Ohio State researchers join forces to improve the treatment and prevention of head and neck cancer
By Darrell E. Ward
Photographs by Roman Sapecki
The survival statistics for advanced head and neck cancer have remained stubbornly grim for decades. Half or more of patients have advanced disease at diagnosis. Of those patients, three in 10 experience local or regional recurrence or second primary tumors and one in five develops distant disease. Those with recurrent disease live six months on average, with 20 percent surviving one year.
Susan R. Mallery, DDS, PhD, oral pathologist
“Head and neck cancers are unusual compared with other malignancies because they have a high incidence of simultaneous or subsequent second primary tumors,” says David E. Schuller, MD, director of the Head and Neck Oncology Program, professor of Otolaryngology and Head and Neck Surgery and the John W. Wolfe Chair in Cancer Research. “Preventing second primary malignancies is crucial for improving patient survival.”
Amit Agrawal, MD, head and neck cancer surgeon, microvascular reconstruction
“The malignancy or its treatment often affect the neck or face, not only altering physical appearance, but also interfering with vital functions such as breathing, speech and swallowing,” says Amit Agrawal, MD, an otolaryngologist and head and neck surgeon who specializes in head and neck cancer and microvascular reconstruction at The Ohio State University Comprehensive Cancer Center-James Cancer Hospital and Solove Research Institute (OSUCCC–James). Treatment and recovery require a tremendous investment of resources and healthcare dollars, he notes.
Cancer of the head and neck refers to malignancies of the oral and nasal cavities, tongue, throat and larynx. Most are squamous-cell carcinomas. About 47,500 new cases and 11,200 deaths are expected in 2008. Of the new cases, 21,000 will affect the oral cavity and tongue, 12,400 will arise in the pharynx, 12,250 will involve the larynx and 1,900 in other areas such as the salivary glands, sinuses, thyroid gland and skull base.
|About 47,500 new cases and 11,200 deaths from head and neck cancer are expected in 2008.|
The disease typically strikes men ages 50 to 75 who have a history of tobacco and alcohol use, though it is occurring in a growing number of women. A newer demographic consists of younger women who lack the usual risk factors but test positive for human papillomavirus infection (HPV). HPV-associated cancers are usually pharyngeal cancers, says Schuller, a nationally respected specialist in head and neck cancer. “This malignancy seems to respond better to therapy and to have a more favorable prognosis.”
“Prompt diagnosis and management of precancerous lesions is the most realistic way to
John Grecula, MD, radiation medicine
improve survival for these malignancies,” says OSUCCC researcher Susan R. Mallery, DDS, PhD, an oral pathologist at Ohio State’s College of Dentistry.
David E. Schuller, MD, Director of the Head and Neck Oncology Program
But the nature of the disease and the people it affects make early detection and improvements in treatment difficult. “Head and neck cancer is a multipronged problem,” Schuller says. “It involves the usual potpourri of genetic abnormalities, and layered on these are the environmental mutagens of tobacco and alcohol that give rise to the disease. It becomes both an educational issue in terms of human behavior and a research issue in defining what types of new and innovative treatment programs will be embraced by this group of patients.”
Patients with this malignancy are often coping with alcoholism or substance abuse; they may have emphysema, diabetes, cirrhosis or heart disease; they may lack money for medication and transportation, and have little support at home. They tend not to seek regular dental or medical care. Some 25 percent are malnourished at diagnosis. Treatment compliance is often low.
Consequently, survival remains poor, with local and regional recurrence the usual cause of death.
“We’ve seen no substantial improvement in survival in these patients in 40 years,” Schuller says, “which is why we at Ohio State have worked for nearly two decades to improve the treatment of patients with locally advanced disease.”
Anterpreet Neki, MD, medical oncology
That work includes conducting five early phase clinical trials for new treatment regimens, building one of the nation’s largest head-and-neck-tumor biorepositories, incorporating state-of-the-art surgical technology and reconstruction techniques, and conducting basic-science studies into the molecular causes of the malignancy.
At the same time, other OSUCCC–James researchers were developing promising chemoprevention strategies that use whole-food formulations for reducing the risk of recurrence, second primaries and disease progression in oral cancer. This work includes four clinical trials.
