The clinical prognostic factors of patients with stage IB lung adenocarcinoma
Original Article

The clinical prognostic factors of patients with stage IB lung adenocarcinoma

Qihai Sui1#, Jiaqi Liang1#, Zhengyang Hu1#, Xinming Xu2, Zhencong Chen1, Yiwei Huang1, Mengnan Zhao1, Cheng Zhan1, Lin Wang1, Zongwu Lin1, Qun Wang1

1Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, Shanghai, China; 2School of Basic Medical Sciences, Shanghai Medical College, Fudan University, Shanghai, China

Contributions: (I) Conception and design: Q Sui, L Wang, C Zhan; (II) Administrative support: C Zhan, Q Wang, Z Lin; (III) Provision of study materials or patients: J Liang, X Xu; (IV) Collection and assembly of data: Z Hu, Y Huang; (V) Data analysis and interpretation: Z Chen; (VI) Manuscript writing: All authors; (VII) Final approval of manuscript: All authors.

#These authors contributed equally to this work.

Correspondence to: Dr. Zongwu Lin, Dr. Lin Wang. 180 Fenglin Road, Xuhui District, Shanghai 200032, China. Email: lin.zongwu@zs-hospital.sh.cn, wang.lin3@zs-hospital.sh.cn.

Background: Lung adenocarcinoma (ADC) at stage IB has its own prognostic characteristics. This study aimed to investigate the clinical factors that may affect the prognosis of patients with stage IB ADC.

Methods: The data of ADC cases were selected from the Surveillance, Epidemiology, and End Results (SEER) database (2010–2016) and patients in Zhongshan Hospital, Fudan University (Department of Thoracic Surgery, 2015–2016). Kaplan-Meier method was used to obtain the overall survival (OS). Factors that significantly related to the prognosis were evaluated by univariate and multivariate analysis (UVA, MVA) using the Cox model. A nomogram was developed and validated to predict the 3-year OSs of those patients.

Results: 7,605 patients with stage IB ADC were included ultimately and were divided into two groups, a training cohort (n=5,324) and a test cohort (n=2,281). Besides, there was a validation cohort (n=272) for the verification of the nomogram model. Those with significantly older age, male, the white race, lower grades of tumor differentiation, larger tumor size (31–40 mm) without pleural layer (PL) invasion as well as receiving sublobectomy suffered from poorer survival (P<0.001), which were identified as independent factors for stage IB ADC (P<0.001), and according to which, a nomogram model was created.

Conclusions: Age, sex, race, histological grade, surgery to the primary site, and tumor size combined with PL invasion were independent risk factors for stage IB ADC, based on which a nomogram was constructed to predict the prognosis.

Keywords: Lung adenocarcinoma; prognosis; stage IB; AJCC

Submitted Jul 05, 2021. Accepted for publication Sep 14, 2021.

doi: 10.21037/tcr-21-1174

Introduction

Lung cancer is the most common malignant tumor with the highest morbidity and mortality worldwide (1). Adenocarcinoma (ADC) has been the primary subtype of lung cancer, accounting for 55% in recent years, with a strong proliferative capacity and a high degree of malignancy. Some patients have localized tumor infiltration or distant metastasis at the time of diagnosis, and the prognosis is poor (2,3).

The 8th edition of the TNM staging of the Lung Cancer, launched by the International Union Against Cancer (UICC) on January 1, 2018, had undergone numerous changes and additions compared to the 7th edition. It is now frequently used to predict the survival of patients with lung adenocarcinoma. In terms of tumor size, the 8th edition staged a more detailed classification of stage Ib tumors (3 cm < T2a ≤4 cm) (4-6). And tumor invasion of the pleural/elastic layer (PL) also belongs to stage IB, which has been reported as a poor prognostic factor in ADC (7,8). Differences and disputes still existed among patients with stage IB lung adenocarcinoma in survival status and related treatment recommendations (6,9-12). The influence of clinical factors on survival status was more or less various in studies (13-16).

SEER recently released the data of patients diagnosed with lung cancer in 2016. Therefore, the purpose of this study was to analyze the factors associated with the prognosis of patients with stage IB lung adenocarcinoma among 2010–2016, especially illustrated whether tumor size and PL play an important role or not, which may help improve the treatment strategy for early-stage lung cancer patients.

We present the following article in accordance with the TRIPOD reporting checklist (available at https://dx.doi.org/10.21037/tcr-21-1174).

