Abstract
Monoclonal antibodies targeting epidermal growth factor receptor (EGFR) or vascular endothelial growth factor (VEGF) have showed clinical benefit in combination with chemotherapeutic cytotoxic drugs in the first-line therapy of metastatic colorectal cancer (mCRC). Data from randomized studies comparing these monoclonal antibodies as initial therapy is conflicting, and their comparative efficacy remains unknown. This study aimed to evaluate the impact of the combination of anti-epidermal growth factor receptor (anti-EGFR) therapy and anti-vascular endothelial growth factor therapy on mCRC patient outcomes by combining the data from randomized clinical trials. Three trials meeting the eligibility criteria, and four randomized studies were included in the meta-analysis. For MCRC patients with KRAS wild type (KRAS-WT), the ORR was superior in patients treated with anti-EGFR compared with those who treated with anti-VEGF therapy. This effect was even better for all RAS-WT patients. Progression-free survival (PFS) rates were not significantly different for KRAS-WT mCRC and all RAS-WT mCRC between the two groups. The overall survival (OS) was higher for RAS wild-type (RAS-WT) mCRC patients who received anti-EGFR, but the KRAS-WT patients compared to the anti-VEGF therapy. The results of our research indicate that superior ORR and OS between the addition of anti-EGFR therapy VS anti-VEGF therapy in all RAS-WT patients with MCRC. There was no significant difference in OS and PFS between the two groups for KRAS-WT mCRC. These results suggest that anti- EGFR monoclonal antibodies can achieve an equivalent efficacy when compared with anti-VEGF therapy of all RAS-WT mCRC patients.
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Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, Parkin DM, Forman D, Bray F (2015) Cancer incidence and mortality worldwide: sources, methods and major patterns in GLOBOCAN 2012. Int J Cancer 136(5):E359–E386. https://doi.org/10.1002/ijc.29210
Torre LA, Bray F, Siegel RL, Ferlay J, Lortet-Tieulent J, Jemal A (2015) Global cancer statistics, 2012. CA Cancer J. Clin. 65(2):87
Van Cutsem E, Nordlinger B, Adam R, Kohne CH, Pozzo C, Poston G, Ychou M, Rougier P, European Colorectal Metastases Treatment G (2006) Towards a pan-European consensus on the treatment of patients with colorectal liver metastases. Eur J Cancer 42(14):2212–2221. https://doi.org/10.1016/j.ejca.2006.04.012
Petrelli F, Borgonovo K, Cabiddu M, Ghilardi M, Barni S (2011) Cetuximab and panitumumab in KRAS wild-type colorectal cancer: a meta-analysis. Int J Color Dis 26(7):823–833. https://doi.org/10.1007/s00384-011-1149-0
Vale CL, Tierney JF, Fisher D, Adams RA, Kaplan R, Maughan TS, Parmar MK, Meade AM (2012) Does anti-EGFR therapy improve outcome in advanced colorectal cancer? A systematic review and meta-analysis. Cancer Treat Rev 38(6):618–625. https://doi.org/10.1016/j.ctrv.2011.11.002
Bokemeyer C, Bondarenko I, Makhson A, Hartmann JT, Aparicio J, de Braud F, Donea S, Ludwig H, Schuch G, Stroh C, Loos AH, Zubel A, Koralewski P (2009) Fluorouracil, leucovorin, and oxaliplatin with and without cetuximab in the first-line treatment of metastatic colorectal cancer. J Clin Oncol 27(5):663–671. https://doi.org/10.1200/JCO.2008.20.8397
