A blood test that detects proteins commonly released by a growing tumor could one day become a useful tool for monitoring the effectiveness of chemotherapy and radiation treatment in people with advanced throat cancer, according to a study published in the June 1, 2007, issue of Clinical Cancer Research. Scientists in the National Institute on Deafness and Other Communication Disorders (NIDCD) and National Cancer Institute (NCI), two of the National Institutes of Health (NIH), in collaboration with researchers of the University of Michigan, found that throat cancer patients who showed a decline in several cancer-related proteins following chemotherapy and radiation treatment were more likely to remain in remission, while those who experienced a large rise over time in those proteins frequently exhibited a return of throat cancer. The findings could help lead to the development of a blood test that enables doctors to detect the recurrence of throat cancer early on, when there is still time to pursue a second line of treatment, such as surgery or drug therapy.

"Cancers of the head and neck are insidious because surgical removal of the tumor can severely impair a person's ability to talk and to swallow," said NIDCD Director, James F. Battey, Jr., M.D., Ph.D. "A blood test that enables doctors to closely monitor a patient's rehabilitation while sparing the patient's voice, speech, and swallowing ability is an excellent example of the predictive, preemptive, and personalized approach to medicine that the NIH strives for."

Roughly 20 years ago, the primary method for treating throat cancer was to surgically remove the tumor. Because this treatment can severely impair a patient's quality of life by damaging voice, speech, and swallowing, in many cases physicians and their patients are now opting for a combination of chemotherapy and radiation as a first line of treatment. However, there is no way to predict which patients will respond well to this treatment or whether a tumor will return later. Clinical exams, X-rays, and magnetic resonance imaging (MRI) are currently used to monitor a patient's progress, but observation by these methods has been difficult due to the scarring that occurs from radiation.

"Finding better markers for detecting cancer as it begins and then monitoring the course of treatment is a major goal of the NCI and this research in head and neck cancer is an excellent example of the type of collaborative study between two NIH institutes that helps advance the field," said NCI Director, John E. Niederhuber, M.D.

It is estimated that more than 34,000 Americans will be diagnosed with cancer of the oral cavity and pharynx (the middle part of the throat that includes the soft palate, tonsils, and tongue) in 2007, and that 7,550 Americans will die from it. Alcohol and tobacco use are the most important risk factors for head and neck cancers, with tobacco use accounting for 85 percent of the cases. Just last month, other NIH-supported doctors reported that sexual transmission of human papillomavirus is strongly associated with throat cancer, especially in cancers arising from the tonsils and base of the tongue.

In the largest long-term study of its kind, NIH and University of Michigan researchers tested the blood of 30 patients who had undergone chemotherapy and radiation treatment for advanced throat cancer. Starting immediately before treatment and continuing every three months for 12 months, the researchers tested the patients' blood for five proteins that, in previous studies, had been found to occur at heightened levels in head and neck cancer patients. These include two cytokines known as Interleukin (IL)-6 and IL-8, and three growth factors known as growth-related oncogene (GRO)-1, vascular endothelial growth factor (VEGF), and hepatocyte growth factor (HGF). These cytokines and growth factors play an important role in the body's inflammatory response and in the growth of cells and new blood vessels. Because the researchers used a bioassay technology that can simultaneously analyze the concentrations of each protein, only a small amount of blood was required for the test.

The majority of the patients had a complete response to therapy. Patients whose blood levels of these cytokines and growth factors dropped and remained low following treatment were more likely to continue in remission. Patients who experienced large increases in protein levels were more likely to exhibit a return of the cancer or to die from it. For example, large increases in IL-6, VEGF, and HGF concentrations over time yielded a 3.8-fold, 3.0-fold, and 2.9-fold higher risk of dying of throat cancer, respectively. Patients with an increase in three or more factors were at highest risk for dying of throat cancer-more than twice as likely as patients with an increase in two or fewer factors. Finally, patients with the sharpest rises in protein levels had lower chances for survival, with patients who had a history of smoking experiencing the largest spikes. (For this reason, estimates of relative risk of death were adjusted to exclude the compounding effects of smoking.)

Because the production of these growth factors and cytokines is controlled by the same "master switch"-a regulator protein known as nuclear factor kappa B (NF-kappaB)-the researchers suggest that this protein may represent a new target for drug therapy. Drugs that help turn off NF-kappaB are currently being tested in clinical trials at NIH and elsewhere.

The researchers note that a few of the patients experienced elevations in cytokine levels related to other illnesses or injuries, and not to throat cancer; therefore, they caution that further studies are needed in larger groups of patients to confirm if this could be a useful tool to monitor for cancer, infection, or other complications. In addition, because IL-6, IL-8, VEGF, and HGF have been detected in the blood of patients with breast, cervical, ovarian, and other cancers, they suggest that this technique may have broader application in the monitoring of other forms of cancer. Further studies would need to be performed on patients with these types of cancer as well.

Posted by the National Cancer Institute

June 1, 2007