ReviewCurrent concepts of management in radiotherapy for head and neck squamous-cell cancer
Introduction
Head and neck squamous-cell carcinoma (HNSCC) is a complex disease that is characterized by clinical, pathological, and biological heterogeneity arising in different localisations of the head and neck region.1 The most important risk factors of HNSCC are tobacco and alcohol consumption, and human papillomavirus (HPV) (especially for oropharyngeal cancer).2 About two-third of patients with HNSCC present with locally advanced disease, with or without regional lymph node involvement. Only a small proportion of patients have distant metastasis at initial presentation.3
Along with surgery, radiotherapy plays a key role in the management of early stage and locally advanced head and neck squamous-cell carcinomas (HNSCC) either alone or, more frequently combined with surgery and/or chemotherapy. Several approaches have been developed to improve the therapeutic ratio of RT, which will be summarized in this review.
Section snippets
Altered fractionated radiotherapy
The majority of patients with HNSCC present with locally advanced, stage III or IV disease that requires a combination of chemotherapy, radiation, or surgery.1 Radiotherapy (RT) plays a key role in the management of these locally advanced stages but its results remain relatively poor in advanced cases and several approaches have been developed to improve its efficacy, while maintaining acceptable toxicities. In the last decades, altered fractionation has been one of the tool shown to improve
Concomitant chemoradiotherapy
Chemotherapy plays an important role in the treatment of locally advanced HNSCC either as concomitant chemoradiotherapy (CT-RT) or as induction chemotherapy. A major advance in the treatment of this stage of disease has been the introduction of concomitant CT-RT.9
Several phase III clinical trials have shown that CT-RT yields better results than radiotherapy alone.10 In a phase III multicenter randomized trial of Head and Neck Oncology and Radiotherapy Group (GORTEC 94–01), comparing
Combination of chemotherapy and altered fractionated radiotherapy
Whether the use of altered fractionated RT instead of conventional RT in combination with chemotherapy could still improve the anti-tumor efficacy with acceptable increased toxicity remains an opened question. The first combinations of altered fractionation schedules and chemotherapy have been tested in randomized trials with promising results. Most of these trials compared altered fractionated RT alone to altered fractionated RT combined with chemotherapy and the magnitude of the benefit
Molecular targeted therapy combined with radiotherapy
The combination of RT with molecular targeted therapy has been show recently to be successful for improving the therapeutic outcome of patients with locally advanced head and neck carcinomas. The epidermal growth factor receptor (EGFR) has been identified as an important target for cancer therapy.23 Head and neck cancer cells generally express EGFR, and high levels of EGFR have been associated with a reduction in overall survival and a higher risk of locoregional relapse in head and neck cancer
Induction (neoadjuvant) chemotherapy based on taxanes and cisplatin
Induction chemotherapy is generally associated with significant tumor response and with a small decrease in the rate of distant metastasis (a major concern in patients with multiple or large lymph nodes1). HNSCC is chemo-responsive malignancy and CDDP-based induction chemotherapy can produce response rates up to of 80%, with complete response rates of 20–40% of locally advanced cases.3
Some randomized trials comparing locoregional therapy with or without CDDP-based induction chemotherapy have
Hypoxia and tumor response to radiotherapy
Tumor hypoxia has been recognized as a potential cause of tumor failure of treatment with ionizing radiation, both in experimental models and in human head and neck carcinomas. The potential importance of hypoxia as a mechanism limiting the cure rate in patients with head and neck cancer treated with radiation has been recognized.43 Recently, a new approach to tumor hypoxia has been developed using drugs that are preferentially cytotoxic to hypoxic cells, such as tirapazamine (TPZ). Preclinical
Prevention and management of treatment related toxicity, new radiotherapy techniques
RT may lead to transient and/or permanent injury to normal tissues within the treatment field. The magnitude of damage depends both on nature and the volume of tissue irradiated, the dose of radiation delivered, and the association with other drugs (cytotoxic or molecular targeted drugs). Most patients treated by RT or RT-CT will be affected to some degree by the acute and chronic side effects, including xerostomia, mucositis, dysphagia etc… Adequate (and often aggressive) management is
Quality assurance in radiotherapy
In a randomised phase III trial of TROG76, 861 patients with locally advanced HNSCC, a careful clinical review showed that 25% patients were found to have major deviations in the RT plan or in the RT daily realisation. This translated into a major adverse impact on tumor control probability and this was associated with an increased risk of death (HR = 1.56; p ⩽ 0.0001), any failure (HR = 1.65; p < 0.0001), and locoregional failure (HR = 1.82; p = 0.0002). This is so far the strongest evidence that the
Conclusion
RT of head and neck cancers has been improved in the last decades, with altered fractionated regimen, concomitant CT-RT etc. Concomitant CT-RT is one of the most commonly used treatment in locally advanced cases. Molecular targeted therapy with cetuximab combined with RT has been shown to improve the efficacy of RT alone while maintaining, acceptable toxicities. In the future, we need to find out whether other molecular targeted therapies could improve the efficacy of concurrent CT-RT, whether
Conflict of Interest Statement
None declared.
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