Methods

Data sources and patient cohort

The data of patients were collected from the Surveillance, Epidemiology, and End Results (SEER) public use database SEER 18 Regs Custom Data (with additional treatment fields), Nov 2018 Sub (2010–2016).

A total of 8,846 patients with complete follow-up data were diagnosed as stage IB (AJCC 8th) ADC and performed surgery between 2010 and 2016 in the SEER database. Among them, 7,605 patients were finally enrolled in cohort I.

The characteristics of these patients are reported in Table 1, which includes age at the time of subsequent cancer diagnosis, race, gender, primary site, pathological classification (histology), grade, laterality, first malignant primary indicator, total no. of malignant and benign tumors, pleural/elastic layer invasion (PL) and tumor size. Finally, 5,324 patients with stage IB ADC from the SEER database were randomly assigned to the training cohort, and 2,281 were in the test cohort.

Table 1

Demographic and disease characteristics of patients with IB lung cancer in SEER and validation cohort

Characteristics Cohort 1 Validation cohort
SEER database, n=7,605 Our database, n=272
n % n %
Age
   ≤60 yr 1,181 15.53% 102 37.50%
   61–70 yr 2,459 32.33% 92 33.82%
   71–80 yr 2,910 38.26% 71 26.10%
   >80 yr 1,055 13.87% 7 2.57%
Race
   Black 686 9.02% 0 0.00%
   Others 53 0.70% 0 0.00%
   Asian or Pacific islander 646 8.49% 272 100.00%
   White 6,220 81.79% 0 0.00%
Sex
   Female 4,097 53.87% 147 54.04%
   Male 3,508 46.13% 125 45.96%
Differentiated grade
   Well differentiated 1,241 16.32% 57 20.96%
   Moderately differentiated 3,767 49.53% 155 56.99%
   Poorly differentiated 2,465 32.41% 60 22.06%
   Undifferentiated 132 1.74% 0 0.00%
Laterality
   Right 4,509 59.29% 172 63.24%
   Left 3,096 40.71% 100 36.76%
Surgery to the primary site
   Sublobectomy 1,533 20.16% 0 0.00%
   Multiple lobes 933 12.27% 5 1.84%
   Lobectomy 5087 66.89% 262 96.32%
   Pneumonectomy 52 0.68% 5 1.84%
Tumor size
   ≤10 mm 210 2.76% 40 14.71%
   11–20 mm 1,603 21.08% 112 41.18%
   21–30 mm 1,684 22.14% 84 30.88%
   31–35 mm 2,557 33.62% 21 7.72%
   36–40 mm 1,551 20.39% 15 5.51%
Pleural/Elastic Layer Invasion (PL)
   PL=0, No evidence of PL invasion 4,149 54.56% 78 28.68%
   PL=1, Invasion beyond the visceral elastic pleura, but limited to the pulmonary pleura 1,995 26.23% 160 58.82%
   PL=2, Invasion to the surface of the pulmonary pleura 1,461 19.21% 34 12.50%
Tumor size & PL
   ≤30 mm, PL=1 or 2 3,497 45.98% 236 86.76%
   31–40 mm, PL=0 3,369 44.30% 12 4.41%
   31–40 mm, PL=1 or 2 739 9.72% 24 8.82%

A total of 272 ADC at stage IB patients performed surgery for primary ADC lesion in the Department of Thoracic Surgery of Zhongshan Hospital Affiliated to Fudan University (ZHTS) were included. The selection process is shown in Figure 1.

Figure 1 The selecting process of all cohorts utilized in this study.

Statistical analysis

The distribution of patients’ characteristics (gender, race, age, primary site, pathological classification, differentiation grade, and chemotherapy, etc.) was summarized using counts and percentages. Statistical analysis was done using R Project (https://www.r-project.org) and SPSS 23.0 software (IBM). Kaplan-Meier method was used for the survival analysis. Multivariate survival analysis was calculated by the Cox proportional hazards regression. The test level was α=0.05, and the difference was statistically significant at P<0.05.

The prognostic model was then used to predict the 3-year outcomes of OS. We validated the nomogram internally and externally both in the training group and in the validation group. Harrell Consistency Index (C-Index) were used to evaluate the nomogram, with a higher C-index indicating a more accurate prognostic predictions (17). The calibration plot was adopted to evaluate nomogram performance. The C-index, nomogram, calibration curves and Kaplan-Meier curves were generated in R with packages “rms”, “survival”, “foreign” and “regplot” respectively (18).

