Reevaluation of the requirement of adjuvant therapy for T2N0M0 gastric cancer following gastrectomy: a SEER database analysis

doi:10.21203/rs.3.rs-3598144/v1

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Reevaluation of the requirement of adjuvant therapy for T2N0M0 gastric cancer following gastrectomy: a SEER database analysis

https://doi.org/10.21203/rs.3.rs-3598144/v1

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Background

Determining the requirement for adjuvant therapy in gastric cancer (GC) patients with stage T2N0M0 remains controversial.

Methods

An eligible population cohort was identified from the Surveillance, Epidemiology, and End Results (SEER) database. The Kaplan-Meier method was used to assess the impact of adjuvant treatment modalities on overall survival (OS) and cause-specific survival (CSS). Multivariate Cox regression and competing risk model were used to investigate the prognostic factors for CSS. Propensity score matching (PSM) analysis was carried out to reduce the selection bias.

Results

A total of 776 patients were finally included. The 5-year OS for patients receiving surgery alone, adjuvant CRT, and adjuvant CT were 64.0%, 74.3%, and 69.0%, respectively (p = 0.004). The 5-year CSS for patients receiving surgery alone, adjuvant CRT, and CT were 73.0%, 84.3%, and 76.9%, respectively (p = 0.081). After PSM, no significant intergroup difference was observed on OS or CSS. When stratified by the number of lymph node (LN) examined, adjuvant CRT was shown to significantly increase the CSS than surgery alone in patients with LN examined ≤ 15 (p = 0.044), rather than in those with sufficient LN dissected (p = 0.590). Multivariate Cox analysis demonstrated that ethnicity, marital status, and number of LN examined > 15 were independent prognostic factors for CSS, of which number of LN examined > 15 was further validated by the competing risk model (SHR 0.701, p = 0.035).

Conclusions

Adjuvant therapy is not necessary for T2N0M0 GC patients undergoing standard radical gastrectomy, but adjuvant CRT should be reserved for those who have insufficient LN dissected patients.

gastric cancer

T2N0M0

Adjuvant therapies

chemoradiation

lymph node examined

Surveillance epidemiology and end results (SEER)

Gastric cancer (GC) is one of the most common malignancies and a leading cause of cancer mortality worldwide¹. Early detection and a timely radical surgical resection are deemed as the optimal treatment to achieve clinical cure². Even so, the majority of patients are at varying degrees of risk for postoperative cancer recurrence³. Therefore, adjuvant therapy should usually be individualized for patients based on the postoperative pathological staging to minimize the risk of tumor recurrence⁴. In the past decades, numerous clinical trials have confirmed the benefit of adjuvant therapy in stage II-III GC, including adjuvant chemoradiation therapy (CRT)⁵ and chemotherapy (CT)⁶. However, there have been limited studies regarding whether stage I GC patients would benefit from adjuvant therapy. Especially, for T2N0M0 (stage IB) GC, surveillance without any adjuvant therapy, or fluoropyrimidine-based chemoradiation therapy for selected patients was recommended according to the National Comprehensive Cancer Network (NCCN) guidelines for GC⁷, leaving no consensus on treatment decisions for patients of this particular stage.

In this study, we included T2N0M0 GC patients from the Surveillance, Epidemiology, and End Results (SEER) database and established three representative cohorts based on the adjuvant treatment modality. We aimed to compare the survival outcome among surgery alone, surgery with adjuvant CRT, and surgery with adjuvant CT. Furthermore, prognostic factors were explored by multiple regression models. These results may help guide the selection of optimal adjuvant treatment modality for T2N0M0 GC patients.

Data source and ethical statement

The present study collected data from Surveillance, Epidemiology, and End Results (SEER) Program (www.seer.cancer.gov) SEER*Stat (Version 8.3.9.2) Database: Incidence - SEER Research Plus Data, 18 Registries, Nov 2020 Sub (2000–2018). Permission was obtained to access the data files from the SEER program with the reference number 23884-Nov2020. As patient data identified from the database were deidentified and available to the public for research purposes, the ethical approval of the present study was waived by the local ethics committee.

