The RapidReporter: Recent Developments, Findings, and Research in Head and Neck Cancer

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THE AMERICAN HEAD AND NECK SOCIETY’S ANNUAL MEETING

San Diego, CA

â–º New Role for Immune Activation of Antibody Therapy May Fine-Tune Approach to Head and Neck Cancer Treatment

Presence of FcyR genotype may point to best therapeutic approach in some patients

Identifying head and neck cancer patients who possess the FcyR genotype may help predict whether they will respond to monoclonal antibodies, which work by killing cancer cells bearing epidermal growth factor receptors (EGFR) on their surface.

“There may be a relationship between patients who possess this certain FcR genotype and their ability to mediate immune activation with certain monoclonal antibody therapies, but this is still to be validated,” said Robert L. Ferris, MD, Associate Professor, Co-Leader of the Cancer Immunology Program and Chief of Head and Neck Surgery at the University of Pittsburgh Cancer Institute. [Dr. Ferris and his colleague, Dr. Andres Lopez-Albaitero, presented their findings at the American Head and Neck Society’s {AHNS} recent Annual Meeting in San Diego.]

New England Journal of Medicine

This finding may be potentially substantial because monoclonal antibodies like Erbitux (cetuximab) by Bristol-Myers Squibb/ ImClone, which was originally approved to treat advanced colorectal cancer, are now used to treat some forms of mouth, tongue and voice box cancer. A study published in the in February 2006, for example, found cetuximab plus radiation therapy nearly doubled the median survival in patients with certain head and neck cancers, particularly oropharyngeal cancers. Another EGFR-specific antibody, panitumumab (Vectibix) is also FDA approved. Identifying patients with the FcyR genotype may further fine-tune whether these monoclonal antibodies will work for them. Until this is proven, however, chemoradiotherapy with cisplatin remains the accepted standard of care for these types of cancers. Toxicity with this platinum-based treatment remains high, however, leading researchers to look for other alternatives.

in vitro

in vivo

“We know that antibody-dependent cell-mediated cytotoxicity (ADCC) can happen even with low levels of EGFR, and the may be due to the presence of the FG gamma receptor,” said Dr. Ferris, who has served as a consultant and investigator for both BMS/Im- Clone and Amgen, respectively. “If the FcyR genotype influences the antitumor response to [a monoclonal antibody such as] cetuximab in squamous cell carcinoma cells of the head and neck and , ADCC activity should be correlated with the FcR genotype and other immune biomarkers.”

â–º Robots and Lasers Change the Face of Head and Neck Cancer Surgery

Precision robotic arms and targeted carbon laser are changing the face of traditional head and neck surgery while preserving the faces of patients, especially those with advanced and hard-to-reach cancers. Surgeons who support these new approaches hope they will one day render the current “saw-to-jaw” approach to many head and neck cancers obsolete.

“Traditional oral cancer surgery often requires making an incision, removing the lymph nodes and moving the jaw bone just to get to the cancer,” said Dr. Michael L. Hinni of the Mayo Clinic in Scottsdale, Arizona. “Transoral laser microsurgery (TLM) allows us to come in right through the mouth, completely remove the tumor, and achieve clear margins.” Dr. Hinni presented his findings and the results of some of his surgeries at an American Head and Neck Cancer meeting this past Spring.

With TLM, a high-powered microscope is threaded down to the larynx, a common site for hard-to-reach and advanced oral cancers. Once the tumor and surrounding cancerous tissue is identified, a CO2 laser carves it out. The advantages, Dr. Hinni says, are many.

“The CO2 laser does not put a lot of heat into surrounding tissues,” he says, “and not taking a patient’s face apart avoids a lot of swelling.” Additionally, Dr. Hinni says, TLM can reduce the need to perform a tracheotomy from the current 100% for cancers located at the base of the tongue to less than 25%, further speeding the patient’s return to normalcy after surgery.

