Baseline characteristics
A total of 340 eligible patients were included in analysis. They were randomly assigned into a training group comprising 227 patients and a validation group with 113 patients. In the whole cohort, there were 64 females and 276 males with the median age of 58 (range from 28–81) years. There were 97 (28.5%) patients diagnosed with stage IIIA disease, 172 (50.6%) with stage IIIB and 71 (20.9%) with stage IIIC. For all patients, the median GTV volume was 101.0 (range, 9.1-664.3) cm3. In the training cohort, the optimal cutoff values of GTV in terms of OS were 71.2 cm3 and 177.2 cm3, which were determined by X-tile program. For the ease of clinical practice, we selected 70 cm3 and 180 cm3 as the uniform cutoff points in order to define patients into low, moderate and high GTV risk groups. GTV risk group I, II and III were defined as < 70 cm3, 70 ~ 180 cm3 and > 180 cm3, respectively. Docetaxel and platinum was the most commonly used regimen of concurrent chemotherapy (70.9%, 241/340). Most patients (254/340, 74.7%) received neoadjuvant chemotherapy before definitive CCRT, and 21.8% patients (74/340) underwent adjuvant chemotherapy. All clinic-pathologic characteristics were similarly distributed between the training and validation groups (Table 2).
Table 2
Characteristic | Training cohort | Validation cohort | P-value |
| n = 227 (%) | n = 113 (%) | |
Sex | | | 0.659 |
Male | 186(81.9) | 90(79.6) | |
Female | 41(18.1) | 23(20.4) | |
Age(y) | | | > 0.999 |
Median(range) | 59(28–79) | 58(31–81) | |
ECOG score | | | 0.126 |
0 | 29(12.8) | 16(14.2) | |
1 | 170(74.9) | 91(80.5) | |
2 | 28(12.3) | 6(5.3) | |
Weight loss ≥ 5Kg | | | 0.153 |
Yes | 23(10.1) | 6(5.3) | |
No | 204(89.9) | 107(94.7) | |
Smoke index ≥ 400 | | | 0.298 |
Yes | 129(56.8) | 57(50.4) | |
No | 98(43.2) | 56(49.6) | |
Pathological types | | | 0.627 |
Squamous cell carcinoma | 130(57.3) | 65(57.5) | |
Adenocarcinoma | 80(35.3) | 41(36.3) | |
Lymphoepithelioma-like carcinoma | 10(4.4) | 5(4.4) | |
Adenosquamous carcinoma | 1(0.4) | 1(0.9) | |
Adenoid cystic carcinoma | 2(0.9) | 0(0) | |
Large cell neuroendocrine carcinoma | 0(0) | 1(0.9) | |
Giant cell carcinoma | 1(0.4) | 0(0) | |
Not otherwise specified(NOS) | 3(1.3) | 0(0) | |
GTV (cm3) | | | > 0.999 |
Median(range) | 100.6(9.1-664.3) | 101.3(10.5-567.7) | |
GTV risk group | | | 0.993 |
I (< 70 cm3) | 65(28.6) | 32(28.3) | |
II (70–180 cm3) | 119(52.4) | 60(53.1) | |
III (> 180 cm3) | 43(19.0) | 21(18.6) | |
TNM stage | | | 0.978 |
IIIA | 65(28.6) | 32(28.3) | |
IIIB | 114(50.2) | 58(51.3) | |
IIIC | 48(21.2) | 23(20.4) | |
Neoadjuvant chemotherapy | | | 0.358 |
Yes | 166(73.1) | 88(77.9) | |
No | 61(26.9) | 25(22.1) | |
Adjuvant chemotherapy | | | 0.127 |
Yes | 55(24.2) | 19(16.8) | |
No | 172(75.8) | 94(83.2) | |
ECOG = Eastern Cooperative Oncology Group, GTV = gross tumor volume. |
Survival outcomes
The median follow-up was 28.9 (range, 1.5 ~ 103.4) months in all patients and 46.6 (range, 6.7 ~ 103.4) months in event-free patients. Our analysis depicted a median estimated OS of 44.7 months in all patients, 45.5 months in the training group, and 38.1 months in the validation group. The 3-year and 5-year OS rate was 59.9% and 44.1% in the training set, compared with 52.9% and 38.0% in the validation set (P = 0.283), respectively. The median estimated PFS was 12.1, 13.0, and 10.4 months in the whole cohort, training cohort and validation cohort. The 1-year and 2-year PFS rate was 52.7% and 31.9% in the training group, versus 44.9% and 25.6% in the validation group (P = 0.181), respectively.
