Frontiers

Thyroid cancer is usually successfully treated by surgeons, endocrinologists and nuclear medicine physicians. However, when traditional therapy fails, patients have few options. New targeted therapies may change that and offer new hope to people with advanced disease.

Eleven years ago, Kim Kessler found a lump in her neck while showering. She had immediately thought of her younger brother. He’d developed a similar lump 13 years earlier at age 19. It proved to be thyroid cancer.

Kim, then 34 years old and eight months pregnant with her third child, was referred to a specialist at Ohio State. They could do nothing, he said, until after the baby’s birth.

“That was hard,” Kessler says. “We knew it was there, but not how advanced it was. Her doctors tried to reassure her. “They said it was very slow growing, and that the risk for the baby from surgery was much greater than the risk posed by the tumor.” Following the birth of a healthy, 9 lb 5 oz baby boy, Kessler’s doctor did a fine-needle biopsy, drawing out a sample of cells that he sent to a pathologist.

“He called that afternoon to tell me I had papillary thyroid cancer that required surgery,” she says. Kessler received the standard treatment for most thyroid- cancers: surgical removal of the thyroid gland followed by oral ingestion of radioactive iodine, or radioiodine. She also needed to take thyroid-hormone pills due to the loss of her thyroid gland and to suppress any residual cancer.

The surgeon attempts to remove all the thyroid tissue, cancerous and normal. The normal tissue must go since it may become cancerous later, and it interferes with the detection and treatment of residual cancer. Radioiodine therapy is intended to kill normal and thyroid cancer cells that may have spread to other parts of the body or were not removed with surgery.

The treatment makes clever use of the thyroid’s need to scoop iodine from the blood and hoard it. The thyroid uses the iodine to make thyroid hormone, which is essential for maintaining the body’s energy balance and for a normal life. In radioiodine therapy, any remaining thyroid cancer cells concentrate the radioactive iodine, killing them.

Surgery and radioiodine therapy are largely responsible for thyroid cancer’s high cure rate, but some cells may be resistant to treatment and may show up 10 or more years later as a recurrence. Hence the need for life-long monitoring—a blood test for thyroglobulin, a protein produced by thyroid cells, and perhaps a neck ultrasound or full-body radioiodine scan. Repeat surgery or radioiodine therapy may be needed to treat recurrences.

GOOD NEWS, BAD NEWS

Thyroid cancer is a good-news, bad-news malignancy. On the one hand, thyroid cancer is relatively uncommon. An estimated 23,600 new cases are expected this year, making up only 1.7 percent of new cancer cases nationally. On the other hand, its incidence is rising faster than other cancers.

Thyroid cancer strikes three times more women than men for uncertain reasons. It is the eighth most common cancer in women, accounting for 3 percent of all cancer cases in females.

It’s good news that thyroid cancer grows exceptionally slowly. But while many cancers are considered cured if there is no sign of disease after five or 10 years, thyroid cancer can recur 10 or more years later. People treated for the disease require life-long monitoring.

It’s also good news that the standard therapy cures thyroid cancer in 80-85 percent of cases (Kessler’s brother has remained cancer free for 23 years, now). The high cure rate has given rise to the ill-advised adage: “If you must develop cancer, thyroid cancer is the one to have.”

But if the standard therapy fails, doctors have limited alternatives. Chemotherapy is largely ineffective. Some 1,460 thyroid cancer deaths are expected this year.

Unfortunately, thyroid cancer’s low incidence and high cure rate keeps research funding for the disease modest, says Richard Kloos, MD, associate professor of endocrinology and nuclear medicine. “Our therapies haven’t changed much in 50 years.”

Here’s the good news, however. “New targeted drugs are coming out that make good biologic sense in thyroid cancer,” Kloos says. “These drugs are still unproven, but they are promising.” And more are in the pipeline. “In the past, we might have had one clinical trial a decade. Now, we’re seeing a new clinical trial every few months,” Kloos says. “We have five or six to launch over the coming year.”

Kloos and Matthew Ringel, MD, associate professor of endocrinology, oncology, and human cancer genetics co-direct a comprehensive, multidisciplinary and translational thyroid cancer unit at The Ohio State University Comprehensive Cancer Center – Arthur G. James Cancer Hospital and Richard J. Solove Research Institute (OSU CCC – James).

