Abstract

Neoadjuvant chemotherapy with cisplatin + 5-fluorouracil followed by radical surgery is the standard treatment for stage II and III esophageal cancers. Although, a more potent regimen comprising cisplatin + 5-fluorouracil with docetaxel, has shown superiority in overall survival compared to the cisplatin + 5-fluorouracil regimen, it involves worsening of Grade 3 or higher adverse events due to docetaxel. Based on these reports, this study aimed to construct a prognostic system for cisplatin + 5-fluorouracil regimens, particularly for locally advanced cancers, to guide selection of neoadjuvant chemotherapy. Biopsy specimens from 82 patients who underwent a cisplatin + 5-fluorouracil regimen plus radical surgery at Saitama Medical University International Medical Center between May 2012 and June 2020 were analyzed. Variants in 56 autophagy- and esophageal cancer-related genes were identified using targeted enrichment sequencing. Overall, 13 single nucleotide variants, including eight non-synonymous group single nucleotide variants predicting recurrence were identified using Fisher’s exact test with recurrence as a two-group event, which showed a significant difference (p < 0.05). Additionally, machine learning was used to predict recurrence using 21 features, including eight patient backgrounds. The results showed that the Naive Bayes was highly reliable with an accuracy of 0.88 and Area Under the Curve of 0.9. Thus, we constructed a machine learning model to predict recurrence in patients with esophageal cancer treated with a cisplatin + 5-fluorouracil regimen. We believe that our results will provide useful guidance for the selection of neoadjuvant adjuvant chemotherapy, including the avoidance of docetaxel.

Competing Interest Statement

The authors have declared no competing interest.

Funding Statement

Funding Information This work was supported by the Hidaka Project (4-D-1-04) and Takeda Science Foundation (MH). MH is the recipient of a grant from the Japan Society for the Promotion of Science (JSPS) KAKENHI (grant number: 21K06825).

Author Declarations

I confirm all relevant ethical guidelines have been followed, and any necessary IRB and/or ethics committee approvals have been obtained.

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The details of the IRB/oversight body that provided approval or exemption for the research described are given below:

Ethics Statement - Approval of the research protocol by an Institutional Reviewer Board. This study adhered to the ethical standards of the Declaration of Helsinki and its subsequent amendments. This study was approved by the Institutional Review Board of the Saitama Medical University International Medical Center (2022-113 and 2024-055). - Informed Consent. The requirement for informed consent was waived by the Institutional Review Board of Saitama Medical University International Medical Center in view of the retrospective nature of this study. - Registry and the Registration No. of the study/trial. N/A. - Animal Studies. N/A.

I confirm that all necessary patient/participant consent has been obtained and the appropriate institutional forms have been archived, and that any patient/participant/sample identifiers included were not known to anyone (e.g., hospital staff, patients or participants themselves) outside the research group so cannot be used to identify individuals.

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I understand that all clinical trials and any other prospective interventional studies must be registered with an ICMJE-approved registry, such as ClinicalTrials.gov. I confirm that any such study reported in the manuscript has been registered and the trial registration ID is provided (note: if posting a prospective study registered retrospectively, please provide a statement in the trial ID field explaining why the study was not registered in advance).

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I have followed all appropriate research reporting guidelines, such as any relevant EQUATOR Network research reporting checklist(s) and other pertinent material, if applicable.

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Data Availability

Availability of data and materials The data are not publicly available because of privacy and ethical restrictions. Access to the data and calculation methods can be obtained from the corresponding author upon request via email (hirasaki@saitama-med.ac.jp).

AbbreviationsCFcisplatin + 5-fluorouracilDCFdocetaxel + CFOSoverall survivalRNA-seqRNA sequencingSNVsingle nucleotide variantAUCarea under the curveROCReceiver Operating CharacteristicCILchemotherapy-induced leukopeniaRFSrecurrence-free survivalINDELsinsertions and deletionsESCCesophageal squamous cell carcinoma