Tumour shrinkage at 6 weeks predicts favorable clinical outcomes in a phase III study of gemcitabine and oxaliplatin with or without erlotinib for advanced biliary tract cancer

Seung Tae Kim, Kee-Taek Jang, Su Jin Lee, Hye-Lim Jang, Jeeyun Lee, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Joon Oh Park, Seung Tae Kim, Kee-Taek Jang, Su Jin Lee, Hye-Lim Jang, Jeeyun Lee, Se Hoon Park, Young Suk Park, Ho Yeong Lim, Won Ki Kang, Joon Oh Park

Abstract

Background: The aim of this study was to determine whether early tumor shrinkage (ETS) at 6 weeks after treatment correlates with progression-free survival (PFS) and overall survival (OS) in advanced biliary tract cancer (BTC) patients receiving gemcitabine plus oxaliplatin (GEMOX), with or without erlotinib.

Methods: This was a multicenter, open label, randomized, phase III trial of 103 BTC patients (ClinicalTrials.gov Identifier; NCT01149122, and Rigistration date; January, 7, 2010), comparing GEMOX with GEMOX plus erlotinib. Tumor shrinkage was expressed as a relative decrease compared to baseline and was dichotomized according to a previously reported cutoff value of 10 %.

Results: Fifty-four patients (52.4 %) received GEMOX and 49 patients (47.6 %) received GEMOX plus erlotinib. The latter achieved a better overall response rate (RR) (40.8 % vs. 18.6 %, p = 0.02) and showed ETS more frequently (63.2 % vs. 40.7 %, p = 0.03). ETS was significantly correlated with the overall RR (correlation coefficient, 0.53; p < 0.01). The median PFS and OS did not differ according to erlotinib administration. However, the median PFS (7.3 vs. 2.1 months, p < 0.01) and OS (10.7 vs. 5.8 months, p < 0.01) were significantly longer amongst patients with ETS at 6 weeks after treatment, irrespective of erlotinib administration. In patients with wild-type KRAS who were treated with GEMOX plus erlotinib, ETS was a significant prognostic factor for PFS (p < 0.01).

Conclusions: ETS might predict PFS and OS in BTC patients treated with GEMOX with or without erlotinib. Additionally, ETS may be an indication for adding erlotinib to chemotherapy for BTC patients wild-type KRAS. These findings need to be prospectively validated.

Figures

Fig. 1
Fig. 1
CONSORT flow diagram
Fig. 2
Fig. 2
Progression-free survival (PFS) (a) and overall survival (OS) (b) of patients treated with gemcitabine and oxaliplatin (GEMOX) alone or GEMOX with erlotinib (GEMOXT)
Fig. 3
Fig. 3
Progression-free survival (PFS) (a) and overall survival (OS) (b) for patients with or without early tumor shrinkage (ETS) 6 weeks after treatment
Fig. 4
Fig. 4
Progression-free survival (PFS) according to treatment with gemcitabine and oxaliplatin (GEMOX) or GEMOX with erlotinib (GEMOXT) (a) and early tumor shrinkage (ETS) 6 weeks after treatment (b) in patients with wild-type KRAS tumors
Fig. 5
Fig. 5
Progression-free survival (PFS) in patients with wild-type KRAS tumors treated with gemcitabine and oxaliplatin plus erlotinib (GEMOXT), stratified according to early tumor shrinkage (ETS)