Ethics approval and consent to participate

The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the ethics committees of Zhongshan Hospital, Fudan University (Shanghai, China) (Approval No.: B2019-232R). Informed consent forms were exempt.

Results

Patient characteristics

Among stage IB patients, the predominant age group was 71–80 years in the SEER database, while ≤60 years was the majority in the validation cohort. For the differentiated grade, the vast majority was moderately differentiated in all databases. Most of the patients enrolled in our study were performed surgery with Lobectomy + LN dissection. Details were described in Table 1.

Survival time analysis

A Kaplan-Meier analysis was conducted to evaluate the cumulative risk for the development of stage IB lung and was illustrated in Figure 2. The risk for development of stage IB lung cancer was neither related to PL (PL=0, PL=1, PL=2, P=0.15, Figure 2A), nor the tumor size (≤1 cm, 1.1–2.0 cm, 2.1–3.0 cm, 3.1–4.0 cm, P=0.2, Figure 2B) alone. However, once tumor size was considered in combination with PL, patients with stage IB lung cancer showed a significantly different survival status (P=0.0038, Figure 2C).

Figure 2 Survival time analysis of 7,605 patients with stage IB lung cancer; (A) for pleural/elastic layer invasion (PL); (B) for tumor size; (C) for the group considering both tumor size and pleural/elastic layer invasion (PL)

Cox survival analysis

Univariate analysis (Table 2) revealed that age at diagnosed (P<0.001), race (P<0.001), sex (P<0.001), tumor differentiation grade (P<0.001), total no. of in situ/malignant tumors for the patient (P<0.001), surgery to the primary site (P<0.001), group (P=0.005) was significant predictors of stage IB lung cancer patients. Multivariate Cox proportional hazard analysis of all IB staged patients (Table 2) demonstrated sex (P<0.001), age (P<0.001), race (P=0.003), tumor differentiation grade (P<0.001), surgery to the primary site (P<0.001), group (P<0.001), were independent prognostic factors for better survival in the IB staged patients (AJCC 8th). No significant difference was caused by tumor size or total no. of in malignant tumors for patient.

Table 2

Results of univariate and multivariate analysis model for stage IB patients

Variable Univariate analysis Multivariate analysis
HR 95% CI P value HR 95% CI P value
Age at diagnosed
   ≤60 yr reference reference
   61–70 yr 0.480 0.414–0.558 < 0.001 1.311 1.120–1.534 0.001
   71–80 yr 1.372 1.225–1.537 < 0.001 1.889 1.625–2.196 <0.001
   >80 yr 0.684 0.617–0.758 < 0.001 2.470 2.091–2.919 <0.001
Race < 0.001* 0.003
   White reference reference
   Others 1.508 0.705–3.225 0.290 0.501 0.238–1.053 0.068
   Asian or Pacific islander 1.889 0.888–4.016 0.098 0.742 0.621–0.886 0.001
   Black 2.139 1.018–4.493 0.045 0.969 0.834–1.126 0.682
Sex <0.001* <0.001*
   Female reference reference
   Male 1.385 1.273–1.506 <0.001 1.326 1.218–1.443 <0.001
Differentiated Grade <0.001* <0.001*
   Well differentiated reference reference
   Moderately differentiated 0.560 0.409–0.767 <0.001 1.432 1.246–1.645 <0.001
   Poorly differentiated 0.837 0.623–1.125 0.239 1.853 1.608–2.135 <0.001
   Undifferentiated 1.100 0.818–1.480 0.528 1.869 1.364–2.560 <0.001
Laterality 0.169 Not included
   Right reference
   Left 1.062 0.975–1.156 0.169
Surgery to the primary site <0.001* <0.001*
   Sublobectomy reference reference
   Multiple lobes 0.732 0.640–4.450 <0.001 0.839 0.727–0.969 0.017
   Lobectomy + LN dissection 0.555 0.504–0.612 <0.001 0.684 0.605–0.773 <0.001
   Pneumonectomy 0.528 0.197–1.413 <0.001 0.698 0.260–1.872 0.474
Tumor size 0.197 Not included
   ≤10 mm reference
   11–20 mm 0.900 0.690–1.172 0.433
   21–30 mm 0.856 0.750–0.976 0.020
   31–35 mm 0.957 0.843–1.087 0.500
   35–40 mm 0.953 0.849–1.069 0.409
Pleural/Elastic Layer Invasion (PL) 0.154 Not included
   No evidence of PL invasion reference
   Invasion beyond the visceral elastic pleura, but limited to the pulmonary pleura 1.074 0.971–1.188 0.164
   Invasion to the surface of the pulmonary pleura 1.101 0.985–1.230 0.090
Tumor size & PL (group) 0.005 0.964 0.868–1.071 <0.001
   ≤30 mm reference reference
   31–40 mm, PL=0 1.032 0.944–1.128 0.494 1.145 1.043–1.256 0.004
   31–40 mm, PL=1 or 2 1.269 1.101–1.463 0.001 1.327 1.149–1.532 <0.001

*, indicate a statistical significance.