Van Cutsem E, Kohne CH, Hitre E, Zaluski J, Chang Chien CR, Makhson A, D'Haens G, Pinter T, Lim R, Bodoky G, Roh JK, Folprecht G, Ruff P, Stroh C, Tejpar S, Schlichting M, Nippgen J, Rougier P (2009) Cetuximab and chemotherapy as initial treatment for metastatic colorectal cancer. N Engl J Med 360(14):1408–1417. https://doi.org/10.1056/NEJMoa0805019
Van Cutsem E, Kohne CH, Lang I, Folprecht G, Nowacki MP, Cascinu S, Shchepotin I, Maurel J, Cunningham D, Tejpar S, Schlichting M, Zubel A, Celik I, Rougier P, Ciardiello F (2011) Cetuximab plus irinotecan, fluorouracil, and leucovorin as first-line treatment for metastatic colorectal cancer: updated analysis of overall survival according to tumor KRAS and BRAF mutation status. J Clin Oncol 29(15):2011–2019. https://doi.org/10.1200/JCO.2010.33.5091
Bokemeyer C, Van Cutsem E, Rougier P, Ciardiello F, Heeger S, Schlichting M, Celik I, Kohne CH (2012) Addition of cetuximab to chemotherapy as first-line treatment for KRAS wild-type metastatic colorectal cancer: pooled analysis of the CRYSTAL and OPUS randomised clinical trials. Eur J Cancer 48(10):1466–1475. https://doi.org/10.1016/j.ejca.2012.02.057
Hurwitz H, Fehrenbacher L, Novotny W, Cartwright T, Hainsworth J, Heim W, Berlin J, Baron A, Griffing S, Holmgren E, Ferrara N, Fyfe G, Rogers B, Ross R, Kabbinavar F (2004) Bevacizumab plus irinotecan, fluorouracil, and leucovorin for metastatic colorectal cancer. N Engl J Med 350(23):2335–2342. https://doi.org/10.1056/NEJMoa032691
Macedo LT, da Costa Lima AB, Sasse AD (2012) Addition of bevacizumab to first-line chemotherapy in advanced colorectal cancer: a systematic review and meta-analysis, with emphasis on chemotherapy subgroups. BMC Cancer 12:89. https://doi.org/10.1186/1471-2407-12-89
Saltz LB, Clarke S, Diaz-Rubio E, Scheithauer W, Figer A, Wong R, Koski S, Lichinitser M, Yang TS, Rivera F, Couture F, Sirzen F, Cassidy J (2008) Bevacizumab in combination with oxaliplatin-based chemotherapy as first-line therapy in metastatic colorectal cancer: a randomized phase III study. J Clin Oncol 26(12):2013–2019. https://doi.org/10.1200/JCO.2007.14.9930
Hurwitz HI, Yi J, Ince W, Novotny WF, Rosen O (2009) The clinical benefit of bevacizumab in metastatic colorectal cancer is independent of K-ras mutation status: analysis of a phase III study of bevacizumab with chemotherapy in previously untreated metastatic colorectal cancer. Oncologist 14(1):22–28. https://doi.org/10.1634/theoncologist.2008-0213
Heinemann V, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Hielscher J, Scholz M, Muller S, Link H, Niederle N, Rost A, Hoffkes HG, Moehler M, Lindig RU, Modest DP, Rossius L, Kirchner T, Jung A, Stintzing S (2014) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab as first-line treatment for patients with metastatic colorectal cancer (FIRE-3): a randomised, open-label, phase 3 trial. Lancet Oncol 15(10):1065–1075. https://doi.org/10.1016/S1470-2045(14)70330-4
Stintzing S, Modest DP, Rossius L, Lerch MM, von Weikersthal LF, Decker T, Kiani A, Vehling-Kaiser U, Al-Batran SE, Heintges T, Lerchenmuller C, Kahl C, Seipelt G, Kullmann F, Stauch M, Scheithauer W, Held S, Giessen-Jung C, Moehler M, Jagenburg A, Kirchner T, Jung A, Heinemann V, investigators F- (2016) FOLFIRI plus cetuximab versus FOLFIRI plus bevacizumab for metastatic colorectal cancer (FIRE-3): a post-hoc analysis of tumour dynamics in the final RAS wild-type subgroup of this randomised open-label phase 3 trial. Lancet Oncol 17 (10):1426–1434. https://doi.org/10.1016/S1470-2045(16)30269-8
