Improved Survival of Primary-Tumor Resection in Metastatic Thoracic Esophageal Cancer: A Population-Based, Propensity Score Matched Study

doi:10.21203/rs.3.rs-4930346/v1

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Improved Survival of Primary-Tumor Resection in Metastatic Thoracic Esophageal Cancer: A Population-Based, Propensity Score Matched Study

https://doi.org/10.21203/rs.3.rs-4930346/v1

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The study aims to assess the survival effect of primary-tumor resection (PTR) on thoracic esophageal cancer with distant metastasis(TECDM). Data of patients with TECDM was collected from the Surveillance, Epidemiology, and End Results database from 2010 to 2020. We used a 1:1 propensity-score matching(PSM) analysis to minimize heterogeneity between different groups. Total 7733 patients with TECDM were included, and 121 patients and 7612 patients underwent primary-tumor resection and did not, respectively. Patients underwent primary-tumor resection had a better median OS and median CSS than those patients did not in overall and PSM cohort. In PSM cohort, the median OS was 11 months (95% CI, 9 months to 13 months) for TECDM patients with PTR and 7 months (95% CI, 5 months to 9 months) for those patients without PTR. Additionally, cox proportional hazard models similarly indicated that PTR was a significantly protective factor for TECDM patients in OS (HR: 0.5529; 95% CI, 0.5196 to 0.7730, P < 0.001) and CSS (HR:0.5869 ; 95% CI, 0.479 to 0.7192, P < 0.001). In conclusion, primary-tumor resection prolongs survival of thoracic esophageal cancer patients with distant metastasis.

Biological sciences/Cancer/Lung cancer

Health sciences/Oncology/Surgical oncology

esophageal cancer

distant metastasis

primary-tumor resection

prognosis

SEER

Esophageal cancer(EC), the ninth most common malignancy, is the sixth leading cause, globally, of malignant tumor deaths (1, 2). Due to lack of consistent and effective early screening algorithms, most esophageal cancer patients were diagnosed at local advanced stage and some of them were even diagnosed with distant metastases (3). For patients with distant metastases, treatment were usually limited to systemic chemotherapy or best supportive care according to patients’ performance status. And local therapies such as radiation or palliative resection of primary tumor could be considered to improve quality of life or reduce the esophageal cancer relative symptoms such as obstruction or bleeding for metastatic esophageal cancer patients (4–6).

However, it was reported that metastatic esophageal cancer patients who underwent palliative esophagectomy had a better survival than those without esophagectomy (7). But after esophagectomy, distant metastatic recurrence frequently occurs (8). Consequently, whether primary-tumor resection improves the prognosis of metastatic esophageal cancer patient remains controversial.

The aim of this present study is to assess the survival effect of primary-tumor resection in TECDM patients.

Baseline characteristics

In the present study, total 9680 thoracic esophageal cancer patients with distant metastasis, diagnosed with histologically confirmation, between 2010 and 2020 were collected from the SEER database. Under the inclusion criteria and exclusion criteria, 7733 patients were included in our study (Fig. 1). Of those patients, 121 patients underwent primary-tumor resection whereas 7612 patients did not. The baseline clinical and pathological characteristics of the included patients are showed in Supplementary Table 1. To balance the possible covariates such as diagnosis year, age, gender, race, marital status at diagnosis, median household income, differentiation of tumor, T stage of tumor, N stage of tumor, histologically type, location of tumor, size of tumor, chemotherapy, radiotherapy between primary-tumor resection group and no-surgery group, a 1:1 Propensity Score Matched(PSM) analysis was performed. After PSM, the clinical and pathological characteristics is well-balanced in the matched cohort (Supplementary Table 1).