Ohio State's Intensification Regimen
Conventional treatment for locally advanced head and neck cancer is highly toxic, grueling and involves a series of steps that can take five and a half months to complete.
Schuller and his colleagues set out to develop an aggressive regimen that uses standard chemotherapy, radiation therapy and surgery, but is less toxic, more compact and has excellent patient compliance.
“If patients do not complete the regimen, its benefits are compromised,” Schuller says.
James Lang, PhD, head and neck cancer researcher
The regimen begins with twice daily radiation therapy, preceded by a dose of a radiosensitizing chemotherapeutic, for four days before surgery. The surgery itself includes intraoperative radiation therapy (IORT). That is followed with more radiation, again including a radiosensitizing drug, along with a second drug, paclitaxel, for treating microscopic distant disease. The average duration of treatment is 52 days.
“Our trial outcomes have shown excellent, durable local and regional control rates, even after more than four years of patient follow-up,” Schuller says.
|Head and neck cancer surgeons at The James perform 40-60 microvascular reconstructions of the tongue,|
jaw and throat.
Five consecutive phase II trials have been conducted over the past 15 years, with the fifth under way now (see sidebar on page 16). “There is no quick fix for this,” he says, “We have to pursue it in a very disciplined fashion.” Each trial involved about 40 patients with stage III or IV head and neck cancer that can be surgically removed.
“The intensification trials have demonstrated that the three traditional therapeutic modalities can be used in innovative combinations to achieve improved compliance, disease control, and quality of life and substantially improved survival,” Schuller says.
Surgical Advances Improve Quality of Life
“Surgery remains the single most effective therapy for high-volume head and neck tumors,” Agrawal says. “For extensive tumors, surgery can dramatically impact form and function. For smaller tumors, however, conservation techniques such as minimally invasive approaches and robotics technology have evolved that often enable us to
preserve organ function.”
Laryngeal cancers no longer necessarily require total laryngectomy, he says. “We may need to remove only part of the larynx, enabling patients to eat without a feeding tube, speak without an electrical larynx or breathe without a tracheostomy.”
Minimally invasive surgery is done endoscopically, often with the assistance of a microscope or laser. “We can often preserve normal tissue and function, particularly for tumors of the larynx, tongue base or palate,” Agrawal says.
Enver Ozer, MD, assistant professor of Otolaryngology and Head and Neck Surgery, is presently developing a program for treating head and neck cancer robotically at Ohio State.
Microvascular reconstructive surgery is another crucial component of head and neck cancer treatment. “The effects of the cancer or its treatment are often obvious to patients and the people around them, making it difficult for many patients to reintegrate with family and friends, return to work or go out in public,” says Agrawal.
Microvascular reconstruction can help restore physical appearance or enable patients to talk clearly or eat in public without need of a feeding tube. The head and neck surgical team has expertise and experience with a variety of tissue transferring reconstruction techniques, including the following:
- Rebuilding the tongue using muscle from the forearm or thigh.
- Reconstructing the jaw by transplanting vascularized bone from the leg or hip, restoring jaw continuity. Often, dentures can be attached to pins implanted in the reconstructed jaw.
- Grafting nerves to rehabilitate a face that could be paralyzed by tumors of the parotid gland and the facial nerve.
The OSUCCC–James multidisciplinary head and neck cancer team also includes radiation therapy specialists and medical oncologists such as Anterpreet Neki, MD. The team also works with neurosurgeons for skull-base involvement, thoracic surgeons for mediastinal surgery, vascular surgeons when arteries in the head and neck area must be removed or replaced, and occasionally with ophthalmologists.
“We also work closely with nurses, social workers, dentists, prosthodontists, speech therapists, nutritionists, psychiatrists and primary-care physicians to help patients through therapy,” Agrawal says.
Tumor recurrence remains a significant problem in head and neck cancer, so OSUCCC researcher James Lang, PhD, and Schuller are studying whether they can predict recurrence risk through a simple blood test. The two researchers teamed up with OSUCCC investigator Jeffrey C. Chalmers, PhD, a chemical and biomolecular engineer, who has developed a magnetic cell-sorting system that may be able to identify cancer cells that have broken from the tumor and are circulating in the blood.
