New therapies may turn the tide for this disfiguring cancer.
Looking at Larry Menkhoff, it’s hard not to be a little skeptical as he launches into his history with oral cavity cancer. In 1999 the discovery of a tumor against his upper teeth and palate resulted in removal of the teeth on the upper left side, half of his palate and jawbone and a sinus cavity. The discovery of another tumor in a salivary gland a few years later meant more surgery and radiation.
But to any but the highly observant, Menkhoff looks normal, a comment that prompts him to remove the prosthesis that fills out his cheek and sinus cavity for closer inspection. “It’s the gift that keeps on giving,” Menkhoff says of his cancer.
Oral cavity cancer is included in the larger category of head and neck cancers, which account for 3 to 5 percent of all cancers diagnosed in the United States and result in nearly 13,000 deaths a year. There are more than 500,000 head and neck cancer survivors living in the United States today. In addition to oral cavity cancer, cancers of the larynx, pharynx, salivary glands and lymph nodes are also included in the designation.
Within each location are subsites, says Nancy Leupold, oral cavity cancer survivor and founder of Support for People with Oral and Head and Neck Cancer (SPOHNC). “There are so many locations for head and neck cancer and then each of those have subsites and then they are divided even further by cell types,” she explains, “meaning no two people’s cancers are quite the same.”
The majority of head and neck cancer diagnoses—about 39,000 Americans each year—are oral cavity cancer, which includes the lips and their lining, cheeks, the small area behind the wisdom teeth, the floor of the mouth, the front two-thirds of the tongue, the top of the mouth (hard palate) and the gums. Most head and neck cancers, like that of Menkhoff and Leupold, are squamous cell carcinomas that develop in the tissue lining the hollow organs of the body.
Leupold felt a painless bump on the floor of her mouth that was diagnosed as malignant in 1990 when she was 51. She lost 11 of her 13 bottom teeth during surgery to remove the tumor. But she is hopeful because, while the side effects of treatment are still a major concern, new treatment options as well as surgical and radiation techniques mean fewer deaths and decreased side effects.
Tobacco and alcohol use appear to cause most squamous cell head and neck cancers, says Merrill Kies, MD, professor of thoracic/head and neck medical oncology at M. D. Anderson Cancer Center in Houston.
In fact, 85 percent of head and neck cancers are linked to tobacco use, and studies show that people who use both tobacco and alcohol are at greater risk for developing these cancers than people who use either tobacco or alcohol alone. In adults who neither smoke nor drink, cancer of the mouth and throat are rare.
Both Menkhoff and Leupold smoked, but not heavily. Leupold described herself as a social smoker. “I never smoked a lot,” says the Locust Valley, New York, resident. “But when I was told I had cancer, I quit for good. ”
In addition to tobacco and alcohol use, leukoplakia (white spots or patches in the mouth) may lead to cancer in approximately one third of patients. People who have had radiation to the head and neck or those exposed to Epstein-Barr virus are also at increased risk.
Oral cavity cancer is usually found as a result of changes in the mouth, such as painful patches, a sore that won’t heal, bleeding, loose teeth or pain when swallowing. Menkhoff, a procurement program manager in Arlington, Texas, says it was a move and a new dentist that saved his life.
“My old dentist kept saying it was a piece of bone or something,” Menkhoff says of the spot on his hard palate that flared up occasionally. “My wife and I moved from South Texas to North Texas and I found a new dentist. He took one look in my mouth and told me to clear my calendar, because I needed to see an oral surgeon.”
Diagnostic tests, which may include X-rays, endoscopic exams and advanced imaging scans, help physicians determine a cancer’s stage. Stage 1 and 2 cancers are small, localized and often curable. Stage 3 and 4A cancers typically are locally advanced or have spread to nearby lymph nodes. Stage 4B cancers are usually metastatic and many times are inoperable.
“The treatment plan for each patient depends on a number of factors, including the exact location of the tumor, the stage of the cancer, the person’s age and general health,” Kies says. “Treatment options should be carefully considered because they might affect the way a patient looks, talks, eats or breathes.”
