A Population-based Study of Primary Chemoradiotherapy in Clinical Stage III
Non-small Cell Lung Cancer: Intensity-modulated Radiotherapy Versus 3D
Conformal Radiotherapy
TE-CHUN HSIA1*, CHIH-YEN TU1*, HUNG-JEN CHEN1*, SHUO-CHUEH
CHEN1*, JI-AN LIANG2, CHIH-YI CHEN3, YAO-CHING WANG2 and CHUN-RU
CHIEN2,4,5
Departments of 1Internal Medicine, 2Radiation Oncology and 3Thoracic
Surgery, China Medical University Hospital, and 4School of Medicine, China
Medical University, Taichung, Taiwan, ROC
*These Authors contributed equally to this study.
Correspondence to: Chun-Ru Chien, School of Medicine, College of Medicine, China
Medical University, 91 Hsueh-Shih Road, North District, Taichung 40402,
Taiwan, ROC, e-mail: d16181@mail.cmu.edu.tw; and Yao-Ching Wang, Department
of Radiation Oncology, China Medical University Hospital, 2 Yude Road, Taichung
40447, Taiwan, ROC. Tel: +886 422052121 Ext. 7450, Fax: +886 422052121 Ext.
7460, e-mail: jauntywang@gmail.com,
Running title: IMRT vs. 3DCRT for Stage III NSCLC
Key Words: 3DCRT, IMRT, lung cancer, population-based study.
Indication: clinical study
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The date of submission: May 6 2014
Abstract. Aim: To compare the effectiveness of intensity-modulated
radiotherapy (IMRT) vs. 3D conformal radiotherapy (3DCRT) for clinical stage
III non-small cell lung cancer (NSCLC) treated with primary
chemoradiotherapy via a population-based retrospective cohort analysis.
Patients and Methods: Using the Collaboration Center of Health Information
Application (CCHIA) database, we identified 99 patients with clinical stage III
NSCLC treated with primary chemoradiotherapy from 2007 to 2009 with
complete data available for analysis. We compared the risk of death within two
years of diagnosis and the hazard ratio for death between those treated with
IMRT and those with 3DCRT. Univariate and multivariate analyses were
conducted to determine the efficacy of IMRT and 3DCRT. Sensitivity analyses
were also conducted to assess relationships in various subgroups. Results:
The risk of death within two years of diagnosis was similar for IMRT and
3DCRT (36% vs. 37%, p=0.97). For the entire follow-up period, the probability
of death was not statistically different when IMRT was compared to 3DCRT
(p=0.8). On multivariate analysis, the adjusted hazard ratio of death was
statistically insignificantly higher for IMRT vs. 3DCRT (hazard ratio of
death=1.54, 95% confidence interval=0.82-2.91, p=0.18). The results
remained similar in the sensitivity analyses. Conclusion: Our population-based
analysis from CCHIA suggests that for patients with clinical stage III NSCLC
treated with primary chemoradiotherapy, the survival outcome of those treated
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with IMRT was not superior to those treated with 3DCRT. Further prospective
study and cost-effectiveness analysis are warranted.
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Primary chemoradiotherapy is an important and curative treatment method for
patients with locally advanced non-small cell lung cancer (NSCLC) (1). The
essential role of radiotherapy is to eradicate the primary tumor and regional
lymphadenopathy, and chemotherapy simultaneously provides the synergic
effect of radiosensitization. Techniques of radiotherapy have obviously been
revolutionized within the past decade (2), and one of the most prominent
advances among the novel radiation techniques is intensity-modulated
radiotherapy (IMRT). Currently, 3D conformal radiotherapy (3DCRT) is the
minimal requirement (3). Dosimetric comparison studies demonstrated the
benefits of tumor coverage and normal organ sparing of IMRT over 3DCRT
(4-7). In addition, some studies described their experience of using IMRT in
NSCLC, and promising outcome and minimized toxicities were announced
(8-10). On the contrary, some studies showed some dosimetric defects on
clinical radiotherapy with IMRT to thoracic malignancy, such as a lower
radiation dose to the lung (6, 10, 11), and substantial toxicity of
treatment-related pneumonitis (12). However, no randomized study result is
currently available for convincingly demonstrating the efficacy of IMRT versus
3DCRT for locally advanced NSCLC (2).
