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. 2023 Oct 1;41(28):4535-4547.
doi: 10.1200/JCO.22.02279. Epub 2023 Jul 12.

Individual Participant Data Network Meta-Analysis of Neoadjuvant Chemotherapy or Chemoradiotherapy in Esophageal or Gastroesophageal Junction Carcinoma

Matthieu Faron  1 , Maurice Cheugoua-Zanetsie  1 , Jayne Tierney  2 , Pierre Thirion  3 , Matthew Nankivell  2 , Kathryn Winter  4 , Hong Yang  5 , Joel Shapiro  6 , Dewi Vernerey  7 , B Mark Smithers  8 , Thomas Walsh  9 , Guillaume Piessen  10 , Magnus Nilsson  11   12 , Jurjen Boonstra  13 , Marc Ychou  14 , Simon Law  15 , David Cunningham  16 , Florent de Vathaire  1 , Michael Stahl  17 , Susan Urba  18 , Michele Valmasoni  19 , Danièle Williaume  20 , Janine Thomas  21 , Florian Lordick  22 , Joel Tepper  23 , Jack Roth  24 , Val Gebski  25 , Bryan Burmeister  21 , Xavier Paoletti  26 , Johanna van Sandick  27 , Jianhua Fu  5 , Jean-Pierre Pignon  1 , Michel Ducreux  28 , Stefan Michiels  1 ; MANATEC-02 Collaborative Group
Affiliations

Individual Participant Data Network Meta-Analysis of Neoadjuvant Chemotherapy or Chemoradiotherapy in Esophageal or Gastroesophageal Junction Carcinoma

Matthieu Faron et al. J Clin Oncol. .

Abstract

Purpose: The optimal neoadjuvant treatment for resectable carcinoma of the thoracic esophagus (TE) or gastroesophageal junction (GEJ) remains a matter of debate. We performed an individual participant data (IPD) network meta-analysis (NMA) of randomized controlled trials (RCTs) to study the effect of chemotherapy or chemoradiotherapy, with a focus on tumor location and histology subgroups.

Patients and methods: All, published or unpublished, RCTs closed to accrual before December 31, 2015 and having compared at least two of the following strategies were eligible: upfront surgery (S), chemotherapy followed by surgery (CS), and chemoradiotherapy followed by surgery (CRS). All analyses were conducted on IPD obtained from investigators. The primary end point was overall survival (OS). The IPD-NMA was analyzed by a one-step mixed-effect Cox model adjusted for age, sex, tumor location, and histology. The NMA was registered in PROSPERO (CRD42018107158).

Results: IPD were obtained for 26 of 35 RCTs (4,985 of 5,807 patients) corresponding to 12 comparisons for CS-S, 12 for CRS-S, and four for CRS-CS. CS and CRS led to increased OS when compared with S with hazard ratio (HR) = 0.86 (0.75 to 0.99), P = .03 and HR = 0.77 (0.68 to 0.87), P < .001 respectively. The NMA comparison of CRS versus CS for OS gave a HR of 0.90 (0.74 to 1.09), P = .27 (consistency P = .26, heterogeneity P = .0038). For CS versus S, a larger effect on OS was observed for GEJ versus TE tumors (P = .036). For the CRS versus S and CRS versus CS, a larger effect on OS was observed for women (P = .003, .012, respectively).

Conclusion: Neoadjuvant chemotherapy and chemoradiotherapy were consistently better than S alone across histology, but with some variation in the magnitude of treatment effect by sex for CRS and tumor location for CS. A strong OS difference between CS and CRS was not identified.

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Conflict of interest statement

The following represents disclosure information provided by authors of this manuscript. All relationships are considered compensated unless otherwise noted. Relationships are self-held unless noted. I = Immediate Family Member, Inst = My Institution. Relationships may not relate to the subject matter of this manuscript. For more information about ASCO's conflict of interest policy, please refer to www.asco.org/rwc or ascopubs.org/jco/authors/author-center.

Open Payments is a public database containing information reported by companies about payments made to US-licensed physicians (Open Payments).

Matthieu Faron

Travel, Accommodations, Expenses: Vifor Pharma, PharmaMar, Ipsen

Pierre Thirion

Honoraria: Janssen

Dewi Vernerey

Consulting or Advisory Role: OSE Immunotherapeutics, Janssen-Cilag, HalioDx, Pfizer, CellProthera, GERCOR, INCYTE, Fondazione Smith Kline, INVECTYS, AC BioScience, Veracyte

Travel, Accommodations, Expenses: MSD

Guillaume Piessen

Consulting or Advisory Role: Bristol Myers Squibb, Nestle Health Science, MSD Oncology, Astellas Pharma

Travel, Accommodations, Expenses: Medtronic

Uncompensated Relationships: Medtronic

Magnus Nilsson

Travel, Accommodations, Expenses: Medtronic

Marc Ychou

Honoraria: Bayer

David Cunningham

Stock and Other Ownership Interests: OVIBIO

Consulting or Advisory Role: OVIBIO

Research Funding: MedImmune (Inst), Bayer (Inst), 4SC (Inst), Clovis Oncology (Inst), Lilly (Inst), Roche (Inst), Leap Oncology (Inst)

