(Laurie Barclay, MD, April 2003)

Head and neck cancers affect the mouth, nasal cavities, sinuses, larynx, and pharynx. Most are squamous cell carcinomas (SCCHN), but others include lymphoepithelioma, spindle cell carcinoma, verrucous cancer, undifferentiated carcinoma, and lymphoma, especially diffuse non-Hodgkins lymphoma.

Head and neck cancers account for 3% of all cancers in the U.S., with 40,000-60,000 cases diagnosed and 12,000 deaths annually. Worldwide, incidence is about half a million new cases annually with nearly 250,000 deaths.

Risk factors for head and neck cancer include male gender, age greater than 50 to 60 years, smoking, use of smokeless tobacco, and alcohol use. Tobacco use contributes to 85% of head and neck cancers, and people who use both tobacco and alcohol are at greater risk than those who use either tobacco or alcohol alone. Leukoplakia is a precancerous mouth lesion which becomes malignant in approximately one-third of patients.

Symptoms warning of head and neck cancer may include a lump or sore that does not heal, persistent sore throat, difficulty swallowing, and hoarseness or other change in the voice. In addition to thorough history and physical, workup may include laryngoscopy, CT or MRI, and biopsy.

If diagnosed early, SCCHN may respond to standard therapy with five-year survival of 70%-90%. However, nearly two- thirds of patients are initially diagnosed with locally advanced or metastatic disease. Only 30% of these patients achieve long-term remission after treatment with surgery and/or radiation. Median length of survival in recurrent or incurable SCCHN is only six months with conventional chemotherapy.

After staging with appropriate diagnostic tests, treatment may include surgery, radiation, chemotherapy, immunotherapy, and gene therapy, alone or in combination. Combined modality therapy is now the preferred regimen for patients with locally advanced disease. Drugs developed for use in other cancers are being tested in SCCHN and in other head and neck cancers, at times with promising results. CenterWatch has identified a pipeline of 13 drugs in various phases of clinical development.

Taxotere (docetaxel) is approved in breast cancer and lung cancer, and now is in phase III testing by Aventis for SCCHN. It is a taxoid which disrupts the cellular microtubular network, thereby preventing cancer cells from dividing.

In a phase II, multicenter study, patients with recurrent or incurable SCCHN who received combination therapy with Taxotere and cisplatin experienced a 40% overall response rate and a median survival rate of 9.6 months, with acceptable safety profile. Mucosal toxicity was less and administration was shorter and more convenient than with the standard cisplatin/5-fluorouracil (5-FU) combination regimen. Severe neutropenia occurred in 80%, but only 17% had severe infection or required intravenous antibiotics.

Also given in combination with cisplatin is Erbitux (IMC-C225)/cisplatin, in Phase III testing by ImClone Systems and in phase II for patients with refractory disease. Erbitux is a highly specific, chimerized, monoclonal antibody that interferes with the effects of epidermal growth factor receptor (EGFR) activation, and that also inhibits angiogenesis. Because EGFR is over-expressed in more than 35% of all solid malignant tumors, Erbitux has activity against colon, lung, pancreatic, and other cancers.

In a phase II study of 78 patients with SCCHN with progressive disease during cisplatin therapy, nine patients (11.5%) achieved a partial response to Erbitux/cisplatin, or at least 50% tumor regression, and 13 patients (16.7%) achieved stable disease, for an overall rate of disease control of 28.2%. The most common adverse events were nausea, occurring in 51% of patients, and asthenia, seen in 49%.

Overall, data from published clinical trials suggest that Erbitux monotherapy and combination therapy have acceptable safety profiles, that Erbitux monotherapy is of doubtful efficacy, and that the efficacy of Erbitux combination therapy with cisplatin or with radiation still needs to be determined.

In a European clinical study of Erbitux combined with cisplatin or carboplatin, 75 patients with recurrent or metastatic SCCHN refractory to cisplatin or carboplatin had an overall response rate of 10.7%, and an overall rate of disease control of 46.7%.

Another EGFR-blocking antibody is TheraCIM h-R3, in Phase II/III testing by YM Biosciences in combination with radiation. Theracim h-R3 inhibits HER-1, an EGFR present in excess amounts in up to 90% of patients with SCCHN. Phase I-II testing demonstrated complete tumor response in more than 60% of 70 subjects with unresectable, locally advanced SCCHN, and partial response in 20%. The complete response rate was twice that expected with radiation alone, even at relatively low doses of TheraCIM. Some patients receiving radiation and Theracim h-R3 have remained tumor-free for up to 28 months.

OSI Pharmaceuticals has completed phase II testing of Tarceva (OSI-774), an orally active inhibitor of EGFR tyrosine kinase, as a single agent for the treatment of patients with refractory SCCHN. Of 124 evaluable patients with advanced, inoperable SCCHN, seven patients (6%) had partial responses, and 49 patients (39%) had disease stabilization for at least three months. Median survival was 174 days, and 14 patients survived for more than 300 days.
At a dosage of 150 mg/day, treatment was generally well tolerated. The most common side effects were a reversible acneiform rash and occasional diarrhea responding to therapy.

Iressa (gefitinib, ZD 1839) is another selective EGFR tyrosine kinase inhibitor, in Phase II testing by AstraZeneca. An in vitro study of six SCCHN lines showed that applying Iressa before radiation was most effective, especially in p53-mutated cell lines expressing the highest levels of EFGR. Similarly, the effects of Iressa with cisplatin and/or 5-FU were greater when Iressa was applied first. Applying Iressa before cisplatin and 5-fluorouracil resulted in a slight synergistic effect, which was enhanced by applying the drug both before and during exposure to chemotherapeutic agents.

Advexin (INGN 201) is a gene therapy targeting the p53 gene, now in Phase III testing by Introgen Therapeutics. In Phase II studies, intratumoral administration offered a survival advantage to patients with recurrent SCCHN not amenable to surgery. Compared with low-dose therapy, high-dose treatment led to a 75-day improvement in median survival, and also stabilized rates of tumor growth and performance status. One patient treated with high-dose Advexin remained on the therapy for more than four years without significant side effects.

An alternative form of gene therapy is suberoylanilide hydroxamic acid (SAHA), in Phase II development by Aton Pharma. This small molecule affects tumor gene expression and limits tumor growth by inhibiting histone deacetylase (HDAC) activity.

Perhaps most encouraging thus far is immunotherapy with MultiKine, a combination therapy in Phase II testing by CEL-SCI. This natural cytokine cocktail includes interleukin-2 (IL-2), IL-b, TNF-a, Gm-CSF and an IFN-g/immunomodulator. As of May 2002, all eight SCCHN patients treated in Hungary with a combination of Multikine, surgery and radiation two years earlier had not had recurrences and were still alive.
A phase III clinical trial planned in Asia has end points of reduction in tumor recurrence rates and increased time to recurrence. If this trial confirms earlier findings, Multikine may become part of standard first-line therapy in the treatment of head and neck cancer.

Continuing the past tradition, a multipronged approach may be most effective in SCCHN. Rather than replacing surgery, radiation therapy, or even chemotherapy, most drugs in the pipeline will probably be most effective in combination with other modalities. With few exceptions, response to gene therapy or EGFR inhibitors has not been dramatic thus far. Although it is still too early to tell, immunotherapy may eventually achieve better results.