Schwartzberg LS, Rivera F, Karthaus M, Fasola G, Canon JL, Hecht JR, Yu H, Oliner KS, Go WY (2014) PEAK: a randomized, multicenter phase II study of panitumumab plus modified fluorouracil, leucovorin, and oxaliplatin (mFOLFOX6) or bevacizumab plus mFOLFOX6 in patients with previously untreated, unresectable, wild-type KRAS exon 2 metastatic colorectal cancer. J Clin Oncol 32(21):2240–2247. https://doi.org/10.1200/JCO.2013.53.2473
Venook AP, Niedzwiecki D, Lenz HJ, Innocenti F, Fruth B, Meyerhardt JA, Schrag D, Greene C, O'Neil BH, Atkins JN, Berry S, Polite BN, O'Reilly EM, Goldberg RM, Hochster HS, Schilsky RL, Bertagnolli MM, El-Khoueiry AB, Watson P, Benson AB 3rd, Mulkerin DL, Mayer RJ, Blanke C (2017) Effect of First-Line Chemotherapy Combined With Cetuximab or Bevacizumab on Overall Survival in Patients With KRAS Wild-Type Advanced or Metastatic Colorectal Cancer: A Randomized Clinical Trial. JAMA 317(23):2392–2401. https://doi.org/10.1001/jama.2017.7105
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21(11):1539–1558. https://doi.org/10.1002/sim.1186
Lenz H, Niedzwiecki D, Innocenti F, Blanke C, Mahony MR, O'Neil BH, Shaw JE, Polite B, Hochster H, Atkins J, Goldberg R, Mayer R, Schilsky RL, Bertagnolli M, Venook A (2014) 501OCALGB/SWOG 80405: PHASE III TRIAL OF IRINOTECAN/5-FU/LEUCOVORIN (FOLFIRI) OR OXALIPLATIN/5-FU/LEUCOVORIN (MFOLFOX6) WITH BEVACIZUMAB (BV) OR CETUXIMAB (CET) FOR PATIENTS (PTS) WITH EXPANDED RAS ANALYSES UNTREATED METASTATIC ADENOCARCINOMA OF THE COLON OR RECTUM (MCRC). Ann Oncol 25(suppl_4):mdu438.413–mdu438.413. https://doi.org/10.1093/annonc/mdu438.13
Venook AP, Niedzwiecki D, Lenz H-J, Innocenti F, Mahoney MR, O'Neil BH, Shaw JE, Polite BN, Hochster HS, Atkins JN, Goldberg RM, Mayer RJ, Schilsky RL, Bertagnolli MM, Blanke CD, Cancer, Leukemia Group B S, ECOG (2014) CALGB/SWOG 80405: phase III trial of irinotecan/5-FU/leucovorin (FOLFIRI) or oxaliplatin/5-FU/leucovorin (mFOLFOX6) with bevacizumab (BV) or cetuximab (CET) for patients (pts) with KRAS wild-type (wt) untreated metastatic adenocarcinoma of the colon or rectum (MCRC). J Clin Oncol 32(15_suppl):LBA3–LBA3. https://doi.org/10.1200/jco.2014.32.15_suppl.lba3
Douillard JY, Siena S, Cassidy J, Tabernero J, Burkes R, Barugel M, Humblet Y, Bodoky G, Cunningham D, Jassem J, Rivera F, Kocakova I, Ruff P, Blasinska-Morawiec M, Smakal M, Canon JL, Rother M, Oliner KS, Tian Y, Xu F, Sidhu R (2014) Final results from PRIME: randomized phase III study of panitumumab with FOLFOX4 for first-line treatment of metastatic colorectal cancer. Ann Oncol 25(7):1346–1355. https://doi.org/10.1093/annonc/mdu141
Khattak MA, Martin H, Davidson A, Phillips M (2015) Role of first-line anti-epidermal growth factor receptor therapy compared with anti-vascular endothelial growth factor therapy in advanced colorectal cancer: a meta-analysis of randomized clinical trials. Clin Colorectal Cancer 14(2):81–90
Maughan TS, Adams RA, Smith CG, Meade AM, Seymour MT, Wilson RH, Idziaszczyk S, Harris R, Fisher D, Kenny SL, Kay E, Mitchell JK, Madi A, Jasani B, James MD, Bridgewater J, Kennedy MJ, Claes B, Lambrechts D, Kaplan R, Cheadle JP, Investigators MCT (2011) Addition of cetuximab to oxaliplatin-based first-line combination chemotherapy for treatment of advanced colorectal cancer: results of the randomised phase 3 MRC COIN trial. Lancet 377(9783):2103–2114. https://doi.org/10.1016/S0140-6736(11)60613-2
