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Jan B Vermorken
University Hospital Antwerp
Head and neck cancer (HNC) ranks sixth on the list of common cancers, representing about 6% of all cancers. Each year, more than half a million new cases are diagnosed worldwide.(1,2) Approximately 60-65% of patients with HNC can be cured with surgery and/or radiotherapy. The prognosis of an individual patient depends on the primary tumour site and its extension, the histological type, nodal involvement and, probably, grading.(3,4) The great majority (>90%) of HNC in the western world is of squamous cell origin.(3) When patients with squamous cell carcinoma of the head and neck (SCCHN) present with early disease (stages I or II) they can be effectively treated with single-modality treatment. Sixty to 90% will be disease-free after five years, the development of second primaries being one of the major threats.(5) However, two-thirds of patients present with locoregionally advanced disease (stages III and IV). In the past, those with resectable disease were usually treated with a combined approach (ie, with surgery and radiation therapy). Despite this, 60% developed local and/or regional recurrences, 20% distant metastases, and others had the risk to develop second primaries. The outcome of patients with unresectable disease was extremely poor, with five-year survival figures <10% and the majority of them dying within 18 months.(6,7) The prognosis of patients with recurrent and/or metastatic SCCHN has hardly changed in the past 25 years. Even with modern chemotherapeutic agents, median survival is still only 6-12 months and depends on prognostic variables such as tumour grade, primary tumour site, prior treatment, performance status and weight loss.(8)
Decision-making in HNC patients is a complex issue, taking into account:
At all times, a multidisciplinary approach to the patient is preferable.(9)
Discussion on locally advanced HNC
The lack of survival benefit in most randomised trials of induction chemotherapy in the past(10) and data from the individual patient-based meta-analysis(11) have changed the attitude of many clinicians towards favouring the concurrent use of chemotherapy and irradiation (chemoradiation) in patients with locally advanced SCCHN. This is true for both patients with resectable disease and those with nonresectable disease. In these settings the use of cisplatin 100mg/m(2) on days 1, 22 and 43 of radiotherapy is considered a standard approach.(10,12,13) However, toxicity issues call for further refinement and alternatives.(12) The development of altered fractionation regimens has recently been shown to improve locoregional control and survival in HNC patients also.(14,15) New techniques such as intensity-modulated radiotherapy (IMRT) represent an advance in treatment and one that is progressively being implemented. However, larger trials are still required to provide evidence for the use of IMRT compared with more conventional techniques.(12)
As mentioned, in the past no consistent impact of induction chemotherapy on locoregional control or overall survival was observed despite many studies showing reduction (or delay) of distant metastases. However, Pignon et al(11) reported in a meta-analysis that the effect of the PF regimen (cisplatin/5-FU) differed significantly in that respect from the other induction chemotherapy regimens and some individual trials using this regimen indeed showed a survival benefit.(7,16,17) The role of induction therapy has been revisited since the introduction of newer agents, in particular the taxanes. Phase II studies already suggested that the addition of a taxane to the classic PF regimen increased its efficacy.(18,19) The superiority of these triple regimens (TPF) over the classic PF regimen has been confirmed recently in several large randomised trials.(20-22) All three trials showed improved outcome with less severe toxicity in the TPF arm and, when this was evaluated, improved quality of life.(23) Induction chemotherapy and chemoradiation might have complementary effects on overall disease control. Combining them seems a new way to go and should be tested in randomised trials. Preliminary data from a phase III trial performed in Spain suggest that induction with docetaxel, cisplatin and 5-FU (TPF) followed by chemoradiation (with cisplatin) is superior to concurrent cisplatin-based chemoradiation alone.(24) The tolerance of cytotoxic chemotherapy after locoregional therapy (adjuvant chemotherapy), in particular after chemoradiation, is poor and does not seem to be a promising approach.(10)
Very interesting data have been obtained in studies with biological agents in the locoregionally advanced disease setting. Results of a phase III trial comparing radiotherapy alone with radiotherapy in combination with weekly cetuximab (a chimeric IgG1 monoclonal antibody targeting the epidermal growth factor receptor) indicated that both duration of locoregional control (24.4 vs 14.9 months; p=0.005) and median duration of survival (49 vs 29.3 months; p=0.03) were significantly better with the combined treatment arm.(25) There was no difference in grade 3-4 acute toxicity except for acneiform rash and infusion reactions. In particular, no increase in mucosal toxicity was observed. This last observation is of extreme importance, because increased mucosal reactions are generally observed when radiotherapy is combined with cytotoxic chemotherapy, and because it shows a possible new way to improve chemoradiation approaches further.(26) Biological agents may also be attractive in the adjuvant setting, because of their more favourable toxicity profile. This is particularly true for the epidermal growth factor receptor tyrosine kinase inhibitors (EGFR TKIs), which can be given orally. Patients who might be appropriate candidates for such agents in the adjuvant setting can be selected by an in-vivo sensitivity testing, as recently reported by Delord et al.(27)
Apart from EGFR inhibitors, many agents interacting with other targets are under study, such as cyclooxygenase (Cox)-2 inhibitors, vascular endothelial growth factor (VEGF) and VEGF receptor inhibitors, aurora kinase inhibitors, proteasome inhibitors, histone deacetylase inhibitors, insulin-like growth factor 1 inhibitors and anti-epithelial cellular adhesion molecule (Ep-CAM) therapies, either alone or in combination with chemotherapy and/or radiotherapy. Without doubt, molecular targeted therapy represents a new way to improve the outcome of patients with SCCHN further.(28)
TPF has established itself as the standard induction regimen in locally advanced SCCHN, being more efficacious and less toxic than the classic cisplatin/5-FU regimen. Its sequential use with chemoradiation should be further explored. The improved survival without an increase in acute mucosal reactions in patients with locally advanced HNC who are treated with cetuximab plus radiotherapy in comparison to those treated with radiotherapy alone should be considered a breakthrough in the treatment of head and neck cancer.