Study cohort

Due to database limitations, our analysis was restricted to a sample from January 2004 to December 2015. The inclusion criteria were as follows: 1) cancer patients aged at least 18 years, with a primary site in the stomach were retrieved using the codes from the International Classification of Disease for Oncology (ICD-O-3: C16.0-C16.6, C16.8-C16.9); 2) since T2aN0M0 according to American Joint committee on Cancer (AJCC) 6th TNM staging system of GC is equivalent to T2N0M0 according to AJCC 7th TNM staging system, both were included; 3) histology code on the basis of the ICD-O-3 codes covered: 8140/3, 8142/3-8145/3, 8210/3, 8211/3, 8255/3, 8260/3, 8261/3, 8263/3, 8323/3, 8480/3, 8481/3, 8490/3; 4) surgical gastrectomy on primary tumor was performed. The patients were excluded if they fulfilled the following exclusion criteria: 1) tumors were diagnosed without histology confirmation; 2) no surgery of primary site, autopsy only, local tumor destruction or excision, or unknown if surgery performed; 3) patients with multiple primary cancers; 4) follow-up information was missing (survival at 0 month). Furthermore, patients were finally included and subdivided into 3 groups according to the items of systemic/surgery sequence and surgery/radiation sequence. Surgery alone group included patients with no adjuvant therapy, adjuvant CRT or CT group included patients with adjuvant chemoradiation therapy or chemotherapy. The patient screening flowchart was shown in Figure. 1.

Variables collected

The following variables were collected from the sample: 1) year of diagnosis; 2) age at diagnosis; 3) gender (Female/male); 4) ethnicity (White/Black/Other); 5) marital status (Married/Divorced/Single/Widowed/Others-Unknown); 6) tumor size (≤ 3cm/3.1-5cm/>5cm/Unknown); 7) tumor location (cardia/non-cardia); 8) Lauren classification (Intestinal/Diffuse/Unclassified); 9) differentiation grade (Well/Moderately/Poorly/Undifferentiated/Unknown); 10) number of lymph node examined (≤ 15/>15); 11) follow-up time (month) and vital status (alive/dead); 12) cause of death.

Statistical analysis

PSM was used to minimize the selection bias from a retrospective study on the assessed outcomes between any two groups among the three postoperative therapeutic selections. The PSM was estimated by using a logistic regression model, with the treatment selection as the dependent variable and all the baseline characteristics outlined in Table 1 as covariates. Subjects were matched by propensity score to their nearest neighbor in a 1:1 ratio without replacement. Validation of PSM was achieved by comparing the histogram of propensity score between any two treatment groups before and after the procedure.

