NEJM 2008;359:1143

HPV is implicated in the development of tumors. For example, infection with HPV has been shown to cause virtually all female cervical cancers. Molecular evidence also suggests a role for HPV, particularly HPV-16, in the pathogenesis of a subgroup of squamous-cell carcinomas of the head and neck,and the HPV viral oncogenes E6 and E7 are frequently overexpressed in the oropharynx. In a case–control study, it was reported that oropharyngeal cancer was significantly associated with the presence of oral HPV-16 infection. HPV DNA was detected in 72% of 100 oropharyngeal tumor specimens, and 64% of the patients in the study were seropositive for HPV-16 E6, HPV-16 E7, or both. Although a cause-and-effect relationship cannot be inferred from this single study, such findings confirm those of other case–control studies. Furthermore, exposure to HPV increased the association with oropharyngeal cancer, regardless of the use of tobacco and alcohol, without evidence of synergy between exposure to HPV and use of tobacco and alcohol. These data suggest that two distinct pathways may be involved in the development of oropharyngeal cancer: one mainly driven by tobacco and alcohol and the other by HPV-induced genomic instability. Additional molecular studies indicated that patients with HPV-positive tumors bearing a unique gene-expression profile with minimal molecular alterations appeared to have more favorable outcomes after therapy, whereas patients with HPV-negative tumors, which show frequent molecular and cytogenetic changes — such as p53 mutations, loss of p16^INK4a, p15^INK4b cyclin D1 overexpression, or an increased copy number of EGFR and chromosome 7 — appeared to have less favorable outcomes.Among young patients, widespread use of oral sexual practices and a trend toward multiple sexual partners may have contributed to an increased incidence of HPV-related head and neck cancers, particularly tonsillar and base-of-the-tongue cancers. Since HPV vaccination is an important strategy to prevent cervical cancer, it would seem logical that HPV-vaccination strategies might be tested as a potential means for preventing HPV-induced head and neck cancers.

Treatment

Strategies for Therapy

The majority of patients with head and neck cancer present with locally advanced, stage III or IV disease that requires a combination of chemotherapy, radiation, or surgery. Patients who present with early stage I or II disease are often treated with either radiation or surgery and have an excellent prognosis. However, these patients are still at high risk for recurrence and second primary tumors and thus should be closely monitored.

A major challenge in treating any cancer is obtaining a high cure rate while preserving vital structures and function. This is especially true for cancers in the anatomically complex region of the head and neck, where major structures and function are affected by both the cancer and its treatment. Organ preservation should be taken into account early on and should be attempted with all treatment approaches. The experience of the treating center plays a big role in this regard.

Advances in treatment strategies have affected all the approaches used in head and neck cancer: radiation therapy, chemotherapy, targeted agents, and surgery. Radiation therapy remains a mainstay of curative therapy for oropharyngeal cancer and advanced hypopharyngeal and laryngeal cancer. Recent advances have focused primarily on fractionation schedules and the use of intensity-modulated radiation therapy, a form of high-precision radiotherapy that delivers radiation more precisely to the tumor while relatively sparing the surrounding normal tissues. Second, chemotherapy is an integral part of treating locally advanced head and neck cancer. It is often administered concurrently with radiotherapy (concurrent chemoradiotherapy) or before radiotherapy in the form of induction chemotherapy. Third, targeted agents such as cetuximab appear to have promise both as single agents and in combination with radiotherapy. Finally, surgical techniques have continued to evolve, with greater focus on minimally invasive procedures where appropriate. Reconstruction and free-tissue-transfer techniques have also improved, resulting in better functional and aesthetic outcomes.

Concurrent Chemoradiotherapy

Concurrent or definitive chemoradiotherapy refers to the administration of chemotherapy in combination with radiation therapy in an effort to treat the tumor without previous initial surgical resection. Surgery in this case is used for persistent disease. In contrast, postoperative concurrent chemoradiotherapy is used after surgical resection when the patient is at an increased risk for local and distant recurrence.