By the time Menkhoff was diagnosed, his cancer had grown from his palate across the teeth line and up into the jawbone. “We didn’t know if it had invaded the sinus, so to be sure, we removed it,” he says. Menkhoff talked with two surgeons before proceeding because his research indicated surgery could be done through the mouth without cutting through the cheek, the method he preferred and received.
Menkhoff was offered chemotherapy but declined, since the oncologist could not guarantee there would be any additional benefit. His second diagnosis two years later in a salivary gland, identified as a metastasis by one physician and a second primary by another, required a neck dissection to look at his lymph nodes followed by radiation.
Joseph Kuhn, MD, assistant director of surgical education at Baylor University Medical Center in Dallas, says diagnosis of any head and neck cancer includes thorough clinical exam, tissue biopsy, X-rays and radiographic staging. From there, Kuhn says, the initial diagnosis of oral cavity cancer may involve not only a head and neck surgeon but also a maxillofacial surgeon, who specializes in restorative surgery.
“Every case gets simultaneous consultation with a radiation oncologist. If there is any radiation that is going to be given, they will see an oral surgeon or someone who knows about radiation effects on the teeth,” he says.
In addition to staging, the choices of surgery, radiation and chemotherapy are determined by where the cancer is found since an inch can mean the difference between the use of one or all three treatment modalities, Kuhn says, trying in all instances to maintain function and cosmetic appearance and reduce side effects.
Leupold’s cancer was diagnosed at stage 1; she had surgery shortly after diagnosis. “I was lucky because I didn’t need radiation,” she says. “But I was not prepared for the bruising, swelling, burning sensation, numbness and dry mouth I had after surgery. And during surgery, a nerve to my tongue was sacrificed, so I have no feeling in half of my tongue.”
Although an increasing number of patients with squamous cell head and neck cancer can be treated with radiation alone or with radiation and chemotherapy, many still require surgery as either the definitive initial treatment or for salvage of primary treatment failure.
Surgery may change a patient’s ability to chew, swallow or talk. The face and neck may be swollen for several weeks. If lymph nodes are affected, the flow of lymph fluid may become sluggish and collect in the tissues; in this case, swelling may last much longer.
Analyzing the lymph nodes becomes important for staging, Kuhn says, and in head and neck cancer there are guidelines regarding which locations may result in node involvement.
“For cancer on the floor of the mouth, the chance of having a positive lymph node is about 40 percent. For a small tongue cancer, the chance is 25 percent,” Kuhn says, adding that studies are under way to determine if sentinel node biopsy, in which only the first lymph node is taken, will be effective and require fewer neck dissections to look at multiple nodes.
“Although an increasing number of patients with squamous cell head and neck cancer can be treated with radiation alone or with radiation and chemotherapy, many still require surgery as either the definitive initial treatment or for salvage of primary treatment failure,” says Dong M. Shin, MD, professor of hematology and oncology, director of the Clinical and Translational Cancer Prevention Program and co-director of the Translational Aerodigestive Tract Malignancies Program at the Winship Cancer Institute of Emory University School of Medicine in Atlanta.
Kuhn says it’s possible to cure a 1-centimeter tongue cancer equally with either surgical removal or radiation. “But once you have given the radiation you can’t give it again, and it does lead to dry mouth and dental problems,” he says. “We rarely operate on the base of the tongue, but instead use radiation and chemotherapy.”
Radiation treatments may cause mouth sores (oral mucositis), dry mouth (see sidebar), thickened saliva or difficulty swallowing. Changes in taste sensations may decrease appetite and affect nutrition. But Kuhn points out that in many cases today’s targeted radiation can pinpoint areas and avoid damage to the salivary glands.
When Menkhoff received radiation for his second diagnosis in the salivary gland, he started injections of Ethyol® (amifostine), a drug that protects salivary function. “It worked somewhat for me. I have limited function.”