Dr. Hinni and his colleagues conducted a multicenter trial where patients with Stage III or Stage IV squamous cell carcinoma of the glottic or supraglottic larynx were treated with TLM and followed up for two years. “The results,” he said, “were quite acceptable.” Dr. Hinni is guarded about stating more exact results because, while no “standard of care” for the treatment of advanced stage laryngeal cancer exists, radiation and chemotherapy remain the accepted standard to approach tumors that have become too large or too inaccessible to safely remove or remove without creating a need for extensive reconstructive facial surgery. However, he hopes that TLM will change this one day soon.

“Laryngeal cancer is a complex disease that poses challenges to patients, their families, and the health care professionals,” he says. “Current surgical approaches can profoundly affect how a patient eats, breathes, or talks. The best treatment should be individualized, and one of these treatment options may be TML.”

Robotic surgery, where surgeons use robotically controlled “hands” to remove tumors with near-perfect precision, is also giving head and neck cancer patients other options besides chemotherapy to shrink tumors. Like laser surgery, fine robotic instruments can now allow doctors easier access to what once may have been near-inaccessible tumors, particularly those located in the parapharygeal space, infratemporal fossa, anterior skull base and other hard-to-reach areas of the head and neck. For cancers located in these areas, according to Bert W. O’Malley, Jr., of the otorhinolaryngology department at the University of Pennsylvania Health System, Philadelphia, surgical options have been extremely limited. Like Dr. Hinni of the Mayo Clinic, Dr. O’Malley concurs that oral cancer surgery with jaw involvement “has a tremendous impact on speech and swallowing, and can cause extensive cosmetic defects, so chemotherapy and radiation has been the only option for some patients.” Since the introduction of robotic instruments at the University of Pennsylvania in 2005, Dr. O’Malley says he and his colleagues “have performed over 130 transoral head and neck procedures involving robotics.” In these procedures, robotic instruments enter through the oral cavity without having to cut away at the jawbone, neck, or other surrounding organs in the region just to get at the tumor. Thus far, according to Dr. O’Malley, 25 head and neck surgeons in the U.S. based at The Mayo Clinic, The University of Alabama, and Mount Sinai Hospital in New York, among others, have been trained to use robotic instruments in surgery. The procedure is currently awaiting FDA approval.

“I think robotics bring surgery back as an option for many head and neck tumors that were once only treatable by chemotherapy,” Dr. O’Malley says, who also presented his findings at the AHNS meeting this spring. “Now we can use the appropriate level of surgery and radiation and prevent many of the traditional side effects.”

Both TLM and robotic surgery for head and neck cancers may potentially impact yet another traditional complication of surgery—operating time and post-op recovery. Transoral laser microsurgery, Dr. Hinni says, has the potential of reducing a head and neck cancer patient’s hospital stay to just over 3 days, as opposed to the current standard of one week. Dr. O’Malley says robotic instruments in the operating room have the potential of reducing operation time from 8 to 15 hours down to about 2. Both doctors say the cost of these advanced procedures is offset by the cost savings realized in postoperative care, including the need for patients to undergo expensive and often extensive reconstructive surgery.

â–º Advances in Head and Neck Cancer Treatment Compel Clinical Trials and Success Measures to Keep Up

Old ways of measuring drug efficacy for traditional drugs may need to catch up with more complex medicines

As more advanced drugs for head and neck cancers emerge, traditional clinical trial designs and measures used to gauge the success of these new agents need to advance, or at least change, along with them.

“Our challenge will soon be not whether there is an agent that will work, but which one to use,” said Dr. Jennifer Rubin Grandis, professor of otolaryngology & pharmacology and leader of the head & neck cancer program at the University of Pittsburgh.

