Prospective phase II trial of nimotuzumab in combination with radiotherapy and concurrent capecitabine in locally advanced rectal cancer

Tengchuan Jin1,2, Yuan Zhu1,2, Luo Jia-bo1,2, Ning Zhou1,2, Dechuan Li3, Ju Hai3, Yong Fan3, Yong Liu3, Yumeng Zhu3, Hao Feng3, Luying Liu1,2
1Department of Radiation Oncology, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China
2Zhejiang Key Laboratory of Radiation Oncology, Hangzhou, People’s Republic of China
3Department of Colorectal Surgery, Zhejiang Cancer Hospital, Hangzhou, People’s Republic of China

Tóm tắt

Từ khóa


Tài liệu tham khảo

Siegel R, Naishadham D, Jemal A (2013) Cancer statistics. CA Cancer J Clin 63:11–30

Bosset JF, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Briffaux A, Collette L (2005) Enhanced tumorocidal effect of chemotherapy with preoperative radiotherapy for rectal cancer: preliminary results—EORTC 22921. J Clin Oncol 23:5620–5627

Bosset JF, Collette L, Calais G, Mineur L, Maingon P, Radosevic-Jelic L, Daban A, Bardet E, Beny A, Ollier JC (2006) EORTC Radiotherapy Group Trial 22921. Chemotherapy with preoperative radiotherapy in rectal cancer. N Engl J Med 355:1114–1123

Gérard JP, Conroy T, Bonnetain F, Bouché O, Chapet O, Closon-Dejardin MT, Untereiner M, Leduc B, Francois E, Maurel J, Seitz JF, Buecher B, Mackiewicz R, Ducreux M, Bedenne L (2006) Preoperative radiotherapy with or without concurrent fluorouracil and leucovorin in T3-4 rectal cancers: results of FFCD 9203. J Clin Oncol 24:4620–4625

Sauer R, Becker H, Hohenberger W, Rödel C, Wittekind C, Fietkau R, Martus P, Tschmelitsch J, Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R, German Rectal Cancer Study Group (2004) Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

Ciardiello F, Tortora G (2008) EGFR antagonists in cancer treatment. N Engl J Med 358:1160–1174

Kopp R, Rothbauer E, Mueller E, Schildberg FW, Jauch KW, Pfeiffer A (2003) Reduced survival of rectal cancer patients with increased tumor epidermal growth factor receptor levels. Dis Colon Rectum 46:1391–1399

Baumann M, Krause M (2004) Targeting the epidermal growth factor receptor in radiotherapy: radiobiological mechanisms, preclinical and clinical results. Radiother Oncol 72:257–266

Giralt J, Eraso A, Armengol M, Rosselló J, Majó J, Ares C, Espin E, Benavente S, de Torres I (2002) Epidermal growth factor receptor is a predictor of tumor response in locally advanced rectal cancer patients treated with preoperative radiotherapy. Int J Radiat Oncol Biol Phys 54:1460–1465

Giralt J, de las Heras M, Cerezo L, Eraso A, Hermosilla E, Velez D, Lujan J, Espin E, Rosello J, Majó J, Benavente S, Armengol M, de Torres I, Grupo Español de Investigacion Clinica en Oncologia Radioterápica (GICOR) (2005) The expression of epidermal growth factor receptor results in a worse prognosis for patients with rectal cancer treated with preoperative radiotherapy: a multicenter, retrospective analysis. Radiother Oncol 74:101–108

Azria D, Bibeau F, Barbier N, Zouhair A, Lemanski C, Rouanet P, Ychou M, Senesse P, Ozsahin M, Pèlegrin A, Dubois JB, Thèzenas S 2005 Prognostic impact of epidermal growth factor receptor (EGFR) expression on loco-regional recurrence after preoperative radiotherapy in rectal cancer. Bmc Cancer. 5:62

Zhang W, Park DJ, Lu B, Yang DY, Gordon M, Groshen S, Yun J, Press OA, Vallböhmer D, Rhodes K, Lenz HJ (2005) Epidermal growth factor receptor gene polymorphisms predict pelvic recurrence in patients with rectal cancer treated with chemoradiation. Clin Cancer Res 11:600–605