Definitive Chemoradiotherapy

A meta-analysis of studies involving patients with head and neck cancer showed an absolute benefit of 8% associated with concurrent chemoradiotherapy, as compared with radiotherapy alone. Bolus cisplatin at a dose of 100 mg per square meter of body-surface area that was administered every 3 weeks during radiation therapy is often used in patients with advanced disease.The side effects of this approach are substantial and can include neuropathy, hearing loss, marked nausea and vomiting, and renal dysfunction. Many patients are not well enough to receive this drug in bolus form and instead receive weekly cisplatin at a lower dose or weekly carboplatin and paclitaxel. However, bolus cisplatin every 3 weeks remains the reference regimen, and no randomized comparisons have been made between this schedule and the weekly regimens.

In one study, patients with newly diagnosed, advanced laryngeal cancer were randomly assigned to receive one of three treatments: induction chemotherapy with cisplatin plus fluorouracil followed by radiotherapy (group A), radiotherapy with concurrent administration of cisplatin (group B), or radiotherapy alone (group C). Preservation of the larynx and local control were best achieved in the group that received concurrent chemoradiotherapy, which had an absolute reduction of 43% in the rate of laryngectomy. No differences in survival were noted among the three groups. Laryngectomy-free survival was best achieved with the concurrent and sequential approaches, both of which were superior to radiotherapy alone. Distant metastasis developed in 15% of the patients in group A, 12% of those in group B, and 22% of those in group C. Concurrent chemoradiotherapy is accepted as a standard approach for patients with advanced laryngeal cancer who want to preserve their larynx.

One of the major advances in radiotherapy has been the implementation of intensity-modulated radiation therapy. In this approach, the radiation dose is designed to conform to the three-dimensional shape of the tumor by modulating the intensity of the radiation beam to focus a higher radiation dose to the tumor while minimizing radiation exposure to surrounding normal tissues. By treating specific targets with a different dose each day, such therapy has the potential to improve outcomes by minimizing doses to normal tissues and increasing doses to tumors,leading to reduced long-term toxicity and xerostomia and improved salivary flow. Recent data suggest that such therapy is as effective as conventional radiotherapy with regard to local control, but it can reduce late toxicity.

Another important consideration in radiotherapy is the fractionation of treatment. Radiotherapy for head and neck cancer is typically provided in a single fraction on a schedule of 5 days per week for 7 weeks. In the past decade, altered fractionation schedules that allow radiotherapy to be accelerated or hyperfractionated have been studied. In accelerated fractionation, the total treatment time is reduced. This reduces tumor repopulation between sessions and may allow for better local control. In hyperfractionated schedules, two or three lower-dose fractions are given daily, which may reduce late toxicity. A recent meta-analysis of 15 randomized trials enrolling more than 6000 patients who had mainly stage III and IV tumors of the oropharynx and larynx examined whether altered fractionation improved survival. In this analysis, there was a small but significant survival benefit of 3.4 percentage points associated with altered fractionation radiotherapy at 5 years. The survival benefit was significantly greater with hyperfractionated radiotherapy than with accelerated radiotherapy; it was also greater among patients under the age of 50 years who had a good performance status, which was defined according to a tool that assessed patients' overall physical condition and the ability to perform activities of daily living. No effect on distant metastasis was noted. The Radiation Therapy Oncology Group (RTOG) has recently completed a phase 3 study (RTOG 0129; ClinicalTrials.gov number, NCT00047008) to examine whether the benefit of altered fractionation persists when combined with chemotherapy. No significant difference in acute or late toxicity was noted; efficacy data are not yet available. It should be noted that the benefit of concurrent chemoradiotherapy or altered fractionation radiotherapy decreases with increasing age, and this benefit is uncertain for patients who are older han 70 years.