Survival outcomes of primary-tumor resection before PSM

Kaplan-Meier analysis were performed to evaluate overall survival (OS) and cancer-specific survival (CSS) of TECDM patients with primary-tumor resection(PTR) before PSM, and the log-rank test was used to compare any survival differences between the two groups. The results showed that TECDM patients with PTR had a significantly better median OS( p < 0.001, Fig. 2A) and CSS(p < 0.001, Fig. 2B) than TECDM patients without PTR. The median OS of TECDM patients with PTR were 11.0 months (95% CI, 9 months to13 months) and of TECDM patients without PTR were 4 months (95% CI, 4 months to 5 months). And the median CSS of those TECDM patients underwent PTR and of those TECDM patients without PTR was 9.0 months (95% CI, 7 months to 11 months) and 4 months (95% CI, 4 months to 4 months), respectively. In addition, Cox proportional hazards regression model was used to identify independent prognostic factors for CSS and OS in overall cohort. Multivariate Cox model analysis in the overall cohort showed that PTR, diagnosis year, age, race, marital status at diagnosis, median household income, differentiation of tumor, T stage of tumor, N stage of tumor, histologically type, location of tumor, size of tumor, chemotherapy, radiotherapy were independent prognostic factors for CSS in TECDM patients(Supplementary Table 2). Multivariate Cox model analysis revealed that PTR, age, marital status at diagnosis, median household income, differentiation of tumor, T stage, histologically type, tumor size, chemotherapy, radiotherapy were independent prognostic factors for OS in TECDM patients(Supplementary Table 2). Interestingly, PTR was a protective factor of OS in TECDM patients (HR:0.5529; 95% CI, 0.4537 to 0.6738, P < 0.001).

Survival outcomes of primary-tumor resection after PSM

In the PSM cohort, TECDM patients with PTR also had a significantly better median OS (p < 0.001, Fig. 2C) and CSS(p < 0.001, Fig. 2D) than TECDM patients without PTR. After PMS, the median OS of those TECDM patients underwent PTR and of those TECDM patients without PTR was 11.0 months (95% CI, 9 months to 13 months) and 7 months (95% CI, 5 months to 9 months), respectively. And the median CSS of those TECDM patients underwent PTR and of those TECDM patients without PTR was 9.0 months (95% CI, 7 months to 11 months) and 6 months (95% CI, 4 months to 9 months), respectively. Furthermore, Cox proportional hazards model was performed to confirm the prognostic significance of PTR in patients with thoracic esophageal cancer with distant metastasis. Furthermore, multivariate Cox analysis in the matched cohort showed that PTR was independent protective factors for OS (Fig. 3) and CSS in TECDM.

Subgroup analysis of survival outcomes of primary-tumor resection

Multivariate Cox model analysis revealed that PTR, age, median household income, differentiation of tumor, T stage of tumor, histologically type, size of tumor, chemotherapy, radiotherapy were independent prognostic factors for OS in TECDM patients. Next, subgroup analysis was performed to further explore the impact of PTR on OS in TECDM patients. In the age subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in year < 65 and year > 65 subgroups(P < 0.001, Fig. 4A); In median household income subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in income > 60 000 and income < 60 000 subgroups( P < 0.001, Fig. 4B); In differentiation of tumor subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in GradeⅠ-Ⅱ and GradeⅢ-Ⅳ subgroups( P < 0.001, Fig. 4C); In T stage of tumor subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in T1-T2 and T3-T4 subgroups( P < 0.001, Fig. 4D); In histologically type subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in Squamous and Adenocarcinoma subgroups( P < 0.001, Fig. 4E); Also, in size of tumor subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in tumor size > 5mm and < 5mm subgroups( P < 0.001, Fig. 4F).

Similarly, subgroup analysis was performed to further explore the impact of other treatments on OS and CSS in TECDM patients. In chemotherapy subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in chemotherapy and no-chemotherapy subgroups( P < 0.001, Fig. 5A; P < 0.001, Fig. 5B); Besides, in radiotherapy subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR in radiotherapy and no-radiotherapy subgroups( P < 0.001, Fig. 5C; P < 0.001, Fig. 5D).

Thoracic esophageal cancer with distant metastasis(TECDM), as one of the severe fatal disease, is considered as an advanced esophageal cancer with poor long-term prognosis (9). Neoadjuvant chemotherapy with or without radiotherapy followed by esophageal surgery is the cornerstone of locally advanced esophageal cancer treatment (10, 11). But thoracic esophageal cancer with distant metastasis was unsuitable for primary tumor resection and recommended treatment for TECDM is systematic therapies (9). According to NCCN Clinical Practice Guideline, systemic therapy regimens were recommended for metastatic thoracic esophageal cancer. And with aim of relieving symptom and improving in quality of life, palliative supportive care in metastatic thoracic esophageal cancers is encouraged (12). Similarly, the European Society for Medical Oncology (ESMO) Clinical Practice Guideline does not consider surgery as a treatment option for thoracic esophageal cancer patients with distant metastasis. And the recommended treatment is palliative chemotherapy (13). Besides, the ESMO Clinical Practice Guidelines state that patients with metastatic esophageal cancer may be considered for different palliative care options such as external radiotherapy, gastrostomy, jejunostomy and metal stent insertion based on their clinical situation (14).

