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



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.



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).



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.
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Elizabeth C
EC
Smyth
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Matteo
M
Fassan
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
David
D
Cunningham
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
William H
WH
Allum
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Alicia F C
AF
Okines
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Andrea
A
Lampis
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Jens C
JC
Hahne
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Massimo
M
Rugge
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Clare
C
Peckitt
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Matthew
M
Nankivell
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Ruth
R
Langley
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Michele
M
Ghidini
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Chiara
C
Braconi
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Andrew
A
Wotherspoon
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands.
Heike I
HI
Grabsch
Elizabeth C. Smyth, David Cunningham, William H. Allum, Alicia F.C. Okines, Clare Peckitt, Chiara Braconi, Andrew Wotherspoon, and Nicola Valeri, Royal Marsden Hospital; Andrea Lampis, Jens C. Hahne, Michele Ghidini, Chiara Braconi, and Nicola Valeri, The Institute of Cancer Research, London and Sutton; Matthew Nankivell and Ruth Langley, Medical Research Council Clinical Trials Unit at UCL, London; Heike I. Grabsch, University of Leeds, Leeds, United Kingdom; Matteo Fassan and Massimo Rugge, University of Padua, Padua, Italy; and Heike I. Grabsch, Maastricht University Medical Center, Maastricht, the Netherlands. nicola.valeri@icr.ac.uk.
Nicola
N
Valeri
D000230:Adenocarcinoma / Q000188:drug therapy* / Q000235:genetics / Q000556:secondary* / Q000601:surgery; D000368:Aged; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D017024:Chemotherapy, Adjuvant; D002945:Cisplatin / Q000008:administration & dosage; D058534:Class I Phosphatidylinositol 3-Kinases; D015251:Epirubicin / Q000008:administration & dosage; D004938:Esophageal Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D005260:Female; D005472:Fluorouracil / Q000008:administration & dosage; D006801:Humans; D008197:Lymph Node Excision; D008198:Lymph Nodes / Q000473:pathology*; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D020360:Neoadjuvant Therapy; D051059:PTEN Phosphohydrolase / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D048493:Proto-Oncogene Proteins B-raf / Q000235:genetics; D016283:Proto-Oncogene Proteins p21(ras) / Q000235:genetics; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000235:genetics; D013274:Stomach Neoplasms / Q000188:drug therapy* / Q000235:genetics / Q000473:pathology* / Q000601:surgery; D015996:Survival Rate; D016159:Tumor Suppressor Protein p53 / Q000235:genetics
D002945:Cisplatin; D058534:Class I Phosphatidylinositol 3-Kinases; D015251:Epirubicin; D005472:Fluorouracil; D051059:PTEN Phosphohydrolase; D019869:Phosphatidylinositol 3-Kinases; D048493:Proto-Oncogene Proteins B-raf; D016283:Proto-Oncogene Proteins p21(ras); D018719:Erb-b2 Receptor Tyrosine Kinases; D016159:Tumor Suppressor Protein p53; C117307:KRAS protein, human; C484760:PIK3CA protein, human; C508053:ERBB2 protein, human; C482119:BRAF protein, human; C494929:PTEN protein, human