Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab

a pooled analysis of five prospective trials

Chiara Cremolini, Massimo Milione, Federica Marmorino, Federica Morano, Gemma Zucchelli, Alessia Mennitto, Michele Prisciandaro, Sara Lonardi, Alessio Pellegrinelli, Daniele Rossini, Francesca Bergamo, Giuseppe Aprile, Lucio Urbani, Luca Morelli, Marta Schirripa, Giovanni Gerardo Cardellino, Matteo Fassan, Gabriella Fontanini, Filippo de Braud, Vincenzo Mazzaferro & 2 others Alfredo Falcone, Filippo Pietrantonio

Research output: Contribution to journalArticle

Abstract

BACKGROUND: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.

METHODS: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.

RESULTS: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).

CONCLUSIONS: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.

Original languageEnglish
Pages (from-to)955-965
Number of pages11
JournalBritish Journal of Cancer
Volume118
Issue number7
DOIs
Publication statusPublished - Apr 2018

Fingerprint

Liver Neoplasms
Colorectal Neoplasms
oxaliplatin
irinotecan
Neoplasm Metastasis
Growth
Survival
Recurrence
Leucovorin
Cetuximab
Bevacizumab
Fluorouracil
Necrosis
Clinical Trials
Weights and Measures
Drug Therapy
Neoplasms

Cite this

Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab : a pooled analysis of five prospective trials. / Cremolini, Chiara; Milione, Massimo; Marmorino, Federica; Morano, Federica; Zucchelli, Gemma; Mennitto, Alessia; Prisciandaro, Michele; Lonardi, Sara; Pellegrinelli, Alessio; Rossini, Daniele; Bergamo, Francesca; Aprile, Giuseppe; Urbani, Lucio; Morelli, Luca; Schirripa, Marta; Cardellino, Giovanni Gerardo; Fassan, Matteo; Fontanini, Gabriella; de Braud, Filippo; Mazzaferro, Vincenzo; Falcone, Alfredo; Pietrantonio, Filippo.

In: British Journal of Cancer, Vol. 118, No. 7, 04.2018, p. 955-965.

Research output: Contribution to journalArticle

Cremolini, C, Milione, M, Marmorino, F, Morano, F, Zucchelli, G, Mennitto, A, Prisciandaro, M, Lonardi, S, Pellegrinelli, A, Rossini, D, Bergamo, F, Aprile, G, Urbani, L, Morelli, L, Schirripa, M, Cardellino, GG, Fassan, M, Fontanini, G, de Braud, F, Mazzaferro, V, Falcone, A & Pietrantonio, F 2018, 'Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials', British Journal of Cancer, vol. 118, no. 7, pp. 955-965. https://doi.org/10.1038/s41416-018-0015-z
Cremolini, Chiara ; Milione, Massimo ; Marmorino, Federica ; Morano, Federica ; Zucchelli, Gemma ; Mennitto, Alessia ; Prisciandaro, Michele ; Lonardi, Sara ; Pellegrinelli, Alessio ; Rossini, Daniele ; Bergamo, Francesca ; Aprile, Giuseppe ; Urbani, Lucio ; Morelli, Luca ; Schirripa, Marta ; Cardellino, Giovanni Gerardo ; Fassan, Matteo ; Fontanini, Gabriella ; de Braud, Filippo ; Mazzaferro, Vincenzo ; Falcone, Alfredo ; Pietrantonio, Filippo. / Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab : a pooled analysis of five prospective trials. In: British Journal of Cancer. 2018 ; Vol. 118, No. 7. pp. 955-965.
@article{74be4e5a175640eba84ee77f09f6f3bc,
title = "Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab: a pooled analysis of five prospective trials",
abstract = "BACKGROUND: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.METHODS: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.RESULTS: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14{\%}, p = 0.013) and infarct-like necrosis (80 vs 64{\%}, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17{\%} in pushing and 22{\%} in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).CONCLUSIONS: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.",
author = "Chiara Cremolini and Massimo Milione and Federica Marmorino and Federica Morano and Gemma Zucchelli and Alessia Mennitto and Michele Prisciandaro and Sara Lonardi and Alessio Pellegrinelli and Daniele Rossini and Francesca Bergamo and Giuseppe Aprile and Lucio Urbani and Luca Morelli and Marta Schirripa and Cardellino, {Giovanni Gerardo} and Matteo Fassan and Gabriella Fontanini and {de Braud}, Filippo and Vincenzo Mazzaferro and Alfredo Falcone and Filippo Pietrantonio",
year = "2018",
month = "4",
doi = "10.1038/s41416-018-0015-z",
language = "English",
volume = "118",
pages = "955--965",
journal = "British Journal of Cancer",
issn = "0007-0920",
publisher = "Nature Publishing Group",
number = "7",

