Our institution has implemented two different adjuvant protocols in treating patients with non-small cell lung cancer (NSCLC): chemotherapy followed by concurrent chemoradiotherapy (CT-CCRT) and sequential postoperative radiotherapy (PORT) followed by postoperative chemotherapy (POCT). We aimed to compare the clinical outcomes between the two adjuvant protocols.
From March 1997 to October 2012, 68 patients were treated with CT-CCRT (n = 25) and sequential PORT followed by POCT (RT-CT; n = 43). The CT-CCRT protocol consisted of 2 cycles of cisplatin-based POCT followed by PORT concurrently with 2 cycles of POCT. The RT-CT protocol consisted of PORT followed by 4 cycles of cisplatin-based POCT. PORT was administered using conventional fractionation with a dose of 50.4–60 Gy. We compared the outcomes between the two adjuvant protocols and analyzed the clinical factors affecting survivals.
Median follow-up time was 43.9 months (range, 3.2 to 74.0 months), and the 5-year overall survival (OS), locoregional recurrence-free survival (LRFS), and distant metastasis-free survival (DMFS) were 53.9%, 68.2%, and 51.0%, respectively. There were no significant differences in OS (p = 0.074), LRFS (p = 0.094), and DMFS (p = 0.490) between the two protocols. In multivariable analyses, adjuvant protocol remained as a significant prognostic factor for LRFS, favouring CT-CCRT (hazard ratio [HR] = 3.506, p = 0.046) over RT-CT, not for OS (HR = 0.647, p = 0.229).
CT-CCRT protocol increased LRFS more than RT-CT protocol in patients with completely resected NSCLC, but not in OS. Further studies are warranted to evaluate the benefit of CCRT strategy compared with sequential strategy.
Because surgery alone is not a satisfactory strategy for the treatment of non-small cell lung cancer (NSCLC), adjuvant treatment with postoperative chemotherapy (POCT) and postoperative radiotherapy (PORT) is usually recommended. Cisplatin-based POCT is the standard of care for stage II-III NSCLC patients who undergo complete resection [
In October 1996, before POCT became a standard of care for stage II-III NSCLC, adjuvant chemotherapy followed by concurrent chemoradiotherapy (CT-CCRT) was established as an institutional protocol for patients showing pathologic N1-2 disease (mainly N2) or a close/positive resection margin. After POCT became a standard of care, sequential PORT followed by POCT (RT-CT) has been a routine protocol in our institution with a consensus of a multidisciplinary team [
In cases where both POCT and PORT are administered after surgery, the optimal way of combining these two therapies has not yet been discovered. In this study, we aimed to compare the clinical outcomes between our two historical protocols (CT-CCRT vs. RT-CT).
Using our institutional tumor registry database, we identified 68 patients who underwent both PORT and POCT after complete surgical resection for NSCLC between 1997 and 2012. For staging work-up, chest computed tomography (CT), bronchoscopy, enhanced brain CT or magnetic resonance imaging (MRI), and bone scan or positron emission tomography (PET) were routinely performed. Lobectomy or pneumonectomy with mediastinal lymph node dissection were performed in patients with clinical N0-1 or single-station minimal N2 disease. Pathologic stages were described according to the 7th edition of American Joint Committee on Cancer (AJCC) TNM classification.
PORT was administered in patients with pathologic N1-2 disease (mainly N2) and positive or close resection margins. Before 2002, PORT was performed using the conventional two-dimensional technique (2D-RT) with megavoltage beams (≥6 MV). Initial anterior/posterior–posterior/anterior fields included an ipsilateral hilum and involved lymph nodal stations plus its next draining stations, and a dose of 30.6–41.4 Gy using conventional fractionation (1.8–2.0 Gy/day) was irradiated. Two off-cord oblique fields were implemented to boost the ipsilateral hilum and involved nodal stations with a dose up to 50.4–60.0 Gy. After 2002, three-dimensional conformal radiation therapy (3D-CRT) was adopted using megavoltage photon beam. For 3D-CRT, CT simulation was scanned under the free-breathing condition. The initial clinical target volume (CTV) included a bronchial stump, involved mediastinal lymph nodal stations, and its next draining stations. The boost CTV only included a bronchial stump and involved nodal stations. The planning target volume (PTV) was expanded in all directions from the CTV with a margin of 1.0–1.5 cm. Conventional fractionation was used with a dose of 44–45 Gy for initial volume, and the boost volume was irradiated up to 50.4–60.0 Gy. In case of a close resection margin (less than 5 mm), the region of the close margin was boosted up to doses of 66 Gy.