Lang, Schuller and Chalmers are using the cell sorter to study blood samples collected from head and neck cancer patients before and after surgery, and at a point during long-term follow-up. They want to learn if tumor cells are present in the blood during any of the time points, and whether their appearance indicates recurrence before clinical symptoms occur.
In other research, Schuller, Lang and their colleagues are studying mechanisms of alcohol-related cancers, looking for gene changes after chronic alcohol exposure in head and neck cancer patients.
A third study looks at changes in glucose transport that enables head and neck cancer cells to derive energy more efficiently from glucose during periods of low oxygen.
Cause and Recurrence
About half of head and neck malignancies affect the tongue and oral cavity. Cancers of the mouth and tongue are more common for a reason. Each drag on a cigarette exposes the tongue and oral cavity to some 250 toxic or cancer-causing chemicals, including 11 known human carcinogens. Alcohol is believed to help some of these compounds enter the cells of the mouth, tongue and throat.
“Together, alcohol and tobacco deliver a one-two punch,” Mallery says.
Saliva plays a role, too. “Tumors of the tongue and oral cavity arise mainly where saliva pools, such as at the front of the mouth and on the underside and margins of the tongue,” Mallery says. These tissues are exposed for prolonged periods to dissolved carcinogens.
These conditions may transform healthy stem cells, which give rise to the epithelial lining of the mouth and covering of the tongue, into cancer stem cells. The progeny of these transformed stem cells may seed the oral cavity with initiated cells that later give rise to recurrent and second primary tumors.
Therapy for advanced head and neck cancer attempts to eliminate those scattered precancerous cells, as well as the tumor itself. Chemoprevention—the use of synthetic or
natural agents to reverse or suppress premalignant or malignant changes before invasive cancer develops—may offer a way of preventing these cells from progressing to cancer or to return them to a more normal state.
Gary D. Stoner, PhD, chemoprevention researcher
A large body of epidemiological and laboratory research suggests that diets high in fruits and vegetables reduce cancer risk. Laboratory research shows that a variety of substances in the plants can inhibit carcinogen activation or induce precancerous and cancerous cells to differentiate to a more normal state.
At the OSUCCC–James, Agrawal and Schuller are working with investigators in the cancer center’s chemoprevention research program to develop new strategies that use black raspberry preparations and other foods to reduce head and neck cancer recurrence and progression.
Oral leukoplakic lesion, underside of tongue. The lesion’s crisp margins and location in a high-risk “pooling” site imply that this adherent white patch of abnormal cells is premalignant. (Photograph by Carl Allen)
“We are taking a natural, whole-food approach that is more straightforward and likely to be better accepted by patients and families,” says Agrawal, who is co-principal investigator on three of the oral-cancer chemoprevention clinical trials along with OSUCCC researcher Christopher M. Weghorst, PhD, associate professor of Environmental Health Science and Public Health.
These strategies grew from seminal research on the cancer-preventing potential of fruits and nuts that began in the mid-1980s by OSUCCC chemoprevention researcher Gary D. Stoner, PhD, who today is professor emeritus. Stoner’s work has led to a number of OSUCCC–James-initiated clinical trials testing the use of berry preparations for preventing cancers of the head and neck, esophagus and colon.
Stoner, whose chemoprevention work at Ohio State began about the time Schuller and his colleagues were planning the first intensification trial, led a series of basic research studies of ellagic acid, a polyphenol with strong antioxidant activity. His laboratory found that feeding animals a diet containing ellagic acid would inhibit cancer in the esophagus and colon by minimizing the genetic damage that carcinogens produce in these tissues. He and his colleagues later found that ellagic acid is particularly abundant in berries.
DOWN IN THE MOUTH
(Illustrations by Christine Armstrong)
Changes in the lining of the mouth can be early precancerous warning signs
Transition of normal epithelia (the lining of the mouth) to oral cancer. Over time, exposure to carcinogens, such as those found in tobacco, can induce abnormal growth (dysplasia). Clinically, these precancerous lesions may appear as either white (leukoplakic), red (erythroplakic) or mixed red and white patches in the mouth. Certain fruits and vegetables such as black raspberries have cancer-preventing compounds that may inhibit or even reverse cancer development by mechanisms that include neutralizing oxygen and nitrogen free-radicals, stimulating cell maturation and death, and preventing proliferation and blood vessel growth.
