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Originally published as JCO Early Release 10.1200/JCO.2005.05.4106 on March 20 2006 © 2006 American Society of Clinical Oncology.
Medullary Thyroid Cancer: Options for Systemic Therapy of Metastatic Disease?Division of Medical Oncology, Seattle Cancer Care Alliance, University of Washington, Seattle, WA
Division of Nuclear Medicine, Seattle Cancer Care Alliance, University of Washington, Seattle, WA
Division of Endocrinology, Seattle Cancer Care Alliance, University of Washington, Seattle, WA
Department of Surgery, Seattle Cancer Care Alliance, University of Washington, Seattle, WA
Divisions of Nuclear Medicine and Endocrinology, Seattle Cancer Care Alliance, University of Washington, Seattle, WA Medullary thyroid carcinoma (MTC) originates from the parafollicular C cells of the thyroid and accounts for roughly 5% of all differentiated types of thyroid cancer. Among well-differentiated thyroid tumors, it is the most aggressive, with 10-year survival rates of 40% to 50%. Early detection followed by total thyroidectomy and central node dissection offers the highest likelihood for a cure.1,2 The hereditary form of MTC is typically discovered early, thanks to the availability of specific diagnostic testing (calcitonin level, RET proto-oncogene). Screening of at-risk populations has resulted in finding preclinical disease, leading to early surgical intervention and high cure rates. Unfortunately, 80% of MTC cases are sporadic, and early detection of this form of MTC is difficult. Routine computed tomography screening of patients with thyroid nodules is not currently recommended in the United States because of the low yield (< 1% of nodules) and too many false-positive results.3 Fine-needle aspiration of thyroid nodules containing MTC has been disappointing (up to 50% false negatives). The consequence of an inability to detect the sporadic form of MTC early is more advanced disease present at the time of surgery with metastases involving cervical nodes, lungs, liver and/or bone marrow in 40% to 50% of cases.1 Available therapies for aggressive metastatic MTC are typically unable to achieve a cure. Current palliative therapy includes repeat surgical exploration, external beam radiation therapy, and chemotherapy, all with limited success. There has been limited success in the use of systemic chemotherapy to treat patients with metastatic MTC.4 Studies using chemotherapy in MTC are usually small, and medullary carcinomas are frequently treated together with other well-differentiated thyroid tumors,5 making it hard to assess results specifically for MTC. The drug studied most is doxorubicin, whose single-agent activity yields a response rate of 10% to 20%. Other single agents have been studied in small, single-institution studies, including some modest success with capecitabine at our center.6 The use of combination chemotherapy does not appear to improve response rate or survival7; however, this has not been studied in large randomized trials. Overall, chemotherapy is not a particularly attractive option for patients with metastatic MTC. Radionuclide therapy presents another systemic treatment option. Since the introduction of iodine-131 (131I–) in treating thyroid cancer, a number of radiopharmaceuticals have been used for treating endocrine cancers. Selective uptake and retention of these radionuclides at the tumor site, either in their naturally occurring form or complexed to specific molecules, underlies their successful and widespread use in malignancies of the thyroid gland and other endocrine cancers, including MTC.8 Radioimunotherapy (RIT) is a particular form of radionuclide therapy wherein the radionuclide is targeted to tumor sites using an antibody or antibody fragment. RIT has been highly successful in hematologic malignancies, such as lymphoma and leukemia, in part because of their exquisite radiosensitivity. High-dose RIT with marrow support delivers the highest possible radiation doses to target tissues while limiting the dose to healthy organs at risk, resulting in superior survival benefits for patients with refractory/relapsed lymphoma and leukemia.9 In solid tumors, RIT has not yielded similarly encouraging results, and there is a need for more effective treatment approaches. The success of RIT in hematologic disorders has provided opportunities to investigate and perfect novel approaches and methodologies10 that can be extended to solid tumors. Pretargeting is a well-studied modification designed to achieve a higher ratio of tumor:nontumor tissue uptake11,12; it involves a multistep approach in which the immune recognition of the tumor site and delivery of the therapeutic radionuclide occur in sequential steps. In this issue of the Journal of Clinical Oncology, Chatal et al,13 from the French Endocrine Tumor Group (GTE), suggest a new option for patients with metastatic MTC. The authors present data on the follow-up of a group of patients with progressive metastatic MTC treated by pretargeted