Postoperative Chemoradiotherapy

Postoperative concurrent chemoradiotherapy has been tested in two phase 3 studies conducted by RTOG (NCT00002670) and the European Organization for Research and Treatment of Cancer (EORTC) (NCT00002555. Both trials aimed to determine whether the addition of cisplatin to radiotherapy improved the outcome, as compared with radiotherapy alone. In both studies, patients with high-risk surgical or pathological features after surgery were randomly assigned to receive either radiotherapy alone or radiotherapy plus cisplatin (at a dose of 100 mg per square meter every 3 weeks for three cycles). High-risk features were defined as the presence of a positive margin, extracapsular spread outside the lymph nodes, lymphovascular invasion, perineural invasion, and multiple positive lymph nodes. In RTOG 9501, concurrent chemoradiotherapy significantly reduced the risk of locoregional recurrence, as compared with radiotherapy alone. No benefit on overall survival was noted. In EORTC 22931, both progression-free survival and overall survival were significantly longer in patients receiving concurrent chemoradiotherapy. Both trials showed that adding cisplatin had no significant effect on the incidence of distant metastases. The metastatic rates were 25% with radiotherapy alone and 20% with combined therapy.

Although postoperative concurrent chemoradiotherapy was more effective than radiotherapy alone, it was also more toxic. Both trials reported a significant increase in acute severe adverse events in the combined-therapy group, including mucositis, hematologic toxicity, and muscular fibrosis. A pooled analysis of data from both trials showed that two risk factors were associated with a significant benefit from concurrent chemoradiotherapy: extracapsular extension and positive surgical margins. It is our practice to offer concurrent chemoradiotherapy to all patients who have a good performance status and any of the high-risk features defined above.

Sequential Chemoradiotherapy

Induction chemotherapy has been studied for more than three decades and has been repeatedly associated with significant tumor shrinkage and with a decrease in the risk of distant metastasis. This is important, since at 2 years, approximately 20% of patients with locally advanced disease who are treated with concurrent chemoradiotherapy have distant metastasis, and their disease is classified as incurable. The effect of induction chemotherapy on overall survival has been more difficult to demonstrate. Various models of induction chemotherapy have been used over the years with different approaches and agents. The interpretation of relevant trials has been difficult, given their heterogeneity. Nevertheless, a meta-analysis of studies of chemotherapy in patients with head and neck cancer showed a survival benefit of 5% for induction chemotherapy with the addition of cisplatin and fluorouracil, and this regimen has been the reference regimen used in induction-chemotherapy protocols. Two recent randomized, phase 3 trials have shown a significant benefit of adding docetaxel  (Taxotere) to cisplatin and fluorouracil induction chemotherapy.

Docetaxel, Cisplatin, and Fluorouracil

            Induction Therapy

The safety and efficacy of a combination of docetaxel, cisplatin, and fluorouracil as induction chemotherapy for patients with squamous-cell carcinoma of the head and neck were evaluated in a multicenter, randomized, phase 3 trial (TAX 323) (NCT00003888.  In this European study, 358 patients with previously untreated, unresectable, locally advanced stage III and IV tumors and a good performance status received either docetaxel, cisplatin, and fluorouracil or cisplatin and fluorouracil. These regimens were administered every 3 weeks for four cycles. Four to 7 weeks after chemotherapy, patients who did not have progressive disease received radiotherapy alone, either as a conventional, accelerated, or hyperfractionated regimen. The primary end point, median progression-free survival, was significantly longer in the group receiving docetaxel, cisplatin, and fluorouracil (11.4 months) than in the group receiving cisplatin and fluorouracil (8.3 months). Median overall survival was significantly longer in the group receiving docetaxel, cisplatin, and fluorouracil (18.6 months) than in the group receiving cisplatin and fluorouracil (14.2 months).

