The role of Cetuximab in Oral Cavity Cancer: Current views and future prospectives
Dimitrios MASTAGKAS, Ioannis CHATZISTEFANOU, Charalampos ANDREADIS*, Vasileios KOGIAS, Konstantinos VAHTSEVANOS, Konstantinos ANTONIADES
Department of Oral and Maxillofacial Surgery, Aristotle University of Thessaloniki, “G. Papanikolaou” General Hospital, (Head: Professor K. Antoniades), *3rd Department of Clinical Oncology, Theagenion Cancer Hospital, Thessaloniki
Hellenic Archives of Oral & Maxillofacial Surgery (2016) 2, 89-97
SUMMARY: Cetuximab, a monoclonal epidermal growth factor receptor (EGFR) antibody (inhibitor), is one of the most recent treatment options for squamous cell head and neck cancer. The aim of this study is to analyse the current views on its role mainly in the treatment of oral cavity cancer, as well as its future prospectives.
We reviewed the most extensive phase III clinical trials on Cetuximab, which played a major role in its approval as a reliable treatment option.
A total of six studies were analysed, most of which prove the efficacy of this biological agent on locally advanced, recurrent and metastatic squamous cell head and neck cancer.
Cetuximab complements the current treatment proto- cols and seems to offer an advantage in terms of re- sponse, locoregional control of the disease and overall survival.
KEY WORDS: Cetuximab; EGFR; oral cancer; head and neck squamous cell cancer
REFERENCES
Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK, Gillison ML, Jor- dan RC, Konski AA, Thorstad WL, Trotti A, Beitler JJ, Garden AS, Spanos WJ, Yom SS, Axelrod RS: Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without Cetuximab for stage III to IV head and neck carcinoma: RTOG 0522: J Clin Oncol 32(27):2940-50, 2014
Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortés-Funes H, Hitt R, Gascón P, Amellal N, Harstrick A, Eckardt A: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody Cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23(24):5568-77, 2005
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945-1952, 2004
Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL: Defining risk levels in locally advanced head and neck cancers: a compara- tive analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27:843-850, 2005
Bonner JA, Raisch KP, Trummell HQ, Robert F, Meredith RF, Spencer SA, Buchsbaum DJ, Saleh MN, Stackhouse MA, LoBuglio AF, Pe- ters GE, Carroll WR, Waksal HW: Enhanced apoptosis with com- bination C225/radiation treatment serves as the impetus for clin- ical investigation in head and neck cancers. J Clin Oncol 18: 47- 53, 2000
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Yous- soufian H, Amellal N, Rowinsky EK, Ang KK: Radiotherapy plus Cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567-578, 2006
Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK: Radiotherapy plus Cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 ran- domised trial, and relation between Cetuximab-induced rash and survival. Lancet Oncol 11(1); 21-8, 2010
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA: Phase III randomized trial of cisplatin plus placebo compared with cis- platin plus Cetuximab in metastatic/recurrent head and neck can- cer: an Eastern Cooperative Oncology Group study. J Clin Oncol 23: 8646-8654, 2005
Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC: Cu- taneous side-effects in cancer patients treated with the antiepi- dermal growth factor receptor antibody C225. Br J Dermatol 144(6):1169-76, 2001
Chung CH, Dignam JJ, Hammond ME, Klimowicz CA, Petrillo KS, Magliocco KS, Jordan R, Trotti A, Spencer S, Cooper SJ, Quynh- Thu Le, Ang KK: Glioma-Associated Oncogene Family Zinc Finger 1 Expression and Metastasis in Patients With Head and Neck Squamous Cell Carcinoma Treated With Radiation Therapy (RTOG 9003). J Clin Oncol 29(10): 1326–1334, 2011
