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Editor's Note: Contributing Editor Ricki Lewis was diagnosed with thyroid cancer in 1993 and had standard treatment. She will be taking a recently approved test this summer and hopes to participate in the clinical trial of another, both discussed below. Michael Levine When a lump in the neck turns out to be thyroid cancer, many doctors announce, "If you had to get cancer, this is the one to get." Fortunately, treatment is straightforward and effective, but follow-up testing can be uncomfortable because it requires a hypothyroid state. Now two new tests promise to ease the lifelong monitoring necessary to detect recurrence and identify patients most likely to benefit from follow-up procedures. Each year in the United States, about 20,000 people are diagnosed with thyroid cancer, and 1,100 die of it. "This requires patients to be monitored at frequent intervals for the rest of their lives," says Michael Levine, a professor of pediatrics, medicine, and pathology at the Johns Hopkins University School of Medicine. Some 200,000 people require monitoring. A 1997 study from the National Cancer Institute predicts that these numbers may rise as individuals who were exposed to radioactive iodine from nuclear testing in western states in the 1950s and 1960s reach 40, the average age at diagnosis.1 The thyroid gland resembles a walnut and is located just below the larynx. Each of the two lobes consists of hollow, fluid-filled sections called follicles that are lined with cells that secrete two iodine-containing hormones, thyroxine (T4) and triiodothyronine (T3). Much of the sticky "colloid" fluid is thyroglobulin, a glycoprotein that binds the hormones, storing them when blood levels temporarily rise too high. The lining cells secrete the hormones when thyrotropin secreted by the pituitary gland binds their receptors. Treatment for thyroid cancer exploits the gland's unique use of iodine, its built-in negative feedback system, and the fact that cancer cells nearly always retain the ability to soak up iodine. Once the gland is removed, the patient undergoes "ablation therapy," which is more peculiar than painful. After a drink of radioactively spiked iodine--it tastes like stale water--the person retires to the farthest reaches of the hospital for a three-day stay in isolation. Every surface is covered with paper, food trays are slid in, and visits come only from people lacking thyroids. "The goal is to make the follow-up easier. The ablation eliminates all thyroid tissue, so that when you do a scan, the patient doesn't have a remnant to suck up all the iodine," explains Paul Gelep, program director for Thyrogen at Genzyme General in Cambridge, Mass. Then a Synthroid pill every morning becomes a way of life, replacing the thyroid hormones. It also tricks the pituitary into suppressing thyrotropin secretion, which could stimulate growth of any lingering cancer cells. Monitoring is necessary to spot a recurrence, which would require another stint in radioactive solitary confinement. Follow-up takes two forms: serum thyroglobulin measurement and a radioiodine whole-body scan. If the thyroid has truly been obliterated, the thyroglobulin level should be near zero, and the scan devoid of hot spots. "Thyroglobulin measurement and a whole-body scan are now recognized as complementary tests. Thyroglobulin is more sensitive than a scan in picking up metastases, but the scan gives the location," says Gelep. The tests are typically given two to three years postsurgery, then the scan is repeated every four to five years as long as thyroglobulin stays low. But both follow-up tests have limitations. In order for thyroid cells to take up the labeled iodine, thyrotropin must be available, and in order for the pituitary to supply it, the body must be free of T3 and T4. This means patients must go several weeks cold turkey from Synthroid, inducing a week or two of severe hypothyroidism as scan day nears. And about 25 percent of patients produce antibodies against thyroglobulin, rendering the immunoassay useless. Genzyme's Thyrogen is recombinant human thyrotropin produced in Chinese hamster ovary cells. Instead of forcing the body to make thyrotropin by starving out the hormones, Thyrogen circumvents the body's negative feedback loop, supplying thyrotropin exogenously. A patient receives intramuscular injections on two consecutive days, radioactive iodine on the third day, and the scan and serum thyroglobulin test on the fifth day, says Gelep. An initial Phase III clinical trial compared the sensitivities of scans done following Thyrogen versus the traditional withdrawal protocol. Results showed that withdrawal led to more sensitive scans,2 but a second trial indicated that adding serum thyroglobulin testing increased the sensitivity of using the new product. But Thyrogen's performance is good enough for the major use, detecting a cancer's spread. "When we use Thyrogen along with a thyroglobulin test, we pick up all the patients with metastases. Just using unstimulated thyroglobulin testing picks up 79 percent of metastases," says Gelep. And Thyrogen may prove to be slightly safer than withdrawal, because it exposes the body to thyrotropin for a few days, compared to weeks. And it avoids the coldness, fatigue, weight gain, depression, and mental confusion of hypothyroidism. While Thyrogen will make scanning more pleasant, another new tool will help physicians select the best candidates for frequent scans. It too is based on biotechnology. The idea to amplify thyroglobulin mRNA had been "mulling around in my brain for awhile," says Levine. Matt Ringel, endocrinologist at Washington Hospital Center and Medlantic Research Institute and clinical assistant professor of medicine at George Washington University, had come to work in Levine's lab on signal transduction in the thyroid. He and Levine started to think about whether reverse transcriptase (RT) PCR could be used to spot mRNA for thyroglobulin much as it is used to detect mRNA for prostate specific antigen (PSA) in late stages of that cancer. "If thyroid cancer [were] metastatic, would we see circulating thyroid cells?" Levine wondered. Patients who had been treated shouldn't have thyroglobulin mRNA, just as they wouldn't have thyroglobulin. In 77 patients and 10 healthy controls, the technique detected the telltale mRNA in all 14 patients with confirmed metastases; serum thyroglobulin testing found only eight. Of 35 patients whose scans were clear, seven (20 percent) had detectable mRNA, compared to two who had detectable serum thyroglobulin. Of 19 patients whose scans showed uptake, 12 had detectable mRNA, yet only four had circulating thyroglobulin. These results suggest that the PCR assay is more sensitive than its protein counterpart,3 which upcoming clinical trials should clarify. It is also more sensitive than attempts by others to use PCR for this purpose, achieving a lower detection limit of three to 10 cells per milliliter of blood. The most surprising result was that individuals with normal thyroids have thyroid cells in the bloodstream. "At first we thought it was contamination. But the thyroid is a very vascular organ. It isn't surprising, with all the blood flow, that occasionally cells would be knocked off and enter the circulation," reports Levine. Thyrogen The test detects thyroid cells when there shouldn't be any, which can mean residual tissue or metastasis. "We hope to screen patients while they are on the hormone. If there is a positive result, we can either withdraw the patient from hormone and do the scan, or use the recombinant thyrotropin that was recently FDA approved," says Levine. The test will be especially useful for patients who have antibodies to thyroglobulin. "Our goal is to achieve another level of monitoring. If the test is successful, we can pick out who should be scanned," he adds. And that should make physicians, insurers, and especially patients very happy. E.S. Gilbert et al., "Thyroid cancer rates and I-131 doses from Nevada atmospheric nuclear bomb tests," Journal of the National Cancer Institute, 90:1654-60, Nov. 4, 1998. P.W. Ladenson et al., "Comparison of administration of recombinant human thyrotropin with withdrawal of thyroid hormone for radioactive iodine scanning in patients with thyroid carcinoma," New England Journal of Medicine, 337:888-96, 1997. M. Ringel et al., "Molecular Diagnosis of Residual and Recurrent Thyroid Cancer by Amplification of Thyroglobulin Messenger Ribonucleic Acid in Peripheral Blood, Journal of Clinical Endocrinology and Metabolism, 83:4435-42, December 1998.

New Tests Monitor Thyroid Cancer

Jan 17, 1999

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