Published in UAB Insight, Winter 2007 Landmark approach began in UAB laboratory
A multinational study comparing radiotherapy alone with radiotherapy plus cetuximab (Erbitux), a chimeric monoclonal antibody produced by Imclone, shows the combined therapy nearly doubles median survival rates in patients with locally advanced head and neck cancers (N Engl J Med. 2006;354[6]:567-578).
“Combining cetuximab and hyperfractionated radiation therapy appears to improve locoregional control and reduce mortality in patients with head and neck cancers that have not advanced beyond cervical lymph nodes,” says James A. Bonner, MD, Department of Radiation Oncology chair, UAB Comprehensive Cancer Center senior scientist, and the study’s lead author. “Furthermore, the combination approach does not increase toxic effects, such as mucositis and dysphagia, commonly associated with head and neck radiotherapy.”
From Infancy to Approval
Cetuximab is an IgG1 monoclonal antibody that targets the epidermal growth factor receptor (EGFR) abnormally activated in epithelial cancers, including squamous cell carcinoma of the oropharynx, hypopharynx, and larynx.
EGFR protein molecules have 3 regions: one extends outside the cell to provide the EGF binding site; a second is embedded in the cell membrane; and a third projects into the cell’s cytoplasm. Cancer cells with abnormally high levels of EGFR tend to divide excessively in the presence of EGF, potentially leading to rapid metastases and poor prognoses.
“Cetuximab targets EGFR by binding to the external domain and inhibits EGF from attaching to the receptor. The antibody blocks activation of the tyrosine kinase of EGFR, thereby preventing a cascade — including cell turnover, metastasis, and invasion — that occurs in malignant cells expressing EGFR,” Bonner says.
More than a decade ago, Bonner began investigating EGFR inhibition and has worked with UAB cancer center scientists Donald J. Buchsbaum, PhD; Kevin P. Raisch, PhD; and Mansoor N. Saleh, MD, PhD, on lab studies of cetuximab. Subsequently, he collaborated with UAB’s Ruby F. Meredith, MD, PhD; Sharon A. Spencer, MD; and Francisco Robert, MD, in phase 1 and 2 clinical trials. Patients were recruited through 2002, and the drug’s survival advantage was unveiled at the 2004 American Society for Clinical Oncology annual meeting.
“Realizing the majority of head and neck cancers heavily express EGFR, and knowing EGFR expression correlates with poor prognoses, we theorized that an EGFR inhibitor, such as cetuximab, could potentially increase these cancers’ sensitivity to radiation,” Bonner explains.
By adding a radiosensitizer to a standard radiation regimen, Bonner’s team achieved better local control and survival. “Radiosensitizers often activate healthy tissues. They can cause radiosensitivity and lead to difficulty swallowing, eating, or breathing in patients with head and neck cancers. Our study found cetuximab improved outcomes without enhancing side effects,” he says.
Boosting Survival
Between 1999 and 2002, Bonner and colleagues in the United States and many other nations, including Spain, Germany, Poland, and South Africa, investigated 424 patients with stage III or IV head and neck cancer. These cancers included tumors in the tonsils, tongue, larynx, pharynx, or lymph nodes that had not spread beyond the clavicle. The phase 3 trial randomized participants to receive radiation therapy alone or radiation plus an initial cetuximab dose of 400 mg per square meter of body surface area, followed by weekly infusions of 250 mg per square meter. For 7 weeks, physicians administered 1 of 3 standard radiotherapy regimens, which investigators selected prior to the study’s start. Investigators followed participants with physical examinations and radiographic imaging every 4 months for 2 years, then every 6 months for up to 5 years, with a median follow-up of 54 months.