Li S, Kim JS, Kim JM, Cho MJ, Yoon WH, Song KS, Yeo SG, Kim JS (2006) Epidermal growth factor receptor as a prognostic factor in locally advanced rectal-cancer patients treated with preoperative chemoradiation. Int J Radiat Oncol Biol Phys 65:705–712

Kim JS, Kim JM, Li S, Yoon WH, Song KS, Kim KH, Yeo SG, Nam JS, Cho MJ (2006) Epidermal growth factor receptor as a predictor of tumor downstaging in locally advanced rectal cancer patients treated with preoperative chemoradiotherapy. Int J Radiat Oncol Biol Phys 66:195–200

Spindler KL, Nielsen JN, Lindebjerg J, Brandslund I, Jakobsen A (2006) Prediction of response to chemoradiation in rectal cancer by a gene polymorphism in the epidermal growth factor receptor promoter region. Int J Radiat Oncol Biol Phys 66:500–504

Mateo C, Moreno E, Amour K, Lombardero J, Harris W, Pérez R (1997) Humanization of a mouse monoclonal antibody that blocks the epidermal growth factor receptor: recovery of antagonistic activity. Immunotechnology 3:71–81

Fernandez A, Spitzer E, Perez R, Boehmer FD, Eckert K, Zschiesche W, Grosse R (1992) A new monoclonal antibody for detection of EGF-receptors in western blots and paraffin-embedded tissue sections. J Cell Biochem 49:157–165

Akashi Y, Okamoto I, Iwasa T, Yoshida T, Suzuki M, Hatashita E, Yamada Y, Satoh T, Fukuoka M, Ono K, Nakagawa K (2008) Enhancement of the antitumor activity of ionising radiation by nimotuzumab, a humanised monoclonal antibody to the epidermal growth factor receptor, in non-small cell lung cancer cell lines of differing epidermal growth factor receptor status. Br J Cancer 98:749–755

Crombet-Ramos T, Rak J, Pérez R, Viloria-Petit A (2002) Antiproliferative, antiangiogenic and proapoptotic activity of h-R3: a humanized anti-EGFR antibody. Int J Cancer 101:567–575

Ramakrishnan MS, Eswaraiah A, Crombet T, Piedra P, Saurez G, Iyer H, Arvind AS (2009) Nimotuzumab, a promising therapeutic monoclonal for treatment of tumors of epithelial origin. MAbs 1:41–48

Ramos TC, Figueredo J, Catala M, González S, Selva JC, Cruz TM, Toledo C, Silva S, Pestano Y, Ramos M, Leonard I, Torres O, Marinello P, Pérez R, Lage A (2006) Treatment of high-grade glioma patients with the humanized anti-epidermal growth factor receptor (EGFR) antibody h-R3: report from a phase I/II trial. Cancer Biol Ther 5:375–379

Ramos TC, Figueredo J, Catala M, González S, Selva JC, Cruz TM, Toledo C, Silva S, Pestano Y, Ramos M, Leonard I, Torres O, Marinello P, Pérez R, Lage A (1997) Pathological features of rectal cancer after preoperative radiochemotherapy. Int J Colorectal Dis 12:19–23

Hager E, Hess CF, Karstens JH, Liersch T, Schmidberger H, Raab R (2004) German Rectal Cancer Study Group. Preoperative versus postoperative chemoradiotherapy for rectal cancer. N Engl J Med 351:1731–1740

Cividalli A, Ceciarelli F, Livdi E, Altavista P, Cruciani G, Marchetti P, Danesi DT (2002) Radiosensitization by oxaliplatin in a mouse adenocarcinoma: influence of treatment schedule. Int J Radiat Oncol Biol Phys 52:1092–1098

Magné N, Fischel JL, Formento P, Etienne MC, Dubreuil A, Marcié S, Lagrange JL, Milano G (2003) Oxaliplatin-5-fluorouracil and ionizing radiation. Importance of the sequence and influence of p53 status. Oncol(Basel) 64:280–287