Risk factors for OS
Table 3 summarized the results of univariate analysis of OS based on data from the training set and validation set.
Table 3
Univariate analysis of risk factors for OS in the training cohort and validation cohort
Factor | Training cohort | | Validation cohort |
3-year OS (%) | P-value | 3-year OS (%) | P-value |
Sex | | 0.100 | | | 0.268 |
Male | 57.9 | | | 50.1 | |
Female | 69.6 | | | 65.1 | |
Age(y) | | 0.088 | | | 0.072 |
< 58 | 66.8 | | | 62.2 | |
≥ 58 | 54.4 | | | 44.9 | |
ECOG score | | 0.001 | | | 0.113 |
0 | 68.2 | | | 76.0 | |
1 | 63.1 | | | 49.1 | |
2 | 33.1 | | | 53.3 | |
Weight loss ≥ 5Kg | | 0.018 | | | 0.308 |
Yes | 38.7 | | | 33.3 | |
No | 62.2 | | | 54.1 | |
Smoke index ≥ 400 | | 0.419 | | | 0.087 |
Yes | 56.8 | | | 44.5 | |
No | 64.2 | | | 62.0 | |
Pathological types | | 0.512 | | | 0.521 |
Squamous cell carcinoma | 56.2 | | | 60.1 | |
Non-squamous cell carcinoma | 65.5 | | | 59.4 | |
GTV risk group | | < 0.001 | | | < 0.001 |
I | 79.2 | | | 85.5 | |
II | 56.8 | | | 46.4 | |
III | 37.4 | | | 18.5 | |
TNM stage | | 0.127 | | | 0.297 |
IIIA | 58.7 | | | 59.6 | |
IIIB | 65.3 | | | 49.5 | |
IIIC | 49.7 | | | 53.2 | |
The integrated GTV-TNM stratification system | | < 0.001 | | | < 0.001 |
Stratum A | 78.4 | | | 82.4 | |
Stratum B | 63.7 | | | 56.8 | |
Stratum C | 38.1 | | | 24.7 | |
Neoadjuvant chemotherapy | | 0.867 | | | 0.475 |
Yes | 59.6 | | | 56.1 | |
No | 60.9 | | | 41.3 | |
Adjuvant chemotherapy | | 0.382 | | | 0.713 |
Yes No | 55.7 | | | 52.6 | |
61.2 | | | 52.9 | |
ECOG = Eastern Cooperative Oncology Group, GTV = gross tumor volume. |
In the training set, GTV risk group (3-year OS, group I vs II vs III, 79.2% vs 56.8% vs 37.4%, P < 0.001) (Fig. 1A), ECOG score (3-year OS, ECOG 0 vs 1 vs 2, 68.2% vs 63.1% vs 33.1%, P = 0.001), weight loss ≥ 5Kg (3-year OS, yes vs no, 38.7% vs 62.2%, P = 0.018) and age (3-year OS, < 58 years vs ≥ 58 years, 66.8% vs 54.4%, P = 0.088) were significantly associated with OS, while TNM stage failed to reach statistical significance (3-year OS, stage IIIA vs IIIB vs IIIC, 58.7% vs 65.3% vs 49.7%, P = 0.127) (Fig. 1B). In addition, neoadjuvant chemotherapy didn’t have tendency to improve OS (3-year OS, yes vs no, 59.6% vs 60.9%, P = 0.867). Then these four variables reached P < 0.1 in univariate analysis were further analyzed by using multivariate Cox proportional hazards model. Multivariate analysis demonstrated significant increased risk of death in GTV risk group II (hazard ratio (HR), 1.71; 95% confidence interval (CI), 1.06–2.78; P = 0.030) and group III (HR, 3.53; 95% CI, 2.00-6.23; P < 0.001) compared with group I, and ECOG score (P = 0.032) was identified as another independent prognostic factor with HR of 1.61 (95% CI, 1.04–2.49).
Similarly, in the validation group, univariate analysis revealed that patients with larger GTV (3-year OS, group I vs II vs III, 85.5% vs 46.4% vs 18.5%, P < 0.001) (Fig. 1E), older age (3-year OS, < 58 years vs ≥ 58 years, 62.2% vs 44.9%, P = 0.072) and smoke index ≥ 400 (3-year OS, yes vs no, 44.5% vs 62.0%, P = 0.087) had impaired OS. Again TNM stage (P = 0.297) (Fig. 1F) and neoadjuvant chemotherapy (P = 0.475) failed to predict OS. Only GTV risk group remained its statistical significance in multivariate analysis with HRs of 2.34 (95% CI, 1.17–4.67; P = 0.016) and 6.27 (95% CI, 2.78–14.16; P < 0.001) for group II and III relative to group I.
