Targeted therapy in addition to radiation may be a viable approach to head and neck squamous cell carcinoma, although more research is needed before such treatment becomes part of the standard of care, according to experts interviewed for this article.
Explore This IssueMay 2006
For example, a new study (N Engl J Med. 354;6:567-578) found that concomitant high-dose radiotherapy plus cetuximab, a monoclonal antibody targeting the epidermal growth factor receptor (EGFR), improves locoregional control and reduces mortality in patients with head and neck cancer without increasing the common toxic effects associated with radiotherapy.
One of the study’s implications is that physicians now have a biologic treatment for patients with head and neck cancer, said one of the study authors Roger B. Cohen, MD, Director of the Phase I Clinical Trials Program at the Fox Chase Cancer Center in Philadelphia, Pa. Incidentally, this is the first new therapy for the disease in more than 30 years, added Dr. Cohen, who was with M.D. Anderson Cancer Center in Houston, Tex., at the time of the study.
One day, researchers will come up with the answer of how targeted therapies should be used, but we don’t have it yet, cautioned Marshall Strome, MD, MS, Professor and Chairman of the Cleveland Clinic Head and Neck Institute (Ohio). Targeted therapies may be a treatment for some patients who aren’t up for full platinum-based chemotherapies with radiation or for those can’t undergo surgery, he said.
Research will evaluate patients who receive radiation therapy and chemotherapy after surgery due to a high risk of recurrence and see if they are also candidates for cetuximab in combination with radiation.
New Data Demonstrate Benefits
In the new randomized study, 213 patients received high-dose radiotherapy alone, while 211 received high-dose radiotherapy plus weekly cetuximab at an initial dose of 400 mg per square meter of body-surface area, followed by 250 mg per square meter weekly for the duration of radiotherapy.
The median duration of locoregional control was 24.4 months among patients treated with the combined therapy and 14.9 months among those given radiotherapy. With a median follow-up of 54.0 months, the median duration of overall survival was 49.0 months among patients treated with combined therapy and 29.3 months among those treated with radiotherapy alone. Radiotherapy plus cetuximab significantly prolonged progression-free survival (hazard ratio for disease progression or death, 0.70; P = 0.006).
We are just in the early stages of translating the work done in the lab, which shows improvement in cancer cell death and animal survival with the use of [monoclonal antibodies’, to the bedside. – mdash;Christine Gourin, MD
With the exception of acneiform rash and infusion reactions, the incidence of grade 3 or greater toxic effects, including mucositis, did not differ significantly between the two groups.
Although drugs like cetuximab definitely have fewer side effects than chemoradiation, the biologic therapy still is associated with some side effects such as rare hypersensitivity reactions and frequent acneiform rash, said Dr. Cohen. However, cetuximab did not seem to exacerbate the common toxic effects associated with radiotherapy of the head and neck, including mucositis, xerostomia, dysphagia, pain, weight loss, and performance-status deterioration, he said.
The study findings also indicated that cetuximab treatment does have its limitations, noted Dr. Strome. While the agent appeared to be beneficial for oral pharyngeal cancer, it did not make any difference in outcomes in patients with larynx or hypopharyngeal cancer, he said. Physicians need to keep in mind that how a newly given drug will affect specific sites of head and neck cancer may vary, he explained.
Chemoradiation continues to be the gold standard for fit, young patients with locally advanced cancer, but patients who can’t receive the standard of care because they aren’t medically fit need options like cetuximab. – -Roger B. Cohen, MD
Additionally, absolute survival at three years was 10%, and 5% of patients died within 60 days of completing therapy, he noted. At five years there will likely be a further fall-off in survival, Dr. Strome explained.
Cetuximab was not effective for metastatic disease in these patients, he added. If you could show me that the therapy decreased metastatic disease, it could be added to current regimens used with surgery, he said.
Additionally, only fractionated radiation therapy tended to have a response, and significant delayed severe radiation therapy complications occurred in 20% of cases, said Dr. Strome.
Future Cetuximab Research
Further studies through the Radiation Therapy Oncology Group and other research consortia will ask the key question of what will happen when investigators add cetuximab to chemotherapy in combination with radiation. In other words, triple therapy, said Dr. Cohen.
Additionally, a head-to-head comparison is necessary to determine whether cetuximab with radiation is as good as chemoradiation, he said.
Research will also evaluate patients who receive radiation therapy and chemotherapy after surgery due to a high risk of recurrence and see if they are also candidates for cetuximab in combination with radiation, Dr. Cohen said.
Changing the Standard of Care?
Chemoradiation continues to be the gold standard for fit, young patients with locally advanced cancer, said Dr. Cohen. But patients who can’t receive the standard of care because they aren’t medically fit need options like cetuximab, he explained.
The combination is a useful and viable option for patients who need chemoradiation but cannot tolerate cisplatin or other types of chemotherapy, added Dr. Cohen. For the many patients who are elderly or have poor kidney function or other significant comorbid conditions such as heart failure or diabetes, cetuximab with radiation provides a more effective treatment option than radiation alone and is well tolerated.