POCT was administered in patients with pathologic stage II/III according to our institutional protocols; 1) CT-CCRT protocol (adjuvant chemotherapy followed by concurrent chemoradiotherapy): two cycles of cisplatin-basted chemotherapy were administered, followed by PORT concurrently with two cycles of chemotherapy [
To assess comorbidity, we calculated an age-adjusted Charlson comorbidity score by using of previous established International Classification of Disease—10 diagnosis codes from inpatient and outpatient records—from the time of first visit of each patient to the date of surgical resection [
We then analyzed the pattern of first failures and clinical parameters influencing locoregional recurrence-free survival (LRFS), distant metastasis-free survival (DMFS) and overall survival (OS). We compared the pattern of first failures and survivals between CT-CCRT and RT-CT protocols. Comparison between the two protocols was analyzed using a chi-square test or Fisher exact test for categorical variables and the Student t-test or the Mann-Whitney U test for continuous variables. Survival time was calculated by the interval between the date of the surgery and the date of the last follow-up or events (death event for OS, first loco-regional failure for LRFS, and first distant metastasis for DMFS). Survivals were calculated using the Kaplan-Meier method. The log-rank test and Cox proportional hazards regression model were used for univariable and multivariable analyses, respectively. Factors with a p-value of less than 0.2 by a univariable analysis were used for a multivariable analysis. Two sided p-values less than 0.05 were regarded as statistically significant. All statistical analyses were performed using R statistical packages [
Among a total of 68 patients, 45 patients (66.2%) were males and the median age was 58 years (range, 30 to 69 years). The CT-CCRT and RT-CT protocols were administered in 25 (36.8%) and 43 patients (63.2%), respectively. The types of surgery included lobectomy in 53 patients (77.9%) and pneumonectomy in 15 (22.1%). Squamous cell carcinoma and adenocarcinoma were observed in 36 patients (52.9%) and 24 patients (35.3%), respectively. Pathologic nodal stages were N1 in 15 patients (22.1%) and N2 in 51 patients (75.0%), while 2 patients with pN0 disease showed a close resection margin of less than 5 mm. The median dose of PORT was 54.0 Gy (range, 39.6 to 64.4 Gy) and the median cycle of POCT was 4 (range, 2 to 6).
Patient characteristics for CT-CCRT and RT-CT protocols are summarized in
The median follow-up time of 68 patients was 43.9 months (range, 3.2 to 74.0 months), and the OS was 53.9% at 5 years. The 5-year LRFS and DMFS were 68.2% and 51.0%, respectively. Patients with CT-CCRT protocol showed favourable LRFS, but unfavourable OS compared to the RT-CT protocol (5-year LRFS, 82.8% vs. 60.3%, p = 0.094; 5-year OS, 44.0% vs. 61.3%, p = 0.074). There was no significant difference in DMFS between the two protocols (5-year DMFS, 53.3% vs. 46.4%, p = 0.490) (
Univariable analyses for clinical variables influencing survival are presented in
The results of multivariable analysis are summarized in
In this study, we compared the outcomes of two institutionally historical protocols (CT-CCRT vs. RT-CT) in patients with completely resected NSCLC, and our results showed that the CT-CCRT protocol had statistically significant favourable prognostic value in LRFS compared with the RT-CT protocol, while there were no differences in OS or DMFS. Patient characteristics were not different between two protocols except age, ECOG PS, preoperative FEV1, radiotherapy technique and radiation dose (
Our CT-CCRT protocol had been adopted during a time before POCT became a standard of care (from October 1996 to mid-2005). But, the RT-CT protocol, which was established in mid-2005, has been implemented as a current active protocol in our institution. Considering the variety of developments in chemotherapy and radiotherapy over time, the recent RT-CT protocol should have showed superior outcomes compared to that of the old CT-CCRT protocol. However, the two protocols did not show significant differences in OS and DMFS. Rather, the CT-CCRT protocol showed superior outcomes compared to the RT-CT protocol in controlling locoregional disease, despite CCRT protocol having mainly adopted 2D-RT (
Although its use has been an issue of debate, PORT can be administered in patients with N2 disease based on several large-scale population-based studies which favored the use of PORT even in the era of POCT [
The result of this study are limited because of the comparison between two protocols were performed consecutively in our institution. This study is also limited by a small sample size, heterogeneous study population (including pN1 disease), and single-institutional retrospective study design. However, despite these limitations, the results of this study suggest again the potential role of adjuvant CCRT in locoregional tumor control.
