A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer

J. S. Chen, C. Hsu, N. J. Chiang, C. S. Tsai, H. H. Tsou, S. F. Huang, L. Y. Bai, I. C. Chang, H. S. Shiah, C. L. Ho, C. J. Yen, K. D. Lee, C. F. Chiu, K. M. Rau, M. S. Yu, Y. Yang, R. K. Hsieh, J. Y. Chang, Y. S. Shan, Y. Chao & 13 others Li Tzong Chen, Yung Hsin Chin, Tsai Rong Chung, Wei Lan Yu, Mei Hua Lee, Ling Fang Lin, Pei Chyi Lin, Ya Ling Wu, Hui Ling Wang, Li Ju Lu, Shiang Yi Chen, Chih Chu Wu, Te Chih Wei

Research output: Contribution to journalArticle

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Abstract

Background: Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. Patients and methods: ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1: 1 to receive GEMOX (800 mg/m2 gemcitabine and 85 mg/m2 oxaliplatin) or C-GEMOX (500 mg/m2 cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). Results: The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P=0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P=0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. Conclusions: Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.

Original languageEnglish
Article numbermdv035
Pages (from-to)943-949
Number of pages7
JournalAnnals of Oncology
Volume26
Issue number5
DOIs
Publication statusPublished - May 1 2015

Fingerprint

oxaliplatin
gemcitabine
Biliary Tract Neoplasms
Mutation
Exanthema
Drug Therapy
Neoplasms
Survival
Neutropenia
Epidermal Growth Factor Receptor
Disease-Free Survival
Cetuximab
Hypersensitivity

Keywords

  • Biliary tract cancer
  • Cetuximab
  • Chemotherapy
  • KRAS mutation

ASJC Scopus subject areas

  • Hematology
  • Oncology

Cite this

A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. / Chen, J. S.; Hsu, C.; Chiang, N. J.; Tsai, C. S.; Tsou, H. H.; Huang, S. F.; Bai, L. Y.; Chang, I. C.; Shiah, H. S.; Ho, C. L.; Yen, C. J.; Lee, K. D.; Chiu, C. F.; Rau, K. M.; Yu, M. S.; Yang, Y.; Hsieh, R. K.; Chang, J. Y.; Shan, Y. S.; Chao, Y.; Chen, Li Tzong; Chin, Yung Hsin; Chung, Tsai Rong; Yu, Wei Lan; Lee, Mei Hua; Lin, Ling Fang; Lin, Pei Chyi; Wu, Ya Ling; Wang, Hui Ling; Lu, Li Ju; Chen, Shiang Yi; Wu, Chih Chu; Wei, Te Chih.

In: Annals of Oncology, Vol. 26, No. 5, mdv035, 01.05.2015, p. 943-949.

Research output: Contribution to journalArticle

Chen, JS, Hsu, C, Chiang, NJ, Tsai, CS, Tsou, HH, Huang, SF, Bai, LY, Chang, IC, Shiah, HS, Ho, CL, Yen, CJ, Lee, KD, Chiu, CF, Rau, KM, Yu, MS, Yang, Y, Hsieh, RK, Chang, JY, Shan, YS, Chao, Y, Chen, LT, Chin, YH, Chung, TR, Yu, WL, Lee, MH, Lin, LF, Lin, PC, Wu, YL, Wang, HL, Lu, LJ, Chen, SY, Wu, CC & Wei, TC 2015, 'A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer', Annals of Oncology, vol. 26, no. 5, mdv035, pp. 943-949. https://doi.org/10.1093/annonc/mdv035
Chen, J. S. ; Hsu, C. ; Chiang, N. J. ; Tsai, C. S. ; Tsou, H. H. ; Huang, S. F. ; Bai, L. Y. ; Chang, I. C. ; Shiah, H. S. ; Ho, C. L. ; Yen, C. J. ; Lee, K. D. ; Chiu, C. F. ; Rau, K. M. ; Yu, M. S. ; Yang, Y. ; Hsieh, R. K. ; Chang, J. Y. ; Shan, Y. S. ; Chao, Y. ; Chen, Li Tzong ; Chin, Yung Hsin ; Chung, Tsai Rong ; Yu, Wei Lan ; Lee, Mei Hua ; Lin, Ling Fang ; Lin, Pei Chyi ; Wu, Ya Ling ; Wang, Hui Ling ; Lu, Li Ju ; Chen, Shiang Yi ; Wu, Chih Chu ; Wei, Te Chih. / A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer. In: Annals of Oncology. 2015 ; Vol. 26, No. 5. pp. 943-949.
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abstract = "Background: Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. Patients and methods: ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1: 1 to receive GEMOX (800 mg/m2 gemcitabine and 85 mg/m2 oxaliplatin) or C-GEMOX (500 mg/m2 cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). Results: The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27{\%} versus 15{\%}; P=0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P=0.91). KRAS mutations, which were detected in 36{\%} of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. Conclusions: Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.",
keywords = "Biliary tract cancer, Cetuximab, Chemotherapy, KRAS mutation",
author = "Chen, {J. S.} and C. Hsu and Chiang, {N. J.} and Tsai, {C. S.} and Tsou, {H. H.} and Huang, {S. F.} and Bai, {L. Y.} and Chang, {I. C.} and Shiah, {H. S.} and Ho, {C. L.} and Yen, {C. J.} and Lee, {K. D.} and Chiu, {C. F.} and Rau, {K. M.} and Yu, {M. S.} and Y. Yang and Hsieh, {R. K.} and Chang, {J. Y.} and Shan, {Y. S.} and Y. Chao and Chen, {Li Tzong} and Chin, {Yung Hsin} and Chung, {Tsai Rong} and Yu, {Wei Lan} and Lee, {Mei Hua} and Lin, {Ling Fang} and Lin, {Pei Chyi} and Wu, {Ya Ling} and Wang, {Hui Ling} and Lu, {Li Ju} and Chen, {Shiang Yi} and Wu, {Chih Chu} and Wei, {Te Chih}",
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TY - JOUR