Table 1

Competing risk regression analysis for cause-specific death
Variable	Univariate analysis		Multivariate analysis
Variable	SHR (95% CI)	P value	SHR (95% CI)	P value
Year of diagnosis
2004–2009	ref
2010–2015	0.822 (0.605–1.120)	0.21
Age (ys)
18–40	ref
41–65	0.897 (0.335-2.400)	0.83
> 65	1.326 (0.506–3.470)	0.57
Gender
Female	ref
Male	1.240 (0.905–1.710)	0.18
Ethnicity
White	ref		ref
Black	0.852 (0536 − 1.350)	0.5	0.894 (0.558–1.433)	0.64
Other	0.691 (0.470–1.020)	0.06	0.792 (0.526–1.191)	0.26
Lauren classification
Intestinal	ref		ref
Diffuse	1.390 (0.621-3.100)	0.42	1.488 (0.623–3.557)	0.37
Undifferentiated	1.530 (0.998–2.330)	0.051	1.416 (0.890–2.253)	0.14
Marital status
Married	ref
Divorced	1.202 (0.708–2.040)	0.5
Single	0.842 (0.496–1.430)	0.52
Widowed	1.177 (0.794–1.750)	0.42
Others	0.610 (0.248-1.500)	0.28
Location
Cardia	ref		ref
Non-cardia	0.653 (0.463–0.921)	0.015	0.727 (0.497–1.063)	0.1
Tumor size
≤ 3cm	ref
3.1-5cm	1.063 (0.750–1.510)	0.73
> 5cm	0.728 (0.455–1.170)	0.19
Unknown	1.394 (0.733–2.650)	0.31
Grade
Well	ref		ref
Moderately	1.230 (0.620–2.460)	0.55	1.305 (0.653–2.609)	0.45
Poorly	1.180 (0.599–2.340)	0.63	1.204 (0.608–2.381)	0.59
Undifferentiated	1.400 (0.482–4.070)	0.54	1.519 (0.521–4.429)	0.44
Unknown	2.530 (0.900–7.090)	0.079	2.303 (0.798–6.643)	0.12
No. of LNs examined
≤ 15	ref		ref
> 15	0.692 (0.499–0.959)	0.027	0.701 (0.504–0.975)	0.035
Treatment strategy
Surgery alone	ref
Adjuvant CRT	0.693 (0.425–1.130)	0.14
Adjuvant CT	0.969 (0.521-1.800)	0.365
LN, lymph node; CRT, chemoradiation therapy; CT, chemotherapy

Continuous variables were presented as mean ± standard deviation or median with interquartile range (IQR), and categorical variables were presented as absolute number (percentage). Continuous variables with or without normal distribution were compared using the Student’s t-test or non-parametric Mann-Whitney U test, as appropriate. The Chi-square and Fisher’s exact tests (when appropriate) were performed for comparison of categorical variables. Survival curves were plotted via the Kaplan-Meier method, and log-rank test was applied to determine the intergroup differences of overall survival (OS) and cause-specific survival (CSS). Associated factors predictive of OS or CSS were assessed by both univariate and multivariate Cox proportional regression analyses. Fine and Gray’s competing risk regression model was employed to explore the potential competing risk contributing to the OS (ref).

All statistical analyses were performed by R software (version 4.1.2, https://www.r-project.org/). The R package of “cmprsk” was used to perform the competing risk analysis. For all statistical tests, a two-sided p value less than 0.05 was regarded statistically significant.

Baseline characteristics

A total of 776 patients were finally included in the data analysis, of whom 619 patients (79.8%) received surgery alone, 102 patients (13.1%) received adjuvant chemoradiation therapy (CRT), and 55 patients (7.1%) patients received adjuvant chemotherapy (CT). In the entire cohort, the three groups were not balanced with regard to the baseline characteristics except gender, ethnicity, Lauren classification, and number of lymph node examined. Notably, the proportion of elderly patients was significantly higher in the surgery alone group than that in adjuvant therapy group. Poorly differentiated tumors accounted for 71.6% of the patients within the adjuvant CRT group, which was the highest of all three cohorts. The detailed comparison of baseline variables among the three cohort groups was shown in Table S1.

Survival analysis

Over a median follow-up of 63 months (IQR: 36–96 months), a total of 168 patients died of GC. In the entire cohort, the median OS was 101 (95% CI: 92–112) months, with a 5-year OS rate of 65.7% (95% CI: 62.3%-69.2%); the median CSS did not reach, with a 5-year CSS rate of 75.0% (95% CI: 71.5%-78.7%). The 5-year OS for patients receiving surgery alone, adjuvant CRT, and adjuvant CT were 64.0% (95% CI: 60.2%-68.0%), 74.3% (95% CI: 66.1%-83.6%), and 69.0% (57.3%-83.1%), respectively (p = 0.004, Figure. 2A). Comparatively, no significant intergroup difference was observed regarding the analysis of CSS, showing 5-year CSSs for patients receiving surgery alone, adjuvant CRT, and CT of 73.0% (95% CI: 69.0%-77.4%), 84.3% (95% CI: 76.9%-92.5%), and 76.9% (65.7%-90.0%), respectively (p = 0.081, Figure. 2B).

