Phase III study of high dose radiation with or without cetuximab in the treatment of locoregionally advanced squamous cell cancer of the head and neck

Reviewer: S. Jack Wei, MD
Abramson Cancer Center of the University of Pennsylvania
Last Modified: June 8, 2004

Presenter: James Bonner
Presenter's Affiliation: Erbitux Head and Neck Study Group
Type of Session: Scientific


  • More that 500,000 people worldwide develop head and neck cancers (HNC) annually including 40,000 people in the United States with 10,000 deaths annually
  • The standard therapy for HNC is radiation therapy (RT) with or without chemotherapy
  • Epidermal growth factor receptor (EGFR) is found on the cellular membrane and is linked to a number of downstream signaling pathways which play a role in cell cycle delay, apoptosis, and angiogenesis
  • ~90% of all HNC have been found to overexpress EGFR, and increased levels of EGFR have been found to be associated with aggressive tumor behavior and poor response to treatment
  • Cetuximab is an IgG1 monoclonal antibody that binds to EGFR and blocks EGFR activation through competitive inhibition
  • In preclinical studies, the addition of EGFR to RT has been found to increase sensitivity of cells to treatment with RT
  • Phase I/II trials have also shown promising response of HNC with the addition of cetuximab to RT
  • This study was undertaken to determine if the addition of cetuximab to RT for patients with locally advanced HNC improves outcomes

Materials and Methods

  • Patients with stage III/IV squamous cell cancer of the oropharynx, hypopharynx, or larynx who had measurable disease were enrolled
  • Patients were stratified by Karnofsky's Performance Status (KPS), nodal status, and T stage
  • Patients were randomized to receive either:
    • Arm 1: RT alone
    • Arm 2: The same RT + cetuximab (400 mg/m2 on week 1 (without RT) and 250 mg/m2 IV weekly on weeks 2-8)
  • Patients were treated with RT in one of three ways
      1. QD: 70 Gy in 35 daily fractions
      2. BID: 72-76.8 Gy in 60-64 bid fractions
      3. Concomitant boost: 72 Gy in 42 fractions with an in-field boost to the gross disease delivered on the last 12 fractions of treatment
  • Individual institutions were allowed to select which RT method they used
  • Post-RT neck dissection was recommend but not required for patients with >N1 disease
  • The study was designed to enroll 208 patients in each arm in order to detect a 50% increase in median time for local-regional control (LRC) with a power of 80%
  • This accrual goal was also found to have 80% power to detect an increase of 50% in median survival with an expected 200 total events


  • A total of 417 patients were enrolled in the trial (Arm 1 n=213, Arm 2 n=214)
  • Median follow-up was 38 mo with a minimum follow-up of 24 mo
  • Treatment arms were well-balanced with regards to KPS, T stage, N stage, age, gender, type of RT received, overall stage, and EGFR expression
  • 56% of patients in both arms received RT with the concomitant boost technique
  • The majority of patients in both arms had oropharyngeal cancers with the RT only arm having a slightly higher percentage of these patients, although this was statistically insignificant
  • 80% of patients and T1-T3 tumors; 20% had T4 tumors
  • 80% of patients had nodal involvement of disease
  • 24-25% of patients underwent neck dissection in both arms
  • Comparing Arm 1 to Arm 2:
    • Median LRC: 19 mo vs. 36 mo (p=0.02)
    • 1-year LRC: 59% vs. 69%
    • 2-year LRC: 48% vs. 56%
    • Median survival: 28 mo vs. 54 mo (p=0.02)
    • 2-year overall survival (OS): 55% vs. 62%
    • 3-year OS: 44% vs. 57% (p<0.02)
  •  41% vs. 47% had a skin reaction; however grade 3/4 skin reactions were seen in 18% vs. 34% (p<0.05)
  • There was no difference between arms in the rate of mucositis, dysphagia, xerostomia, or fatigue

Author's Conclusions

  • The addition of cetuximab to RT improves LRC and OS in a statistically and clinically meaningful way compared to RT alone
  • Minimal additive toxicities are noted with the addition of cetuximab.  In particular, there was no increase in the rates of mucositis or dysphagia
  • Further investigation of cetuximab is warranted in other epithelial malignancies were RT plays a central role in treatment

Clinical/Scientific Implications

Cetuximab is one of the emerging drugs that have shown significant benefit in this new era of targeted therapy in oncologic treatment.  This study shows an impressive improvement in LRC and OS with the addition of cetuximab to RT over RT alone.  The benefits seen with cetuximab are comparable to those seen with the addition of chemotherapy to RT in locally advanced HNC with the important distinction that while concurrent chemotherapy and RT have significantly increased acute toxicities, cetuximab resulted in very little additional acute toxicity.  In addition, this benefit was seen despite the fact that a variety of radiation techniques were used.   Subgroup analyses were not performed and these data will be presented at a later date.  It will be important to see if the different radiation techniques had an impact on the results of this trial.  It is clear that altered fractionation strategies (hyperfractionation or accelerated fractionation) improve the overall outcome and have become standard in locally advanced head and neck cancer.  Further follow-up is needed to determine whether this survival benefit holds and whether late toxicities may emerge.
It is important to note that the experimental arm of the trial was compared to RT alone.  While there is a subset of patients who are appropriately treated with RT alone, increasingly, combined modality therapy has been used in patients with locally advanced HNC.  The role of chemotherapy in addition to cetuximab and RT remain unclear, and future studies will need to examine the interplay of RT, chemotherapy, and targeted therapies such as cetuximab.  In the meantime, the addition of cetuximab to patients with locally advance HNC who are treated with RT alone should be considered a reasonable approach. 

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