Published in UAB Insight, Fall 2004

CME Exam Coming Soon!

ABSTRACT: Combining cetuximab with radiation offers hope for head and neck cancer.

CME OBJECTIVE: The reader will be familiar with the risk factors, warning signs, and therapuetic options for head and neck cancer.
James A. Bonner, MD, consultant and honoria ImClone Systems; Bristol-Myers Squibb

A large, international phase 3 study, sponsored by ImClone Systems, Inc., and Merck KGA and led by UAB's Comprehensive Cancer Center, indicates adding cetuximab (Erbitux) to high-dose radiation therapy can nearly double survival in patients with head and neck cancer that has not spread beyond the lymph nodes in the neck.

UAB scientists presented the findings of this Food and Drug Administration reviewed study at the 40th Annual Meeting of the American Society of Clinical Oncology in June 2004. The University of Wisconsin in Madison, Vall D'Hebron University Hospital in Barcelona, Spain, University of Virginia in Charlottesville, and M.D. Anderson Cancer Center in Houston, Texas were among participating institutions in the trial, which examined the combination therapy's impact on locoregional disease control and survival in patients with locally advanced head and neck cancer.

Combination Therapy

"The use of cetuximab and radiation therapy may become an excellent choice of therapy for these patients," says James A. Bonner, MD, Department of Radiation Oncology chair, Cancer Center senior scientist, and the study's lead author. "Future studies are needed to examine combinations of chemotherapy, radiation therapy, and cetuximab."

The Study At A Glance

This international phase 3 study followed 424 patients with locoregionally advanced squamous cell carcinoma of the head and neck to determine efficacy of administering cetuximab in conjunction with radiation therapy. Participants were divided into two groups: 211 patients received high-dose radiation therapy plus cetuximab weekly, and 213 patients received radiation therapy alone for 6-7 weeks. The study found: Median survival was nearly doubled in the cetuximab-radiation group, compared with the radiation-only group — 54 months vs 28 months. More of the cetuximab-radiation patients were alive at 2 years (62% vs 55%) and 3 years (57% vs 44%), compared with the radiation-only group. The cetuximab regimen was well-tolerated, and skin reactions were the most common side effect.

For more than 2 decades, the Cancer Center has been an international leader in the research and development of monoclonal antibodies, including cetuximab, which attaches to and blocks the epidermal growth factor receptor (EGFr) on cancer cells. EGFr is associated with aggressive tumor behavior and poor clinical outcome.

The Cancer Center has conducted several clinical trials of cetuximab, including a pivotal Food and Drug Administration-reviewed study in colorectal cancer patients who previously failed to respond to irinotecan chemotherapy. During that phase 2 study, 22.9% of participants with colorectal cancer responded positively to the combination of cetuximab and irinotecan. The trial's positive results led to the drug's approval in February 2004 as the first monoclonal antibody approved for colorectal cancer.

Blocking Growth Factors

"Since the majority of head and neck cancers heavily express EGFr and EGFr expression correlates with poor prognosis, we hypothesized that treating patients with an EGFr-blocking drug such as cetuximab could potentially make these cancers more sensitive to radiation," Bonner says. Trial participants were patients with locoregionally advanced squamous cell carcinoma of the oropharynx, hypopharynx, or larynx with measurable disease.

"Initial treatment options for patients with advanced head and neck cancer include radiation therapy, chemotherapy combined with radiation treatment, or surgery followed by radiation, and/or chemotherapy plus radiation for patients whose tumors can be resected."

During the head and neck cancer trial, researchers randomized 424 people in the United States and Europe to cetuximab plus high-dose radiation therapy (211 participants) or radiation alone (213 people). Median age was 57 years, and 80% of enrollees were men. After treatment, people were followed with physical examination and radiographic imaging every 4 months for 2 years, then every 6 months for up to 5 years.

Improved Survival

"Median survival was nearly twice as high in the cetuximab plus radiation group compared with the radiation-only group — 54 months versus 28 months," Bonner says. More of those patients who received cetuximab and radiation were alive, compared with those who received radiation only at 2 years (62% vs 55%) and 3 years (57% vs 44%). The cetuximab-radiation regimen was well-tolerated, with skin reactions noted as the most common side effect. The incidence of grade 3/4 mucositis, a serious adverse effect of high-dose radiation therapy for head and neck cancer, was similar in both groups.

Warning Signs And Risk Factors For Head And Neck Cancer

Successful treatment of head and neck cancer depends on early detection and avoiding tobacco use and excessive alcohol consumption. As many as 90% of head and neck cancers arise after prolonged exposure to these risk factors. Warning signs of head and neck cancer include: A lump in the neck that lasts >2 wks Hoarseness or other voice change lasting >2 wks Oral growths that bleed easily and fail to heal >2 wks Difficulty swallowing

"Overall, the toxicity profile was consistent with recognized effects of high-dose head and neck radiation, although cetuximab caused some additional toxicity," Bonner says. "A promising new treatment for head and neck cancer, this new regimen has the potential to help many patients."

Cancer Center Acting Director Peter D. Emanuel, MD, adds, "Head and neck cancer is difficult to treat. Giving cetuximab in combination with radiation therapy and possibly chemotherapy may offer more effective treatment options and improved outcomes for a variety of cancers."

More than 55,000 Americans developed cancer of the head and neck in 2004, and the disease accounts for 3% of all cancers in the US. Among major cancers, the survival rate for head and neck cancer is one of the poorest, resulting in nearly 13,000 deaths annually. Because the disease is not often detected until the advanced stages, less than 50% of patients survive 5 years after initial diagnosis. The new combination offers improved survival.

For more information
Dr. James Bonner
1.800.UAB.MIST
mist@uabmc.edu