The majority of trial participants who took cetuximab tolerated the standard radiation and cetuximab doses. Some experienced side effects, including infusion-site erythema, rash, asthenia, nausea, vomiting, constipation, and dysphagia. Only 4 patients discontinued cetuximab because of hypersensitivity reactions, and an additional 8 participants stopped the drug because of a grade 3 acneiform rash. About 50% of patients in both groups developed severe mucositis, underscoring that cetuximab does not increase risk for this adverse effect, but neither does it eliminate its occurrence.
Adding cetuximab boosted survival rates by nearly 20 months. The average time of locoregional control was 14.9 months for those in the radiation-only group and 24.4 months for those receiving combination therapy. Average overall survival was 29.3 months in the radiation-only group and 49 months for those in the combination group. Patients with oropharyngeal cancer experienced the greatest survival benefit.
A second clinical trial of 103 patients with recurrent or metastatic squamous cell carcinoma of the head and neck found cetuximab helped shrink patients’ tumors after they no longer responded to platinum-based therapy.
In November 2005, Bonner and others personally presented research to the US Food and Drug Administration that led to the drug’s priority review and February 2006 approval for primary curative treatment of oropharyngeal and laryngeal cancers, which may be extended to oral cavity lesions.
Newest Option
In 1998, when human studies of cetuximab were initiated in patients with head and neck cancers, radiation alone was the gold standard. Since then, more physicians have added chemotherapy to radiotherapy regimens to slow disease spread, but this introduces the risk of chemotherapeutic toxicity. Chemoradiotherapy regimens increase incidence of mucositis and dysphagia compared with radiotherapy alone.
“Initial treatment options for patients with advanced head and neck cancer include radiation therapy, chemoradiotherapy, surgery followed by radiation, and chemotherapy for patients with resectable tumors,” Bonner says. “Until now, cisplatin-based chemoradiotherapy has been considered the standard approach for unresectable tumors.”
Limitations
In an editorial accompanying Bonner’s published study (N Engl J Med. 2006;354[6]:634-636), some critics expressed concern that cetuximab plus radiotherapy had not been directly compared with one existing standard of care, platinum-based chemoradiotherapy. However, the editorialists note that cetuximab plus radiotherapy is a promising regimen and future studies should compare it with chemoradiotherapy. Also, they state it is an excellent choice for patients who cannot tolerate chemotherapy.
“Direct comparison studies are often available when physicians have more than one treatment option. Ideally, it would be best to compare the two regimens, but consensus-building has been difficult, as many investigators wish to study other questions,” Bonner says. “Future studies should examine combinations of chemotherapy, radiation therapy, and cetuximab.”
In 2006, the National Cancer Institute’s Radiation Therapy Oncology Group began comparing radiation and chemotherapy with radiation and chemotherapy plus cetuximab in 1000 patients with head and neck cancers. Large-scale clinical studies of treatment options for head and neck cancers present a difficult challenge; together, oral cavity and pharynx cancers represent only 3% of newly diagnosed cancers in the United States, and the malignancies have historically been associated with significant mortality. Furthermore, although tumors in the oropharynx, hypopharynx, larynx, and oral cavity have the same biologic features, each presents differently and responds uniquely to various types of treatment.
Chemoradiotherapy is not always better than radiation alone for head and neck cancers, Bonner says. In 2000, a meta-analysis of more than 75 studies comparing radiotherapy with chemoradiotherapy concluded that the routine addition of chemotherapy to radiotherapy was debatable. Since 2000, additional studies have shown adding chemotherapy to radiation produces 5% to 15% absolute benefits in 2 to 3 year survival.
“Although recent chemoradiation therapies have shown positive survival results, each patient must work with his team of doctors to choose an individualized approach,” Bonner says. “The definition of optimal outcomes will continue to evolve slowly. Surgical procedures are more refined, radiotherapy with targeted radiosensitizers can spare healthy tissues, and we can control chemotherapeutic toxicity better than ever before. Cetuximab offers a new option for head and neck cancers.”
For more information
Dr. James A. Bonner
1.800.UAB.MIST
mist@uabmc.edu