Adjuvant chemotherapy to eradicate micrometastases following local therapy has not been studied extensively in HNSCC. The principal objectives of adjuvant trials have been to control subclinical persistent disease after surgery or radiotherapy and to decrease the rates of locoregional and distant relapse. The ideal study design would include enrollment of (high-risk) patients with resectable advanced disease, early administration after local therapy to avoid drug resistance, and an effective regimen. Although no study has met all of these criteria, promising leads for future studies have emerged.

A number of randomized studies have evaluated the impact of adjuvant multiagent chemotherapy with no clear survival impact. The most definitive data of adjuvant therapy were recently reported. The preliminary analysis of a phase III prospective adjuvant chemotherapy trial conducted by the RTOG in a “high-risk group” of patients with HNSCC was reported recently by Cooper and colleagues. Patients were randomized to receive radiotherapy alone (60 to 66 Gy) (231 patients) versus radiotherapy plus cis-diamminedichloroplatinum (CDDP) (100 mg/m² on days 1, 22, and 43) (228 patients), and the primary endpoint was locoregional control. In the postoperative adjuvant setting, there was no significant improvement in locoregional control or overall survival in the concurrent CDDP/radiotherapy arm.

Disease-free survival was significantly improved but at the cost of significant acute and total toxicity. The preliminary primary finding was surprising since the same concurrent regimen has been shown to increase overall and disease-free survival (when compared with radiotherapy alone) in advanced NPC and unresectable HNSCC.

Neoadjuvant (or Concomitant) plus Adjuvant Chemotherapy
This is an important primary therapy study design. The largest of these is an National Cancer Institute (NCI)-sponsored multi-institutional trial, begun in 1978, called the Head and Neck Contracts Program. Over 400 patients with resectable stage III or IV disease were randomized to (1) induction chemotherapy (one cycle of cisplatin and bleomycin) followed by standard therapy (surgery and radiotherapy in all study arms); (2) induction chemotherapy followed by standard therapy followed by six cycles of adjuvant monthly cisplatin (80 mg/m²) by 24-h continuous infusion; or (3) standard local therapy only. At a median follow-up of more than 5 years, the disease-free and overall survivals were not significantly different among the three arms. This study has been criticized because of its one cycle of induction chemotherapy, considered suboptimal (3% complete response, 34% objective response), and a striking noncompliance rate in the adjuvant-therapy arm (47% never received any maintenance therapy). Subset analyses of this study suggested improved disease-free and/or overall survival in three subgroups: lesions of the oral cavity, T1-2 primary lesions, and N1-2 regional disease. This approach is under active study with newer induction and concomittant regimens.

Summary and Future Directions
Advanced local disease is the focus of primary chemotherapy investigation in HNSCC. Advanced local HNSCC is not controlled adequately by standard surgery and/or radiotherapy alone; the 2-year disease-free survival rate after standard therapy is less than 40%. Preclinical work strongly supports the early integration of chemotherapy into the primary management of advanced HNSCC.

Primary chemotherapy in HNSCC falls into three main treatment categories: (1) neoadjuvant chemotherapy, designed to reduce tumor burden prior to definitive local control; (2) concomitant chemoradiotherapy, designed to be a third definitive treatment (in addition to surgery and radiotherapy) for controlling advanced local HNSCC; and (3) adjuvant chemotherapy, designed to maintain patients (or to prevent recurrence) after definitive local control.

