Chemoradiation for Head and Neck Cancer
In this article, we use the example of head and neck cancer to show how concurrent chemoradiotherapy is used to treat a cancer where locoregional control is central for treatment success. The advent of concurrent chemoradiation has significantly contributed to the curability of head and neck cancer, including locoregionally advanced disease. Preserving organ function and reducing toxic effects are increasingly the focus of clinical trials. We review the available chemoradiotherapy platforms used for head and neck cancer, with initial discussions focused on single-agent cytotoxic-based regimens. We then assess the literature on multiagent-based regimens and include a discussion of the integration of novel agents, such as EGFR inhibitors, and antiangiogenic drugs into treatment platforms. Although single-agent cisplatin-based chemoradiotherapy is still widely used as a standard therapy, we propose that evidence increasingly shows that multiagent-based chemoradiotherapy, and EGFR-inhibitor-based treatments, offer distinct advantages. We provide guidance for clinicians based on current clinical trial evidence on how to choose appropriate treatment platforms for their patients.

For many tumors, concurrent chemoradiotherapy has a central role in the treatment of locoregional disease. In this article, we explore the use of chemoradiotherapy in head and neck cancer (HNC), where locoregional control is pivotal. HNC is the fifth most common cancer worldwide, with an estimated annual global incidence of 533,100 cases. Approximately 44,660 people in the US, and 76,000 in Europe per year are diagnosed with HNC. In the US, 30–40% of patients diagnosed with HNC eventually die from their disease. Most HNC diagnoses are squamous cell carcinomas ([HNSCC] 90–95%) and the following text, therefore, focuses on this disease subtype. However, concurrent chemoradiotherapy can also be used for other types of HNC.

HNC staging is complex and depends on the anatomic location of the tumor ( Table 1 ). For practical purposes, HNC is divided into three clinical stages: early, locoregionally advanced, and metastatic or recurrent. Treatment approaches can vary depending on the disease stage, and an evidence-based overview is provided in Figure 1. Treatment for locoregionally advanced disease remains challenging, and an aggressive treatment approach is necessary to achieve a cure. Concurrent chemoradiotherapy is aimed at improving the outcome for this group of patients (Figure 1).


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Evidence-based treatment algorithm for management of locally advanced head and neck squamous cell carcinomas. Four levels of evidence support the recommendations: level 1, multiple consistent phase III studies or one large, high-quality, multicenter, phase III trial; level 2, a smaller single phase III trial; level 3, multiple consistent phase II studies; and level 4, expert opinion or evidence of less than level 3. aReferral to an experienced center with an adequate support system is recommended. bLevel 1 evidence compared with radiotherapy as a single modality. No data are available for CRT comparisons; therefore, no clear recommendation can be made in comparison with CRT. This treatment option is an excellent choice for patients with a low performance status who are poor candidates for chemoradiotherapy. cHigh-risk features for recurrence are as follows: involved margins of resection, extranodal or extracapsular spread, perineural invasion, and the presence of two or more involved regional lymph nodes. dCetuximab-based CRT can also be considered as an option, but this therapy has not been studied postoperatively. On the basis of experience with other regimens, the therapy should be considered as a reasonable option, especially in patients who cannot tolerate more-toxic regimens. Abbreviations: CRT, concurrent chemoradiotherapy; ENT, ears, nose, and throat; HNSCC, head and neck squamous cell carcinoma; TFHX, paclitaxel, 5-fluorouracil, hydroxyurea and concurrent radiotherapy.

In the past, survival at 5 years for locoregionally advanced disease was reported to be only 40% (10–30% for patients with stage IVa and IVb tumors) and locoregional failure was the predominant cause of recurrence. More than 50% of patients who die from HNC have locoregional disease as the only site of failure, and almost 90% of patients with distant failure also have persistent locoregional disease. Therefore, the efficacy of any curative approach is measured by its ability to achieve locoregional control.

Historically, locoregionally advanced tumors were treated with surgery (with or without adjuvant radiotherapy) or radiotherapy alone. Only a minority of patients with locoregionally advanced disease can undergo adequate surgical resection, and the outcomes were poor with respect to survival and organ preservation. Furthermore, radiotherapy alone is not sufficient to successfully treat most HNC cancers at intermediate or advanced stages. During the past 5–10 years, chemoradiotherapy was shown to markedly improve survival and organ preservation. Currently, three multimodality treatment approaches are used. The first approach is surgery followed by adjuvant concurrent chemoradiotherapy, which enables precise pathologic staging and identification of high-risk features that influence the choice of adjuvant treatment. This approach can have limitations, such as poor organ preservation, depending on the anatomic location (e.g. larynx), and the majority of locoregionally advanced tumors are unresectable, especially if organ preservation is the goal.

The second approach is definitive concurrent chemoradiotherapy with surgery as an optional salvage or completion treatment. Although no pathologic information is obtained with this approach, it has the advantage of improved organ preservation. This benefit is most clearly established for laryngeal cancer but is increasingly recognized for other anatomic locations; however, this approach remains controversial for oral cavity tumors.

The third approach is the use of induction chemotherapy followed by definitive local therapy. Advantages include the potential to decrease the risk of distant failure and a rapid reduction in tumor bulk in responders. A response to induction appears to predict responsiveness to chemoradiotherapy. Nonetheless, this can result in prolonged treatment and additional chemotherapy-related toxic effects from systemic doses. This approach remains controversial, but data from recent clinical trials seem to support its use. The role of this approach in the context of concomitant chemoradiotherapy is currently being investigated in several large, multicenter, randomized trials. Induction chemotherapy lies beyond the scope of this article and is discussed elsewhere.