The term "head and neck cancer" refers to tumors arising from the epithelial lining of the oral cavity, larynx, pharynx, and paranasal sinuses. In addition, cancers arising from the major and minor salivary glands are usually included in this classification. Approximately 45,000 new cases of squamous carcinoma of the head and neck are diagnosed annually in the United States. It occurs predominantly in the sixth and seventh decades of life and is more prevalent in males. The major risk factors associated with head and neck cancer are smoking and alcohol(Drug information on alcohol) abuse. In addition, viral associations include human papillomavirus and Epstein-Barr virus.
Outcome for patients with squamous carcinoma of the head and neck is dependent on the stage at presentation. While approximately one-third of patients are diagnosed at an early stage (T1, N0, M0 or T2, N0, M0), the vast majority present with locally advanced disease (T3, T4, or N+). Only a small number of patients will have metastatic disease at the time of diagnosis (1% to 5%).[3,4] The cure rate is between 70% and 90% for patients with early-stage disease and 20% to 70% for those with locally advanced disease, depending on tumor size, stage, and primary site. Unfortunately, patients who present with metastatic disease have a poor prognosis; median survival for patients treated with standard treatment regimens is about 6 months, with a 1-year survival rate of 20%.
Historically, head and neck cancer has been a disease treated by surgery or radiation therapy, or both. Chemotherapy has been reserved for patients who have failed primary treatment. For early-stage disease, single-modality treatment with either radiation therapy or surgery produces equally high cure rates. Thus, the decision regarding which modality to use is based on the relative morbidity.[5,6] For example, radiation is often used to treat early larynx cancers with the intent being to preserve voice quality. Surgery may be used to treat a small oral cavity lesion in order to avoid undue long-term sequelae of radiation therapy. Clinical research efforts have focused on strategies to optimize functional outcome and to prevent second primary tumors.
Owing to the high cure rates, treatment strategies for early-stage disease have remained relatively unchanged over the past decade. In contrast, treatment options for locally advanced disease have changed dramatically. In the past, patients were categorized according to whether their tumor could be resected surgically. Resectability has been defined by the treating surgeon, and, with improvements in operative techniques, this definition has changed over time. Nonetheless, there remains a cohort of patients whose disease is bulky and for whom resection is unlikely to produce a cure; these patients are considered unresectable.
Historically, patients deemed resectable underwent surgery and postoperative radiation therapy to prevent local recurrence. Surgery for tumors of the larynx, hypopharynx, or base of the tongue often required total laryngectomy or total glossectomy. This resulted in marked functional deficits and an adverse effect on quality of life.
During the 1980s and 1990s, numerous phase II studies demonstrated that use of chemoradiation might provide a reasonable function-sparing alternative for patients with locally advanced disease. Subsequently, phase III studies were undertaken to determine whether chemoradiation adversely affected survival.
In a trial by the Veterans Affairs Laryngeal Cancer Study Group, 332 patients with locally advanced (stage III/IV) squamous carcinoma of the larynx were randomly assigned to receive a total laryngectomy with postoperative radiation, or induction chemotherapy with three cycles of cisplatin(Drug information on cisplatin) (Platinol) and fluorouracil(Drug information on fluorouracil) (5-FU) followed by radiation (66-76 Gy), with surgical salvage therapy for nonresponders or those with recurrences. Survival in both treatment arms was equivalent (68%). A total of 64% of patients treated with induction chemotherapy and radiation were able to preserve their larynx.
Similarly, the European Organization for the Research and Treatment of Cancer (EORTC) randomly assigned patients with hypopharynx cancer to surgery followed by radiation or induction treatment with cisplatin and 5-FU followed by radiation with surgical salvage therapy for recurrence. At 3 years, 42% of patients receiving induction chemotherapy and radiation retained a "functional larynx." Median survival was 44 months for patients receiving function-sparing therapy vs 25 months for those undergoing surgery with postoperative radiation (P = NS). Thus, tissue-sparing therapy using induction chemotherapy followed by radiation did not compromise survival for patients with either laryngeal or hypopharyngeal primary tumors.
For patients with unresectable squamous carcinoma of the head and neck, the rate of long-term survival using radiation therapy alone was less than 20%. Over the past two decades, the use of combined chemoradiation therapy has been evaluated in such patients in the hopes of improving cure rates. Because squamous carcinoma of the head and neck has historically been a locoregional disease process, investigators hypothesized that chemotherapy used as a radiation sensitizer to enhance radiation effectiveness might result in improved local control and overall survival.
Numerous phase III trials have confirmed the efficacy of chemoradiation, which has now become the standard of care. As an example, Calais et al reported data from a randomized trial in stage III/IV oropharyngeal carcinoma. Patients received radiotherapy alone (70 Gy/7 wk) vs concomitant radiotherapy and carboplatin(Drug information on carboplatin) (Paraplatin) at 70 mg/m2/d × 4 days and 5-FU at 600 mg/m2/d by continuous infusion × 4 days, with cycles administered on days 1, 22, and 43. The addition of chemotherapy resulted in improved 3-year actuarial survival rates (51% vs 31%, P = .002) and locoregional control (66% vs 42%). In the Eastern Cooperative Oncology Group (ECOG) 1392 three-arm trial, radiation alone was compared with radiation and concomitant cisplatin at 100 mg/m2 on days 1, 22, and 43 vs split-course radiation with concomitant cisplatin and 5-FU × 3 cycles. The results of this trial showed a statistically significant improvement in 3-year survival with concurrent administration of cisplatin plus radiation (20% vs 37%, P = .016).
In addition to the recently published phase III trialsthree meta-analyses, two literature-based and one patient-basedevaluating the role of chemotherapy in the primary treatment of head and neck cancer have been reported.[12-14] All three identified a survival advantage for patients receiving concomitant chemoradiation. The Bourhis data showed a 19% relative risk reduction and an 8% absolute survival benefit at 5 years (P = .0001). Thus, both randomized phase III trials and three meta-analyses have demonstrated superior survival and local control rates for patients treated with concomitant chemoradiation.
As chemoradiation has become a standard treatment option for patients with locally advanced disease, interest in identifying new active agents in squamous carcinoma of the head and neck has intensified. Initial studies of new chemotherapy agents are usually conducted in metastatic or recurrent disease. This allows investigators to establish the efficacy of a new agent prior to incorporation into more complex combined-modality treatment regimens. A number of chemotherapy agents have demonstrated single-agent response rates of at least 10% to 15% in recurrent or metastatic squamous carcinoma of the head and neck. These include paclitaxel (Taxol), docetaxel(Drug information on docetaxel) (Taxotere), cisplatin, carboplatin, 5-FU, methotrexate(Drug information on methotrexate), ifosfamide(Drug information on ifosfamide) (Ifex), and vinblastine(Drug information on vinblastine).[15-17]
The use of combination therapy results in a statistically significant increase in the response rate to a range of 30% to 40%.[18,19] While some evidence suggests a survival advantage for single-agent chemotherapy vs best supportive care, there is no conclusive evidence that survival with multidrug chemotherapy regimens using currently available drugs is superior to that of single-agent therapy in the treatment of metastatic or recurrent squamous carcinoma of the head and neck. Improved survival for recurrent or metastatic squamous carcinoma of the head and neck will require the identification of new, more active agents.