This team of physician scientists— surgeons, endocrinologists, oncologists, nuclear medicine physicians, clinical cancer geneticists, and pathologists— veterinary scientists and laboratory scientists at the OSU CCC – James are seeking new and better ways to help people with thyroid cancer. Their work adds to more than 40 years of thyroid cancer research at Ohio State.

DATABASE AIDS TREATMENT DECISIONS

Seven years passed and Kessler’s follow-up tests showed no sign of cancer. Then the X-ray-like image from a body scan revealed a small spot of cancer cells lodged in a lymph node in her chest. They were not life-threatening, and removing the node would require major surgery, which carried its own dangers. Kloos, who is certified in both nuclear medicine and endocrinology, treated her with high-dose radioiodine.

Two years later, a small spot was still there. Kessler took high-dose radioiodine again. A tiny amount of tumor stubbornly remained.

“We decided to watch it,” Kessler says. “It may do nothing, or it could grow and spread.”

How did Kloos and Kessler decide that watching the tumor had less risk than chest surgery? In part because of knowledge gained from a research database begun at Ohio State in the 1960s by Ernest Mazzaferri, MD, professor emeritus and an international expert on thyroid cancer. As chief of endocrinology and later as chair of the Department of Medicine, Mazzaferri built Ohio State’s thyroid cancer national and international reputation.

Mazzaferri’s database now contains information from more than 2,000 thyroid cancer cases. It is invaluable for tracking the natural history of the disease and the effectiveness of treatments.

“The database showed us that patients can be diagnosed with ‘recurrent’ disease decades after therapy,” Kloos says, “suggesting that patients need life-long follow-up, rather than five or ten years of follow-up. This brought an awareness that ‘recurrent’ disease may actually be remaining ‘persistent’ disease that went undetected by the technology of the time.”

In the mid-1980s through the ‘90s, the database helped Mazzaferri, Kloos and thyroid surgeons recognize the value of the thyroglobulin blood test for detecting persistent or recurrent cancer, and later the value of neck ultrasound for guiding surgeons to cancerous nodules and small, swollen lymph nodes.

“The data suggested that surgery should be more aggressive,” says William Farrar, MD, a surgical oncologist who specializes in breast and thyroid surgery. “We began removing the entire thyroid rather than just the lobe with the cancerous nodules and lymph nodes that we couldn’t feel but that ultrasound showed were enlarged.”

Today, says Kloos, a recognized expert at neck ultrasonography for thyroid cancer metastases, “we use ultrasound routinely in our clinic, and our surgeons attempt to remove metastatic disease that cannot be felt on exam or seen by CT scan.”

More recently, research by Kloos and Mazzaferri also supports the use of a new synthetic hormone, Thyrogen, during thyroglobulin testing (see sidebar). The drug should greatly simplify follow-up testing for hundreds of thousands of thyroid cancer patients.

TARGETED DRUGS HOLD PROMISE

Because of their expertise in long-term follow-up and detection of residual disease, Mazzaferri and Kloos are both involved in developing and updating thyroid-cancer treatment guidelines for the National Comprehensive Cancer Network and the American Thyroid Association. This will help establish the standard of care for the disease. That standard may soon rise if new drugs now in early testing prove effective.

The drugs target specific changes in cancer cells (as opposed to chemotherapy drugs, which kill mainly all fast-growing cells). Manisha Shah, MD, a medical oncologist and a clinical researcher at the OSU CCC – James, is leading several clinical trials testing four such drugs that show promise for thyroid cancer.

Shah works very closely with the National Cancer Institute (NCI) to bring some of these promising new drugs to clinical trials for thyroid cancers. One NCI-funded trial examines the experimental drug BAY 43-9006. OSU is a leading center for this multicenter clinical trial. The drug targets a protein known as RAF kinase, which is mutated in about 35 percent of papillary thyroid cancers and may be activated by other means in another 20 percent of papillary cancers. The drug also can block the activity of a second protein, RAS, which is increased in about 20 percent of follicular thyroid cancers. Thus, this drug may help treat both common forms of thyroid cancer.

