title: Phase II study of cetuximab in combination with cisplatin and radiation in unresectable, locally advanced head and neck squamous cell carcinoma: Eastern cooperative oncology group trial E3303.
abstract: OBJECTIVE
  Treatment with cisplatin or cetuximab combined with radiotherapy each yield superior survival in locally advanced squamous cell head and neck cancer (LA-SCCHN) compared with radiotherapy alone. Eastern Cooperative Oncology Group Trial E3303 evaluated the triple combination.
  
  
  METHODS
  Patients with stage IV unresectable LA-SCCHN received a loading dose of cetuximab (400 mg/m(2)) followed by 250 mg/m(2)/week and cisplatin 75 mg/m(2) q 3 weeks ×3 cycles concurrent with standard fractionated radiotherapy. In the absence of disease progression or unacceptable toxicity, patients continued maintenance cetuximab for 6 to 12 months. Primary endpoint was 2-year progression-free survival (PFS). Patient tumor and blood correlates, including tumor human papillomavirus (HPV) status, were evaluated for association with survival.
  
  
  RESULTS
  A total of 69 patients were enrolled; 60 proved eligible and received protocol treatment. Oropharyngeal primaries constituted the majority (66.7%), stage T4 48.3% and N2-3 91.7%. Median radiotherapy dose delivered was 70 Gy, 71.6% received all three cycles of cisplatin, and 74.6% received maintenance cetuximab. Median PFS was 19.4 months, 2-year PFS 47% [95% confidence interval (CI), 33%-61%]. Two-year overall survival (OS) was 66% (95% CI, 53%-77%); median OS was not reached. Response rate was 66.7%. Most common grade ≥3 toxicities included mucositis (55%), dysphagia (46%), and neutropenia (26%); one attributable grade 5 toxicity occurred. Only tumor HPV status was significantly associated with survival. HPV was evaluable in 29 tumors; 10 (all oropharyngeal) were HPV positive. HPV(+) patients had significantly longer OS and PFS (P = 0.004 and P = 0.036, respectively).
  