The current role of IMRT in NSCLC is still debated in the literature. A
recent systematic review reported that there is insufficient data to make
evidence-based recommendation (13). Our previous preliminary report
revealed similar survival outcome when patients were treated with either
3DCRT or IMRT (14). The aim of our current study was to compare the
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efficacy of IMRT versus 3DCRT for clinical stage III NSCLC treated with
primary chemoradiotherapy via a population-based retrospective cohort
analysis using updated and more comprehensive data.
Patients and Methods
Data source. The Collaboration Center of Health Information Application
(CCHIA) database is a set of databases providing complete information
regarding cancer registry, death registration, and reimbursement data for the
whole Taiwanese population (15-17). The Cancer Registry within CCHIA
provides information for patients with lung cancer regarding individual
demographics, tumor histology, location, stage of disease, and primary
surgical, radiation, and systematic treatment. National Health Insurance (NHI,
as a single payer) is a compulsory social insurance program in Taiwan with
coverage of more than 99.6% of the Taiwanese population (18).
Reimbursement data files from NHI in CCHIA provide information regarding
occupation of the insured, details of treatment received and the characteristics
of healthcare providers (physicians and hospitals).
Study population and study design. Our study population identification and
study design is depicted in Figure 1. Our target populations were those
patients newly diagnosed with clinical stage III NSCLC within 2007-2009 and
treated with primary chemoradiotherapy. The date of diagnosis was used as
the index date. We decided the explanatory variable of interest (IMRT versus
3DCRT) based on the Cancer Registry. We also collected other covariables
(see next paragraph) for adjustment of potential non-randomized treatment
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selection and the efficacy data from CCHIA. This study was exempt from
Institutional Review Board review because the CCHIA contains de-identified
data and is publicly available through the proper application process (20).
Other possible explanatory covariables. We included patient demographic
factors (age, gender, and patient residency, period), patient characteristics
(socioeconomic status (SES), pre-diagnostic Charlson comorbidity index),
clinical variables (histological type, treatment sequence), and characteristics of
the health services provider (treating hospital and physician). Age was
categorized by a binary variable indicating at least 65 years old or not. Patient
residency was classified as northern Taiwan or not. Period was defined as the
year of diagnosis. We used the occupational types of the insured as the surrogate
for SES and classified SES as white collar, blue collar, and other. Comorbidity
index was reported as with or without comorbidity. Both hospital and physician
were classified as high or low case volume with threshold at roughly median
level. Histological types were classified as adenocarcinoma or squamous cell
carcinoma. Sequence was classified as concurrent or sequential
chemoradiotherapy. These classification rules were based on our clinical
experience or previous NHI- or CCHIA-related research (21-31).
Efficacy assessment. We obtained the survival status from the death registry.
Then we compared the risk of death within two years (the minimal potential
follow-up period) of diagnosis between those treated with IMRT and those with
3DCRT. We also compared the hazard ratio of death for the entire follow-up
period (censored on 1st January 2012).
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Statistical and sensitivity analysis. We used log-rank test and chi-square tests
in univariate analysis and Cox proportional hazard regression in multivariate
analysis. We also performed two sensitivity analyses: (a) stratified analysis
analyzing the effect of IMRT versus 3DCRT in either concurrent or sequential
chemoradiotherapy subgroups; (b) subgroup analysis using a
propensity-score (PS) matching subgroup. We used the above covariables to
estimate the PS of receiving IMRT/3DCRT for each subject then constructed a
1:1 PS matching subgroup (32). We used tabulation to assess the balance of
covariates between PS-matched groups then used Cox proportional hazards
model with robust standard errors to estimate the hazard ratio of death (33).