However, considering the benefits of primary-tumor surgery for patients with colorectal cancer and liver metastases, an increasing number of surgeons are focusing on the role of primary tumor surgery in metastatic cancer patients (15, 16). For metastatic esophageal cancer, a retrospective study have shown that primary-tumor surgery significantly improve survival in patients with TECDM (17). But limited by small samples and single center data, the survival benefit of primary- tumor surgery to thoracic esophageal cancer patients with distant metastases need to be further confirmed. In a word, primary-tumor resection in metastatic esophageal cancer remains controversial and debated.

In our present study, total 121 patients from multiple centers in USA underwent esophageal primary tumor resection. As a result, primary-tumor resection, an independent prognostic factor, improves overall survival and cancer-specific survival of the thoracic esophageal cancer patients with distant metastasis. First of all, using the SEER data of demographics and survival information, the study showed that great improvements of OS and CSS for TECDM patients with primary-tumor resection in overall cohort. What is more, after Propensity Score Matching, aiming to balance the possible covariates between PTR group and no-PTR group, PTR improves overall survival and cancer-specific survival of the thoracic esophageal cancer patients with distant metastasis in PSM cohort. And multivariate Cox model analysis revealed that PTR, age, median household income, differentiation of tumor, T stage of tumor, histologically type, size of tumor, chemotherapy, radiotherapy were independent prognostic factors for OS in TECDM patients. Last but not the least, in all subgroups, the median OS and median CSS of TECDM patients with primary-tumor resection was better than the patients without PTR.

The results align with previous retrospective studies in other metastatic gastric, ovarian, kidney and neuroendocrine tumors, primary- tumor resection can lead to the better survival (18–22). We used propensity score matched (PSM) analysis to reduce the possible influence of some potential covariates, between primary-tumor resection group and no-surgery group, that might distort the real relation of primary-tumor resection with CSS and OS. In other words, our study minimized the selection bias of patients to receive PTR. Besides, the present studies focused specifically on metastatic thoracic esophageal cancer patients that are more suitable for surgical resection than other sites.

Why primary-tumor surgery is able to prolong the survival of tumor patients with metastasis remains unclear. It was reported that one possible mechanism that primary-tumor resection decreased circulating tumor cells of the blood contributing to distant metastases (23, 24). Besides, primary-tumor resection might recover the immune system to prolong the survival of patients with metastatic tumor (25–27). Hence, in the present study, primary-tumor resection might improve overall survival and cancer-specific survival of the thoracic esophageal cancer patients with distant metastasis by decreasing circulating tumor cells of the blood and restoring the function of immune system.

However, some opponents consider that primary-tumor resection might accelerate metastasis, which is related to the angiogenesis and growth of metastases after primary tumor resection (28). Additionally, primary-tumor resection for patients with metastatic esophageal cancer does not significantly improve five-year survival, but increase preoperative or postoperative complications and thus delay systemic therapy (29). Besides, primary-tumor resection increases medical costs and might lead to low quality of life after surgery (30). Consequently, the multidisciplinary team should assess whether thoracic esophageal cancer patients with distant metastasis are suitable for resection of primary tumor.

There are also some limitations in the present study. First of all, the present study, as a retrospective research, has its natural limitation of selection bias. Consequently, propensity score matched (PSM) was used to reduce the possible confounding bias between the PTR group and no-PTR group, making our conclusions more reliable. What is more, due to limitation of incomplete information from SEER database, some information such as performance status is unreported. Therefore, well-designed randomized control trials should be performed to verify our findings.

In conclusion, the retrospective study showed that primary-tumor resection is associated with good overall survival and cancer-specific survival in thoracic esophageal cancer patients with distant metastasis.