The major goals of neoadjuvant chemotherapy are to prolong disease-free and overall survivals and to improve the quality of life for surviving patients by providing effective organ-preservation approaches for the control of advanced HNSCC. Data from the numerous phase I and II neoadjuvant studies reveal many positive features of this approach, including multiagent response rates of 70% to 90% (complete responses in 20% to 50% of patients), with 30% to 70% of clinically complete responders showing complete pathologic tumor regression in biopsy or surgical specimens. Initial tumor stage or extent - whether defined by overall stage, T stage, N stage, or resectability - is predictive of response to chemotherapy and survival. Response to chemotherapy is predictive of response to radiotherapy. Furthermore, chemotherapy responders have a better prognosis than do nonresponders, but whether this is a benefit of chemotherapy or a result of unknown factors in the responding subset of patients is not clear. Locoregional control is adequate with surgery or radiotherapy alone in selected patients who respond completely to induction. Induction chemotherapy does not significantly increase the toxicity of subsequent radiotherapy, surgery, or chemotherapy. Major concerns about the neoadjuvant approach are the possibilities of delaying and compromising definitive local therapy and the risk that responding patients may refuse definitive local therapy. Furthermore, neoadjuvant chemotherapy definitely prolongs the treatment course, is expensive, and compromises later palliative chemotherapy in recurring patients. Of the over 40 phase III trials incorporating neoadjuvant chemotherapy, only one (using single-agent regional chemotherapy) reported significantly improved survival over that of patients receiving standard local therapy. These trials were flawed in many aspects, including study size, heterogeneous patient populations/disease sites/local therapies, and ineffective chemotherapy (median complete response rate of 10% or less in trials).

One randomized neoadjuvant trial, the VACSP trial, did have a large sample size, a relatively homogeneous patient population (patients with advanced operable laryngeal cancer), and a relatively effective regimen of chemotherapy (cisplatin and infusion 5-fluorouracil at full doses). Although this trial produced a respectable complete response rate, it did not indicate increased survival. Still, neoadjuvant chemotherapy could not be evaluated as an independent variable because the locoregional treatments in the two study arms were not identical. Even so, this study achieved the positive results of laryngeal preservation in 60% of patients and a significant decrease in distant relapse rate in the neoadjuvant arm.

Phase I and phase II trials must continue to translate the preclinical study data into trials of new, more active regimens of EGFR inhibitors, p53-targeting agents, and FTIs, among other agents.

The second major category of primary chemotherapy is that of regimens designed to achieve definitive local and distant control. So far, concomitant chemoradiotherapy is the only approach in this category that has shown potential by increasing survival in randomized testing. This survival benefit has appeared in trials with both resectable and unresectable HNSCC. Although early trials used suboptimal intensities, concomitant chemoradiotherapy is designed ultimately to maximize the dose intensities of both treatment modalities. All the positive single-agent concomitant trials used suboptimal doses of active drugs (eg, bleomycin and methotrexate) and full doses of relatively inactive drugs (eg, mitomycin C). This indicates that chemotherapy enhances radiotherapy. Recent data from numerous phase II trials now support the promise of concomitant cisplatin/radiotherapy. The lack of overlapping toxicities allows the optimal administration of both modalities. Randomized trials are required, however.

Concomitant multiagent chemoradiotherapy (which includes synchronous therapy with split-course radiotherapy and alternating chemoradiotherapy) greatly increases acute toxicity and so requires creative study designs to make this approach feasible. The major problem with multiagent regimens is the need to lower the radiotherapy’s dose intensity, which compromises local control rates. Paradoxically, “aggressive” multiagent chemoradiotherapy programs ultimately may be of decreased rather than increased dose intensity. Nevertheless, early results from all 10 randomized trials are encouraging, with survival favoring the experimental (concomitant) arm in most of these studies. Concomitant therapy does not appear to significantly increase surgical complications, and it has clearly altered the natural history of locally advanced unresectable HNSCC. It has produced lower locoregional failure rates, which suggests that a direct chemotherapy- radiotherapy interaction occurs at primary sites. The lack of impact on distant relapse rates, however, suggests that concomitant chemoradiotherapy should be followed by adjuvant therapy, and support for this approach comes from randomized trials.

No survival benefit is evident in trials of adjuvant chemotherapy, the third major treatment category. Ultimately, the optimum control of advanced HNSCC certainly may require primary chemotherapy in all three of its strategic roles (ie, as neoadjuvant, concomitant, and adjuvant therapy). New approaches integrating novel agents are necessary.