“Our work indicated that the pulp and seed of berries contained ellagic acid, but not the juice,” Stoner says. “Since berries are about 90 percent juice, we decided to remove the water by freeze-drying and grind
the dried berry into a powder. This concentrated the ellagic acid and, we now know, many other preventive agents in berries about tenfold.”
By the mid-1990s, Stoner had evidence showing that freeze-dried strawberries and black raspberries, when present as 5 or 10 percent of the diet, inhibit initiation and progression of esophageal cancer in rats.
Like ellagic acid, the berries reduce carcinogen-induced genetic damage in the esophagus. In addition, they prevent progression of premalignant lesions by reducing the growth rate of premalignant cells, stimulating programmed cell death (apoptosis), inhibiting new blood vessel formation (angiogenesis), inhibiting oxidative damage to tissues, reducing inflammation and promoting cell-cell adhesion and communication.
“Recent molecular studies show that berries modulate the expression of genes associated with all of these cellular functions,” says Stoner.
Stoner’s findings piqued the interest of OSUCCC investigator Weghorst, who worked with Schuller, Agrawal and Lang studying gene changes that lead to cancer in oral tissues. He wondered if the berries would also have the same effect on that disease.
Weghorst, Stoner and a group of colleagues conducted the study using a hamster model of oral cancer and published their findings in 2002. “We showed for the first time that dietary black raspberries could inhibit tumor development in the oral cavity, suggesting that food-based chemoprevention might inhibit oral-cancer growth in humans,” Weghorst says.
Weghorst teamed up with Agrawal and ultimately obtained funding for three clinical trials testing the use of black raspberries to prevent oral cancer.
|“We showed for the first time that dietary black raspberries could inhibit tumor development in the oral cavity, suggesting that food-based chemoprevention might inhibit oral-cancer growth in humans.”—Christopher M. Weghorst, Ph.D.|
“We advanced from our initial animal studies to translational clinical trials in about three years, which is phenomenally fast,” Weghorst says.
Christopher M. Weghorst, PhD, oral cancer researcher
This was possible, he notes, because of the resources available to Ohio State as an NCI-designated Comprehensive Cancer Center. It had the clinical, laboratory and statistical resources for such studies, as well as a highly experienced team of head and neck surgeons, which included Schuller, Agrawal and Ozer. In addition, they had Ohio State’s Center for Advanced Functional Foods Research and Entrepreneurship, which is helping them develop berry formulations needed for future trials.
Three Chemo-Prevention Trials
Of the three oral-cancer chemoprevention trials, the first is funded by National Institute of Health’s Institute of Dental and Craniofacial Research and assesses whether black raspberries alter the expression of genes that might serve as biomarkers for head and neck cancer development. The study collects tumor and normal tissues from each of 60 participants at the time of their cancer diagnosis. The participants then use lozenges of freeze-dried black raspberries four times daily until their surgery, a period of four days to a month.
These samples are then compared with tumor and normal tissue taken during surgery to learn whether the treatment altered gene expression in the cancer cells. “We hope to identify berry-modulated changes in gene expression associated with critical molecular pathways that might favor an anti-proliferative scenario,” Weghorst says. “These molecular events might then serve as biomarkers in short-term studies that could predict the long-term chemopreventive potential of berries or even tell us which patients may or may not respond to the putative chemopreventive effects of berries.”
|Joan’s Fund, an endowment at the Ohio state university, has raised more than $550,000 for head and neck cancer research at The James. |
The second trial, funded by the American Cancer Society, focuses on people living in Appalachia and treated for cancers of the mouth or throat. For this study, 120 volunteers will use black raspberry lozenges for six months after completing therapy. The study should reveal whether berry use reduces recurrence or increases the period of disease-free survival. Cheek cells, saliva, urine and blood samples will be monitored for effects of berry treatment.
Peter Larsen, DDS, oral and maxillofacial surgeon
The third study is a $1.4 million, NCI-funded, placebo-controlled, randomized trial of 240 patients with a history of tobacco and alcohol use and treated for stage I or stage II head and neck cancer.
Participants are being randomized to use a placebo or one of two black raspberry formulations—lozenges in the form of lollipops or a mouth rinse—four times daily. The study uses two doses of each formulation, to provide either four or eight grams of powdered berries per day.