The TAX 324 study (NCT00273546) took a different approach from that of the TAX 323 study in that instead of undergoing radiotherapy only after induction chemotherapy, all patients received concurrent chemoradiotherapy. The goal was to combine both induction chemotherapy and concurrent chemoradiotherapy in one study. In this international, multicenter, randomized, phase 3 trial, 501 patients had previously untreated, locally advanced squamous-cell carcinoma of the head and neck (either resectable or unresectable) and had a good performance status. Patients received either docetaxel, cisplatin, and fluorouracil or cisplatin and fluorouracil every 3 weeks for three cycles. All patients who did not have progressive disease after induction chemotherapy received 7 weeks of concurrent chemoradiotherapy with carboplatin, with an area under the curve (AUC) of 1.5, administered weekly for a maximum of seven doses. The median survival time was 70.6 months in the group receiving docetaxel, cisplatin, and fluorouracil, as compared with 30.1 months in the group receiving cisplatin and fluorouracil (P=0.006). These two studies were key parts of the package considered by the Food and Drug Administration (FDA) when they approved induction chemotherapy with docetaxel, cisplatin, and fluorouracil in patients with either operable or inoperable squamous-cell carcinoma of the head and neck.

            Toxic Effects

The use of combination therapy with docetaxel, cisplatin, and fluorouracil has been associated with an increased incidence of neutropenia and febrile neutropenia; an increased incidence of stomatitis and diarrhea has been associated with the use of cisplatin and fluorouracil. A substantial number of patients did not receive radiation therapy or concurrent chemoradiotherapy as specified in the protocol in both the TAX 323 and TAX 324 trials (30% and 20%, respectively). Disease progression and adverse events were the major reasons for noncompletion. In the TAX 323 study, 44 of 358 patients did not receive any radiotherapy. A total of seven treatment-related deaths occurred in these two studies.

Pros and Cons of Induction Therapy

Concurrent chemoradiotherapy has a long track record of improving local and regional control. However, its effect on distant metastases is at best questionable. Induction chemotherapy clearly reduces distant metastases, and the induction regimen used in the TAX 324 study had an effect on local control. Ongoing randomized, phase 3 studies are comparing sequential therapy with concurrent chemoradiotherapy; these studies will take 4 to 5 more years to complete. Thus, until that time, the treating multidisciplinary team has two treatment options to choose from: sequential chemoradiotherapy or concurrent chemoradiotherapy. Both approaches are reasonable and have been shown to improve the outcome. For each patient, physicians will need to decide on a treatment plan on the basis of perceived risks of local and distant metastases.

Experience is important during the delivery of induction chemotherapy in order to avoid unnecessary delays in starting radiotherapy. Thus, the use of a multidisciplinary clinic is of extreme importance. The treating team needs to be ready to abort induction chemotherapy and move to radiotherapy if treatment is poorly tolerated by the patient. It seems reasonable, off protocol, to consider induction chemotherapy for patients with a good performance status and fairly advanced primary and nodal presentations — for example, those with grade T3, T4, N2b, N2c, or N3 disease. It is also reasonable to offer induction chemotherapy to symptomatic patients in need of immediate therapy.

Cetuximab (Erbitux)

            Role of Biologic Agents

Cetuximab, a monoclonal antibody, has been approved by the FDA for treating head and neck cancer as a single agent in patients with platinum-resistant disease. It is also approved for use in combination with radiation in previously untreated patients.

            With Radiation Therapy

In a recent phase 3 trial (NCT00004227 ), cetuximab in combination with radiotherapy improved locoregional control and overall survival in patients with locally advanced tumors.In a trial involving 424 patients, 213 patients were randomly assigned to receive radiotherapy alone and 211 were assigned to receive cetuximab plus radiotherapy. Concomitant boost radiotherapy was the most common schedule used (56%). Cetuximab was initiated 1 week before radiotherapy with a loading dose of 400 mg per square meter, followed by 250 mg per square meter weekly throughout radiotherapy. Locoregional control and both progression-free and overall survival were significantly improved with combination radiotherapy plus cetuximab. Treatment with the combination regimen decreased the risk of locoregional progression by 32% and the risk of death by 26%. However, the rates of distant metastases at 1 year and 2 years were similar in the two study groups. In an unplanned analysis, the survival benefit was increased in patients with primary oropharyngeal tumors (tonsil and tongue base) and those receiving a concomitant boost schedule, a type of accelerated radiation-therapy protocol in which patients receive 4 weeks of once-daily treatment, followed by 2 weeks of two fractions per day, which "boosts" the treatment at the end of the protocol.