anti–carcinoembryonic antigen RIT. In this series, 29 patients with metastatic MTC and calcitonin doubling times less than 5 years underwent RIT using a bispecific anti-CEA monoclonal antibody and an 131I-labeled hapten carrying the therapeutic payload. Overall survival (OS) was compared with a contemporaneous control group with untreated progressive MTC with similar clinical characteristics. The authors found that although OS in the entire treated group was not different from that in the untreated group, there was a significant gain in OS (median survival, 159 v 109 months) in the subset of patients with calcitonin doubling times less than 2 years. These gains came at the price of toxicity: More than 20% of patients had grade 4 neutropenia or thrombocytopenia lasting a mean of 20 days, and one patient developed myelodysplastic syndrome. Interestingly, diffuse bone marrow uptake on the post-therapy scan was a predictor of response and improved survival, perhaps as an indicator of therapy delivery to involved bone and bone marrow metastases. The results of the Chatal et al study are notable in that this is one of the few trials to show an improvement in survival for RIT of solid tumors. MTCs differ from most of the other solid tumors for which RIT has been tested, in that even progressive metastatic MTC is relatively indolent, with median survival of more than 100 months in the untreated control group in the Chatal et al study. Unlike other progressive metastatic solid tumors, for MTC, a modest impact on the course of the disease by treatment may yield a large pay-off in the number of months of life gained. On the other hand, some endocrine tumors progress so slowly that potentially toxic systemic therapy may not be warranted. This point is emphasized by the finding in the Chatal et al study that only the most aggressive cancers, those with calcitonin doubling times less than 2 years, had an improvement in survival. There were no deaths in the treated or control groups for patients with calcitonin doubling times between 2 and 5 years, whereas 33% of patients with doubling times less than 2 years died. Simply put, systemic therapy has little impact on OS for disease that is unlikely to cause patient death. Therefore, in the case of many endocrine cancers such as MTC and differentiated thyroid cancer, potentially toxic systemic therapy should be reserved for patients at the highest risk of dying as a result of their disease. This emphasizes the need for better prognostic markers for endocrine tumors to guide appropriate use of systemic therapy for MTC and other endocrine tumors. The use of anti-CEA RIT in the Chatal et al study represents a form of targeted cancer treatment, in this case targeting CEA expressed by MTC. Other forms of targeted therapy may also be applicable to MTC. It has been a mere 5 years since the landmark study by Slamon et al.14 This study was the first to show survival improvement with the addition of a monoclonal antibody to chemotherapy in patients whose tumors overexpressed a molecular target. Since then, the research and treatment of solid tumors has yielded approved drugs like imatinib, erlotinib, and sorafenib, and bevacizumab, which have improved the outcome of patients with sarcoma, colon cancer, breast cancer, lung cancer and renal cell carcinoma.15 Would these targeted agents also improve the outcome for less common malignancies, such as MTC? When considering this question, it is important to remember that an absence of data is not the same as negative results. In rare diseases, such as MTC, it may be necessary to accept therapies based on phase II data because phase III studies are difficult to conduct, taking many years to complete. Agents directed at some of these targets have begun testing in advanced thyroid cancers.16 Some targets are specific to endocrine tumors, such as MTC. One example is the RET protoconcogene, which has a high frequency of aberrant expression in MTC and differentiated thyroid cancer.17 Early clinical trials of agents directed against the RET tyrosine kinase and other targets expressed in MTC are ongoing. With the success of targeted therapy in preliminary studies such as that described by Chatal et al, there may soon more attractive options for systemic therapy of progressive metastatic MTC. These results remind us not to forget the uncommon cancers such as endocrine tumors in early studies of new therapeutic approaches, since there may be surprising results that would be missed if only the more common cancers were studied. Authors' Disclosures of Potential Conflicts of Interest
Although all authors completed the disclosure declaration, the following authors or their immediate family members indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. For a detailed description of the disclosure categories, or for more information about ASCO's conflict of interest policy, please refer to the Author Disclosure Declaration and the Disclosures of Potential Conflicts of Interest section in Information for Contributors.