After more than a 45-year lull in the development of new drugs for head and neck cancers, a host of new and advanced therapies are now either in use or under investigation, Dr. Grandis pointed out at a head and neck cancer presentation earlier this year. Monoclonal antibodies that disable epidermal growth factor receptors (EGFR), overexpressed by the cells of many head and neck cancer tumors, are already being used (erlotinib, gefitinib, cetuximab), to treat patients. Angiogenesis inhibitors like bevacizumab (Avastin), which successfully cut offtumor blood supply in cancers elsewhere in the body, are now being investigated for cancers of the head and neck. Proteosome inhibitors, vaccine therapies, gene therapies and farnesyl transferase inhibitors (FITs) are also being investigated to treat head and neck cancers with or without additional surgery or radiation.

But along with these new options, Dr. Grandis says, comes the need for change in the way clinical trials are conducted and outcomes are measured. Dr. Grandis points to the new EGFR targeting agents as an example. “We know EGFR targeting works, but the challenge now is how to use it right; how to test our patients for their sensitivity to these agents before treating them with it or whether we should be enrolling them in new trials. If we knew this ahead of time we can use resources more wisely. I have a strong bias that every patient should be treated, but if there’s no evidence a particular agent will work for them, we should try to put them in another protocol or on another molecular agent.”

Success outcomes, Dr. Grandis says, may also need to be reconsidered in the age of targeted therapies. Clinical endpoints traditionally measure survival time and time to disease progression to judge whether an agent is working or not in clinical trials. Dr. Grandis suggests it may be time to test tumor responses (or lack of) to agents more frequently during the trial. Additionally, Dr. Grandis says, it may be time to consider improvement in disease-related systems as an endpoint, as many of the new agents do vastly improve a patient’s quality of life and ability to function normally.

Dr. Grandis concedes the ability to prescreen which patients may respond to the new agents may be limited and testing tumor responses at more regular intervals during trials may be complicated, but thinks it behooves patients and the medical community to be proactive. “If we don’t do it electively,” she says, “the insurance companies are going to find ways to stop spending money on things they don’t think work.”

â–º Clear Connection Between Diagnosis of Advanced Head and Neck Cancer and Insurance Coverage, ACS Study Reports

Study Gives Glimpse Into Current National Debate on Health Care Accesibility

While anecdotal evidence and mainstream thought suggest a connection between the quality of a person’s medical insurance—or lack thereof—and their health for some time, a recent study from the American Cancer Society on head and neck cancer has come up with some statistical insights.

Dr. Amy Y. Chen, MD, MPH, an associate professor of otolaryngology at Emory in Atlanta and director of health service research for the American Cancer Society, conducted a retrospective cohort study using the National Cancer Database spanning the years 1996 to 2003.

The study looked at the records of over 40,000 patients who had been diagnosed with invasive oropharyngeal cancer and whose insurance status was known: lack of insurance, private insurance, or Medicaid. After adjusting for what the paper calls “other sociodemographic characteristics” (data collected from the Census Bureau by zip code) the study found patients with advanced oropharyngeal cancer at the time of their diagnosis were more likely to be insured or covered by Medicaid compared wih those who had private insurance.

While Dr. Chen and her colleagues note the results of the Medicaid group “may have been influenced by the post-diagnostic enrollment of uninsured patients, insurance coverage appeared to be a highly modifiable predictor of cancer stage.” These preliminary findings are potentially concerning because screening for head and neck cancer, which can be done during normal health check-ups and dental exams, can prevent many of these types of cancers from advancing to such serious, life-threatening stages.

Dr. Chen says the findings in the head and neck cancer study are indicative of a larger problem. “This is the whole national debate on health care,” she says. “If a patient is diagnosed with cancer, they should have equal access to care and sufficient resources to deal with it, whether by Medicaid or another policy. As a clinician, I see the effects of not having adequate health care coverage every day, and it’s up to us as a society to take care of these patients.” Dr. Chen is currently working on another paper looking at the presentation of cancers other than head and neck in relation to insurance coverage and says she is seeing similar results “across the board.”

“Most of the uninsured and underinsured are treated at academic centers, which are then unfairly burdened with the cost of caring for these patients,” Dr. Chen says. “So eventually we’re all going to have to pay for it.”