}

TY - JOUR

T1 - Differential histopathologic parameters in colorectal cancer liver metastases resected after triplets plus bevacizumab or cetuximab

T2 - a pooled analysis of five prospective trials

AU - Cremolini, Chiara

AU - Milione, Massimo

AU - Marmorino, Federica

AU - Morano, Federica

AU - Zucchelli, Gemma

AU - Mennitto, Alessia

AU - Prisciandaro, Michele

AU - Lonardi, Sara

AU - Pellegrinelli, Alessio

AU - Rossini, Daniele

AU - Bergamo, Francesca

AU - Aprile, Giuseppe

AU - Urbani, Lucio

AU - Morelli, Luca

AU - Schirripa, Marta

AU - Cardellino, Giovanni Gerardo

AU - Fassan, Matteo

AU - Fontanini, Gabriella

AU - de Braud, Filippo

AU - Mazzaferro, Vincenzo

AU - Falcone, Alfredo

AU - Pietrantonio, Filippo

PY - 2018/4

Y1 - 2018/4

N2 - BACKGROUND: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.METHODS: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.RESULTS: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).CONCLUSIONS: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.

AB - BACKGROUND: Many factors, including histopathologic parameters, seem to influence the prognosis of patients undergoing resection of colorectal cancer liver metastases (CRCLM), although their relative weight is unclear. Histopathologic growth patterns (HGPs) of CRCLM may affect sensitivity to antiangiogenics. We aimed at evaluating differences in histopathologic parameters of response according to the use of bevacizumab or cetuximab as first-line targeted agents, and at exploring the prognostic and predictive role of HGPs.METHODS: We performed a comprehensive histopathologic characterisation of CRCLM from 159 patients who underwent secondary resection, after receiving triplets FOLFOXIRI (folinic acid, 5-fluorouracil, oxaliplatin, and irinotecan) or COI (capecitabine, oxaliplatin, and irinotecan) plus bevacizumab (N = 103) vs cetuximab (N = 56) in five first-line no-profit clinical trials.RESULTS: Both major histopathologic response (tumour regression grade TRG1-2, 32 vs 14%, p = 0.013) and infarct-like necrosis (80 vs 64%, p = 0.035) were significantly higher in the bevacizumab than in the cetuximab group. Achieving major response positively affected relapse-free survival (RFS) (p = 0.012) and overall survival (OS) (p = 0.045), also in multivariable models (RFS, p = 0.008; OS, p = 0.033). In the desmoplastic HGP (N = 28), a higher percentage of major response was reported (57 vs 17% in pushing and 22% in replacement HGP, p < 0.001) and an unsignificant advantage from cetuximab vs bevacizumab was evident in RFS (p = 0.116). In the pushing HGP (N = 66), a significant benefit from bevacizumab vs cetuximab (p = 0.017) was observed. No difference was described in the replacement HGP (N = 65, p = 0.615).CONCLUSIONS: The histopathologic response is the only independent determinant of survival in patients resected after triplets plus a biologic. When associated with triplet chemotherapy, bevacizumab induces a higher histopathologic response rate than cetuximab. The assessment of HGPs should be further explored as a predictor of benefit from available targeted agents.

U2 - 10.1038/s41416-018-0015-z

DO - 10.1038/s41416-018-0015-z

M3 - Article

VL - 118

SP - 955

EP - 965

JO - British Journal of Cancer

JF - British Journal of Cancer

SN - 0007-0920

IS - 7

ER -