Dollar Amount Codes (A) < $10,000 (B) $10,000-99,999 (C) > $100,000 (N/R) Not Required
Author Contributions
REFERENCES 1. Gharib H, McConahey WM, Tiegs RD, et al: Medullary thyroid carcinoma: Clinicopathologic features and long term follow up of 65 patients treated during 1946 through 1970. Mayo Clin Proc 67:934-940, 1992[Medline] 2. Gagel RF, Robinson MF, Donovan DT, et al: Medullary thyroid carcinoma: Recent progress. J Clin Endocrinol Metab 76:809-814, 1993[CrossRef][Medline] 3. Hodak SP, Burman KD: The calcitonin conundrum: Is it time for routine measurement of serum calcitonin in patients with thyroid nodules? J Clin Endocrinol Metab 89:511-514, 2004 4. Massoll N, Mazzaferri EL: Diagnosis and management of medullary thyroid carcinoma. Clin Lab Med 24:49-83, 2004[CrossRef][Medline] 5. Gottlieb JA, Hill CS: Chemotherapy for thyroid cancer with adriamycin: Experience with 30 patients. N Engl J Med 290:193-197, 1974[Medline] 6. Gilliam LK, Mankoff DA, Pickett CA, et al: Potential efficacy of capecitabine (Xeloda) in medullary and follicular thyroid carcinoma: A case series. Thyroid 14:694, 2004 7. Shimaoka K, Schoenfeld DA, DeWys WD, et al: A randomized trial of doxorubicin versus doxorubicin and cisplatin in patients with advanced thyroid carcinoma. Cancer 56:2155-2160, 1985[CrossRef][Medline] 8. Pasieka JL, McEwan AJ, Rorstad O: The palliative role of 131I-MIBG and 111In-octreotide therapy in patients with metastatic progressive neuroendocrine neoplasms. Surgery 136:1218-1226, 2004[CrossRef][Medline] 9. Gopal AK, Gooley TA, Maloney DG, et al: High-dose radioimmunotherapy versus conventional high-dose therapy and autologous hematopoietic stem cell transplantation for relapsed follicular non-Hodgkin lymphoma: A multivariable cohort analysis. Blood 102:2351-2357, 2003 10. Press OW: Radioimmunotherapy for non-Hodgkin's lymphomas: A historical perspective. Semin Oncol 30:10-21, 2003[Medline] 11. Sharkey RM, Goldenberg DM: Perspectives on cancer therapy with radiolabeled monoclonal antibodies. J Nucl Med 46:115S-127S, 2005 (suppl 1) 12. Hamblett KJ, Press OW, Meyer DL, et al: Role of biotin-binding affinity in streptavidin-based pretargeted radioimmunotherapy of lymphoma. Bioconjug Chem 16:131-138, 2005[Medline] 13. Chatal J-F, Champion L, Kraeber-Bodere F, et al: Survival improvement in medullary thyroid carcinoma patients who undergo pretargeted anti–carcinoembryonic-antigen radioimmunotherapy: A Study by the French Tumor Endocrine Group. J Clin Oncol 24:10.1200/JCO.2005.04.4917 14. Slamon DJ, Leyland-Jones B, Shak S, et al: Use of chemotherapy plus a monoclonal antibody against HER2 for metastatic breast cancer that overexpresses HER2. N Engl J Med 344:783-792, 2001 15. Adjei AA, Hidalgo M: Intracellular signal transduction pathway proteins as targets for cancer therapy. J Clin Oncol 23:5386-5403, 2005 16. Braga-Basaria M, Ringel MD: Clinical review 158: Beyond radioiodine—A review of potential new therapeutic approaches for thyroid cancer. J Clin Endocrinol Metab 88:1947-1960, 2003 17. Le HN, Norton JA: Perspective on RET proto-oncogene and thyroid cancer. Cancer J 6:50-57, 2000[Medline]
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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