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Cetuximab in the Treatment of Locally Advanced Head and Neck Cancer


recently, the addition of a taxane such as docetaxel (or, less commonly, paclitaxel) to the PF regimen (a triple combination known as TPF) is emerging as a more effective and less toxic standard compared with PF for induction chemotherapy.9


Recent studies suggest that there is a


lower risk of distant metastases after induction chemotherapy than after primary radiotherapy or chemoradiotherapy.10


Advances in the treatment of LA SCCHN over the past 30 years have provided some improvement in prognosis.11,12


Much of this


improvement has been gained from the combination of different treatments rather than relying on a single treatment modality.


However, there is a continuing requirement for more effective therapies to prevent both relapses and metastases and to improve overall survival. Improved understanding of the pathogenesis of SCCHN has led to the introduction of molecularly targeted strategies. The rationale behind these strategies is that by exploiting specific molecular modifications associated with cancer, transformed cells may be selectively targeted with less impact on healthy tissues. Such therapies are expected to have lower toxicity than chemotherapy, and may also have the potential to eliminate metastases that may not be eradicated with radiotherapy and/or surgery.13,14


Effective


targeted therapy may specifically impede processes on which the cancer is dependent.


In one study, aberrant EGFR copy numbers were found in 32 of 134 tumours (24%) in patients with SCCHN and EGFR overexpression was associated with poor prognosis.16


Epidermal growth factor receptor (EGFR) is a member of the human epidermal receptor (HER)/Erb-B family of receptor tyrosine kinases that transduce extracellular signals to intracellular responses. EGFR has been implicated in the growth, survival and invasive potential of tumour cells and studies in SCCHN have shown that 80–100% of tumours and many cells adjacent to tumour tissue have abnormal levels of EGFR.15


Clinical Development


A number of clinical trials have studied cetuximab in LA SCCHN. The use of cetuximab as an adjunct to radiotherapy was first investigated in 2001 in a phase I study29


in which patients were given an initial dose


of 100–500mg/m2 followed by weekly doses of 100–250mg/m2. During a median 28-month follow-up period, 13 out of 15 patients showed a complete response and two had partial remissions. Fever, asthenia, transaminase elevation, nausea and skin toxicities (grade 1–2 in most patients) were the most frequent adverse events. It was concluded that cetuximab can be safely given with radiotherapy at an initial dose of 400–500mg/m2 and a weekly dose of 250mg/m2.


The subsequent phase II and III studies investigating cetuximab in LA SCCHN can be divided into two general types: firstly, those using cetuximab concurrently with either radiotherapy or chemoradiotherapy; and secondly, those using cetuximab as part of induction or post-induction therapy regimens. An overview of the subsequent phase II and III studies both completed and ongoing is given in Table 1.


Clinical Studies Including Cetuximab with Concurrent Radiotherapy or Chemoradiotherapy for LA SCCHN Cetuximab with Radiotherapy


To date, the largest trial completed using cetuximab in LA SCCHN was a phase III study in which patients with locoregionally advanced unresectable cancers of the oropharynx, hypopharynx or pharynx received either radiotherapy alone or radiotherapy plus cetuximab at 73 treatment centres.30


Patients were randomised to high-dose


Therefore, much current research has been directed towards targeting abnormal EGFR activity in SCCHN. The EGFR inhibitors currently being studied include monoclonal antibodies, such as cetuximab and panitumumab and low-molecular-weight tyrosine kinase inhibitors, such as gefitinib and erlotinib.1,17


To date, small-scale


studies investigating the use of gefitinib or erlotinib in combination with chemoradiotherapy in the treatment of LA SCCHN have shown some encouraging efficacy and safety findings.18–21


Newer dual


tyrosine kinase inhibitors are also undergoing clinical trials in SCCHN, of which the furthest developed is lapatinib.1


Cetuximab Cetuximab (Erbitux®


antibody that inhibits ligand binding to the EGFR,22


) is an immunoglobulin G1 (IgG1) monoclonal resulting in


It also enhances the activity of several chemotherapeutic agents, including cisplatin and 5-FU, and sensitises cancer cells to the effects of radiation therapy.26–28


suppression of tumour growth, invasion, metastasis, DNA repair and angiogenesis.23,24 cytotoxicity.25


Currently cetuximab is the only targeted therapy approved for use in combination with radiotherapy in patients with LA SCCHN. Cetuximab has been approved for this indication in over 70 countries worldwide including, the US, EU, Russia, Australia, South Africa and countries in Central and South America, the Middle East and South East Asia.


EUROPEAN ONCOLOGY & HAEMATOLOGY Moreover, cetuximab induces cell-mediated


radiotherapy alone (≤76.8Gy total dose depending on site and regimen used) (213 patients) or high-dose radiotherapy plus weekly cetuximab (211 patients) at an initial dose of 400mg/m2, followed by weekly 250mg/m2 for the duration of radiotherapy. Three-year data from this study showed that in the radiotherapy plus cetuximab group compared with the group that received radiotherapy alone, there was a 32% reduction in the risk of locoregional progression (hazard ratio [HR] 0.68, 95% confidence interval [CI] 0.52–0.89; p=0.005) and a 26% reduction in the risk of death (HR 0.74, 95% CI 0.57–0.97; p=0.03). Median progression-free survival was 17.1 months in patients receiving radiotherapy with cetuximab and 12.4 months for radiotherapy alone (HR 0.70, 95% CI 0.54–0.90; p=0.006). Patient compliance with radiotherapy and the rates of distant metastases at one and two years were similar in the two groups.


Cetuximab did not increase the incidence of toxic effects normally associated with radiotherapy in SCCHN. After three years of treatment, in the groups receiving radiotherapy alone and radiotherapy plus cetuximab, the more common severe (grade ≥3) adverse events included mucositis (52 and 56%, respectively), acneiform rash (1 and 17%, respectively), radiation dermatitis (18 and 23%, respectively), weight loss (7 and 11%, respectively), xerostomia (3 and 5%, respectively) and dysphagia (30 and 26%, respectively). Compared with the group receiving radiotherapy alone, grade ≥3 adverse events that were reported at a significantly higher frequency in the group receiving cetuximab plus radiotherapy were acneiform rash (1 versus 17%; p<0.001) and infusion reaction (0 versus 3%; p<0.001). A summary of the main findings from this study is given in Table 2.


Recently, five-year data for the Bonner study were published and showed an overall survival of 45.6% in the combined treatment group


17


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