Development and validation of a novel integrated GTV-TNM stratification system
In order to optimize a prognostic sub-staging system for LANSCLC undergoing CCRT by integrating GTV risk group with the current TNM stage, nine subgroups were categorized and ordered as mentioned above, which eventually brought up a novel integrated GTV-TNM stratification system comprising three stratums (Table 4): Stratum A (Group G1-IIIA ~ B); Stratum B (Group G2-IIIA ~ B and Group G1-IIIC); Stratum C (Group G2-IIIC and Group G3-IIIA ~ C).
Table 4 The integrated GTV-TNM stratification system
![](https://myfiles.space/user_files/58892_7798ecd9a40b82f9/58892_custom_files/img1600850892.png)
The integrated GTV-TNM stratification system (P < 0.001) significantly predicted OS in the training cohort, according to univariate analysis (3-year OS, Stratum A vs B, 78.4% vs 63.7%, P = 0.024; Stratum B vs C, 63.7% vs 38.1%, P = 0.002; Stratum A vs C, 78.4% vs 38.1%, P < 0.001) (Fig. 1C). Multivariate Cox regression analysis indicated increased risk of death in Stratum B (HR, 1.87; 95% CI, 1.07–3.27; P = 0.028) and Stratum C (HR, 3.66; 95% CI, 2.07–6.45; P < 0.001) compared with Stratum A, and ECOG score (P = 0.019) and weight loss ≥ 5Kg (P = 0.045) were independent prognostic factors of OS with HRs of 1.71 (95% CI, 1.10–2.67) and 1.83 (95% CI, 1.01–3.31), respectively.
In the validation cohort, univariate Kaplan–Meier analysis demonstrated that the integrated GTV-TNM stratification system was statistically significantly associated with OS (3-year OS, Stratum A vs B, 82.4% vs 56.8%, P = 0.029; Stratum B vs C, 56.8% vs 24.7%, P = 0.001; Stratum A vs C, 82.4% vs 24.7%, P < 0.001) (Fig. 1G). Furthermore, the integrated GTV-TNM stratification system was recognized as the only independent prognostic factor for OS in multivariate analysis with HRs of 2.25 (95% CI, 1.02–4.97; P = 0.045) and 5.62 (95% CI, 2.46–12.80; P < 0.001) for Stratum B and C relative to Stratum A.
Concordance and discordance between the integrated GTV-TNM stratification system and TNM stage
The integrated GTV-TNM stratification system had significant association with TNM stage in both the training cohort (P < 0.001) and validation cohort (P < 0.001). Concordance between the integrated GTV-TNM stratification system TNM stage means that the integrated GTV-TNM stratum TNM stage are in the same order. In the training cohort, of 65 patients with stage IIIA, the integrated GTV-TNM stratum and TNM stage were concordant in 21 patients (32.3%) and discordant in 44 patients (67.7%). The concordance rates in stage IIIB and IIIC were 50.9% (58/114) and 75.0% (36/48) (Fig. 2A). In the training group, there were totally 112 patients (49.3%) discordant between the integrated GTV-TNM stratum and TNM stage, however the majority of them (46.3%) deviated by one above or below order, while the rate of deviating by more than one order was 3.1%. Similarly, in the validation set, the concordance rates in stage IIIA, IIIB and IIIC were 31.3% (10/32), 51.7% (30/58) and 73.9% (17/23), respectively (Fig. 2B). And only 3 patients (2.7%) discordant between the integrated GTV-TNM stratum and TNM stage deviated by more than one order.
Concordance and discordance between the integrated GTV-TNM stratification system and GTV risk group
The integrated GTV-TNM stratification system was statistical significantly related to GTV risk group in both the training set and validation set (all P < 0.001). In the training set, the integrated GTV-TNM stratum and GTV risk group were concordant in 53 patients (81.5%) with GTV risk group I, 95 patients (79.8%) with group II and 43 patients (100%) with group III (Fig. 2C). In the training group, the integrated GTV-TNM stratum and GTV risk group was discordant in 36 patients (15.9%), all of whom deviated by one above or below order. Besides, in the validation set, the concordance rates in GTV risk group I, II and II were 81.3% (26/32), 81.7% (49/60) and 100% (21/21), respectively (Fig. 2D). Equally no patient deviated by more than one order.
