Many factors can influence survival and locoregional control after primary treatment of head and neck cancers. In two randomized trials, the role of adjuvant chemoradiation was clarified. In randomized EORTC 22931 trial, 334 patients with resected locally advanced head and neck cancer were randomly assigned to radiotherapy alone or with concomitant cisplatin (100 mg/m², on days 1, 22, and 43 of radiotherapy) [35]. High-risk disease was defined as T3 or T4 primary with any nodal stage (except T3N0 laryngeal cancer), positive surgical margins, positive extracapsular extension, positive perineural invasion, or vascular invasion. In EORTC trial, 5-year PFS, OS, and locoregional control were significantly improved in postoperative concurrent chemoradiotherapy arm compared to postoperative radiotherapy alone arm (47 % vs. 36 %; P = 0.04, 53 % 40 %; P = 0.02 and 82 % vs. 69; P = 0.007, respectively) with a median 60-month follow-up.

In RTOG (the Radiation Therapy Oncology Group) 9501 trial , 459 patients with resected high-risk HNSCC randomly assigned to radiotherapy alone or the same doses of RT with concomitant cisplatin (100 mg/m², on days 1, 22, and 43 of radiotherapy) as EORTC trial [36]. In RTOG 9501 trial, high-risk factors were defined as positive surgical margins, positive two or more lymph nodes, or extracapsular nodal extension. In concurrent chemoradiotherapy arm, 2-year locoregional control and DFS were significantly improved compared to radiotherapy arm alone but OS did not differ significantly between treatment groups with a median of 45.9-month follow-up. In the updated results of RTOG 9501 trial at 10 years, locoregional control and DFS were significantly improved only in patients with extracapsular nodal spread or positive margins [37].

In the combined analysis of EORTC 22931 and RTOG 9501 trials for defining risk levels in operated locally advanced HNSCC, extracapsular nodal extension and/or positive surgical margins were found the only risk factors associated with the benefit of concomitant adjuvant chemotherapy and radiotherapy [38]. Thus, the presence of extracapsular nodal extension and/or positive surgical margins is considered a definitive indication of adjuvant treatment according to the current guidelines [3, 4].

The median OS was generally less than 1 year for incurable recurrent or metastatic HNSCC despite intensive chemotherapy and targeted agents [6]. Cisplatin, carboplatin, docetaxel, paclitaxel, methotrexate, fluorouracil, capecitabine, and pemetrexed are commonly used single agents for palliative treatment of incurable recurrent or metastatic HNSCC patients [4]. Despite platinum doublets studies in phase III trials significantly improved response rate, no significant effect on OS was observed [39, 40]. Also no specific platin-based regimen superior to another platin-based regimen despite adding different schedules of taxanes [6, 41]. In symptomatic patients, to increase response rate, platinum-based, multi-agent combination regimens can be given, and single-agent chemotherapy regimens can be given to asymptomatic patients with low tumor burden.

Overexpression of EGFR was observed approximately in 90 % of HNSCC patients and is associated with poor prognosis [5, 42]. EGFR gene amplification was also associated with poor survival and locoregional recurrence in head and neck cancer. Cetuximab is a chimeric IgG1 monoclonal antibody that specifically binds to EGFR. Cetuximab inhibits DNA double-strand break repair that demonstrates synergistic activity with chemotherapy and radiotherapy [43].

In a randomized phase III trial, 424 patients with locoregionally advanced head and neck cancer were randomly assigned to treatment with high-dose radiotherapy alone or high-dose radiotherapy plus weekly cetuximab [8]. Cetuximab was initiated as loading dose 400 mg/m² 1 week before radiotherapy followed by a weekly dose of 250 mg/m² during radiotherapy. The primary end point of this study was the duration of control of locoregional disease. Locoregional control was significantly improved in patients treated with cetuximab plus radiotherapy compared to radiotherapy alone arm (24.4 months vs. 14.9 months, P = 0.005). The median OS also significantly improved in cetuximab plus radiotherapy compared to radiotherapy alone arm with a median 54-month follow-up (49.0 months vs. 29.3 months, P = 0.03). In the subgroup analysis, the beneficial effect was prominent especially oropharyngeal cancers. In the long-term evaluation of this trial, 5-year OS was 45.6 and 36.4 % in cetuximab plus radiotherapy and radiotherapy alone arms, respectively (P = 0.018) [9]. Additionally, OS benefit was limited to only patients who developed an acneiform rash of at least grade 2 severity.

In phase III EXTREME trial , 442 patients with incurable or metastatic HNSCC randomly assigned to receive platinum-based therapy alone or in combination with cetuximab as a first-line palliative regimen [7]. In cetuximab plus chemotherapy arm, cetuximab monotherapy was given until disease progression or unacceptable toxicity if at least stable disease was achieved after a maximum of six cycles of chemotherapy. The primary end point was OS. EXTREME trial demonstrated a significant OS benefit with the addition of cetuximab to platinum-based therapy; median OS improved from 7.4 to 10.1 months (P = 0.04).

The OS benefit of cetuximab was shown either as curative treatment or palliative treatment. Cetuximab is the only targeted therapy to be routinely used in clinical practice in the treatment of recurrent or metastatic HNSCC. Other EGFR agents and various biologic agents are under study. Several phase III trials of both cetuximab and novel targeting agents are still ongoing.