Effect of Pathologic Tumor Response and Nodal Status on Survival in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy Trial

Elizabeth C Smyth, Matteo Fassan, David Cunningham, William H Allum, Alicia F C Okines, Andrea Lampis, Jens C Hahne, Massimo Rugge, Clare Peckitt, Matthew Nankivell, Ruth Langley, Michele Ghidini, Chiara Braconi, Andrew Wotherspoon, Heike I Grabsch, Nicola Valeri, Elizabeth C Smyth, Matteo Fassan, David Cunningham, William H Allum, Alicia F C Okines, Andrea Lampis, Jens C Hahne, Massimo Rugge, Clare Peckitt, Matthew Nankivell, Ruth Langley, Michele Ghidini, Chiara Braconi, Andrew Wotherspoon, Heike I Grabsch, Nicola Valeri

Abstract

Purpose: The Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial established perioperative epirubicin, cisplatin, and fluorouracil chemotherapy as a standard of care for patients with resectable esophagogastric cancer. However, identification of patients at risk for relapse remains challenging. We evaluated whether pathologic response and lymph node status after neoadjuvant chemotherapy are prognostic in patients treated in the MAGIC trial.

Materials and methods: Pathologic regression was assessed in resection specimens by two independent pathologists using the Mandard tumor regression grading system (TRG). Differences in overall survival (OS) according to TRG were assessed using the Kaplan-Meier method and compared using the log-rank test. Univariate and multivariate analyses using the Cox proportional hazards method established the relationships among TRG, clinical-pathologic variables, and OS.

Results: Three hundred thirty resection specimens were analyzed. In chemotherapy-treated patients with a TRG of 1 or 2, median OS was not reached, whereas for patients with a TRG of 3, 4, or 5, median OS was 20.47 months. On univariate analysis, high TRG and lymph node metastases were negatively related to survival (Mandard TRG 3, 4, or 5: hazard ratio [HR], 1.94; 95% CI, 1.11 to 3.39; P = .0209; lymph node metastases: HR, 3.63; 95% CI, 1.88 to 7.0; P < .001). On multivariate analysis, only lymph node status was independently predictive of OS (HR, 3.36; 95% CI, 1.70 to 6.63; P < .001).

Conclusion: Lymph node metastases and not pathologic response to chemotherapy was the only independent predictor of survival after chemotherapy plus resection in the MAGIC trial. Prospective evaluation of whether omitting postoperative chemotherapy and/or switching to a noncross-resistant regimen in patients with lymph node-positive disease whose tumor did not respond to preoperative epirubicin, cisplatin, and fluorouracil may be appropriate.

Conflict of interest statement

Authors’ disclosures of potential conflicts of interest are found in the article online at www.jco.org. Author contributions are found at the end of this article.

© 2016 by American Society of Clinical Oncology.

Figures

Fig 1.
Fig 1.
CONSORT diagram summarizing the analysis of pathologic tumor regression grading in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. Tumor regression was assessed by two independent pathologists using the Mandard tumor regression grading system.
Fig 2.
Fig 2.
Tumor regression grade (TRG) and treatment in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. Proportion of patients in each treatment arm according to TRG category. Tumors from patients treated with neoadjuvant chemotherapy were significantly more likely to show substantial tumor regression (TRG 1 or 2) than were tumors from patients treated with surgery alone (P < .001).
Fig 3.
Fig 3.
Overall survival by tumor regression grade (TRG) in patients treated with chemotherapy plus surgery in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. Patients were dichotomized into two groups: TRG 1-2 responders and TRG 3-4-5 nonresponders. Differences in overall survival were assessed using the Kaplan-Meier method and compared using the log-rank test. A P value of < .05 was considered significant. HR, hazard ratio.
Fig 4.
Fig 4.
Overall survival by tumor regression grade (TRG) and lymph node status in patients treated with chemotherapy plus surgery in the Medical Research Council Adjuvant Gastric Infusional Chemotherapy (MAGIC) trial. Patients were stratified into four groups: ypN0 and TRG 1 or 2 (node-negative responders); ypN1+ TRG 1 or 2 (node-positive responders); ypN0 and TRG 3, 4, or 5 (node-negative nonresponders); and ypN1+ and TRG 3, 4, or 5 (node-positive nonresponders). Differences in overall survival were assessed using the Kaplan-Meier method and compared using the log-rank test. A P value of < .05 was considered significant. HR, hazard ratio.

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