Michael Stahl

Honoraria: Bristol Myers Squibb/Medarex, MSD Oncology, Novartis/Pfizer, Roche/Genentech

Consulting or Advisory Role: BMS GmbH & Co KG, MSD Oncology, Lilly/ImClone

Florian Lordick

Honoraria: Lilly, Merck Sharp & Dohme, Bristol Myers Squibb, AstraZeneca, Elsevier, BioNTech, SERVIER, Merck KGaA, Roche, Medscape, Incyte, Art Tempi, Medupdate, Streamed Up!, Daiichi Sankyo Europe GmbH, Novartis, Falk Foundation

Consulting or Advisory Role: Merck Sharp & Dohme, Bristol Myers Squibb, Astellas Pharma, Zymeworks, Amgen, Daichi Sankyo, Novartis

Research Funding: Bristol Myers Squibb (Inst), MSD (Inst)

Travel, Accommodations, Expenses: Bristol Myers Squibb, Lilly

Joel Tepper

Consulting or Advisory Role: EMD Serono

Other Relationship: Elsevier

Jack Roth

Stock and Other Ownership Interests: Genprex

Consulting or Advisory Role: Genprex

Research Funding: Genprex, Varian Medical Systems

Patents, Royalties, Other Intellectual Property: Patents licensed by Genprex

Bryan Burmeister

Employment: GenesisCare Oncology

Research Funding: Regeneron (Inst)

Travel, Accommodations, Expenses: GenesisCare Oncology

Xavier Paoletti

Honoraria: MSD Oncology

Consulting or Advisory Role: MSD Oncology, Daiichi Sankyo

Speakers' Bureau: Ipsen

Michel Ducreux

Employment: Sandoz

Honoraria: Bayer, TERUMO, Pierre Fabre, Roche/Genentech

Consulting or Advisory Role: Roche, Merck Serono, Servier, Amgen, Novartis, Ipsen, Lilly, Pierre Fabre, HalioDx, Daiichi Sankyo/Astra Zeneca, AstraZeneca, Basilea, Bayer, GlaxoSmithKline, MSD, Rafael Pharmaceuticals, Sotio, Zymeworks

Speakers' Bureau: Roche, Merck KGaA, Bayer, SERVIER, Amgen, Pierre Fabre, AstraZeneca, HalioDx, GlaxoSmithKline, Lilly, MSD

Research Funding: Roche (Inst), Keocyt (Inst)

Travel, Accommodations, Expenses: Roche, Merck Serono, Bayer, Pierre Fabre, SERVIER

Stefan Michiels

Consulting or Advisory Role: Sensorion, Biophytis, SERVIER, Yuhan, Roche, Kedrion Biopharma, IQVIA

No other potential conflicts of interest were reported.

Figures

FIG 1.
FIG 1.
PRISMA flowchart. aOne trial with 2 × 2 factorial design contributing to the three comparisons. CRS, chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; IPD, individual participant data; S, surgery.
FIG 2.
FIG 2.
MANATEC-02 network. The numbers above the arrows describe the comparison. The first numbers correspond to the number of trials (or contrasts for multiarm trials) for each comparison, and the second between parentheses to the number of patients. The direction of the arrow indicates the arbitrary-chosen direction of the hazard ratio. One multiarm trial (Scandinavia) provided two estimates (contrasts) for CS-S, one from CRS-RS and one from CS-S, and therefore, the numbers above the arrows can sum up to more than the number within the circles that gives the number of patients randomly assigned to receive the corresponding treatment. CRS, chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; RS, radiotherapy followed by surgery; S, surgery.
FIG 3.
FIG 3.
Kaplan-Meier estimated overall survival in the trials comparing S with CS (left), CRS with S (middle), and CRS with CS (right). The shaded area corresponds to the 95% CI. Absolute benefits are differences in overall survival rates at 5 years. CRS, chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; OS, overall survival; S, surgery.
FIG 4.
FIG 4.
Forest plot of the treatment effect on overall survival according to prespecified subgroups for (A) CS-S, (B) CRS-S, and (C) CRS-CS comparison. Number of patients (n) and number of events (event) are those from the complete case population of the direct comparisons, whereas HR and P values are from the full adjusted models. AC, adenocarcinoma; CRS, chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; GEJ, gastroesophageal junction; HR, hazard ratio; S, surgery; SCC, squamous cell carcinoma; TE, thoracic esophagus.
FIG 5.
FIG 5.
Forest plot of the treatment effect on disease-free survival according to prespecified subgroups for (A) CS-S, (B) CRS-S, and (C) CRS-CS comparison. Number of patients (n) and number of events (event) are those from the complete case population of the direct comparisons, whereas HR and P values are from the full adjusted models. AC, adenocarcinoma; CRS, chemoradiotherapy followed by surgery; CS, chemotherapy followed by surgery; GEJ, gastroesophageal junction; HR, hazard ratio; S, surgery; SCC, squamous cell carcinoma; TE, thoracic esophagus.
See this image and copyright information in PMC

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