Menkhoff also developed oral mucositis but resisted having a feeding tube inserted, which is frequently required for patients whose treatment makes eating extremely difficult. “I bought some weight gain products and mixed it with sweet milk and bananas and had those three times a day. It was high in calories and protein.”
Chemotherapy, especially for later stage head and neck cancers, has shown increasing efficacy as a treatment modality. Initially, single agents were used, but more recently combination chemotherapy has brought together numerous drugs that, when used together, offer greater response rates than when used alone.
“Chemotherapy drugs, such as 5-FU, cisplatin, carboplatin, Taxol and Taxotere, are widely used to treat more advanced head and neck cancers, particularly those in the nasopharynx, hypopharynx and larynx. Their effectiveness against other head and neck cancers has been tested in clinical trials,” Shin remarks.
At the 2004 meeting of the American Society of Clinical Oncology, investigators reported superior overall survival rates in patients who received Taxotere® (docetaxel) plus a standard therapy (Platinol® [cisplatin]/5-FU) for non-resectable locally advanced squamous cell carcinoma of the head and neck. Patients in this phase III trial had statistically significant improved progression-free survival and cancer response rates, as well as fewer severe side effects compared with standard therapy alone.
“In this trial, investigators reported that the Taxotere/Platinol/5-FU regimen was well tolerated and had a generally predictable and manageable safety profile, ” says Kies.
Chemotherapy, like radiation, brings with it a wide array of possible side effects that may include destruction of not only cancer cells but also other rapidly growing cells, including healthy blood cells that fight infection, cells in the lining of the mouth and digestive tract and those in hair follicles. As a result, patients may have lower resistance to infection, sores in the mouth and on the lips, loss of appetite, nausea, vomiting, diarrhea and hair loss. They may also feel unusually tired and experience skin rash, itching, joint pain or other discomforts.
Other treatments are being tested to prevent recurrence and/or second primary cancer. In a recent issue of the Archives of Otolaryngology-Head and Neck Surgery, Shin and Barbara A. Murphy, MD, associate professor of medicine and director of the Head & Neck Oncology Program and the Pain & Symptom Management Program at Vanderbilt-Ingram Cancer Center in Nashville, and colleagues published results of a phase II study combining isotretinoin, interferon-alpha and vitamin E as bioadjuvant therapy after definitive local therapy.
“In this study, we report the long-term (49.4 month median) follow-up from our previous chemoprevention trial using these substances,” says Shin. “Among the 45 patients with stage 3 and 4 squamous cell carcinoma of the head and neck treated under the protocol, 80 percent experienced progression-free survival for at least five years. These results are significantly better than the historical five-year overall survival of about 40 percent.
“We conclude that the bioadjuvant combination is highly effective in preventing recurrence or second primary cancer,” he adds, “and its role as standard therapy in advanced head and neck cancer is currently being investigated in a randomized phase III trial.”
Shin says that one of the biggest treatment challenges is to find effective ways to destroy the cancer while preserving normal organ function, particularly in the voice box, and suppressing debilitating side effects. “There are several therapeutic agents now in clinical trials that show promise,” he says.
Among the new drugs being tested are Erbitux (cetuximab), Tarceva (erlotinib) and Iressa (gefitinib). Although each targeted therapy may work differently, most focus their activity on proteins that stimulate cancer cell growth, such as the epidermal growth factor (EGF). These growth-stimulating factors act by either binding to specific receptors on the cell’s surface or by using the receptor as an entry point, disrupting molecular signals that stimulate cell growth. Many cancers, including lung, breast, ovarian, bladder, prostate, colorectal, kidney and head and neck, produce too many EGF proteins and depend on these proteins for growth.
ImClone Systems, the maker of Erbitux, submitted a supplemental new drug application on August 30 for approval in treating squamous cell carcinoma of the head and neck. Erbitux, a monoclonal antibody, is currently approved in combination with Camptosar (irinotecan) for treating colorectal cancer that has stopped responding to Camptosar-based chemotherapy.