To eliminate the effect on the survival analysis caused by the imbalance of the baseline characteristics among the three groups, PSM was performed between each two of the three groups. After PSM manipulation, the disparities were completely resolved, and each two groups were well balanced in terms of the baseline variables (Table S2-S4). For the Kaplan-Meier analysis, there was no significant difference on OS between group of surgery alone and adjuvant CRT (p = 0.200, Figure S1A), of surgery alone and adjuvant CT (p = 0.390, Figure S1B), or of adjuvant CRT and CT (p = 0.610, Figure S1C). Similarly, no significant difference was observed on CSS between group of surgery alone and adjuvant CRT (p = 0.120, Fig. 3A), of surgery alone and adjuvant CT (p = 0.480, Fig. 3B), or of adjuvant CRT and CT (p = 0.900, Fig. 3C).

Considering that the number of LN dissected is an essential factor affecting the prognosis of GC, subgroup analysis was performed stratified by the number of LN examined. Compared with surgery alone, adjuvant CRT was shown to significantly increase the CSS in patients with LN examined less than 15 (p = 0.044, Fig. 4A), rather than in those with sufficient LN dissected (p = 0.590, Fig. 4B). However, there was no significant difference on CSS in the comparison of surgery alone versus adjuvant CT (Figure S2), or of adjuvant CRT versus CT (Figure S3), regardless of the adequacy of LN dissection.

Univariate and multivariate Cox analysis for CSS and OS

Univariate Cox analysis indicated that age, ethnicity, marital status, tumor size, number of LN examined, and adjuvant treatment modality were related to OS of GC (Table S5). Given the limitations of univariate analysis, multivariate Cox analysis was performed to investigate the independent factors associated with OS. The results confirmed that age over 65 years (HR 2.842, p = 0.025), ethnicity of non-black or white (HR 0.737, p = 0.028) were independent prognostic factors for OS (Table S5). Regarding the CSS, univariate analysis revealed the potential related factors including year of diagnosis, ethnicity, marital status, tumor differentiation grade, number of LN examined, and adjuvant treatment modality (Table S6). Multivariate analysis demonstrated that ethnicity of non-black or white (HR 0.681, p = 0.047), widowed marital status (HR 1.510, p = 0.033), and number of LN examined > 15 (HR 0.691, p = 0.023) were independent prognostic factors for CSS (Table S6).

Competing risk analysis CSS

To rule out the confounding effect of non-oncological related death events in CSS analysis, a competing risk model was employed to further explore the cause-specific prognostic factors. As shown in the cumulative incidence curve (Fig. 5), when other causes of death were taken into account as competing risk (dotted lines), cumulative incidence function (CIF) failed to display significant difference among surgery alone, adjuvant CRT, or CT (p = 0.336); whereas instead, a significant difference was detected on CIF for causes of death other than GC among the three adjuvant therapy groups (p = 0.008).

Furthermore, multivariate Fine and Gray’s proportional subdistribution hazards analysis, in which deaths not related to GC was regarded as competing risks, was performed to explore the prognostic factors for CSS. The results revealed that number of LN examined > 15 (SHR 0.701, p = 0.035) was the only independent prognostic factor for CSS (Table 1).

Radical gastrectomy combined with D2 lymphadenectomy has currently been widely accepted as the standard treatment for GC⁸. However, there still exists a risk of tumor recurrence and metastasis after gastrectomy, which has long been a critical issue affecting the long-term survival of GC patients⁹. Postoperative adjuvant treatment is deemed as an important complementary treatment to eliminate the occult residual tumors, which help reduce the risk of cancer recurrence. Accordingly, clinical trials have shown that postoperative adjuvant treatment is beneficial for potential curable GC, such as INT 0116 trial⁵, ACTS-GC trial¹⁰, and CLASSIC trial⁶. However, the majority of the patients included in these previous landmark studies are at stage II or III, which leaves the question on whether adjuvant treatment is necessary for patients with T2N0M0 unanswered.