Contribution and validations of the nomogram

A nomogram relating to 6 independent risk factors (age, race, sex, tumor histological, grade, surgery, and group), which were concluded from MVA (Figure 3). 3-year overall survival (OS) could be calculated by the Points at the top of the model (Figure 3A). The internal evaluation was performed (Figure 3B) as well as the external evaluation (Figure 3C) with the same database. The C-indexes for 3-year OS were 0.644±0.015 (training cohort, SEER database) and 0.625±0.024 (test cohort, SEER database).

Figure 3 A nomogram model of stage IB ADC and its calibration curve for validations. (A) A nomogram for prediction of 3-year overall survival (OS) rates of patients with lung adenocarcinoma (ADC) in the training cohort; (B) Calibration curve of the nomogram predicting the 3-year OS rate of patients with lung ADC in the training cohort, the X-axis displays the nomogram-predicted OS and the Y-axis is the actual OS of the certain patients; (C) Calibration curve of the nomogram predicting the 3-year OS rate of patients with lung ADC in the test cohort, the X-axis displays the nomogram-predicted OS and the Y-axis is the actual OS of the certain patients.

Furthermore, we verified our nomogram model by individuals with entirely different characteristics of the data (Figure 4), the C-index of which was 0.690±0.079 (database in our department).

Figure 4 Calibration curve of the nomogram predicting the 3-year OS rate of patients in the Department of Thoracic Surgery of the Fudan University (Zhongshan Hospital).

In general, IB ADC patients who had a younger age, female sex, non-black-or-white race, lower differentiated level or performed pneumonectomy had longer predicting survival time. For the groups, those in group 1, which meant the tumor size was less than 30 mm had the best clinical outcomes, followed by 31–40 mm tumor size with no PL invasion, and those with 31–40 mm tumor size with PL invasion behaved worst in survival time.

Discussion

In our study, we found that in patients with stage IB ADC, the differences in tumor size or PL invasion didn’t cause differences in living conditions, while the survival times appeared different once both of them were considered together. In all, six independent risk factors (age, race, sex, tumor histological, grade, surgery, and group) were concluded from MVA and contributed for nomogram model. Recently, study considering stage IB NSCLC concluding similar independent risk factors, including age, sex, histology, tumor differentiation (19), and it was widely proved that among lung cancer patients, female patients have a better prognosis (20), which was also revealed in our research.

The pleural invasion was well-positioned as a T2 descriptor and led to a worse prognosis even after adjusting for the current tumor size cut points (21-25). Our result was similar to the research result that IB patients with both pleural invasion and tumor size between 3.1–4.0 cm had a closer survival status to the stage IIA patients (14). Rami-Porta’s study also suggested that 3-cm cutoff point still separates T1 from T2 tumors, but tumor size arises as a more important prognostic factor, because, from ≤1 to 5 cm, each centimeter separates tumors with a significantly different prognosis (21), while Nitadori et al. found that PL distinguished OS in patients with lung adenocarcinoma with a tumor size of 2–3 cm, but failed to stratify patients with a tumor size of ≤2 cm (26). Other researchers showed that the presence of PL, not the depth of invasion, was associated with postoperative survival (23,27,28), but conflicted to the conclusion that survival differences existed among different PL stages (29,30). More studies can be focused on this phenomenon to illustrate the probable mechanism.

In addition to the tumor size and the degree of local invasion, for patients with stage IB lung adenocarcinoma, men, blacks, whites, etc., are related to poorer prognosis, so they are more likely to require further treatment. In addition, patients undergoing sublobectomy and multiple lobectomy also have a poorer prognosis, which may be related to the failure of complete removing of the lesion. Therefore, the follow-up after the operation should be more closely to better determine whether it is necessary to apply further treatment. In conclusion, those results indicate we should take different clinical decisions for different patients, even if they have the same clinical stage.