Ringel’s laboratory will examine the mutation status of RAF and RAS genes in thyroid cancer specimen obtained from the patients being treated on the BAY 43-9006 trial. In addition, BAY 43-9006 inhibits new blood-vessel growth in tumors by blocking a protein called VEGF. The OSU trial will measure this effect using dynamic contrast-enhanced MRI to monitor tumor bloodflow before treatment and after treatment. Michael Knopp, MD, PhD, chair of radiology and Novartis Chair of Imaging Research leads this part of the study.

The other studies examine whether the nonsteroidal antiinflammatory drug celecoxib or the targeted drug known as a histone deacetylase inhibitor drug SAHA, slows thyroid cancer progression. OSU is also the coordinating center for an international study of the drug combination irofulvin and capecetabine for metastatic thyroid cancer.

TARGETED RESEARCH AIMS TO IMPROVE SURVIVAL

Researchers at the OSU CCC – James are studying the changes that occur in thyroid cancer cells when they metastasize and stop taking up iodine. “If we can understand that, perhaps we can design drugs to block those changes and prevent progression of this disease,” says Ringel.

Ringel’s lab has discovered a pathway that suppresses metastasis. “This pathway normally blocks cell motility, but metastatic cancer cells seem to lose it,” Ringel says. “That may explain in part why these cells gain the ability to move.”

Ringel works closely with Ching-Sheh Chen, PhD, professor of medicinal chemistry, OSU College of Pharmacy, and of internal medicine and a researcher with the OSU CCC – James Molecular Carcinogenesis and Chemoprevention Program.

“Our laboratory is defining new molecular targets in thyroid cancer cells, and Dr. Chen is designing drugs to strike those targets,” Ringel says. “We are also working with compounds developed earlier by Dr. Chen’s lab that effect targets common to many cancers, including thyroid cancer.”

The collaboration of physician scientists and laboratory scientists like Ringel and Chen to answer medical questions is known as translational research. It is one of the most effective ways to improve cancer care.

For example, researcher Sissy Jhiang, PhD, professor of physiology and cell biology and a member of the OSU CCC – James Molecular Biology and Cancer Genetics Program, studies the protein that pulls iodine into thyroid cells. The protein, called the sodium iodine symporter, is essential for life and makes radioiodine therapy possible. Jhiang, an international expert on the symporter, led the team that first cloned the human symporter gene.

Jhiang is studying why the symporter protein stops working in advanced thyroid cancer. She also collaborates with Ringel to study how mutations in the RET gene influence thyroid cancer development.

Two years ago, Jhiang and Kloos joined to understand a side effect of radioiodine therapy. It began when Kloos noticed that high-dose radioiodine therapy caused the eyes of some patients to water heavily, at times causing tears to flow down their cheeks.

Jhiang found the symporter protein in the cells lining the duct that drains tears from the corner of the eye and into the nose. “So those cells also suck up radioiodine during therapy,” Kloos says. “The radioiodine damages the tissue, causing scarring that blocks the duct.” Now, he says, “perhaps we can find a way to prevent the problem.”

COMBING GENES FOR CLUES

Scientists know little about why thyroid cancer arises. One cause is clear: radiation exposure during childhood, including radioactive fallout from atomic weapons testing and nuclear power-plant leaks. The fallout injects radioactive iodine into the food chain, humans consume the iodine, the thyroid gland concentrates it, leading to cancer.

Medical treatments in the 1950s and ‘60s that used radiation to treat acne and tonsillitis are another proven cause.

Sometimes, radiation therapy for Hodgkin’s disease may cause thyroid cancer, and a tiny percentage of cases are inherited, and some others are suspected to be.

But doctors don’t know why thyroid cancer incidence is increasing. “We’ve seen about a 50 percent rise in the past 30 years,” Kloos says. Some doctors believe the use of ultrasound is simply finding more tumors earlier. In addition, Kloos suspects something in the environment is responsible, as well as an individual’s genetic predisposition. New clues about thyroid cancer’s causes may emerge from genetic research under way at the OSU CCC – James.

