METHODS
Patients with stage III NSCLC who received RCT between January 2008 and December 2014 were evaluated
retrospectively with respect to patients, tumor, and treatment characteristics; PFT parameters
before RCT; 1, 6, and 12 months after RCT; response rates; progression-free survival (PFS); and 5-year
overall survival (OS). PFT parameters at 1, 6, and 12 months after RCT were compared with the same
patients" baseline values. RP was assessed both clinically and radiologically.
RESULTS
A total of 61 patients were analyzed in the study. Median follow-up was 20 (4?116) months, and PFS was 14
(2?122) months. Five-year OS was 18%. All PFT parameters declined after RCT, but only decreases in forced
expiratory volume in 1 second at 6 and 12 months and in diffusion capacity of the lung for carbon monoxide
(DLCO) at 6 months were found to be statistically significant. None of the baseline PFT parameters was
found to be predictive of RP except the baseline DLCO; patients who had a baseline DLCO value <65%
(52%?75%) developed RP in contrast to patients who had baseline DLCO value >75% (71%?95%) (p=0.023).
CONCLUSION
There has been prominent and persistent decrease in PFT after RCT. However, the clinical outcome of
this finding has to be evaluated. Further prospective studies with larger scales are needed to verify the
predictive value of baseline DLCO on the development of RP.
Keywords: Non-small cell lung cancer; pulmonary function tests; radiochemotherapy
Radiation pneumonitis (RP) is the major radiation-
induced toxicity after thoracic radiotherapy
(RT), and there has been no algorithm for radiation oncologists to predict RP before RT with today's clinical
practice.[
The primary aim of the present study was to evaluate
the extent of change in PFTs in early and late term
after concurrent RCT and whether baseline PFTs and
percentage of changes in PFTs after RCT would predict
RP after RCT in LA-NSCLC. The secondary aim was
to investigate if baseline forced expiratory volume in
1 second (FEV1) could be a prognostic factor for survival.
PFTs included percentage of predicted FEV1%, forced vital capacity (FVC), vital capacity, and diffusion capacity of the lung for carbon monoxide (DLCO). We select percentages instead of absolute values to minimize the confounding effects of age, gender, and height.
In patients who had more than one PFT before RCT, the one closest to RCT initiation was used for analysis. Treatment outcomes, response rates, progression- free survival (PFS), overall survival (OS), and 5-year survival were reviewed. PFS was calculated from the last day of RCT until locoregional relapse or distant metastasis occurred. OS was measured from the date of diagnosis to the date of death. OS data were collected from the national database.
RT Planning
The patients were treated mostly with three-dimensional
conformal RT (3D-CRT) and intensity-modulated
RT. RT was delivered using conventional fractionation
(1.8 Gy/day, 5 days/week) with a total dose of
60?63 Gy using 6/18 MV photon beams. Involved field
technique was used for RT planning. The gross tumor
volume (GTV) consisted of the primary tumor and the
regional lymph nodes considered positive (SUVmax
>2.5) on positron emission tomography (PET) scan even if not involved by computed tomography (CT)
scan. Any intrathoracic lymph nodes with a diameter
>10 mm in the short axis were included in GTV regardless
of the PET scan. For GTV definition on CT,
pulmonary window settings were used to contour the
pulmonary tumor and hilum, and the predefined mediastinal
window settings were used to contour the
mediastinal lesions. Margins for GTV to clinical target
volume (CTV) were 6 mm for squamous cell carcinoma
and 6?8 mm for other histologies. To generate
the planning target volume (PTV), 5-10 mm margin
was added to the CTV to compensate set-up errors and
target motion. After 45?46 Gy, RT was delivered to a
boosts volume encompassing the primary tumor and
lymph nodes known to be involved with disease. The
corrections for tissue inhomogeneities were applied.
QUANTEC normal tissue dose constraints were administered.
Dosimetric factors, mean lung dose (MLD), and percentage of normal lung volume that receive 20 Gy (V20) were assessed from dose volume histograms.
Chemotherapy
Concurrent CT scheme was cisplatin 50 mg/m2 on
days 1, 8, 29, and 36 and etoposide 50 mg/m2 on days
1?5 and 29-33. The consolidation CT was never used.
PFT values after RCT at 1, 6, and 12 months were
compared with the same patients" baseline PFT values.