The addition of cetuximab to radiotherapy was associated with similar rates of grade 3 or 4 toxic effects in the two study groups. The incidence of acneiform rash and infusion reactions was significantly higher in the combination cetuximab–radiotherapy group than in the group receiving radiotherapy alone. Rash and nail changes appeared to be the most common side effects associated with cetuximab, as with other EGFR inhibitors.

The interpretation of the results of the cetuximab–radiotherapy trial is quite difficult, since chemotherapy was not part of the study, making it difficult to assess whether the combination of cetuximab and radiotherapy was as effective as concurrent chemoradiotherapy. The RTOG is conducting a large, randomized, phase 3 study comparing chemoradiotherapy with chemoradiotherapy plus cetuximab (RTOG 0522) (NCT00265941. The chemotherapy agent used in RTOG 0522 is cisplatin, and the primary end point is disease-free survival. Until more data become available, it may make sense, in our view, to offer cetuximab in combination with radiotherapy to patients who cannot tolerate chemoradiotherapy.

            After Recurrence

Cetuximab was tested as a single agent in 103 patients with recurrent or metastatic head and neck cancer that was resistant to platinum-based therapy. The response rate was 13%, and the rate of disease control (i.e., patients who had a complete response, a partial response, or stable disease) was 46%. The median time to disease progression was 70 days, and median overall survival was 178 days. There appeared to be no benefit in adding cisplatin to cetuximab in these patients.

The situation was different in patients whose disease has progressed after curative therapy and who were receiving first-line chemotherapy. For such patients, the addition of cetuximab to cisplatin and fluorouracil was superior to cisplatin and fluorouracil alone in the Erbitux [Cetuximab] in First-Line Treatment of Recurrent or Metastatic Head and Neck Cancer (EXTREME) (NCT00122460 ) study. In this trial, 442 patients were randomly assigned either to group A, which received either cetuximab (at an initial dose of 400 mg per square meter and then 250 mg per square meter weekly) plus cisplatin and fluorouracil every 3 weeks for a maximum of six cycles (at a dose of 100 mg per square meter intravenously on day 1) or carboplatin (at a dose of AUC 5 on day 1) and fluorouracil (a continuous infusion of 1000 mg per square meter per day for the first 4 days of each cycle), or to group B, which received either cisplatin or carboplatin plus fluorouracil in the same regimen as the one used in group A. Median survival was significantly better in the group receiving cisplatin, fluorouracil, and cetuximab (10.1 vs. 7.4 months). Approximately 60% of the patients who were enrolled in this trial had not received chemotherapy before. The benefit appeared to be more pronounced in patients under the age of 65 years who had a good performance status and were receiving cisplatin-based treatment.

Other EGFR inhibitors are being tested as therapeutic agents for patients with head and neck cancer. These agents include cetuximab and other monoclonal antibodies and tyrosine kinase inhibitors. Tyrosine kinase inhibitors are administered orally. The two agents that have been studied the most are gefitinib (Iressa) ⁽and erlotinib (Tarceva). Both appear to have only modest antitumor activity in head and neck cancer. For example, a recently completed phase 3 study of gefitinib did not show a survival advantage over methotrexate.

Future Directions

The treatment of head and neck cancer is continuing to evolve, and physicians who are treating patients with locally advanced disease have multiple treatment options. The treatment team should consider the patient's overall condition and his or her ability to tolerate aggressive therapy. The risk of local and distant recurrence needs to be considered as a treatment is implemented, and a multi-disciplinary approach is crucial. We continue to search for new molecularly targeted agents for head and neck cancer. The incorporation of such therapies into current treatment regimens is a priority, in conjunction with a better understanding of the underlying mechanisms of action of such targeted agents.