Thyroid Cancer and ChemoTherapy
In 2009, at least 36,000 persons in the United States were diagnosed with one of the various forms of thyroid cancer, a number that has been increasing at a surprisingly rapid rate (See Dr. Cooper’s piece on pages 8-9 and our handout on pages 19-20). Fortunately, most of these persons will do very well, and live long enough to die from something other than their thyroid cancer. Surgery to remove the cancerous thyroid gland, often including neck lymph nodes as well, is the primary treatment used. For the most common thyroid cancers (papillary or follicular cancer), many patients are also treated with radioactive iodine and high doses of thyroid hormone. Some individuals may experience cancer reoccurrence, and often additional surgery and/or radioactive iodine therapies are capable of adequately treating these patients.
Some patients with thyroid cancer, however, develop serious problems, including cancer that metastasizes (or spreads) outside the neck to the lungs, bones, or other organs. More than 1,500 persons die each year because of complications of thyroid cancer. For these patients, traditional therapies are often ineffective. Surgery, radioactive iodine, and radiation treatments can occasionally reduce symptoms or treat problems that emerge because of progressing cancer. But, these treatments rarely cure metastatic thyroid cancer. Like other malignancies, chemotherapies have been tried. Drugs that are used for other forms of cancer, like doxorubicin (Adriamycin®) or cisplatinum (Cisplatin®), were studied in the 1970s and 1980s, with little evidence of benefit. Only about one out of five patients with metastatic thyroid cancer that did not respond to prior therapy saw significant tumor shrinkage when treated with one or both of these chemotherapies, and cure was rare. Side effects were considerable, including reduced blood counts, increased risk for infections, hair loss, nausea, and vomiting. As a result, traditional chemotherapies have only been recommended for patients with very advanced disease as a “last ditch” effort.
“As drug companies have recently created many new drugs that attack angiogenesis or the abnormal cancer proteins, new opportunities have emerged for testing novel treatments for advanced thyroid cancer.”
As disappointing as these poor results from chemotherapy were, even more frustrating was the lack of success in developing more effective or safer treatments. Between 1975 and 2000, few clinical trials testing new therapies for thyroid cancer were started, and they usually failed to attract enough participants to test adequately new treatments. Further, pharmaceutical companies were reluctant to devote sufficient resources to support new drug development for the disease, given the small numbers of patients who needed help and the failure of earlier studies.
The past five years have seen a remarkable turnaround in these trends. First, scientists have discovered many key steps involved in the development of thyroid cancers that provide potential “targets” for therapy. For example, many cancers require the creation of new blood vessels (called “angiogenesis”) for them to grow larger than a few millimeters or to invade and spread to other parts of the body. Angiogenesis appears to be as critical for thyroid cancers as for more common malignancies like colon or lung cancer. Additionally, genetic mutations in thyroid DNA that cause most thyroid cancers have been discovered. These abnormal genes lead to production of abnormal proteins in the tumor cell that promote the growth of the cancer, but these abnormal proteins can also be targeted by drugs as a way to treat the disease. As drug companies have recently created many new drugs that attack angiogenesis or the abnormal cancer proteins, new opportunities have emerged for testing novel treatments for advanced thyroid cancer. Second, patients and their physicians have become more aware of the availability of clinical trials testing new therapies. Thyroid cancer patients are now being referred by their physicians to participate in all phases of trials of promising drugs, with considerable success.
An example of this new approach was the early testing of the drug motesanib, an inhibitor of angiogenesis. Nearly one in ten of the cancer patients in the earliest trials testing this drug were patients with advanced thyroid cancer, and several of them had good responses to the treatment. An international clinical trial was then performed to test the drug specifically in patients with growing papillary or follicular thyroid cancers that would not respond to more conventional treatments like radioactive iodine. Unlike previous attempts at clinical trials, this one succeeded, filling up with more patients than were actually needed months ahead of schedule. More importantly, nearly three-quarters of patients with previously growing metastatic thyroid cancers either experienced significant tumor shrinkage or at least saw their tumors stop growing, often for many months. Other drugs have also been tested this way in the past several years as well. Evidence is mounting that the drug sorafenib (Nexavar®) might similarly stop the growth of metastatic thyroid cancer by blocking angiogenesis as well as by affecting one of the mutated proteins found in papillary thyroid cancer (called BRAF).
Much research is now ongoing to try to find better treatments for advanced thyroid cancers. At The University of Texas M. D. Anderson Cancer Center (www.mdanderson.org), where I work, we are studying several different approaches and new drugs. Our thyroid cancer research team involves endocrinologists, surgeons, and medical oncologists including those who specialize in the very earliest of drug studies (called “phase I trials”). Patients can find information about our studies as well as those being done elsewhere through the web site www.clinicaltrials.gov.
Side effects from these treatments definitely occur, and patients need to be aware that problems like high blood pressure, diarrhea, fatigue, and bad skin rashes frequently occur with these new drugs. In some cases, skin cancers are appearing while patients are treated with certain drugs. Therefore, patients need to be carefully selected who truly need these treatments, and they and their physicians must be on the lookout for development of side effects that themselves could require treatment. But, for many of our patients, as long as the benefits of the new chemotherapies outweigh the side effects, we carefully push forward with their treatments.
With these advances, organizations such as the American Thyroid Association and the National Comprehensive Cancer Network now recommend that patients with progressing or symptomatic metastatic thyroid cancer, not responding to more traditional therapies like surgery or radioiodine, should be referred to participate in clinical trials of new or experimental drug treatments. Such research is absolutely necessary if we are to develop improved therapies that can cure metastatic thyroid cancer. However, for those patients who cannot or choose not to enter a clinical trial, treatment with angiogenesis inhibitors like sorafenib which are available for the treatment of other cancers can now be considered as a potential helpful option.
Steven I. Sherman, MD, is the Naguib Samaan Distinguished Professor in Endocrinology, the Chair of the Department of Endocrine Neoplasia and Hormonal Disorders, and Medical Director of the Endocrine Multidisciplinary Center at The University of Texas M. D. Anderson Cancer Center in Houston, Texas. After graduating from Harvard College magna cum laude in Biochemistry and Molecular Biology, Dr. Sherman earned his medical degree from the Johns Hopkins School of Medicine in Baltimore, Maryland. He stayed at Johns Hopkins for his internship and residency in internal medicine, and clinical fellowship in endocrinology and metabolism. He joined the faculty at Johns Hopkins upon completion of his training, and in 1993 was recruited to the M.D. Anderson Cancer Center. Specializing in the management of patients with advanced endocrine malignancies, Dr. Sherman is Director of the National Thyroid Cancer Treatment Cooperative Study Group and serves as Treasurer of the International Thyroid Oncology Group. He has led numerous phase II clinical trials evaluating novel therapies for metastatic thyroid cancer. He is author or co-author of more than 80 peer-reviewed journal articles, including New England Journal of Medicine, Annals of Internal Medicine, Lancet, Journal of Clinical Endocrinology and Metabolism, and Journal of Clinical Oncology.