Toxicity Grading
Statistical Analysis
Pulmonary toxicity was graded according to the Radiation
Therapy Oncology Group/European Organization
for Research and Treatment of Cancer acute and late
radiation morbidity scoring system.[
All survival analysis was performed using the Kaplan-
Meier method. Continuous variables were expressed
as mean±standard deviation or median (min-max)
where available. To assess the differences between PFTs
at 1, 6, and 12 months relative to baseline, repeated
measures ANOVA test was used. The relationship between
the clinical (age, gender, weight loss, location of
tumor, and PTV) and dosimetric variables (MLD and
V20) that are considered to be related with the decline in PFT values or RP risk was tested in univariate analysis.
Since all patients had stage III, ECOG 0-1, received
the same concurrent CT scheme, and treated with the
same fractionation and mostly 3D-CRT, these factors
were not included in the univariate analysis. p-values
were derived from two-tailed tests. A p-value<0.05 was
considered as statistically significant.
The mean baseline PFT values are shown in Table
In univariate analysis, none of the clinical characteristics
or dosimetric factors of the patients was found
to be associated with the decline in PFT values or RP
risk. Univariate analysis of clinical and dosimetric variables
that are considered to be related with the decline
in PFT values and RP risk are represented in Tables
The incidences of grade 0, 1, 2, 3, and 5 pneumonitis were 14 (23%) patients, 20 (33%) patients, 22 (36%) patients, 4 (7%) patients, and 1 (1%) patient, respectively.
None of the baseline PFT values was found to be predictive of RP except the baseline DLCO; patients who had a baseline DLCO value <65% (52%?64%) developed RP in contrast to patients who had a baseline DLCO value >75% (76%?95%) (p=0.023). When the RP criteria were changed as clinically important RP (≥ grade 2), DLCO was not associated with RP development. There was no any correlation between the percentages of changes in PFT values and development of RP. There was no any correlation between clinical and dosimetric factors and development of RP.
When we repeated the analysis by excluding the 5 patients relapsing in the thorax to avoid the effect of recurrent tumor or current therapies on PFT parameters, the results did not change. Baseline FEV1 was not found to be a prognostic factor for survival.
We observed that FEV1 and DLCO values did not
recover and decreased to almost 20% of their baseline
1 year after RCT. Similarly, Borst et al.[
In addition, the re-evaluation of the results by excluding
the relapsing patients in the thorax enabled us
to eliminate the confounding effects of the recurrent
tumor and salvage therapies on PFT that might have
clarified the effect of RCT on PFT.
In the literature, it has been stated that the largest
change in PFT occurs in DLCO after RT and may
predict RP.[
In our findings, the patient characteristics were
not found to be correlated with RP, which is a similar
finding with the literature.[
In our study, there was no any association between
gender and RP. The effect of gender on lung function after thoracic RT is also conflicting in the literature.
[
The mean baseline PFT values and incidence of
RP of our cohort are in accordance with the literature.
[
In contrast to many studies, we did not find the
baseline FEV1 as a prognostic factor for survival.
[
Limitations of the Study
On the other hand, homogenous study population,
composed of only stage III patients treated with the
same concurrent RCT protocol over a relatively short
period, assessment of RP retrospectively by reviewing
the radiological findings during follow-up by radiation
oncologist and chest physician together one by one in
each case, and relatively longer follow-up time could be
suggested as the strengths of our study. In addition, we
repeated the analysis by excluding relapsing patients;
by this way, we were able to exclude the effect of salvage
therapies and confounding factors related to recurrence
that might have negative impact on PFTs.
Our study has several limitations. The retrospective nature
of the study that makes it subject to multiple biases
and relatively small number of patients are the major
limitations. In addition, data on COLD and smoking
history are lacking. Moreover, loss of patients during
follow-up to have PFT is another limitation. The quality
of life (QoL) data is also missing.
Conflict of Interest: None declared.
Peer-review: Externally peer-reviewed.
Ethics Committee Approval: This study was conducted in
accordance with local ethical rules.
Financial Support: None declared.
Authorship contributions: Concept - E.K.K., U.Y.; Design
- E.K.K., U.Y.; Supervision - U.Y.; Materials - U.Y.; Data collection
&/or processing - E.K.K.; Analysis and/or interpretation
- E.K.K.; Literature search - E.K.K.; Writing - E.K.K.,
U.Y.; Critical review - U.Y.