Countries differ in their treatment expertise and research results regarding GC; hence, treatment guidelines are diverse based on evidence and medical situations¹¹. Currently, there is still no consensus on the adjuvant treatment for T2N0M0 GC patients worldwide. Both the NCCN and the Chinese Society of Clinical Oncology (CSCO) guidelines recommend adjuvant CRT for patients who received less than a D2 lymph node dissection, even if an R0 resection is achieved^12,13. The Japanese gastric cancer treatment guidelines (JGCG) recommend no adjuvant therapy for those with T2N0M0 GC¹⁴, whereas postoperative adjuvant CT or CRT was recommended by the European Society of Medical Oncology (ESMO) guidelines¹⁵. Therefore, the general view is that adjuvant therapy may not be necessary for all patients with T2N0M0 GC following radical gastrectomy with sufficient LN dissection, but should be reserved for those with high-risk factors.

In the present SEER population based retrospective cohort study, we attempted a comparative analysis of the survival prognosis of GC patients with T2N0M0, who received different adjuvant treatment modalities. The comparison of OS among surgery alone, adjuvant CRT and adjuvant CT groups indicated a statistical significance. However, as analysis of OS cannot exclude deaths due to non-cancer reasons, and a significant intergroup imbalance in baseline characteristics exists, the clinical significance of this result is questionable, and may even seem a bit misleading to clinicians. Therefore, we used three approaches for further analysis. Firstly, CSS, in which deaths due to other reasons were excluded, did not show any difference among the three groups. Secondly, the difference on OS disappeared completely when PSM was performed to balance the intergroup baseline characteristics. Similarly, there is no difference on the comparison on CSS between any two groups. Thirdly, in consistent with the analysis of CSS, the competing risk model also failed to show any statistical significance on death incidence among the three groups. These results indicated that adjuvant therapy cannot further improve the survival for the overall T2N0M0 GC population, and these patients may benefit from sparing of treatment-induced toxicity.

Until now, there have only been very few published studies with inconsistent conclusions drawn concerning the adjuvant treatment on early stage GC¹⁶. A previous SEER population-based study indicated that adjuvant radiotherapy did not improve the overall survival for stage I GC patients¹⁷. However, another SEER-based cohort study revealed that stage IB GC patients could benefit from adjuvant CRT compared with surgery alone, when patients with stage IA disease were excluded from the analysis¹⁸. In addition, a multi-institutional US population-based retrospective study indicated that aggressive adjuvant therapy was recommended only to T3-4N0M0 rather than the T2N0M0 GC patients, because T2N0M0 patients had a significantly longer time to recurrence and a relatively better prognosis than their T3-4N0M0 counterparts¹⁹. In comparison to the U.S., adjuvant CT, instead of CRT, is more commonly applied as the adjuvant treatment modality in East Asia. Zheng et al²⁰ reported that adjuvant CT had no effect on the prognosis in T2N0 patients. Consistent with our findings, a recent retrospective study comprising only stage IB GC showed that the OS rates in the adjuvant CT group were 95.1% compared with 93.3% in surgery alone group, with no significant difference detected²¹.