Cancer and Leukemia Group B 899011, Ryan DP, Niedzwiecki D, Hollis D, Mediema BE, Wadler S, Tepper JE, Goldberg RM, Mayer RJ (2006) Phase I/II study of preoperative oxaliplatin, fluorouracil, and external-beam radiation therapy in patients with locally advanced rectal cancer: cancer and Leukemia Group B 89901. J Clin Oncol 24:2557–2562

Aschele C, Friso ML, Pucciarelli S, Lonardi S, Sartor L, Fabris G, Urso ED, Del Bianco P, Sotti G, Lise M, Monfardini S (2005) A phase I-II study of weekly oxaliplatin, 5-fluorouracil continuous infusion and preoperative radiotherapy in locally advanced rectal cancer. Ann Oncol 16:1140–1146

Fakih MG, Bullarddunn K, Yang GY, Pendyala L, Toth K, Andrews C, Rustum YM, Ross ME, Levea C, Puthillath A, Park YM, Rajput A (2008) Phase II study of weekly intravenous oxaliplatin combined with oral daily capecitabine and radiotherapy with biologic correlates in neoadjuvant treatment of rectal adenocarcinoma. Int J Radiat Oncol Biol Phys 72:650–657

Carraro S, Roca EL, Cartelli C, Rafailovici L, Castillo Odena S, Wasserman E, Gualdrini U, Huertas E, Barugel M, Ballarino G, Rodriguez MC, Masciangioli G (2002) Radiochemotherapy with short daily infusion of low-dose oxaliplatin, leucovorin, and 5-FU in T3-T4 unresectable rectal cancer: a phase II IATTGI study. Int J Radiat Oncol Biol Phys 54:397–402

Aschele C, Cionini L, Lonardi S, Pinto C, Cordio S, Rosati G, Artale S, Tagliagambe A, Ambrosini G, Rosetti P, Bonetti A, Negru ME, Tronconi MC, Luppi G, Silvano G, Corsi DC, Bochicchio AM, Chiaulon G, Gallo M, Boni L (2011) Primary tumor response to preoperative chemoradiation with or without oxaliplatin in locally advanced rectal cancer: pathologic results of the STAR-01 randomized phase III trial. J Clin Oncol 29:2773–2780

Rödel C, Liersch T, Becker H, Fietkau R, Hohenberger W, Hothorn T, Graeven U, Arnold D, Lang-Welzenbach M, Raab HR, Sülberg H, Wittekind C, Potapov S, Staib L, Hess C, Weigang-Köhler K, Grabenbauer GG, Hoffmanns H, Lindemann F, Schlenska-Lange A, Folprecht G, Sauer R, German Rectal Cancer Study Group (2012) Preoperative chemoradiotherapy and postoperative chemotherapy with fluorouracil and oxaliplatin versus fluorouracil alone in locally advanced rectal cancer: initial results of the German CAO/ARO/AIO-04 randomised phase 3 trial. Lancet Oncol 13:679–687

Fernández-Martos C, Nogué M, Cejas P, Moreno-García V, Machancoses AH, Feliu J (2012) The role of capecitabine in locally advanced rectal cancer treatment: an update. Drugs 72:1057–1073

Rödel C, Arnold D, Hipp M, Liersch T, Dellas K, Iesalnieks I, Hermann RM, Lordick F, Hinke A, Hohenberger W, Sauer R (2008) Phase I-II trial of cetuximab, capecitabine, oxaliplatin, and radiotherapy as preoperative treatment in rectal cancer. Int J Radiat Oncol Biol Phys 70:1081–1086

Horisberger K, Treschl A, Mai S, Barreto-Miranda M, Kienle P, Ströbel P, Erben P, Woernle C, Dinter D, Kähler G, Hochhaus A, Post S, Willeke F, Wenz F, Hofheinz RD (2009) MARGIT (Mannheimer Arbeitsgruppe für Gastrointestinale Tumoren). Cetuximab in combination with capecitabine, irinotecan, and radiotherapy for patients with locally advanced rectal cancer: results of a phase II MARGIT trial. Int J Radiat Oncol Biol Phys 74:1487–1493

Bertolini F, Chiara S, Bengala C, Antognoni P, Dealis C, Zironi S, Malavasi N, Scolaro T, Depenni R, Jovic G, Sonaglio C, Rossi A, Luppi G, Conte PF (2009) Neoadjuvant treatment with single-agent cetuximab followed by 5-FU, cetuximab, and pelvic radiotherapy: a phase II study in locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 73:466–472