Data source and patients selection

The SEER*Stat software (version 8.4.3) was used to download detailed information including patient demographics and survival information. All thoracic esophageal cancer patients with distant metastasis(TECDM) at diagnosis between the years 2010 and 2020 were identified(Fig. 1). Firstly, thoracic esophageal cancer patients with distant metastasis were retrieved using the Primary Site - labeled value{Site - labeled = 'C15.1-Thoracic esophagus', 'C15.3-Upper third of esophagus', 'C15.4-Middle third of esophagus', 'C15.5-Lower third of esophagus', 'C15.8-Overlapping lesion of esophagus'}. Secondly, TECDM with microscopically diagnosed at diagnosis between the years 2010 and 2020 were selected. The inclusion criteria were as follows: (1) diagnosed with esophageal cancer only; (2)confirmed distant metastases; (3) diagnosed with histologically confirmation; (4) treatment information of primary tumor was known. The exclusion criteria were as follows: (1) patients diagnosed with over one primary tumor; (2) treatment information of primary tumor was unknown. Thirdly, demographics and survival information was collected as followed: (1)diagnosis year; (2)age; (3)gender; (4)race record; (5)marital status at diagnosis; (6) median household income; (7) residence record; (8)PRCDA record; (9) reporting source; (10) differentiation of tumor; (11) T stage; (12)N stage; (13) histologically type; (14)tumor location; (15)tumor size (16)Chemotherapy; (17) Radiotherapy; (19) resection of primary tumor; (19) survival months; (20)Vital status record.

Propensity Score Matched (PSM)

Propensity score matched (PSM) was used to reduce the possible influence of potential covariates between primary-tumor resection group and no-surgery group. With the nearest neighbor matched method of setting caliper value 0.1, included patients were matched 1:1 into primary-tumor resection and no-surgery group. In the present study, the covariates used for PSM were as follows: diagnosis yea, age record, gender, race record, marital status at diagnosis, median household income, differentiation of tumor, T stage of tumor, N stage of tumor, histologically type, location of tumor, size of tumor, Chemotherapy, Radiotherapy.

Statistical Analysis

The chi-square test was performed to compare categorical variables in the present study with the aims of revealing any differences of clinical and pathological characteristics between the primary-tumor resection group and no-surgery group. Kaplan-Meier analysis was performed to evaluate overall survival (OS) and cancer-specific survival (CSS) of TECDM patients with primary tumor resection(PTR) before and after PSM, and the log-rank test was used to compare any survival differences between the primary-tumor resection group and no-surgery group. Cox proportional hazards regression model was used to identify independent prognostic factors for CSS and OS in our study. Variables with P < 0.05 in the univariate Cox model were further put into the multivariate Cox model analysis. All statistical analyses in the present study were performed using R software(version 4.3.1 ), and a two sided P value less than 0.05 was considered statistical significance.

Ethics Statement

Approval of the study was given by the Ethics Committee of the Sixth Affiliated Hospital of Sun Yat-sen University(2023ZSLYEC-342). This study strictly complied with the Declaration of Helsinki, and all data in the present study was obtained from the SEER database with no need for informed patient consent.

Conflicts of Interest:

All authors declare no conflict of interest.

Data Sharing Statement
The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

Funding statement:

This work was supported by National Key Clinical Discipline & the National Natural Science Foundation of China [grant number 82102955] & No.2: the Guangzhou Basic Research Project [grant number 202201011326].

Author Contribution

JY W, XY Q , GF W and HS z wrote the main manuscript text; F Q, Z L, BZ J, YZ Z, JG C and HY L prepared figures 1-5. All authors reviewed the manuscript.

Data Availability

The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

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You are reading this latest preprint version

Improved Survival of Primary-Tumor Resection in Metastatic Thoracic Esophageal Cancer: A Population-Based, Propensity Score Matched Study

Status:

Version 1

Abstract

Figures

Introduction

Results

Baseline characteristics

Survival outcomes of primary-tumor resection before PSM

Survival outcomes of primary-tumor resection after PSM

Subgroup analysis of survival outcomes of primary-tumor resection

Discussion

Conclusions

Material and Methods

Data source and patients selection

Propensity Score Matched (PSM)

Statistical Analysis

Ethics Statement

Declarations

Conflicts of Interest:

Data Sharing Statement
The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

Funding statement:

Author Contribution

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1

Improved Survival of Primary-Tumor Resection in Metastatic Thoracic Esophageal Cancer: A Population-Based, Propensity Score Matched Study

Status:

Version 1

Abstract

Figures

Introduction

Results

Baseline characteristics

Survival outcomes of primary-tumor resection before PSM

Survival outcomes of primary-tumor resection after PSM

Subgroup analysis of survival outcomes of primary-tumor resection

Discussion

Conclusions

Material and Methods

Data source and patients selection

Propensity Score Matched (PSM)

Statistical Analysis

Ethics Statement

Declarations

Conflicts of Interest:

Data Sharing Statement The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.

Funding statement:

Author Contribution

Data Availability

References

Additional Declarations

Supplementary Files

Status:

Version 1

Data Sharing Statement
The datasets generated during and analysed during the current study are available from the corresponding author on reasonable request.