The researchers want to learn whether the formulations reduce recurrence in these patients; if they work as well as the plain lozenges; if there is a dose effect; if the formations modulate genes involved in head-and-neck cancer development; and whether
or not participants will use the treatment as often as required each day.
Other studies led by Weghorst have shown that strawberries also have chemopreventive effects in the hamster oral cancer model that are equal to those of black raspberries. “But the chemical makeup of the two types of berries is somewhat different,” he says.
“This suggests that different foods might influence different molecular pathways in cancer cells to elicit a chemopreventive effect.
"His lab is now working to identify the tumor-cell pathways that are influenced by each berry type. “If we can understand the way different chemopreventive foods work, perhaps we can design drugs, or develop supercharged berries or other functional foods that target those pathways to our advantage,” Weghorst says.
Mallery and her laboratory want to learn if black raspberries can stop or reverse precancerous changes in the mouth from progressing to invasive cancer.
She, in collaboration with Stoner, Peter Larsen, DDS, chief of Oral and Maxillofacial Surgery at Ohio State’s College of Dentistry, and others, recently completed a human trial testing the use of a bioadhesive gel containing 10 percent freeze-dried black raspberries.
“The findings were exciting and encouraging,” Mallery says.
The study involved 20 patients with precancerous lesions of the oral cavity—red or white patches in the mouth—and 10 healthy volunteers. Half of the lesion was surgically removed at the time of initial treatment in each of the patients. Next, the patients applied a half-gram dose of the adhesive gel to the lesion four times daily for six weeks, when the remaining precancerous tissue was removed.
Following treatment, eight of the 20 patients showed histologic improvement, eight patients maintained stable disease and four individuals showed disease progression. Furthermore, the treated epithelium showed statistically significant reduction in loss of heterozygosity (LOH, an indicator of tumor-suppressor-gene loss) and in levels of the proinflammatory enzyme, cyclooxygenase 2 (COX-2). Application of the gel also modulated gene expression profiles and upregulating genes associated with normal epithelial maturation.
Mallery speculates that the improvements in histologic grade and reductions in COX-2 and LOH occurred because the berry compounds induced apoptosis or terminal differentiation in the abnormal cells. “They seemed to cull out the precancerous cells,” she says.
The researchers were particularly surprised to detect a drop in microvascular density—a shutting down of the lesion’s blood supply—in three of seven patients evaluated for this parameter. The study also showed differences in patients’ responses to the therapy, which may reflect differences in metabolism that stabilize or “bioactivate” berry chemopreventive compounds.
Another study by Mallery, in collaboration with Stoner and Steve P. Schwendeman, PhD, at the University of Michigan, targets recurrent head and neck cancer. It compares the therapeutic efficacy of three naturally occurring compounds: N-acetylcysteine, an amino-acid derivative; endostatin, which inhibits tumor blood-vessel formation; and a water-ethanol extract of freeze-dried black raspberries. The agents will be delivered from locally implantable, controlled-release delivery vehicles.
|Jeanette Ferguson was 26 when diagnosed with tongue cancer. After chemotherapy and radiation, OSUCCC doctors rebuilt her tongue using muscles from her arm. Ferguson now assists in oral-cancer research OSUCCC.|
VOICE OF EXPERIENCE
Jeanette Ferguson was 24 years old when she noticed a sore on her tongue. It persisted for two years. Her braces were the cause, she was told.
After the braces came off, her tongue swelled to the size of a golf ball. A biopsy showed cancer, and she was referred to David E. Schuller, MD, director of the Head and Neck Oncology Program at the James Cancer Hospital and Solove Research Institute.
Ferguson, who didn’t smoke or use alcohol, was working on her PhD research at the time. She loved to sing, and she’d been married just seven months.
Anger at her diagnosis gave way to a resolve to beat the disease. She agreed to an intensified treatment according to a protocol that included chemotherapy and radiation, followed by surgery and more radiation and chemotherapy.
Schuller also told her that rather than use muscle from her chest to reconstruct her tongue, “I’m going to take muscle from your arm because I know that someday you’re going to have a child, and you’re going to want to breastfeed, and I don’t want to compromise that.”
“Hearing that sentence made all the difference in the world to me,” Ferguson says. She describes the treatment as hell on Earth. “But I’m almost six years out now, so it worked.”