Debucquoy A, Haustermans K, Daemen A, Aydin S, Libbrecht L, Gevaert O, De Moor B, Tejpar S, McBride WH, Penninckx F, Scalliet P, Stroh C, Vlassak S, Sempoux C, Machiels JP (2009) Molecular response to cetuximab and efficacy of preoperative cetuximab-based chemoradiation in rectal cancer. J Clin Oncol 27:2751–2757

Kim SY, Hong YS, Kim DY, Kim TW, Kim JH, Im SA, Lee KS, Yun T, Jeong SY, Choi HS, Lim SB, Chang HJ, Jung KH (2011) Preoperative chemoradiation with cetuximab, irinotecan, and capecitabine in patients with locally advanced resectable rectal cancer: a multicenter Phase II study. Int J Radiat Oncol Biol Phys 81:677–683

Pinto C, Di Fabio F, Maiello E, Pini S, Latiano T, Aschele C, Garufi C, Bochicchio A, Rosati G, Aprile G, Giaquinta S, Torri V, Bardelli A, Gion M, Martoni A (2011) Phase II study of panitumumab, oxaliplatin, 5-fluorouracil, and concurrent radiotherapy as preoperative treatment in high-risk locally advanced rectal cancer patients (StarPan/STAR-02 Study). Ann Oncol 22:2424–2430

Weiss C, Arnold D, Dellas K, Liersch T, Hipp M, Fietkau R, Sauer R, Hinke A, Rödel C (2010) Preoperative radiotherapy of advanced rectal cancer with capecitabine and oxaliplatin with or without cetuximab: a pooled analysis of three prospective phase I-II trials. Int J Radiat Oncol Biol Phys 78:472–478

Czito BG, Willett CG, Bendell JC, Morse MA, Tyler DS, Fernando NH, Mantyh CR, Blobe GC, Honeycutt W, Yu D, Clary BM, Pappas TN, Ludwig KA, Hurwitz HI (2006) Increased toxicity with gefitinib, capecitabine, and radiation therapy in pancreatic and rectal cancer: phase I trial results. J Clin Oncol 24:656–662

Machiels JP, Sempoux C, Scalliet P, Coche JC, Humblet Y, Van Cutsem E, Kerger J, Canon JL, Peeters M, Aydin S, Laurent S, Kartheuser A, Coster B, Roels S, Daisne JF, Honhon B, Duck L, Kirkove C, Bonny MA, Haustermans K (2007) Phase I/II study of preoperative cetuximab, capecitabine, and external beam radiotherapy in patients with rectal cancer. Ann Oncol 18:738–744

Sun PL, Li B, Ye QF (2012) Effect of neoadjuvant cetuximab, capecitabine, and radiotherapy for locally advanced rectal cancer: results of a phase II study. Int J Colorectal Dis 27:1325–1332

Okamoto W, Yoshino T, Takahashi T, Okamoto I, Ueda S, Tsuya A, Boku N, Nishio K, Fukuoka M, Yamamoto N, Nakagawa K (2013) A phase I, pharmacokinetic and pharmacodynamic study of nimotuzumab in Japanese patients with advanced solid tumors. Cancer Chemother Pharmacol 72:1063–1071

Zhao KL, Hu XC, Wu XH, Fu XL, Fan M, Jiang GL (2012) A phase I dose escalation study of Nimotuzumab in combination with concurrent chemoradiation for patients with locally advanced squamous cell carcinoma of esophagus. Invest New Drugs 30:1585–1590

Choi HJ, Sohn JH, Lee CG, Shim HS, Lee IJ, Yang WI, Kwon JE, Kim SK, Park MS, Lee JH, Kim JH (2011) A phase I study of nimotuzumab in combination with radiotherapy in stages IIB-IV non-small cell lung cancer unsuitable for radical therapy: Korean results. Lung Cancer 71:55–59

Velenik V, Oblak I, Anderluh F 2010 Long-term results from a randomized phase II trial of neoadjuvant combined-modality therapy for locally advanced rectal cancer. Radiat Oncol. 5:88