  
  CONCLUSIONS
  Concurrent cetuximab, cisplatin, and radiotherapy were well tolerated and yielded promising 2-year PFS and OS in LA-SCCHN with improved survival for patients with HPV(+) tumors.
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania. egloffam@upmc.edu.
authors.forename: Ann Marie
authors.initials: AM
authors.lastname: Egloff
authors.affiliation: Dana-Farber Cancer Institute, Boston, Massachusetts.
authors.forename: Ju-Whei
authors.initials: JW
authors.lastname: Lee
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Corey J
authors.initials: CJ
authors.lastname: Langer
authors.affiliation: University of Pennsylvania, Philadelphia, Pennsylvania.
authors.forename: Harry
authors.initials: H
authors.lastname: Quon
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Alec
authors.initials: A
authors.lastname: Vaezi
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Jennifer R
authors.initials: JR
authors.lastname: Grandis
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Raja R
authors.initials: RR
authors.lastname: Seethala
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Lin
authors.initials: L
authors.lastname: Wang
authors.affiliation: Emory University, Atlanta, Georgia.
authors.forename: Dong M
authors.initials: DM
authors.lastname: Shin
authors.affiliation: University of Pittsburgh, Pittsburgh, Pennsylvania.
authors.forename: Athanassios
authors.initials: A
authors.lastname: Argiris
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Donghua
authors.initials: D
authors.lastname: Yang
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Ranee
authors.initials: R
authors.lastname: Mehra
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: John Andrew
authors.initials: JA
authors.lastname: Ridge
authors.affiliation: Northwestern University, Chicago, Illinois.
authors.forename: Urjeet A
authors.initials: UA
authors.lastname: Patel
authors.affiliation: Fox Chase Cancer Center, Philadelphia, Pennsylvania.
authors.forename: Barbara A
authors.initials: BA
authors.lastname: Burtness
authors.affiliation: Johns Hopkins University School of Medicine and Sydney Kimmel Comprehensive Cancer Center, Baltimore, Maryland.
authors.forename: Arlene A
authors.initials: AA
authors.lastname: Forastiere
mesh_terms: D000328:Adult; D000368:Aged; D061067:Antibodies, Monoclonal, Humanized / Q000008:administration & dosage; D000971:Antineoplastic Combined Chemotherapy Protocols / Q000627:therapeutic use*; D002294:Carcinoma, Squamous Cell / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D000068818:Cetuximab; D002945:Cisplatin / Q000008:administration & dosage; D018450:Disease Progression; D005260:Female; D006258:Head and Neck Neoplasms / Q000188:drug therapy* / Q000209:etiology / Q000401:mortality / Q000473:pathology / Q000532:radiotherapy*; D006801:Humans; D008297:Male; D008875:Middle Aged; D009362:Neoplasm Metastasis; D009367:Neoplasm Staging; D011878:Radiotherapy; D012307:Risk Factors; D000077195:Squamous Cell Carcinoma of Head and Neck; D016896:Treatment Outcome
chemical_list: D061067:Antibodies, Monoclonal, Humanized; D000068818:Cetuximab; D002945:Cisplatin
references.citation: Cancer Res. 1999 Apr 15;59(8):1935-40
references.pmid: 10213503
references.citation: N Engl J Med. 1993 Jan 21;328(3):184-94
references.pmid: 8417385
references.citation: N Engl J Med. 1998 Jun 18;338(25):1798-804
references.pmid: 9632446
references.citation: Crit Rev Oncol Hematol. 1996 Oct;24(2):97-116
references.pmid: 8889368
references.citation: Cancer. 2012 Aug 15;118(16):3882-92
references.pmid: 22281752
references.citation: Clin Adv Hematol Oncol. 2007 Feb;5(2):79-81
references.pmid: 17344795
references.citation: Cancer Clin Oncol. 2013;2(1):51-61
references.pmid: 23935769
references.citation: Oral Oncol. 2011 Oct;47(10):961-6
references.pmid: 21889392
references.citation: Int J Radiat Oncol Biol Phys. 2007 Feb 1;67(2):568-72
references.pmid: 17236972
references.citation: J Clin Oncol. 1998 Apr;16(4):1318-24
references.pmid: 9552032
references.citation: J Natl Cancer Inst. 1998 Jun 3;90(11):824-32
references.pmid: 9625170
references.citation: J Biol Chem. 1994 Nov 4;269(44):27595-602
references.pmid: 7961676
references.citation: J Clin Oncol. 2007 Jun 1;25(16):2171-7
references.pmid: 17538161
references.citation: Cancer Res. 2009 Sep 1;69(17):6831-8
references.pmid: 19723666
references.citation: J Natl Cancer Inst. 1999 Dec 15;91(24):2081-6
references.pmid: 10601378
references.citation: Clin Cancer Res. 2000 Feb;6(2):701-8
references.pmid: 10690556
references.citation: J Clin Oncol. 2003 Jul 15;21(14):2787-99
references.pmid: 12860957
references.citation: Oncogene. 2012 Jun 21;31(25):3039-50
references.pmid: 22020333
references.citation: Cancer Res. 2002 Dec 15;62(24):7350-6
references.pmid: 12499279
references.citation: Lancet Oncol. 2010 Jan;11(1):21-8
references.pmid: 19897418
references.citation: Int J Radiat Oncol Biol Phys. 2003 Sep 1;57(1):246-54
references.pmid: 12909240
references.citation: J Clin Oncol. 2006 Sep 1;24(25):4170-6
references.pmid: 16943533
references.citation: N Engl J Med. 2008 Sep 11;359(11):1116-27
references.pmid: 18784101
references.citation: J Clin Oncol. 2006 Mar 1;24(7):1072-8
references.pmid: 16505426
references.citation: J Clin Oncol. 2010 Dec 20;28(36):5294-300
references.pmid: 21079141
references.citation: N Engl J Med. 2006 Sep 7;355(10):983-91
references.pmid: 16957145
references.citation: Clin Cancer Res. 2000 Jun;6(6):2166-74
references.pmid: 10873065
references.citation: Int J Radiat Oncol Biol Phys. 2004 Mar 1;58(3):959-65
references.pmid: 14967456
references.citation: J Clin Oncol. 2009 Oct 20;27(30):5068-74
references.pmid: 19738126
references.citation: J Clin Oncol. 2007 Aug 1;25(22):3230-7
references.pmid: 17664471
references.citation: Int J Radiat Oncol Biol Phys. 1994 May 15;29(2):243-7
references.pmid: 8195014
references.citation: Int J Radiat Oncol Biol Phys. 2004 Feb 1;58(2):561-6
references.pmid: 14751528
references.citation: Clin Cancer Res. 2005 Aug 15;11(16):5856-62
references.pmid: 16115926
references.citation: Proc Natl Acad Sci U S A. 2012 Jan 10;109(2):570-5
references.pmid: 22203985
references.citation: J Clin Oncol. 2003 Jan 1;21(1):92-8
references.pmid: 12506176
references.citation: Head Neck. 1997 Oct;19(7):567-75
references.pmid: 9323144
references.citation: J Natl Cancer Inst. 2000 Feb 2;92(3):205-16
references.pmid: 10655437
references.citation: N Engl J Med. 2008 Sep 11;359(11):1143-54
references.pmid: 18784104
references.citation: Am J Surg Pathol. 2012 Jul;36(7):945-54
references.pmid: 22743284
references.citation: Lancet. 2000 Mar 18;355(9208):949-55
references.pmid: 10768432
references.citation: Clin Cancer Res. 2012 Apr 15;18(8):2278-89
references.pmid: 22351687
references.citation: N Engl J Med. 2006 Feb 9;354(6):567-78
references.pmid: 16467544
references.citation: Cancer Biother Radiopharm. 1999 Dec;14(6):451-63
references.pmid: 10850332
references.citation: Clin Cancer Res. 2013 Dec 1;19(23):6633-43
references.pmid: 24088734