D2 gastrectomy has been accepted as the standard procedure for advanced GC in eastern countries, while less extensive surgery with insufficient lymph node dissection is more commonly performed in western countries. Since removal of > 15 regional LNs is required for sufficient LN dissection and accurate postoperative pathological staging²², we used 15 as the cutoff points for the factor of number of examined LN. In the present study, we employed two different regression models to comprehensively explore the predictive factors for survival in T2N0M0 GC patients. Both the Cox and competing risk regression models indicated that > 15 LN examined is the only independent treatment-related prognostic factor for CSS. More importantly, compared with surgery alone, adjuvant CRT positively influenced CSS in patients with less than 15 LN examined, but not in those with sufficient LN dissection. These results are in consistent with a previous study by In et al²³, who reported that adjuvant CRT after an R0 resection for T2N0M0 GC could bring about extra survival benefit when suboptimal lymphadenectomy was performed. This is attributed to the fact that incomplete LN dissection might cause stage migration²⁴, the node-negative patients may thus actually have already had LN metastasis. Notably, we reviewed a previous SEER based study regarding stage I GC²⁵. Since the authors did not perform the subgroup analysis, they drew a conclusion without PSM to show that T2N0M0 GC does not benefit from adjuvant therapy due to its good prognosis²⁵. In contrast, our study implies that adjuvant CRT should also be reserved for those who have insufficient LN dissected T2N0M0 GC patients.

Additionally, we demonstrated that none of the former frequently considered pathological variables including tumor size, Lauren classification, or differentiation grade was an independent CSS prognostic factor for T2N0M0 GC patients. Partially consistent with our findings, Jin et al²⁶ divided patients with T2N0M0 into four subgroups according to the prognostic factors, and found that only patients with characteristics of both size > 3cm and number of LN examined ≤ 15 yielded improved CSS benefit from adjuvant CT. Contrary to our findings, Du et al²⁷ established a risk stratification model for T2N0M0 tumors based on three pathological characteristics, including lymphatic and/or vessel invasion, tumor size > 3cm, and perineural invasion. They proposed that adjuvant therapy should be considered for high-risk patients who were defined as with at least two of the aforementioned characteristics. Since only very few literatures published on this issue, more studies including larger number of patients are still warranted to help identify candidates who might benefit from adjuvant therapy.

Some limitations need to be clarified in this study. Firstly, data on cancer recurrence is not available from the SEER database. Therefore, we are unable to determine recurrence patterns and investigate factors associated with disease-free survival and locoregional relapse-free survival. Secondly, although multiple regression models were employed to explore the potential prognostic factors, we are still far from a definitive model to predict those high-risk patients who might benefit from proper adjuvant treatment, since many critical pathological data were not available from SEER database. Thirdly, the patients included in the analysis are all Americans, with White as the majority. Therefore, the generalizability of the findings to population with different races, ethnics, or geographical environments may be limited. Finally, selection bias existed among the three groups, and it cannot be eliminated absolutely although a PSM was performed. knowing that a retrospective study is underpowered, a prospective randomized trial is warranted to draw a firm conclusion in future.

In conclusion, adjuvant therapy is not necessary for T2N0M0 GC patients undergoing standard radical gastrectomy, but adjuvant CRT should be reserved for those who have insufficient LN dissected patients.

Ethical Approval

As patient data identified from the database were deidentified and available to the public for research purposes, the ethical approval of the present study was waived by the local ethics committee.

Competing interests

The authors declare that they have no conflict of interest.

Availability of data and materials

In the study, the authors obtained the data from the SEER database, which was open access for research purposes. The authors were permitted to access the data at the website (http://www.seer.cancer.gov) with the identifier, 23884-Nov2020.

Conflict of interest statement

The authors declare no potential conflicts of interest.

Author contributions

XZ, RY, and WW: designed this study. XZ and FL: acquire and analyze the data. XZ and HF: wrote and edited the manuscript. All authors reviewed the manuscript.

Funding

This study was supported by grants from the National Natural Science Foundation of China (81773049, 81402359).

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No competing interests reported.

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Reevaluation of the requirement of adjuvant therapy for T2N0M0 gastric cancer following gastrectomy: a SEER database analysis

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Abstract

Background

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Results

Conclusions

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Introduction

Methods

Data source and ethical statement

Study cohort

Variables collected

Statistical analysis

Results

Baseline characteristics

Survival analysis

Univariate and multivariate Cox analysis for CSS and OS

Competing risk analysis CSS

Discussion

Declarations

References

Additional Declarations

Supplementary Files

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