In conclusion, CT-CCRT protocol increased LRFS compared to RT-CT protocol in patients with completely resected NSCLC, but not in OS and DMFS. Further large-scaled randomized studies are warranted to evaluate the benefit of CCRT strategy compared with sequential CT-RT or RT-CT strategy.
This work was supported by the new faculty research fund of Ajou University School of Medicine. The authors thank Stephen Kim for assistance with manuscript editing.
Kaplan-Meier survival curves. (A) Overall survival. (B) Locoregional recurrence-free survival. (C) Distant metastasis-free survival between adjuvant chemotherapy followed by concomitant chemoradiotherapy (CT-CCRT) and sequential postoperative radiotherapy followed by adjuvant chemotherapy (RT-CT) protocols.
Patient characteristics according to treatment protocols
Characteristic | CT-CCRT (n = 25) | RT-CT (n = 43) | p-value |
---|---|---|---|
Age (yr) | 58.7 ± 8.4 | 52.9 ± 10.7 | 0.025 |
Gender | 0.106 | ||
Male | 13 | 32 | |
Female | 12 | 11 | |
Smoking history | 0.579 | ||
Yes | 10 | 13 | |
No | 15 | 30 | |
ECOG PS | 0.050 | ||
0–1 | 25 | 37 | |
2 | 0 | 6 | |
Comorbidity index | 0.206 | ||
<3 | 13 | 29 | |
≥3 | 12 | 14 | |
Preoperative FEV1 (L) | 2.2 ± 0.5 | 2.7 ± 0.7 | 0.002 |
Postoperative FEV1 (L) |
2.2 ± 0.9 | 2.0 ± 0.6 | 0.718 |
Tumor histology | 0.694 | ||
Squamous cell | 13 | 23 | |
Adenocarcinoma | 10 | 14 | |
Others | 2 | 6 | |
Type of surgery | 0.550 | ||
Lobectomy | 18 | 35 | |
Pneumonectomy | 7 | 8 | |
Pathologic T stage | 0.347 | ||
T1 | 5 | 4 | |
T2 | 13 | 29 | |
T3 | 7 | 10 | |
Pathologic N stage | 0.095 | ||
N0 | 2 | 0 | |
N1 | 7 | 8 | |
N2 | 16 | 35 | |
Radiotherapy technique | <0.001 | ||
Two-dimensional | 21 | 1 | |
Three-dimensional | 4 | 42 | |
Radiotherapy dose (Gy) | 52.8 ± 5.5 | 55.8 ± 4.3 | 0.013 |
Values are presented as mean ± standard deviation or number.
CT-CCRT, adjuvant chemotherapy followed by concomitant chemoradiotherapy; RT-CT, sequential postoperative radiotherapy followed by adjuvant chemotherapy; ECOG PS, Eastern Cooperative Oncology Group performance status; FEV1, forced expiratory volume in 1 second.
Postoperative FEV1 was available in 35 patients (51.5%).
Pattern of first failures according to treatment protocols
First failure site | CT-CCRT (n = 25) | RT-CT (n = 43) | p-value |
---|---|---|---|
Locoregional | 0 (0) | 2 (4.7) | 0.528 |
Distant metastasis | 6 (24.0) | 7 (16.3) | 0.527 |
Both locoregional and distant metastasis | 4 (16.0) | 13 (30.2) | 0.251 |
Values are presented as number (%).
CT-CCRT, adjuvant chemotherapy followed by concomitant chemoradiotherapy; RT-CT, sequential postoperative radiotherapy followed by adjuvant chemotherapy.
