mediastinum
lymph node failures [one low paratracheal node (ATS LN-4) and one aortopul-
monary node (ATS-LN5)]; IPE-1, one malignant ipsilateral pleural effusion
without obvious mass; CPE-1, one contralateral malignant pleural effusion
without obvious mass.
Table 3. Intra-thoracic failure pattern (number of relapses)
Group A, 10 patients receiving radical operation; group B, seven stage I/II patients receiving definitive radiotherapy (RT) as
local therapy; group C, 16 stage III patients receiving definitive radiotherapy (RT) as local therapy; ‘in-field’ relapse, relapse in
RT boost volume; ‘partial in-field’ relapse, relapse between initial RT volume and boost volume; ‘out-field’ relapse, relapse
outside initial RT volume; iLN, ipsilateral mediastinum lymph node; iPE, malignant ipsilateral pleural effusion without obvious
mass; cPE, contralateral malignant pleural effusion without obvious mass.
LocationGroup A Group BGroup CTotal
‘In-field’ relapseTumor site/tumor bed1146
‘Partial in-field’ relapse Pleural nodules22
‘Out-field’ relapse Pleural nodules11
Jpn J Clin Oncol 2001;31(2)
for either omission of ENI or not (5 year OS: ENI/non-ENI
39/40%) (26) and Slotman et al. also reported a good result
(76% 3 year disease specific survival) with omission of ENI
(27). Of the 16 LRR-CT in our study, there were two ipsilateral
mediastinal lymph nodes (ATS LN stations 4 and 5). Hence it
may be reasonable to exclude contralateralmediastinum lymph
node stations from the CTV and even to exclude ENI from the
beginning for stage I cases.
Concerning CTV-T, the intra-thoracic recurrence rate for
stage I/II cases had been reported to be 5–22% and even higher
in more advanced stages (3). However, the problem depends
on how we detect local relapse. The earlier study used chest X-
ray as a major tool (28,29). Chest CT has an important role in
detecting local relapse. In one study, 75% of tumor recurrence
was recognizable only by CT (30). Positron emission tomogra-
phy (PET) scanning has a better sensitivity/specificity (100%/
92%) to detect recurrent/residual lung cancer than does chest
CT(sensivity/specificity71/95%)(31). Withregardtothe rela-
tionship between intra-thoracic relapse and the initial RT field,
Perez et al. reported 35% local relapse (diagnosed by chest X-
ray) in irradiated lung and 30% local relapse in non-irradiated
lung (19% in both fields) for inoperable NSCLC patients
receiving an RT dose of 60 Gy (8). Byhardt et al. (9) reported
an intra-thoracic failure rate of ~41–50% after definitive RT
for stage II–IIIB NSCLC, which is composed of five Radiation
Therapy Oncology Group (RTOG) studies (32–36). However,
it was not clearly mentioned in these studies whether the fail-
ure pattern was based only on chest CT studies or not, except
in the report by Byhardt et al. (32). Whether 3DCRT is used in
these studies was also not mentioned. Further, the failure
or ‘both’. The failure rate of primary, thorax and both were 17–
22, 16–18 and 5–9%, respectively. Of the 16 LRR-CT in our
study, nine were found to be totally in our RT field. Another
three were partially in our field. On the other hand, eight of the
16 LRR-CT were chest wall metastasis (three), pleural nodules
(three) and malignant pleural effusion (two). These were not
easily included in the ordinary idea of CTV (risky tumor
bed/site plus regional lymphatics) (3,5,6,15). How to define
the optimal ‘margin’ for CTV-T to include the risky pleurae/
chest wall deserves further studies. Recent meta-analysis
showed the effect of C/T in the treatment of NSCLC (37).
Perhaps systemic chemotherapy will help in this situation.
The RT dose also influenced the local results. Perez et al. had
suggested that a higher dose of irradiation would be necessary
in order to improve the intra-thoracic tumor control (the failure
rate within the irradiated lung was 38% for a tumor dose of 50
Gy and 27% for a tumor dose of 60 Gy) (8). The current ten-
dency also showed that a high dose was favored (median dose
ranging from 66 to 70.2 Gy) (1,22,27). In our study, local fail-
ure was noted in 25 cases (75%). This may be due to the high
(7/16) non-‘in-field’ relapse rate or the RT dose in our study
was not effectively high enough (maximum 64.8 Gy). The
optimum RT dose for NSCLC deserves further study.
After the disclosure of the human genome, the genetics of
cancer may be better understood in the future. Perhaps molecu-
lar staging can help us in assessing the risk of lymph node
metastasis (38) and the concept of biological target volume
(BTV) (39) can further help us in defining the optimum
volume of RT for NSCLC in the future.
Our preliminary retrospective study showed that most of the
intra-thoracic relapses were within the initial large RT field.
LN failure as first failure site was noted in only 12.5% LRR-
CT. Also, there was a high percentage (43%) of ‘out-field’ or
‘partial in-field’ relapses. Chest wall/pleural relapses may be
contributory to the intra-thoracic failure after RT for NSCLC.
Selective omission of the ENI region (especially contralateral
mediastinum lymph node region) from the RT field may be
Special thanks are due to Hsin-Ju Hsien for her help with the
statistical analysis and An-Cheng Shiau for his help with
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