Furthermore, FDG-PET/CT SUVmax, the value of which reflects the biological activity of tumors, is also closely related to tumor proliferation, invasion, progression and metastasis (31). Kawakita/Toba reported that FDG-PET/CT SUVmax, total tumor size, and could predict the prognosis of pStage I lung adenocarcinoma based on the 7th edition of the TNM staging system (32). it was also found that solid predominant types have high SUVmax values and a shorter PFS than the other histologic subtypes (33).

Recently, the therapy strategy for IB lung cancer patients had been widely discussed. The recent National Comprehensive Cancer Network (NCCN) guidelines stated that adjuvant chemotherapy could be used for patients with stage IB NSCLC having high-risk factors including poorly differentiated tumors, vascular invasion, wedge resection, tumors >4 cm, visceral pleural involvement, and unknown lymph node status (Nx), which independently may not be an indication and may be considered when determining treatment with adjuvant chemotherapy (34). NSCLC Meta-analysis Collaborative Group’s meta-analysis (35), mainly on stage IB–IIIA patients, achieved the conclusion that preoperative chemotherapy significantly improves overall survival in resectable NSCLC and some other studies reached the similar conclusion that adjuvant chemotherapy may improve the OS of completely resected patients with a solid predominant tumor pattern in stage IB ADC (36,37). In contrast, there were also studies that showed that adjuvant chemotherapy was associated with worse OS than observation or no significant survival advantage for patients with stage IB NSCLC, but with significant OS benefit in stage IIA setting based on the 8th edition staging (6,9).

According to our research, visceral pleural involvement was not an independent prognostic factor in patients with stage IB lung cancer based on the 8th editions of AJCC TNM staging system. To decide whether patients should be treated with adjuvant chemotherapy, both tumor size and PL can be considered.

The limitation of this study is that, firstly, because the SEER database used in this study has no chemotherapy-related records for lung cancer patients diagnosed in 2016, it is unable to conduct further statistical analysis on lung cancer treatment. Since the SEER database is predominantly white, certain biases will be introduced when analyzing the impact of race on the prognosis, and further research is needed to explore whether race is really a factor influencing the prognosis of lung cancer. Furthermore, the patients’ detailed clinical information is limited in the SEER database, as there is no record of PET/CT SUVmax value and other prognosis-related figures for the further analyze. In addition, this study is only a retrospective study, and further experiments are needed to verify or clarify the relevant conclusions.

Conclusions

The combination of tumor size and PL invasion is a significant clinical character of different prognosis in patients with stage IB lung adenocarcinoma (AJCC 8th TNM classification), which may help the selection of patients who might benefit from chemotherapy and more advanced treatment.

Acknowledgments

The authors thank International Science Editing (http://www.internationalscienceediting.com) for editing this manuscript.

Funding: This work was supported by the Zhengyi Scholar Foundation of School of Basic Medical Sciences, Fudan University (S22-11).

Footnote

Reporting Checklist: The authors have completed the TRIPOD reporting checklist. Available at https://dx.doi.org/10.21037/tcr-21-1174

Data Sharing Statement: Available at https://dx.doi.org/10.21037/tcr-21-1174

Conflicts of Interest: All authors have completed the ICMJE uniform disclosure form (available at https://dx.doi.org/10.21037/tcr-21-1174). The authors have no conflicts of interest to declare.

Ethical Statement: The authors are accountable for all aspects of the work in ensuring that questions related to the accuracy or integrity of any part of the work are appropriately investigated and resolved. The study was conducted in accordance with the Declaration of Helsinki (as revised in 2013). This study was approved by the ethics committees of Zhongshan Hospital, Fudan University (Shanghai, China) (Approval No.: B2019-232R). Informed consent forms were exempt.

Open Access Statement: This is an Open Access article distributed in accordance with the Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International License (CC BY-NC-ND 4.0), which permits the non-commercial replication and distribution of the article with the strict proviso that no changes or edits are made and the original work is properly cited (including links to both the formal publication through the relevant DOI and the license). See: https://creativecommons.org/licenses/by-nc-nd/4.0/.

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Cite this article as: Sui Q, Liang J, Hu Z, Xu X, Chen Z, Huang Y, Zhao M, Zhan C, Wang L, Lin Z, Wang Q. The clinical prognostic factors of patients with stage IB lung adenocarcinoma. Transl Cancer Res 2021;10(11):4727-4738. doi: 10.21037/tcr-21-1174

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