References

    1. Won YJ, Sung J, Jung KW, Kong HJ, Park S, Shin HR, et al. Nationwide cancer incidence in Korea, 2003–2005. Cancer Res Treat. 2009;41:122–31. doi: 10.4143/crt.2009.41.3.122.
    1. Glimelius B, Hoffman K, Sjoden PO, Jacobsson G, Sellstrom H, Enander LK, et al. Chemotherapy improves survival and quality of life in advanced pancreatic and biliary cancer. Ann Oncol. 1996;7:593–600. doi: 10.1093/oxfordjournals.annonc.a010676.
    1. Thongprasert S. The role of chemotherapy in cholangiocarcinoma. Ann Oncol. 2005;16 Suppl 2:ii93–6.
    1. Valle JW, Wasan H, Johnson P, Jones E, Dixon L, Swindell R, et al. Gemcitabine alone or in combination with cisplatin in patients with advanced or metastatic cholangiocarcinomas or other biliary tract tumours: a multicentre randomised phase II study - The UK ABC-01 Study. Br J Cancer. 2009;101:621–7. doi: 10.1038/sj.bjc.6605211.
    1. Valle J, Wasan H, Palmer DH, Cunningham D, Anthoney A, Maraveyas A, et al. Cisplatin plus gemcitabine versus gemcitabine for biliary tract cancer. N Engl J Med. 2010;362:1273–81. doi: 10.1056/NEJMoa0908721.
    1. Lee J, Park SH, Chang HM, Kim JS, Choi HJ, Lee MA, et al. Gemcitabine and oxaliplatin with or without erlotinib in advanced biliary-tract cancer: a multicentre, open-label, randomised, phase 3 study. Lancet Oncol. 2012;13:181–8. doi: 10.1016/S1470-2045(11)70301-1.
    1. Janes H, Pepe MS, Bossuyt PM, Barlow WE. Measuring the performance of markers for guiding treatment decisions. Ann Intern Med. 2011;154:253–9. doi: 10.7326/0003-4819-154-4-201102150-00006.
    1. De Roock W, Piessevaux H, De Schutter J, Janssens M, De Hertogh G, Personeni N, et al. KRAS wild-type state predicts survival and is associated to early radiological response in metastatic colorectal cancer treated with cetuximab. Ann Oncol. 2008;19:508–15. doi: 10.1093/annonc/mdm496.
    1. Lievre A, Bachet JB, Boige V, Cayre A, Le Corre D, Buc E, et al. KRAS mutations as an independent prognostic factor in patients with advanced colorectal cancer treated with cetuximab. J Clin Oncol. 2008;26:374–9. doi: 10.1200/JCO.2007.12.5906.
    1. Amado RG, Wolf M, Peeters M, Van Cutsem E, Siena S, Freeman DJ, et al. Wild-type KRAS is required for panitumumab efficacy in patients with metastatic colorectal cancer. J Clin Oncol. 2008;26:1626–34. doi: 10.1200/JCO.2007.14.7116.
    1. Piessevaux H, Buyse M, Schlichting M, Van Cutsem E, Bokemeyer C, Heeger S, et al. Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. J Clin Oncol. 2013;31:3764–75. doi: 10.1200/JCO.2012.42.8532.
    1. Piessevaux H, Buyse M, De Roock W, Prenen H, Schlichting M, Van Cutsem E, et al. Radiological tumor size decrease at week 6 is a potent predictor of outcome in chemorefractory metastatic colorectal cancer treated with cetuximab (BOND trial) Ann Oncol. 2009;20:1375–82. doi: 10.1093/annonc/mdp011.
    1. Suzuki C, Blomqvist L, Sundin A, Jacobsson H, Bystrom P, Berglund A, et al. The initial change in tumor size predicts response and survival in patients with metastatic colorectal cancer treated with combination chemotherapy. Ann Oncol. 2012;23:948–54. doi: 10.1093/annonc/mdr350.
    1. Modest DP, Laubender RP, Stintzing S, Giessen C, Schulz C, Haas M, et al. Early tumor shrinkage in patients with metastatic colorectal cancer receiving first-line treatment with cetuximab combined with either CAPIRI or CAPOX: an analysis of the German AIO KRK 0104 trial. Acta Oncol. 2013;52:956–62. doi: 10.3109/0284186X.2012.752580.
    1. Heun JM, Grothey A, Branda ME, Goldberg RM, Sargent DJ. Tumor status at 12 weeks predicts survival in advanced colorectal cancer: findings from NCCTG N9741. Oncologist. 2011;16:859–67. doi: 10.1634/theoncologist.2011-0064.
    1. Choi H, Charnsangavej C, Faria SC, Macapinlac HA, Burgess MA, Patel SR, et al. Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria. J Clin Oncol. 2007;25:1753–9. doi: 10.1200/JCO.2006.07.3049.
    1. Steel GG. The case against apoptosis. Acta Oncol. 2001;40:968–75. doi: 10.1080/02841860152708251.
    1. Wahl RL, Jacene H, Kasamon Y, Lodge MA. From RECIST to PERCIST: Evolving Considerations for PET response criteria in solid tumors. J Nucl Med. 2009;50(Suppl 1):122S–50S. doi: 10.2967/jnumed.108.057307.
    1. Hezel AF, Deshpande V, Zhu AX. Genetics of biliary tract cancers and emerging targeted therapies. J Clin Oncol. 2010;28:3531–40. doi: 10.1200/JCO.2009.27.4787.
    1. Zhu AX, Hezel AF. Development of molecularly targeted therapies in biliary tract cancers: reassessing the challenges and opportunities. Hepatology. 2011;53:695–704. doi: 10.1002/hep.24145.
    1. De Roock W, Claes B, Bernasconi D, De Schutter J, Biesmans B, Fountzilas G, et al. Effects of KRAS, BRAF, NRAS, and PIK3CA mutations on the efficacy of cetuximab plus chemotherapy in chemotherapy-refractory metastatic colorectal cancer: a retrospective consortium analysis. Lancet Oncol. 2010;11:753–62. doi: 10.1016/S1470-2045(10)70130-3.
    1. Massarelli E, Varella-Garcia M, Tang X, Xavier AC, Ozburn NC, Liu DD, et al. KRAS mutation is an important predictor of resistance to therapy with epidermal growth factor receptor tyrosine kinase inhibitors in non-small-cell lung cancer. Clin Cancer Res. 2007;13:2890–6. doi: 10.1158/1078-0432.CCR-06-3043.

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