The blanket statement that chemoradiation therapy is the standard of care for advanced disease is troublesome for me, said Dr. Strome. Stage 3 cancers, for example, can have small primary tumor sites that can be treated with endoscopic surgery, while avoiding the side effects of chemoradiation.
More and more head and neck surgeons are doing endoscopic surgery for small primary lesions in the voice box and pharynx, said Dr. Strome. For example, some patients with T-2 lesions of the larynx with a positive neck node can be out of the hospital in five days, and talk and swallow within two weeks.
The problem is, a lot of people don’t understand what modern surgery can accomplish as opposed to 10 years ago, he said. I can take a small tumor out through the mouth with a laser and cryotherapy. While not all centers offer this treatment, patients need to understand it is an option.
Impact on the Otolaryngologist’s Role
The impact of cetuximab and other biological agents on otolaryngologist-head and neck surgeon’s role in providing care for head and neck cancer patients is significant, said Robert Dolan, MD, Senior Staff in the Lahey Clinic Medical Center’s Department of Otolaryngology-Head and Neck Surgery in Burlington, Mass.
While the agent appeared to be beneficial for oral pharyngeal cancer, it did not make any difference in outcomes in patients with larynx or hypopharyngeal cancer.
Counseling the patient regarding prognosis may be impacted, he said. For example, if the outcome of the phase III clinical trials using cetuximab is positive as anticipated, then the otolaryngologist may justifiably predict an improved outcome with regard to tumor control and ultimately survival, he explained.
The otolaryngologist will also need to be aware of the potential side effects of cetuximab. In the long term, there is a potential for these biologic agents to supplant standard chemotherapy either as single agents or more likely as multiple agents targeting unique pathways of tumor growth and spread, he said.
Patients need to be given the various options that are available to them, said Dr. Strome. Physicians should let patients know the side effects of radiation, the potential 10% improvement in survival at three years with cetuximab and how these therapies compare with surgery. Chemotherapies are also becoming more effective, he said.
Patients need to be selected and properly informed about the side effects of cetuximab and the potential for a slight improvement in overall survival, added Dr. Strome.
Other Agents Being Studied
In addition to, cetuximab, researchers are evaluating a number of other agents for head and neck cancer.
Monoclonal antibodies directed at the external domain of EGFR, inhibition of EGFR tyrosine kinase phosphorylation, and inhibition of angiogenesis by blocking VEGF are some areas of clinical investigation, said Christine Gourin, MD, Assistant Professor of Otolaryngology at the Medical College of Georgia Health System in Augusta. We are just in the early stages of translating the work done in the lab, which shows improvement in cancer cell death and animal survival with the use of such agents, to the bedside, she said.
Data regarding agents other than cetuximab are primarily results from preclinical work in head and neck squamous cell carcinoma, she added. Most clinical work has been performed in patients with lung or colon cancer because there are so many more cases of those kinds of tumors than head and neck squamous cell carcinoma.
Targeted small molecule agents such as the EGFR inhibitors gefitinib (Iressa) or erlotinib (Tarceva), which are presently used to treat lung cancer, are being studied in combination with radiation and chemotherapy in head and neck cancer patients, noted Dr. Cohen.
An important research question would be will you get the same results as [our] study if you gave Tarceva, for example, instead of cetuximab, he said.
Whether angiogenesis inhibitors like bevacizumab (Avastin) have a role in this setting by themselves, with radiation and/or chemotherapy or together with drugs like cetuximab also needs to be investigated, said Dr. Cohen.
Such research will help to answer some of the many questions regarding what role targeted agents will play in the future treatment of head and neck cancer, he concluded.
Cancer Then & Now: 1946-2006
- In 1946 the five-year survival rate for all cancers combined was about 35%; today it is 65%.
- In 1946 nearly 25% of Americans thought cancer was contagious, and many thought it could be contracted from drinking milk. Now it is known that at least half of all US cancer deaths are related to tobacco, poor nutrition, physical inactivity, overweight/obesity, and other lifestyle factors.
- In 1946 physicians used radioactive materials and a Geiger counter to try to detect breast cancer. Today, largely due to mammography screening, almost two thirds of all breast cancer cases are diagnosed at an early stage, for which the five-year survival is nearly 98%.
- In 1946 cancer was treated with surgery, x-rays, and radium. But more offbeat treatments were also used, such as Russian life serum estrogen tablets for prostate cancer; Coley’s Toxin, which used streptococcal infections to induce tumor regression in sarcomas; and nitrogen mustard gas to treat lymphoma. The standard treatment for breast cancer was a radical mastectomy. Today, there is increasing emphasis on using targeted therapies against cancer that do not harm healthy cells, and radical mastectomy is rarely used for breast cancer due to the proven efficacy of less disfiguring surgery, such as lumpectomy followed by radiation.
Source: American Cancer Society
©2006 The Triological Society