Rödel C, Martus P, Papadoupolos T, Füzesi L, Klimpfinger M, Fietkau R, Liersch T, Hohenberger W, Raab R, Sauer R, Wittekind C (2005) Prognostic significance of tumor regression after preoperative chemoradiotherapy for rectal cancer. J Clin Oncol 23:8688–8696

Eriksen JG, Steiniche T, Overgaard J, Danish Head and Neck Cancer study group (DAHANCA) (2005) The influence of epidermal growth factor receptor and tumor differentiation on the response to accelerated radiotherapy of squamous cell carcinomas of the head and neck in the randomized DAHANCA 6 and 7 study. Radiother Oncol 74:93–100

Wu YL, Liao ML, Qin SK, Sun Y, Zhou CC (2010) Efficacy and safety of Erlotinib in the treatment for advanced non-small cell lung cancer in Chinese patients. Zhonghua Zhong Liu Za Zhi 32:148–151

Wu YL, Kim JH, Park K, Zaatar A, Klingelschmitt G, Ng C (2012) Efficacy and safety of maintenance erlotinib in Asian patients with advanced non-small-cell lung cancer: a subanalysis of the phase III, randomized SATURN study. Lung Cancer-J Iaslc 77:339–345

Diaz Miqueli A, Blanco R, Garcia B, Badia T, Batista AE, Alonso R, Montero E (2007) Biological activity in vitro of anti-epidermal growth factor receptor monoclonal antibodies with different affinities. Hybridomas (Larchmt) 26:423–431

Kim DY, Jung KH, Kim TH, Kim DW, Chang HJ, Jeong JY, Kim YH, Son SH, Yun T, Hong CW, Sohn DK, Lim SB, Choi HS, Jeong SY, Park JG (2007) Comparison of 5-fluorouracil/leucovorin and capecitabine in preoperative chemoradiotherapy for locally advanced rectal cancer. Int J Radiat Oncol Biol Phys 67:378–384

De Paoli A, Chiara S, Luppi G, Friso ML, Beretta GD, Del Prete S, Pasetto L, Santantonio M, Sarti E, Mantello G, Innocente R, Frustaci S, Corvò R, Rosso R (2006) Capecitabine in combination with preoperative radiation therapy in locally advanced, resectable, rectal cancer: a multicentric phase II study. Ann Oncol 17:247–251

Das P, Lin EH, Bhatia S, Skibber JM, Rodriguez-Bigas MA, Feig BW, Chang GJ, Hoff PM, Eng C, Wolff RA, Delclos ME, Krishnan S, Janjan NA, Crane CH (2006) Preoperative chemoradiotherapy with capecitabine versus protracted infusion with locally advanced rectal cancer; a matched-pair analysis. Int J Radiat Oncol Biol Phys 66:1378–1383

Dupuis O, Vie B, Lledo G, Hennequin C, Noirclerc M, Bennamoun M, Jacob JH (2007) Preoperative treatment combining capecitabine with radiation therapy in rectal cancer: a GERCOR phase II study. Oncology 73:169–176

Capirci C, Valentini V, Cionini L, De Paoli A, Rodel C, Glynne-Jones R, Coco C, Romano M, Mantello G, Palazzi S, Mattia FO, Friso ML, Genovesi D, Vidali C, Gambacorta MA, Buffoli A, Lupattelli M, Favretto MS, La Torre G (2008) Prognostic value of pathologic complete response after neoadjuvant therapy in locally advanced rectal cancer: Long-term analysis of 566 ypCR patients. Int J Radiat Oncol Biol Phys 72:99–107

Dewdney A, Cunningham D, Tabernero J, Capdevila J, Glimelius B, Cervantes A, Tait D, Brown G, Wotherspoon A, de Castro Gonzalez D, Chua YJ, Wong R, Barbachano Y, Oates J, Chau I (2012) Multicenter randomized phase II clinical trial comparing neoadjuvant oxaliplatin, capecitabine, and preoperative radiotherapy with or without cetuximab followed by total mesorectal excision in patients with high-risk rectal cancer (EXPERT-C). J Clin Oncol 30:1620–1627