Ferguson did have a baby, a son, about two years ago. Amazingly, she painstakingly retaught herself to sing, even performing the National Anthem at a 2004 Cleveland Indians game.
Today, she assists in oral-cancer research in the laboratory of OSUCCC investigator Christopher Weghorst and is on the board of Joan’s Fund, which raises money for head and neck cancer research. She also educates people about oral cancer. “It’s important for people to realize that this disease can strike anyone.”
This series of laboratory and animal studies will help determine the ability of the compounds to suppress head and neck cancer development. “We chose to investigate natural compounds because patients may need to use a chemopreventive agent for life, and they are more likely to find a natural compound acceptable,” Mallery says.
Improvements in outcome for head and neck cancer have been slow in coming. “It is a multipronged problem that requires a multipronged response,” Schuller says.
The goal of Schuller and his colleagues is to develop an intensified treatment program for advanced head and neck cancer that will show a statistically significant improvement in survival, excellent patient compliance, and improved quality of life and functional outcomes measures.
“We then hope to initiate a limited-group, multi-center phase II trial to learn if other institutions can achieve equivalent success with the regimen,” Schuller says, “followed by a large-scale phase III trial that involves many patients and institutions to learn if the regimen will benefit large numbers of patients nationwide.”
Beyond this, he says, better cure and control rates will require improved nerve- and function-sparing (speech and swallowing) surgical techniques; improved radiation therapy; improved chemotherapy, especially more effective and targeted drugs; and enhanced rehabilitation techniques.
More needs to be done to reduce the risk of the disease and recurrence through smoking cessation.
“Chemoprevention using agents such as the freeze-dried black raspberry formulations being developed here by Ohio State investigators are promising and exciting advances,” he says.
Early detection and management of precancerous lesions is another effective way to control the disease, says Mallery, who also teaches dental students each year.
“People see dentists more often than they see doctors, and dentists do the oral exams,” she says. “We instruct our students to perform a thorough head-and-neck evaluation on every patient, every six months. A subset of cases have subtle lesions, but most are crisply defined white patches or plaques that have almost a velvety appearance.
“If an ulcer in the mouth hasn’t healed in seven to 10 days, or if a patient has a red or white patch that can’t be explained, order a biopsy,” she tells them. “If we can catch head and neck cancer early,” she says, “we can stop it before starts.”
BLAZING A NEW TRIAL
The key elements of the five OSUCCC–James intensification regimen clinical trials (years indicate period of patient accrual). Each subsequent trial was modified based on earlier findings to improve distant disease control, and ultimately survival.
Intensification Regimen (IR) 1
Established the safety and effectiveness of preoperative, intraoperative and postoperative radiation therapy for these patients. The treatment provided excellent local-regional control; compliance was excellent, with 34 of 37 participants completing the treatment. A modest improvement in survival indicated that stronger systemic therapy was needed to prevent distant metastatic disease. Concurrent pharmacodynamic studies of paclitaxel, then an experimental drug, were done, along with tests of the drug’s activity in head and neck cancer patients.
Paclitaxel was added to the regimen to control distant metastases. The trial had good patient compliance and local-regional disease control, but the dose of paclitaxel, well tolerated by gynecologic patients, proved too toxic for this patient population. The drug did, however, dramatically decrease the rate of distant disease.
The paclitaxel regimen was changed to a lower but more frequent dosage. It was better tolerated, with good control of distant metastases. But some patients developed severe soreness in the mouth (mucositis), requiring an interruption in their treatment.
The fourth protocol added a drug during the days of the concurrent chemoradiotherapy to control mucositis. The drug proved unhelpful, but local, regional and distant disease control all remained excellent.
Trial five uses Intensity Modulated Radiotherapy (IMRT), a new type of radiation therapy that delivers less radiation to normal tissues while delivering an effective dose to the tumor. “With IMRT, we should achieve excellent tumor control while reducing the severity of dry mouth and mucositis,” says John C. Grecula, MD, director of Clinical Research, Department of Radiation Medicine, who was involved in all five trials. The regimen also includes a surgical technique that protects a major salivary gland from radiation damage to prevent dry mouth, which seriously affects patients’ quality of life. Studies will attempt to correlate treatment outcomes with possible molecular markers and quality of life indicators.