Chan D, Pavlakis N, Price TJ, Karapetis CS, Tebbutt NC, Shapiro JD, Segelov E (2014) Impact of chemotherapy partner on efficacy of targeted therapy in metastatic colorectal cancer (mCRC): a meta-analysis. Asia Pac J Clin Oncol 10:104–104
Piessevaux H, Buyse M, Schlichting M, Van CE, Bokemeyer C, Heeger S, Tejpar S (2013) Use of early tumor shrinkage to predict long-term outcome in metastatic colorectal cancer treated with cetuximab. Journal of clinical oncology official journal of the. Proc Am Soc Clin Oncol 31(30):3764
Mansmann UR, Sartorius U, Laubender RP, Giessen CA, Esser R, Heinemann V (2013) Deepness of response: a quantitative analysis of its impact on post-progression survival time after first-line treatment in patients with mCRC. J Clin Oncol 31(4)
Ciardiello F, Bianco RR, Caputo R, Damiano V, Troiani T, Melisi D, De VF, De PS, Bianco AR, Tortora G (2004) Antitumor activity of ZD6474, a vascular endothelial growth factor receptor tyrosine kinase inhibitor, in human cancer cells with acquired resistance to antiepidermal growth factor receptor therapy. Clin Cancer Res 10(2):784
Viloria-Petit A, Crombet T, Jothy S, Hicklin D, Bohlen P, Schlaeppi JM, Rak J, Kerbel RS (2001) Acquired resistance to the antitumor effect of epidermal growth factor receptor-blocking antibodies in vivo: a role for altered tumor angiogenesis. Cancer Res 61(13):5090–5101
Yang YH, Lin JK, Chen WS, Lin TC, Yang SH, Jiang JK, Lan YT, Lin CC, Yen CC, Tzeng CH (2014) Comparison of cetuximab to bevacizumab as the first-line bio-chemotherapy for patients with metastatic colorectal cancer: superior progression-free survival is restricted to patients with measurable tumors and objective tumor response—a retrospective stu. J Cancer Res Clin Oncol 140(11):1927–1936
Ye LC, Liu TS, Ren L, Wei Y, Zhu DX, Zai SY, Ye QH, Yu Y, Xu B, Qin XY (2013) Randomized controlled trial of cetuximab plus chemotherapy for patients with KRAS wild-type unresectable colorectal liver-limited metastases. Journal of clinical oncology official journal of the. Proc Am Soc Clin Oncol 31(16):1931
Okines A, Del PO, Cunningham D, Chau I, Van CE, Saltz L, Cassidy J (2009) Surgery with curative-intent in patients treated with first-line chemotherapy plus bevacizumab for metastatic colorectal cancer first BEAT and the randomised phase-III NO16966 trial. Br J Cancer 101(7):1033
Folprecht G, Gruenberger T, Bechstein WO, Raab HR, Lordick F, Hartmann JT, Lang H, Frilling A, Stoehlmacher J, Weitz J (2010) Tumour response and secondary resectability of colorectal liver metastases following neoadjuvant chemotherapy with cetuximab: the CELIM randomised phase 2 trial. Lancet Oncol 11(1):38–47
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Wang, JX., Wu, HL., Zhu, M. et al. Role of Anti-Epidermal Growth Factor Receptor Therapy Compared with Anti-Vascular Endothelial Growth Factor Therapy for Metastatic Colorectal Cancer: an Update Meta-Analysis of Randomized Clinical Trials. Pathol. Oncol. Res. 26, 159–166 (2020). https://doi.org/10.1007/s12253-017-0365-5
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DOI: https://doi.org/10.1007/s12253-017-0365-5