Serving as support for the new indication is a phase III trial presented at the 2004 ASCO meeting that tested Erbitux with and without radiation in 424 patients with advanced head and neck cancer. Those who received radiation plus Erbitux showed significant improved survival (54 months) compared with those receiving radiation alone (28 months). Furthermore, adding Erbitux to radiation prevented the spread of cancer beyond the head and neck region more effectively than radiation alone. Other studies indicate Erbitux is also effective as second-line therapy in patients who received platinum-based therapy.
Overall, it’s a very exciting time in the treatment of head and neck cancer. Using a multidisciplined approach, we’re starting to develop efficacious treatments combining targeted therapies and conventional treatments.
In other studies, researchers are trying to find ways to make radiation therapy more effective against cancer and less damaging to healthy tissue by using drugs that make cancer cells more sensitive to treatment while protecting normal cells from radiation damage. Researchers are also testing new methods of aiming radiation therapy more accurately, and studying how differences in fractionation (how often radiation is given) help or hinder effectiveness.
In gene therapy approaches, researchers have found that many head and neck cancers have mutations (genetic changes) of the p53 tumor suppressor gene. Scientists are studying several gene therapies that target this gene by replacing it with a normal gene, or using a modified adenovirus (cold virus) to inactivate the p53 gene.
Past attempts to inject therapeutic genes directly into solid tumors have shown promise, but treating metastatic cancer has been less successful because either a patient’s immune system reacts against the therapy or the genes can’t find their way to cancer cells.
“Overall, it’s a very exciting time in the treatment of head and neck cancer,” says Kies. “Using a multidisciplined approach, we’re starting to develop efficacious treatments combining targeted therapies and conventional treatments. I believe we will make great strides in preserving function with no marked increase in toxicity.”
Murphy agrees, adding, “It took nearly two decades of study to find out that combination chemotherapy and radiation treatment improves outcome compared with radiation alone. The role of induction chemotherapy remains unclear. Our next challenge will be to determine which chemotherapy agents combined with radiation provide the best outcome and whether induction therapy can benefit selected patients. It will be years before we are able to complete the cohort of studies that will answer these questions.”
“Although we have a long way to go,” Shin says, “I am increasingly optimistic about new gene therapy and advanced drug delivery by nanotechnology approaches for earlier treatment and, ultimately, to a strategy that may help prevent cancer development.”
Patients undergoing both chemotherapy and radiation experience severe side effects that dramatically affect their day-to-day lives, says Murphy, who defines the side effects as acute, occurring during treatment, or late, occurring after treatment. Kuhn adds that for his patients, quality of life is difficult the first year after treatment.
After treatment, head and neck cancer patients may need rehabilitation that, depending on location of the cancer and type of treatment, may include physical therapy, dietary counseling and speech therapy. Reconstructive and plastic surgery may be needed as well.
Menkhoff has grown accustomed to his prosthesis, which he removes twice a day to irrigate the cavity in his jaw and sinus. But he still has to work daily for 35 minutes to an hour to have the ability to open his mouth, a result of the muscles tightening after surgery.
Murphy says medical professionals must help the patient with their physical as well as emotional needs. Leupold agrees, adding, “Sometimes, I was seeing a different health professional once or twice a day because there were different specialists treating me.”
But Leupold found she needed more; she needed support from those going through similar experiences. When she couldn’t find a support group, she started her own in 1991. Today, her organization, SPOHNC (800-377-0928, ), has about 40 chapters throughout the nation and is expanding internationally.
Menkhoff, now an active member of SPOHNC, says he wishes he had found the organization with his first diagnosis instead of his second. Today he mentors the newly diagnosed and continues to actively research the disease.
Leupold has remained cancer-free and devoted to promoting awareness about head and neck cancer. “I learn more about the disease in hopes of finding new information to pass along to those who are newly diagnosed and to support those who are living with the disease,” she says. “A patient support organization like SPOHNC is a vital component of the healing process. It can have a positive impact on meeting the psychosocial needs of head and neck cancer survivors as well as preserving, restoring and promoting their physical and emotional health.”