Papillary thyroid cancer (PTC), responsible for 80 percent of thyroid cancers, occurs in patterns suggesting that it might sometimes be inherited. Albert de la Chapelle, MD, PhD, the Leonard and Charlotte Immke Professor of Cancer Genetics, and former director of the OSU CCC – James Human Cancer Genetics Program, is working to identify genes that predispose people to PTC.

De la Chapelle’s laboratory is searching for germline mutations (mutations that people inherit) that predispose individuals to papillary thyroid cancer. Progress has been encouraging but slow because the number of people with thyroid cancer is low, de la Chapelle says. “But we are closing in.

“It is very difficult to identify these genes,” he says. “These are genes about which we know nothing. We don’t know where they are in the genome, and we don’t know what sort of gene we’re expecting to find.”

If de la Chapelle and his colleagues do find the gene and the mutations, he says, “it should enable us to develop a test to tell who in a family is at risk and who is not.”

De la Chapelle works closely with Kloos, Ringel, and others in the thyroid cancer group. In addition, the Comprehensive Cancer Center’s Clinical Cancer Genetics Program provides cancer genetic counselors, backed by attending clinical cancer geneticists, counselor-coordinators for research protocols, and a database of clinical features, genotype and sample tracking.

MASTERING THE FEAR FACTOR

Kim Kessler has learned to live with her cancer.

“My cancer occurred when I was young and had young children running around. I decided I had two choices: either I let it control what I think and do, or I control it. I prefer to not let it take over what I’m doing.”

Living with cancer means being forthright with friends and loved ones, Kessler says. “They are very fearful. If you don’t give them information , they act like they’re walking on egg shells all the time. I told family and friends what I was told about survival rates and other details. It seemed comforting to them. The kids, too.”

Kloos’s aggressive treatment of her cancer helped ease Kessler’s worries. “Even though I know it’s lingering there, I know that he’s on it all the time. He’s always up-front and honest, and gives me the whole picture; he enables me to put it into perspective.

“I also have a good quality of life. If you have a good quality of life, and you know you’re being monitored closely, you almost come to view it as more of an inconvenience.”

To learn more about living with thyroid cancer, visit the Thyroid Cancer Survivors Association Web site at http://www.thyca.org.

OSU Thyroid Cancer Group Research Landmarks

OSU’s multidisciplinary thyroid cancer unit is composed of 18 faculty members from the departments of surgery; medicine; pathology; molecular virology, immunology and medical genetics; physiology and cell biology; pharmacy and medicinal chemistry; radiology; and veterinary medicine. It is built on more than four decades of clinical and basic research accomplishments. Significant achievements in clinical research include the following:

• In the 1960s and 70s, OSU researchers helped define modern surgical approaches to thyroid cancer and performed early studies involving radioiodine therapy for thyroid cancer patients.
• Subsequent studies were among the first and largest to define the value of radioiodine therapy, thyroid hormone therapy, surgery and early treatment in improving thyroid cancer outcome.
• More recent clinical research has established the incidence and cause of side effects of radioiodine therapy.
• Finally, OSU researchers have developed a premier clinical trials unit for thyroid cancer patients, attracting referrals from around the United States and other countries.

In the laboratory, OSU researchers have made seminal observations regarding the genetic causes of thyroid cancer and the pathways responsible for its progression. This work has helped improve the diagnosis of thyroid cancer, define the risk of developing thyroid cancer in individual patients, and identify targets for treating patients with aggressive forms of thyroid cancer. Significant accomplishments include the following:

• The initial cloning of genes that can cause thyroid cancer.
• The cloning of genes that regulate radioiodine uptake in thyroid cancers.
• The identification of groups of genes found only in thyroid cancers, but not in normal tissues.
• The identification of pathways involved in thyroid cancer progression. Novel drugs that target these pathways are being developed by the OSU College of Pharmacy.

Today, the Thyroid Cancer Unit is a fully translational research group. Some of its basic scientists are defining the genetics and disease pathways of thyroid cancer; others use those findings to design agents that target molecules specific to the disease. Still others conduct preclinical tests on these possible new drugs. Finally, the unit’s physician-scientists conduct human studies of agents developed at OSU and elsewhere through clinical trials.

By Darrell E. Ward, Photography by Will Shively