Cohen RB: Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC). Cancer Treat Rev 40(4): 567-77, 2014
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK: Postoperative concurrent ra- diotherapy and chemotherapy for high-risk squamous-cell carci- noma of the head and neck. N Engl J Med 350:1937-1944, 2004
Fan Z, Lu Y, Wu X, Mendelsohn J: Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine pro- liferation of A431 squamous carcinoma cells. J Biol Chem 269(44): 27595-602, 1994
Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31(7):845-52, 2013
Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ: Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. Natl Cancer Inst 90(11):824-32, 1998
Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and ra- diosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59(8):1935-40, 1999
Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM: Struc- tural basis for inhibition of the epidermal growth factor receptor by Cetuximab. Cancer Cell 7(4):301-311, 2005
Machiels JP, Subramanian S, Ruzsa A, Repassy G, Lifirenko I, Flygare A, Sørensen P, Nielsen T, Lisby S, Clement PM: Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open- label, randomised phase 3 trial. Lancet Oncol 12(4): 333-43, 2011
Magrini SM, Buglione M, Corvò R, Pirtoli L, Paiar F, Ponticelli P, Petrucci A, Bacigalupo A, Crociani M, Lastrucci L, Vecchio S, Bonomo P, Pasinetti N,Triggiani L, Cavagnini R, Costa L,Tonoli S, Maddalo M, Grisanti S: Cetuximab and Radiotherapy Versus Cisplatin and Ra- diotherapy for Locally Advanced Head and Neck Cancer: A Ran- domized Phase II Trial. J Clin Oncol 34(5):427-35, 2016
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Head and Neck cancers. NCCN.org
RTOG Clinical Trials, Study Number 0920: https://www.rtog.org/Clin- icalTrials/ProtocolTable/StudyDetails.aspx?study=0920
Saleh MN, Raisch KP, Stackhouse MA, Grizzle WE, Bonner JA, Mayo MS, Kim HG, Meredith RF, Wheeler RH, Buchsbaum DJ: Com- bined modality therapy of A431 human epidermoid cancer using anti-EGFr antibody C225 and radiation. Cancer Biother Radio- pharm 1999 14(6):451-63, 1999
Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D, Vodvarka P, Rischin D, Garin AM, Hirsch FR, Varella- Garcia M, Ghiorghiu S, Hargreaves L, Armour A, Speake G, Swais- land A, Vokes EE: Phase III study of gefitinib compared with intra- venous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 27(11): 1864-71, 2009
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Be- nasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R: Platinum-based chemotherapy plus Cetuximab in head and neck cancer. N Engl J Med 359(11):1116-1127, 2008
Department of Oral and Maxillofacial Surgery, Aristotle University of Thessaloniki, “G. Papanikolaou” General Hospital, (Head: Professor K. Antoniades), *3rd Department of Clinical Oncology, Theagenion Cancer Hospital, Thessaloniki
Hellenic Archives of Oral & Maxillofacial Surgery (2016) 2, 89-97
SUMMARY: Cetuximab, a monoclonal epidermal growth factor receptor (EGFR) antibody (inhibitor), is one of the most recent treatment options for squamous cell head and neck cancer. The aim of this study is to analyse the current views on its role mainly in the treatment of oral cavity cancer, as well as its future prospectives.
We reviewed the most extensive phase III clinical trials on Cetuximab, which played a major role in its approval as a reliable treatment option.
A total of six studies were analysed, most of which prove the efficacy of this biological agent on locally advanced, recurrent and metastatic squamous cell head and neck cancer.
Cetuximab complements the current treatment proto- cols and seems to offer an advantage in terms of re- sponse, locoregional control of the disease and overall survival.