The prognostic validity of the integrated GTV-TNM stratification system
We used ROC curve to evaluate the prognostic validity of the integrated GTV-TNM stratification system, comparing with TNM stage and GTV risk group. In all patients, the AUC for OS was 0.636 (95%CI, 0.577–0.695) for the integrated GTV-TNM stratification system, versus 0.570 (95%CI, 0.509–0.631; P = 0.027) for TNM stage and 0.605 (95%CI, 0.545–0.665; P = 0.033) for GTV risk group (Fig. 3A). Bootstrap analysis demonstrated a significant increasing F1-scores in the integrated GTV-TNM stratification system (0.655 ± 0.052), compared to GTV risk group (0.638 ± 0.054, P = 0.013) and TNM stage (0.615 ± 0.056, P < 0.001), respectively (Fig. 3B).
First failure patterns and the prognosis of PFS
With a median follow-up of 28.9 months, a total of 238 patients exhibited failure, but 9 patients had no record of failure pattern. The most common type of first failure pattern is distant metastasis (58.0%, 192/331), while the rate of locoregional recurrence was 39.9% (132/331). Meanwhile, 25.1% (83/331) patients had synchronous failure experiencing distant metastasis and locoregional recurrence at the same time (Table 5). The integrated GTV-TNM stratification system had significant association with failure (P = 0.018) and distant metastasis (P = 0.023), and Stratum C had a higher risk to experience failure and distant metastasis.
Table 5
The distribution of first failure patterns among patients with the integrated GTV-TNM stratification system in the whole cohort
The integrated GTV-TNM stratification system | First failure patterns |
Locoregional recurrence (%) | P-value | Distant metastasis (%) | P-value | Synchronous failure (%) | P-value | Total (%) | P-value |
Stratum A (n = 79) | 28(35.4) | 0.393 | 40(50.6) | 0.023 | 18(22.9) | 0.222 | 50(63.3) | 0.018 |
Stratum B (n = 157) | 61(38.9) | | 86(54.8) | | 35(22.3) | | 110(70.1) | |
Stratum C (n = 95) | 43(45.3) | | 66(69.5) | | 30(31.6) | | 78(82.1) | |
Total (n = 331)a | 132(39.9) | | 192(58.0) | | 83(25.1) | | 238(71.9) | |
a, 9 patients had no record of failure pattern, but their deaths were documented, thus a total of 331 patients were enrolled in this analysis of first failure patterns. |
GTV = gross tumor volume. |
In the prediction of PFS, univariate analysis showed that patients with higher stratum in the integrated GTV-TNM stratification system tended to have impaired PFS in both the training group (1-year PFS, Stratum A vs B vs C, 67.5% vs 58.8% vs 31.3%, P < 0.001) (Fig. 1D) and validation group (1-year PFS, Stratum A vs B vs C, 65.4% vs 46.6% vs 25.0%, P < 0.001) (Fig. 1H). Even though the prognosis failed to reach statistical significance when Stratum A vs Stratum B (P = 0.097 and P = 0.176, respectively), the integrated GTV-TNM stratification system could be a potential strong prognostic factor for PFS.
Therapeutic toxicities
The documented therapeutic toxicities were mostly grade 1 or 2. Forty-three cases of grade 3–5 acute pneumonitis were reported in our cohorts, including two patients with grade 5 pneumonitis. There were 16.5% of patients (56/340) developed grade 3–4 radiation esophagitis, and 17.9% patients (61/340) had grade 3–4 myeloctoxicity. The integrated GTV-TNM stratification system significantly correlated with Grade ≥ 3 pneumonitis (P = 0.026), and Stratum C had a higher risk to develop Grade ≥ 3 pneumonitis (Table 6).
Table 6
Grade ≥ 3 therapeutic toxicities among patients with the integrated GTV-TNM stratification system in the whole cohort
The integrated GTV-TNM stratification system | toxicities |
Grade ≥ 3 pneumonitis (%) | P-value | Grade ≥ 3 esophagitis (%) | P-value | Grade ≥ 3 myeloctoxicity (%) | P-value |
Stratum A (n = 79) | 7(8.9) | 0.026 | 10(12.7) | 0.395 | 15(19.0) | 0.857 |
Stratum B (n = 162) | 16(9.9) | | 26(16.0) | | 30(18.5) | |
Stratum C (n = 99) | 20(20.2) | | 20(20.2) | | 16(16.2) | |
Total (n = 340) | 43(12.6) | | 56(16.5) | | 61(17.9) | |