Univariable analyses for clinical variables affecting survivals
Variable | 5-yr LRFS (%) | p-value (log-rank) | 5-yr DMFS (%) | p-value (log-rank) | 5-yr OS (%) | p-value (log-rank) |
---|---|---|---|---|---|---|
Age (<58 vs. ≥58 yr) | 68.6 vs. 67.2 | 0.632 | 50.0 vs. 52.0 | 0.793 | 65.3 vs. 43.3 | 0.072 |
Gender (male vs. female) | 73.0 vs. 59.4 | 0.071 | 55.3 vs. 42.7 | 0.084 | 53.6 vs. 54.6 | 0.855 |
Smoking history (no vs. yes) | 65.3 vs. 69.5 | 0.223 | 48.0 vs. 52.0 | 0.233 | 60.8 vs. 50.7 | 0.472 |
ECOG PS (0–1 vs. 2) | 69.3 vs. 53.3 | 0.188 | 54.7 vs. 0.0 | 0.174 | 53.4 vs. 62.5 | 0.955 |
Comorbidity index (<2 vs. ≥2) | 62.8 vs. 70.4 | 0.873 | 51.5 vs. 50.6 | 0.861 | 66.2 vs. 49.4 | 0.081 |
Preoperative FEV1 (<2.5 L vs. ≥2.5 L) | 64.3 vs. 73.8 | 0.189 | 47.5 vs. 57.5 | 0.407 | 46.7 vs. 61.9 | 0.378 |
Surgery (lobectomy vs. pneumonectomy) | 65.3 vs. 82.5 | 0.375 | 49.5 vs. 54.5 | 0.961 | 56.0 vs. 45.7 | 0.242 |
Tumor histology (squamous vs. others) | 63.7 vs. 74.1 | 0.297 | 42.7 vs. 61.5 | 0.165 | 55.3 vs. 51.6 | 0.786 |
Pathologic T stage (1–2 vs. 3) | 69.4 vs. 63.5 | 0.747 | 54.8 vs. 41.7 | 0.612 | 55.9 vs. 49.3 | 0.573 |
Pathologic N stage (0–1 vs. 2) | 67.0 vs. 68.7 | 0.424 | 44.7 vs. 52.8 | 0.835 | 50.4 vs. 55.2 | 0.999 |
Radiation dose (<54 Gy vs. ≥54 Gy) | 72.2 vs. 64.4 | 0.548 | 59.0 vs. 44.9 | 0.675 | 51.2 vs. 56.1 | 0.885 |
Protocol (CT-CCRT vs. RT-CT) | 82.8 vs. 60.3 | 0.094 | 59.9 vs. 46.4 | 0.490 | 44.0 vs. 61.3 | 0.074 |
LRFS, locoregional recurrence-free survival; DMFS, distant metastasis-free survival; OS, overall survival; ECOG PS, Eastern Cooperative Oncology Group performance status; FEV1, forced expiratory volume in 1 second; CT-CCRT, adjuvant chemotherapy followed by concomitant chemoradiotherapy; RT-CT, sequential postoperative radiotherapy followed by adjuvant chemotherapy.
Multivariable analyses for clinical variables affecting survivals
Variable | LRFS |
DMFS |
OS |
||||||
---|---|---|---|---|---|---|---|---|---|
HR | 95% Cl | p-value | HR | 95% Cl | p-value | HR | 95% Cl | p-value | |
Age (<58 vs. ≥58 yr) | - | - | - | - | - | - | 1.284 | 0.535-3.082 | 0.575 |
Gender (male vs. female) | 2.525 | 0.827-7.712 | 0.104 | 1.525 | 0.647-3.592 | 0.334 | - | - | - |
ECOG PS (0-1 vs. 2) | 0.754 | 0.183-3.100 | 0.696 | 1.567 | 0.504-4.867 | 0.430 | - | - | - |
Comorbidity index (<2 vs. ≥2) | - | - | - | - | - | - | 1.594 | 0.532-4.772 | 0.405 |
Preoperative FEV1 (<2.5 L vs. ≥2.5 L) | 0.581 | 0.195-1.720 | 0.326 | - | - | - | - | - | - |
Tumor histology (squamous vs. others) | - | - | - | 0.775 | 0.315-1.909 | 0.580 | - | - | - |
Protocol (CT-CCRT vs. RT-CT) | 3.506 | 1.020-12.053 | 0.046 | - | - | - | 0.647 | 0.318-1.315 | 0.229 |
LRFS, locoregional recurrence-free survival; DMFS, distant metastasis-free survival; OS, overall survival; HR, hazard ratio; CI, confidence interval; ECOG PS, Eastern Cooperative Oncology Group performance status; FEV1, forced expiratory volume in 1 second; CT-CCRT, adjuvant chemotherapy followed by concomitant chemoradiotherapy; RT-CT, sequential postoperative radiotherapy followed by adjuvant chemotherapy.