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July 22, 2008 • Volume 5 / Number 15 E-Mail This Document  |  Download PDF  |  Bulletin Archive/Search  |  Subscribe

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Special ReportA Closer Look

The New Face of Head and Neck Cancer Treatment

Rarely do cancer clinical trials have a poster patient. But a current randomized phase II trial led by researchers from the University of Chicago has just that. Grant Achatz has been the subject of feature stories in magazines like The New Yorker and Chicago, partly because he's a highly celebrated young chef, but also because he had a malignant tumor that, prior to treatment, had engulfed most of his tongue.

Cross-section illustration of the adult head and neck (Illustration courtesy of the American Society of Clinical Oncology)Achatz's case cast a spotlight on head and neck cancer, which includes cancers of the mouth, nasal cavity, and throat. It has also highlighted the significant progress made in treating patients with large, localized tumors but no apparent metastases (which represents three-quarters of head and neck cancer patients), including the option in many cases to avoid disfiguring surgery and save vital organs without risking survival.

Much of that progress is a result of the innovative use of two traditional treatments, chemotherapy and radiation. And new research is pointing to more treatment options on the horizon, including molecularly targeted agents and potential markers that may define who the best candidates are for a given treatment.

No surgery needed
Oncologists at three leading head and neck programs saw Achatz and recommended a glossectomy, removal of most of his tongue. He chose, however, to follow a fourth opinion, enrolling in a clinical trial testing an "organ preservation" regimen. And according to media reports, he is currently disease-free. The fact that there was an option that allowed him to avoid surgery and keep his tongue shows just how far treatment for these cancer types has come.

"It's a very exciting time in head and neck cancer research," says Dr. Arlene Forastiere from the Johns Hopkins School of Medicine, who led the clinical trial that established the concurrent use of chemotherapy and radiation to successfully treat cancers of the larynx in place of surgical removal. Similar results have been seen for cancers of the oropharynx, which includes the tonsils and base of the tongue.

"We've achieved a lot with current therapies that are cisplatin-based chemoradiation," she says. "But we certainly still have room to improve in terms of cure rates," she acknowledges. Five-year survival rates for oropharynx cancers, for example, hover around 59 percent.

Achatz's case, explains Dr. Everett Vokes, who is leading the trial in which Achatz is enrolled, is fairly rare. The tumor began on the side of the tongue - often called the "oral tongue," and not considered part of the oropharynx - whereas most tongue cancers begin at the base. It also took several years to develop, while most cancers in the oral cavity are thought to progress rapidly. Achatz did not smoke and drank alcohol only moderately, eliminating two significant causative factors in such a young patient.

For small tongue lesions, Dr. Vokes explains, surgery is typically the best option. And for a case like Achatz's, for which there is little published data, most head and neck cancer programs would recommend surgery. "And we said, 'Maybe he should…but let's try concurrent chemoradiation first,'" Dr. Vokes recalls.

Beyond concurrent chemoradiation, the trial in which Achatz is enrolled compares the addition of cetuximab (Erbitux) - a monoclonal antibody that targets the epidermal growth factor receptor (EGFR), which is often overexpressed in head and neck cancers - to either of two different chemoradiation regimens. Trial participants also receive induction chemotherapy, which is given before "definitive" therapy to prevent metastases.

Based on clinical trial findings published in 2006, cetuximab is already approved for the treatment of head and neck cancer, in combination with radiation therapy. But, explains Dr. Francis Worden, of the University of Michigan Comprehensive Cancer Center, its use at this point is limited to patients who, for various reasons, would not be candidates for the toxic platinum-based chemotherapy used in standard chemoradiation.

In addition to helping better define the role of EGFR-targeted agents, the phase II trial in which Achatz is enrolled, as well as four large phase III trials underway, will provide further evidence about the value of induction chemotherapy, which, while extensively studied, is not yet a standard of care.

Even concurrent chemoradiation - which comes at the cost of severe toxicities that can significantly inhibit a patient's ability to swallow, talk, and taste for a period of time - is under investigational scrutiny. Dr. Vokes and colleagues, for example, just published the results of a phase II clinical trial showing that the radiation dose can be gradually lowered throughout treatment without sacrificing efficacy.

A Surprising "Benefit" of HPV Infection?

Head and neck cancer rates had been declining thanks to lower smoking rates. However, that downturn has stagnated thanks to a rise in oropharynx cancers, mostly among people aged 45 or younger, that has been traced to human papillomavirus (HPV) infections, namely infection with HPV 16.

If there is a positive note to be taken from this concerning trend, researchers say, it's that a number of observational studies have shown that HPV-positive patients have better outcomes than HPV-negative patients.

"We know now that these are two different tumors," says Dr. Worden, whose group just published results from a small trial in which nearly four out of five HPV-positive patients with advanced oropharynx cancer were alive 4 years after starting treatment, compared with approximately one in four HPV-negative patients. The available data, he adds, suggest that HPV-positive patients could be treated with a less toxic regimen.

That's a theory that's ready to be tested, says Dr. Forastiere. The NCI-sponsored Eastern Cooperative Oncology Group is launching clinical trials that will stratify participants by their HPV status, reserving a less demanding regimen of chemotherapy and radiation for HPV-positive patients, while HPV-negative patients will be treated with standard chemoradiation and an EGFR-targeted agent.

—By Carmen Phillips