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Validity of Using Pathological Response as a Surrogate for Overall Survival in Neoadjuvant Studies for Esophageal Cancer: A Systematic Review and Meta-analysis

  • Thoracic Oncology
  • Published:
Annals of Surgical Oncology Aims and scope Submit manuscript

Abstract

Background

Pathological response is a critical factor in predicting long-term survival of patients with esophageal cancer after preoperative therapy. However, the validity of using pathological response as a surrogate for overall survival (OS) for esophageal cancer has not yet been established. In this study, a literature-based meta-analysis was conducted to evaluate pathological response as a proxy endpoint for survival in esophageal cancer.

Methods

Three databases were systematically searched to identify relevant studies investigating neoadjuvant treatment for esophageal cancer. The correlation between pathological complete response (pCR) and OS were assessed using a weighted multiple regression analysis at the trial level, and the coefficient of determination (R2) was calculated. The research design and histological subtypes were considered in the performance of subgroup analysis.

Results

In this meta-analysis, a total of 40 trials, comprising 43 comparisons and 55,344 patients were qualified. The surrogacy between pCR and OS was moderate (R2 = 0.238 in direct comparison, R2 = 0.500 for pCR reciprocals, R2 = 0.541 in log settings). pCR could not serve as an ideal surrogate endpoint in randomized controlled trials (RCTs) (R2 = 0.511 in direct comparison, R2 = 0.460 for pCR reciprocals, R2 = 0.523 in log settings). A strong correlation was observed in studies comparing neoadjuvant chemoradiotherapy and neoadjuvant chemotherapy (R2 = 0.595 in direct comparison, R2 = 0.840 for pCR reciprocals, R2 = 0.800 in log settings).

Conclusions

A lack of surrogacy of pathological response for long-term survival at trial level is established in this study. Hence, caution should be exercised when using pCR as the primary endpoint in neoadjuvant studies for esophageal cancer.

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Data availability

All data generated or analyzed during this study are included in this published article and its supplementary information files. The data are available online, and additional materials are available by contacting with authors.

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Acknowledgement

This work is supported by the National Natural Science Foundation of China (81400681), China Postdoctoral Science Foundation Grant (2018M631394), and Science and Technology Innovation Plan of Shanghai Science and Technology Commission (22Y11907200). The funding agencies had no role in study design, collection and analyses of data, decision to publish, or manuscript preparation.

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  1. Feng Su and **nyu Yang contributed equally to the manuscript.

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  1. Department of Thoracic Surgery, Zhongshan Hospital, Fudan University, 180 Fenglin Road, Shanghai, China

    Feng Su MD, **nyu Yang MD, Jun Yin MD, Yaxing Shen MD & Lijie Tan MD, FACS

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Contributions

FS and XY searched the databases, and extracted and analyzed the data. JY, FS and XY screened and selected the qualified literatures. YS and LT designed and conceived the study. FS, and YS formulated the manuscript. All authors read and approved the final manuscript.

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Supplementary Figure 1. Risk of bias assessment for included results (PNG 46 kb)

10434_2023_13778_MOESM3_ESM.png

Supplementary Figure 2. Correlations between effects of esophageal cancer treatment on event free survival (EFS) and overall survival (OS) and reverse pathological response in the main analysis. Each circle represents a trial, and the surface area of the circle is proportional to the number of events observed in the corresponding trial. (A) OS and reciprocals of complete pathological response (rpCR) in main analysis; (B) OS and rpCR in prospective studies; (C) OS and rpCR in retrospective studies; (D) OS and rpCR in adenocarcinoma; (E) OS and rpCR in squamous cell carcinoma; (F) OS and reciprocals of major pathological response (rmPR) in main analysis; (G) EFS and rmPR in main analysis Solid lines represent weighted regression lines and dotted lines represent the 95% prediction interval. (PNG 59 kb)

10434_2023_13778_MOESM4_ESM.png

Supplementary Figure 3. Correlations between effects of esophageal cancer treatment on event free survival (EFS) and overall survival (OS) and major pathological response (mPR) in the main analysis. Each circle represents a trial, and the surface area of the circle is proportional to the number of events observed in the corresponding trial. Solid lines represent weighted regression lines and dotted lines represent the 95% prediction interval. (PNG 60 kb)

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Su, F., Yang, X., Yin, J. et al. Validity of Using Pathological Response as a Surrogate for Overall Survival in Neoadjuvant Studies for Esophageal Cancer: A Systematic Review and Meta-analysis. Ann Surg Oncol 30, 7461–7471 (2023). https://doi.org/10.1245/s10434-023-13778-9

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