SAS 9.3 (SAS Institute, Cary, NC, USA) was used for all statistical analyses.
Results
Patient characteristics of the study cases. As revealed in Figure 1, 150
patients with newly diagnosed (within 2007-2009) clinical stage III NSCLC
treated with primary chemoradiotherapy were identified as the initial study
population. After exclusion of those with incompatible or missing data, the final
study population included 99 patients. Their characteristics are described in
Table I. These two groups were not statistically different except for residency
region and hospital volume.
Univariate analysis. The risk of death within two years of diagnosis was
similar for IMRT and 3DCRT (36% vs. 37%, p=0.97). For the entire follow-up
period, the probability of death was not statistically different when IMRT was
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compared to 3DCRT (p=0.8). The Kaplan–Meier survival curve is depicted as
Figure 2.
Multivariate analyses. The adjusted hazard ratio of death was statistically
insignificantly higher for IMRT versus 3DCRT (hazard ratio of death=1.54,
95% confidence interval=0.82-2.91, p=0.18). Age (≥65), gender (male), and
diagnosis period (2009) were also significant predictors for death (Table II).
Sensitivity analysis. In the first sensitivity analysis, we found that the adjusted
risk of death when IMRT was compared to 3DCRT was not statistically
different in either concurrent or sequential chemoradiotherapy subgroups
(p-value=0.28 and 0.99, respectively). In the second sensitivity analysis, we
identified 27 patients who received IMRT who were quite comparable to
another 27 patients who received 3DCRT (Table III). These two groups were
not statistically different for these covariables. The hazard ratio of death was
1.67 (p=0.14) when IMRT was compared to 3DCRT in this PS-matched
subgroup.
Discussion
In this population-based study, we demonstrated that both IMRT and 3DCRT
for stage III NSCLC contributed to similar 2-year overall survival. However,
older age age, male gender, and early diagnosis period were significant
predictors for death by multivariate analyses.
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To our knowledge, no prospectively randomized trial proved clinical
outcome to be more favorable by IMRT than 3DCRT in NSCLC (34). Hence,
no rigorous evidence supports the concept that IMRT can extensively
substitute for 3DCRT in thoracic radiotherapy. However, the use of IMRT has
become more and more prevalent worldwide. Shirvani et al. showed IMRT for
stage III NSCLC
rapidly increased from 0.5% in 2001 to 14.7% in 2007
(p<0.001) in the United State (9). To think the best of IMRT, it could provide
more conformal target coverage and the potential for dose escalation within
the normal organ constraints than 3DCRT. Financial cost issues also influence
the application of radiation delivery techniques. This CCHIA database is a set
of databases providing complete information regarding cancer registry, death
registration, and reimbursement data for the whole Taiwanese population. Our
previous preliminary report revealed similar median survival outcome when
patients were treated with either 3DCRT or IMRT, of 20 months and 18 months,
respectively (14). The results of the current updated study could reflect the
clinical experiences of IMRT during the advancement of radiation techniques
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in Taiwan. Ultimately, the survival rate of those treated with IMRT was not
superior to that of those treated with 3DCRT in this population-based study.
Only two larger retrospective studies from the same institution compared
radiation pneumonitis and outcome between IMRT and 3DCRT combined with
concurrent chemotherapy for locally advanced NSCLC (10, 35). Yom et al.
showed grade 3 or more radiation pneumonitis occurred 32% in the 3DCRT
group and 8% in the IMRT group (p=0.002) (35). Liao et al. showed a
significant survival benefit and decreased radiation pneumonitis of grade 3 or
more in the IMRT group (10). Bezjak et al. reviewed this critical issue of
potential dose benefits and toxicities, and suggested careful delivery of IMRT
to lung cancer until randomized studies are available (13).
