Cetuximab (Erbitux®) Plus Radiation Beneficial for Patients with Head and Neck Cancer
Compared to radiation alone, cetuximab plus radiation therapy improves overall survival of patients with advanced head and neck cancer that has not spread to other parts of the body.
Lancet Oncology, published online November 7, 2009 (see the journal abstract).
Initial treatment options for patients with advanced squamous cell cancer of the head and neck (a category that includes most head and neck cancer) include radiation therapy, chemotherapy combined with radiation treatment (called chemoradiotherapy), surgery followed by radiation and/or chemotherapy, or initial (induction) chemotherapy followed by chemoradiotherapy. The current standard of care for such patients is chemoradiotherapy using one of the platinum drugs, such as cisplatin.
However, severe mucositis often develops as a result of such treatment, a condition that can make it difficult to eat without use of a gastric tube. Researchers are trying to find effective treatments that are less toxic.
Cetuximab, a monoclonal antibody that blocks the epidermal growth factor receptor, is a potentially less toxic targeted therapy. Early studies suggested that treatment with cetuximab might boost the effectiveness of radiation therapy in patients with advanced head and neck cancer.
Some people treated with cetuximab develop a temporary acneiform skin reaction (rash) to the face and body that usually disappears after treatment. The presence and intensity of this rash has been associated with better survival in several cancers.
Between 1999 and 2002, a total of 424 patients with stage III or IV head and neck cancer were enrolled in this phase III trial at multiple locations in the United States and Europe. All patients had tumors in their tonsils, tongue, throat, or larynx that may have involved lymph nodes but had not spread to other parts of the body.
Patients were randomly assigned to receive either radiation therapy alone (213 patients) or radiation plus weekly cetuximab (211 patients). Doctors treated the patients with one of three radiation therapy regimens, depending on each patient's disease characteristics. The overall radiation dose was about the same for all three regimens, but they differed in terms of fractionation.
All patients were followed for a median of five years. The study’s principal investigator was James A. Bonner, M.D., of the University of Alabama at Birmingham. ImClone Systems, Bristol-Myers Squibb, and Merck KGaA supported the trial and also provided the drugs. (See the protocol summary.)
The original report, published in the New England Journal of Medicine in 2006 (see the journal abstract), compared outcomes after three years. The new report includes information on survival outcomes after five years. The researchers also analyzed subgroups of patients to determine whether development of a rash among cetuximab-treated patients was associated with overall survival.
In the original analysis, the addition of cetuximab led to an improvement in overall survival (45 percent of those who received radiation therapy alone were alive after three years, versus 55 percent of those who received cetuximab plus radiation therapy). Median survival for patients treated with cetuximab plus radiation therapy was 49 months, compared with 29 months for patients who received radiation therapy alone. The combined treatment also did better in keeping cancer from progressing or recurring (called “locoregional control”). Locoregional control was achieved in 47 percent of patients who received combined therapy, compared with 34 percent of those who received radiation alone.
The updated overall survival results show that the survival benefit of cetuximab was maintained through at least five years. Forty-six percent of the cetuximab-treated patients were alive after five years, compared with 36 percent of those in the radiation-only group. Median survival times were unchanged in the updated analysis.
The original analysis found that rates of severe acneiform skin reactions were much higher in the cetuximab group (17 percent) than the radiation-alone group (1 percent). Infusion reactions were also more common in the cetuximab group, but all other side effects occurred at similar rates.
At least mild acneiform skin reactions occurred in 174 of the patients who received cetuximab (84 percent), about the same rate as would be expected using cetuximab without radiotherapy. In 127 of these patients, the rash was prominent. Such patients survived for a median of 69 months, whereas patients who had no reaction or only a mild rash had a median survival of 26 months.
Earlier published results of this study demonstrated that cetuximab helps patients with locoregionally advanced head and neck cancer live longer without negatively affecting their quality of life. “These latest overall survival data are important,” said Claudio Dansky Ullmann, M.D., from NCI’s Clinical Investigations Branch, “because that benefit continues for at least five years.” Cetuximab plus radiotherapy is now an accepted treatment option for these patients, although he added that the precise group of patients for whom this treatment could be considered standard needs to be further defined.
The observation that patients treated with cetuximab suffered more frequently from a skin rash on the face and body is something that “we expect from cetuximab,” said Dansky Ullmann. Not only did the rash not appear to reduce the effectiveness of treatment, but, the authors suggested, “it is possible that the acneiform rash is a biomarker of an immunological response that is conducive for optimal outcome.” A similar pattern has been shown for other types of cancer, said Dansky Ullmann.
In an editorial in the New England Journal of Medicine that accompanied the original trial results, Marshall R. Posner, M.D. and Lori J. Wirth, M.D., noted that the trial did not compare the cetuximab combination with the standard platinum-based chemoradiotherapy treatment. They also noted that the administration of different radiation regimens complicates interpretation of the results.
In addition, the survival benefit was not the same across all types of head and neck cancer. "The benefit of cetuximab in terms of survival was evident for oropharyngeal cancer, the diagnosis in more than half the patients," the editorialists wrote, but “the use of the antibody did not improve the survival among patients with hypopharyngeal or laryngeal cancer.”
In this context, and complicating the interpretation of the results, is the lack of information on the human papillomavirus (HPV) status of the tumors. HPV is increasingly being found in head and neck cancers—almost exclusively in tumors of the oropharynx (the part of the throat just behind the mouth). It has recently been found that patients with HPV-positive oropharyngeal tumors generally have better outcomes than those with HPV-negative tumors.
The prognostic importance of HPV in head and neck cancer was not known when the study was designed, and the investigators did not test tumor samples for HPV. It is possible, Dansky Ullmann noted, that patients in this study who lived longer “might have had HPV-positive tumors. It remains to be seen if this particular subgroup of patients is the one that may have benefited more from the addition of cetuximab.” Currently planned studies in head and neck cancer will select patients by HPV status, Dansky Ullmann explained. “These studies will help better define the patient populations where a less intense and toxic regimen such as the one in this study would constitute the primary option, or those where a more intense chemoradiotherapy-based approach is needed.”
Finally, Posner and Wirth wrote, "oncologists should keep in mind that all studies of platinum-based chemoradiotherapy have shown greater improvement in patients than [this trial] found with cetuximab.... At present, for patients who can tolerate it, chemoradiotherapy with cisplatin remains the standard of care." Dansky Ullmann added that a trial that recently completed accrual is testing whether cetuximab might improve outcome when added to this current standard for these patients.
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