T1 - A KRAS mutation status-stratified randomized phase II trial of gemcitabine and oxaliplatin alone or in combination with cetuximab in advanced biliary tract cancer

AU - Chen, J. S.

AU - Hsu, C.

AU - Chiang, N. J.

AU - Tsai, C. S.

AU - Tsou, H. H.

AU - Huang, S. F.

AU - Bai, L. Y.

AU - Chang, I. C.

AU - Shiah, H. S.

AU - Ho, C. L.

AU - Yen, C. J.

AU - Lee, K. D.

AU - Chiu, C. F.

AU - Rau, K. M.

AU - Yu, M. S.

AU - Yang, Y.

AU - Hsieh, R. K.

AU - Chang, J. Y.

AU - Shan, Y. S.

AU - Chao, Y.

AU - Chen, Li Tzong

AU - Chin, Yung Hsin

AU - Chung, Tsai Rong

AU - Yu, Wei Lan

AU - Lee, Mei Hua

AU - Lin, Ling Fang

AU - Lin, Pei Chyi

AU - Wu, Ya Ling

AU - Wang, Hui Ling

AU - Lu, Li Ju

AU - Chen, Shiang Yi

AU - Wu, Chih Chu

AU - Wei, Te Chih

PY - 2015/5/1

Y1 - 2015/5/1

N2 - Background: Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. Patients and methods: ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1: 1 to receive GEMOX (800 mg/m2 gemcitabine and 85 mg/m2 oxaliplatin) or C-GEMOX (500 mg/m2 cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). Results: The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P=0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P=0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. Conclusions: Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.

AB - Background: Previous clinical trials have not proved that adding epidermal growth factor receptor inhibitors to chemotherapy confers a survival benefit for patients with advanced biliary tract cancer (ABTC). Whether the KRAS mutation status of tumor cells confounded the results of past studies is unknown. Patients and methods: ABTC patients stratified by KRAS status, Eastern Cooperative Oncology Group performance status, and primary tumor location were randomized 1: 1 to receive GEMOX (800 mg/m2 gemcitabine and 85 mg/m2 oxaliplatin) or C-GEMOX (500 mg/m2 cetuximab plus GEMOX) every 2 weeks. The primary end point was objective response rate (ORR). Results: The study enrolled 122 patients between December 2010 and May 2012 (62 treated with C-GEMOX and 60 with GEMOX). Compared with GEMOX alone, C-GEMOX was associated with trend to better ORR (27% versus 15%; P=0.12) and progression-free survival (PFS, 6.7 versus 4.1 months; P = 0.05), but not overall survival (OS, 10.6 versus 9.8 months; P=0.91). KRAS mutations, which were detected in 36% of tumor samples, did not affect the trends of difference in ORR and PFS between C-GEMOX and GEMOX. The two treatment arms had similar adverse events, except that more patients had skin rashes, allergic reactions, and neutropenia in the C-GEMOX arm. Of patients with C-GEMOX, the presence of a grade 2 or 3 skin rash was associated with significantly better ORR, PFS, and OS. Conclusions: Addition of cetuximab did not significantly improve the ORR of GEMOX chemotherapy in ABTC, although a trend of PFS improvement was observed. The trend of improvement did not correlate with KRAS mutation status.

KW - Biliary tract cancer

KW - Cetuximab

KW - Chemotherapy

KW - KRAS mutation

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U2 - 10.1093/annonc/mdv035

DO - 10.1093/annonc/mdv035

M3 - Article

VL - 26

SP - 943

EP - 949

JO - Annals of Oncology

JF - Annals of Oncology

SN - 0923-7534

IS - 5

M1 - mdv035

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