KEY WORDS: Cetuximab; EGFR; oral cancer; head and neck squamous cell cancer
REFERENCES
Ang KK, Zhang Q, Rosenthal DI, Nguyen-Tan PF, Sherman EJ, Weber RS, Galvin JM, Bonner JA, Harris J, El-Naggar AK, Gillison ML, Jor- dan RC, Konski AA, Thorstad WL, Trotti A, Beitler JJ, Garden AS, Spanos WJ, Yom SS, Axelrod RS: Randomized phase III trial of concurrent accelerated radiation plus cisplatin with or without Cetuximab for stage III to IV head and neck carcinoma: RTOG 0522: J Clin Oncol 32(27):2940-50, 2014
Baselga J, Trigo JM, Bourhis J, Tortochaux J, Cortés-Funes H, Hitt R, Gascón P, Amellal N, Harstrick A, Eckardt A: Phase II multicenter study of the antiepidermal growth factor receptor monoclonal antibody Cetuximab in combination with platinum-based chemotherapy in patients with platinum-refractory metastatic and/or recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 23(24):5568-77, 2005
Bernier J, Domenge C, Ozsahin M, Matuszewska K, Lefèbvre JL, Greiner RH, Giralt J, Maingon P, Rolland F, Bolla M, Cognetti F, Bourhis J, Kirkpatrick A, van Glabbeke M: Postoperative irradiation with or without concomitant chemotherapy for locally advanced head and neck cancer. N Engl J Med 350:1945-1952, 2004
Bernier J, Cooper JS, Pajak TF, van Glabbeke M, Bourhis J, Forastiere A, Ozsahin EM, Jacobs JR, Jassem J, Ang KK, Lefèbvre JL: Defining risk levels in locally advanced head and neck cancers: a compara- tive analysis of concurrent postoperative radiation plus chemotherapy trials of the EORTC (#22931) and RTOG (# 9501). Head Neck 27:843-850, 2005
Bonner JA, Raisch KP, Trummell HQ, Robert F, Meredith RF, Spencer SA, Buchsbaum DJ, Saleh MN, Stackhouse MA, LoBuglio AF, Pe- ters GE, Carroll WR, Waksal HW: Enhanced apoptosis with com- bination C225/radiation treatment serves as the impetus for clin- ical investigation in head and neck cancers. J Clin Oncol 18: 47- 53, 2000
Bonner JA, Harari PM, Giralt J, Azarnia N, Shin DM, Cohen RB, Jones CU, Sur R, Raben D, Jassem J, Ove R, Kies MS, Baselga J, Yous- soufian H, Amellal N, Rowinsky EK, Ang KK: Radiotherapy plus Cetuximab for squamous-cell carcinoma of the head and neck. N Engl J Med 354(6):567-578, 2006
Bonner JA, Harari PM, Giralt J, Cohen RB, Jones CU, Sur RK, Raben D, Baselga J, Spencer SA, Zhu J, Youssoufian H, Rowinsky EK, Ang KK: Radiotherapy plus Cetuximab for locoregionally advanced head and neck cancer: 5-year survival data from a phase 3 ran- domised trial, and relation between Cetuximab-induced rash and survival. Lancet Oncol 11(1); 21-8, 2010
Burtness B, Goldwasser MA, Flood W, Mattar B, Forastiere AA: Phase III randomized trial of cisplatin plus placebo compared with cis- platin plus Cetuximab in metastatic/recurrent head and neck can- cer: an Eastern Cooperative Oncology Group study. J Clin Oncol 23: 8646-8654, 2005
Busam KJ, Capodieci P, Motzer R, Kiehn T, Phelan D, Halpern AC: Cu- taneous side-effects in cancer patients treated with the antiepi- dermal growth factor receptor antibody C225. Br J Dermatol 144(6):1169-76, 2001
Chung CH, Dignam JJ, Hammond ME, Klimowicz CA, Petrillo KS, Magliocco KS, Jordan R, Trotti A, Spencer S, Cooper SJ, Quynh- Thu Le, Ang KK: Glioma-Associated Oncogene Family Zinc Finger 1 Expression and Metastasis in Patients With Head and Neck Squamous Cell Carcinoma Treated With Radiation Therapy (RTOG 9003). J Clin Oncol 29(10): 1326–1334, 2011
Cohen RB: Current challenges and clinical investigations of epidermal growth factor receptor (EGFR)- and ErbB family-targeted agents in the treatment of head and neck squamous cell carcinoma (HNSCC). Cancer Treat Rev 40(4): 567-77, 2014