The interpretation of our study is not that IMRT is inferior to 3DCRT for
radiotherapy in NSCLC but that there are insufficient data to decide which is
really better at the population level currently. Either the potential concern of
more lung tissue receiving a low dose of radiotherapy in IMRT (12, 36) or the
implementation of IMRT for lung cancer in Taiwan is less mature, or other
factors may be related to our finding.
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There were several limitations in our study. Firstly, the study design was
retrospective and non-randomized. The sample size was also only moderate.
However, these data provide a population-based efficacy assessment.
Secondly, the follow-up period was modest; a longer period of follow-up might
be helpful to clarify this relationship between IMRT and 3DCRT in NSCLC.
Thirdly, some potential confounding factors such as tumor volume, exact
tumor extent, and dosimetric parameters were not available from this database
at time of writing. Fourthly, we did not take the radiotherapy dose into
consideration given the negative result of RTOG0617 (2, 37), although
promising results had been reported in some early trials (38). Finally, the
impact of different kinds of systemic therapies, such as the novel epidermal
growth factor (EGF) inhibitors, was not considered because of the
development of EGF receptors resistance (39) and are not part of the curative
treatment yet.
Despite these limitations, this study uniquely contributes to the literature
by documenting the statistically insignificant inferior result in radiotherapy for
NSCLC when IMRT was compared to 3DCRT. Similarly, Harris et al. used the
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Surveillance, Epidemiology, and End Result Medicare database and
demonstrated similar overall survival and cause-specific survival between
IMRT versus 3DCRT in stage III NSCLC (40). No survival impact of IMRT for
esophageal cancer was also discussed recently (41). Our result is also
important in that it is population-based from an Asian country in which the
ethnic response to treatment might be different than that of patients from
Western countries (42). The implication of our observation, together with the
lack of high-level evidence as revealed in the recent systematic review (13), is
that the implementation of IMRT for lung cancer should be cautious. More
studies are needed to elucidate whether IMRT is superior or inferior to 3DCRT
in radiotherapy for NSCLC.
Conclusion
Our population-based analysis suggests that for patients with clinical stage III
NSCLC treated with primary chemoradiotherapy, the survival outcome of
those treated with IMRT was not superior to that of those treated with 3DCRT.
Further prospective study and cost-effectiveness analysis are warranted for a
detailed understanding of the role of IMRT in the treatment of clinical stage III
NSCLC.
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Competing interests
The Authors declare that they have no competing interests
Acknowledgements
The data analyzed in this study were provided by the Collaboration Center of
Health Information Application (CCHIA), Ministry of Health and Welfare,
Executive Yuan. This study was partly supported by the grand from China
medical University Hospital to Chien C.R. (DMR-103-043). This work was
partly supported by grants from the Ministry of Health and Welfare, Taiwan to
Chen C.Y. (MOHW103-TD-Ｂ-111-03), but the funding bodies had no role in
study design, the collection, analysis, and interpretation of data, the writing of
the manuscript, and the decision to submit the manuscript for publication.
Legends:
Figure 1. Study flowchart and identification of the study population.1We only
included those treated by a single institution to ensure data consistency.
2Clinical
staging was recorded according to the Sixth American Joint
Committee on Cancer staging (19) before 2010, hence we only include
cT1-3N2-3M0 or cT3N1M0 to ensure these cases were still stage III based on
the current (Seventh) American Joint Committee on Cancer staging. 3Included
only adenocarcinoma and squamous cell carcinoma since the number of other
histologies among NSCLC was small and reporting of this small value was
prone to violate the policy of CCHIA. 4Limited to those who received EBRT
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dose ≥50 Gy with conventional fraction size (1.8-2.2 Gy/fraction) delivered
within 1-2 months to ensure radiotherapy quality; the interval between
diagnosis and the beginning of radiotherapy was limited to within four months.
5Occupational
types of the insured as the surrogate for SES, classified SES as
white collar, blue collar, and other.
Figure 2. Kaplan–Meier curve of overall survival (OS)( Intensity-modulated
Radiotherapy Versus 3D Conformal Radiotherapy) for the entire study
population.
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