Cooper JS, Pajak TF, Forastiere AA, Jacobs J, Campbell BH, Saxman SB, Kish JA, Kim HE, Cmelak AJ, Rotman M, Machtay M, Ensley JF, Chao KS, Schultz CJ, Lee N, Fu KK: Postoperative concurrent ra- diotherapy and chemotherapy for high-risk squamous-cell carci- noma of the head and neck. N Engl J Med 350:1937-1944, 2004
Fan Z, Lu Y, Wu X, Mendelsohn J: Antibody-induced epidermal growth factor receptor dimerization mediates inhibition of autocrine pro- liferation of A431 squamous carcinoma cells. J Biol Chem 269(44): 27595-602, 1994
Forastiere AA, Zhang Q, Weber RS, Maor MH, Goepfert H, Pajak TF, Morrison W, Glisson B, Trotti A, Ridge JA, Thorstad W, Wagner H, Ensley JF, Cooper JS: Long-term results of RTOG 91-11: a comparison of three nonsurgical treatment strategies to preserve the larynx in patients with locally advanced larynx cancer. J Clin Oncol 31(7):845-52, 2013
Grandis JR, Melhem MF, Gooding WE, Day R, Holst VA, Wagener MM, Drenning SD, Tweardy DJ: Levels of TGF-alpha and EGFR protein in head and neck squamous cell carcinoma and patient survival. Natl Cancer Inst 90(11):824-32, 1998
Huang SM, Bock JM, Harari PM: Epidermal growth factor receptor blockade with C225 modulates proliferation, apoptosis, and ra- diosensitivity in squamous cell carcinomas of the head and neck. Cancer Res 59(8):1935-40, 1999
Li S, Schmitz KR, Jeffrey PD, Wiltzius JJ, Kussie P, Ferguson KM: Struc- tural basis for inhibition of the epidermal growth factor receptor by Cetuximab. Cancer Cell 7(4):301-311, 2005
Machiels JP, Subramanian S, Ruzsa A, Repassy G, Lifirenko I, Flygare A, Sørensen P, Nielsen T, Lisby S, Clement PM: Zalutumumab plus best supportive care versus best supportive care alone in patients with recurrent or metastatic squamous-cell carcinoma of the head and neck after failure of platinum-based chemotherapy: an open- label, randomised phase 3 trial. Lancet Oncol 12(4): 333-43, 2011
Magrini SM, Buglione M, Corvò R, Pirtoli L, Paiar F, Ponticelli P, Petrucci A, Bacigalupo A, Crociani M, Lastrucci L, Vecchio S, Bonomo P, Pasinetti N,Triggiani L, Cavagnini R, Costa L,Tonoli S, Maddalo M, Grisanti S: Cetuximab and Radiotherapy Versus Cisplatin and Ra- diotherapy for Locally Advanced Head and Neck Cancer: A Ran- domized Phase II Trial. J Clin Oncol 34(5):427-35, 2016
NCCN Clinical Practice Guidelines in Oncology (NCCN Guidelines) Head and Neck cancers. NCCN.org
RTOG Clinical Trials, Study Number 0920: https://www.rtog.org/Clin- icalTrials/ProtocolTable/StudyDetails.aspx?study=0920
Saleh MN, Raisch KP, Stackhouse MA, Grizzle WE, Bonner JA, Mayo MS, Kim HG, Meredith RF, Wheeler RH, Buchsbaum DJ: Com- bined modality therapy of A431 human epidermoid cancer using anti-EGFr antibody C225 and radiation. Cancer Biother Radio- pharm 1999 14(6):451-63, 1999
Stewart JS, Cohen EE, Licitra L, Van Herpen CM, Khorprasert C, Soulieres D, Vodvarka P, Rischin D, Garin AM, Hirsch FR, Varella- Garcia M, Ghiorghiu S, Hargreaves L, Armour A, Speake G, Swais- land A, Vokes EE: Phase III study of gefitinib compared with intra- venous methotrexate for recurrent squamous cell carcinoma of the head and neck. J Clin Oncol 27(11): 1864-71, 2009
Vermorken JB, Mesia R, Rivera F, Remenar E, Kawecki A, Rottey S, Erfan J, Zabolotnyy D, Kienzer HR, Cupissol D, Peyrade F, Be- nasso M, Vynnychenko I, De Raucourt D, Bokemeyer C, Schueler A, Amellal N, Hitt R: Platinum-based chemotherapy plus Cetuximab in head and neck cancer. N Engl J Med 359(11):1116-1127, 2008
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