Rapid Response to Sorafenib in Metastatic Medullary Thyroid Carcinoma

Abstract

Objective: To investigate the efficacy of sorafenib in progressive metastatic Medullary Thyroid Carcinoma (MTC), for which there is currently no effective treatment.

Design: Off-label observational study.

Methods: Sorafenib 400 mg twice daily was evaluated. The primary endpoint was the objective Response Evaluation Criteria in Solid Tumours (RECIST) score assessed on day 28 and every 12 weeks thereafter. Additional endpoints were time to response, duration of tumour response, tumour-related symptoms, and changes in tumour markers, calcitonin, and CEA measured initially, at 2 weeks, and then every 4 weeks. Therapy duration was 2 weeks, and 3–12 months.

Results: The 5 patients meeting study criteria received sorafenib 400 mg orally twice a day until disease progression or unacceptable toxicity developed. 2 patients showed a partial response with tumour regression of −46% and −36% after 6 and 9 months, respectively, and 2 patients exhibited tumour regression of −14% and −29%, respectively (stable disease). Ultrasound-documented regression of −37% within 2 weeks occurred in 1 patient. Calcitonin decreased within 2 weeks in all patients by −69, −90, −75, −96, and −39%, respectively. 1 patient died because of progressive ascites from acute renal and hepatocellular failure. 2 patients developed grade 3 hand-foot syndrome within the first month, so that sorafenib was interrupted or reduced; other side effects were rash, fatigue, and hair loss. 3 patients remain on sorafenib, 2 at a reduced dosage (600 mg/d).

Conclusion: These data suggest a possible role for sorafenib in the treatment of progressive metastatic MTC.

Key words

medullary thyroid carcinoma - RET proto-oncogene - sorafinib - tyrosine kinase inhibitors

References

• 1 Kloos RT, Eng C, Evans DB. et al . Medullary thyroid cancer: management guidelines of the American Thyroid Association.  Thyroid. 2009;  19 565-612
• 2 Frank-Raue K, Fabel M, Delorme S. et al . Efficacy of imatinib mesylate in advanced medullary thyroid carcinoma.  Eur J Endocrinol. 2007;  157 215-220
• 3 de Groot JW, Zonnenberg BA, van Ufford-Mannesse PQ. et al . A phase II trial of imatinib therapy for metastatic medullary thyroid carcinoma.  J Clin Endocrinol Metab. 2007;  92 3466-3469
• 4 Schlumberger MJ, Elisei R, Bastholt L. et al . Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer.  J Clin Oncol. 2009;  27 3794-3801
• 5 Cohen EE, Rosen LS, Vokes EE. et al . Axitinib is an active treatment for all histologic subtypes of advanced thyroid cancer: results from a phase II study.  J Clin Oncol. 2008;  26 4708-4713
• 6 Wells Jr SA, Gosnell JE, Gagel RF. et al . Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.  J Clin Oncol. 2010;  28 767-772
• 7 Kurzrock R, Sherman S, Pfister D. et al . Preliminary results of a phase 1 study of XL184, a Met, VEGFR2 and Ret kinase inhibitor (TKI), administered orally to patients with medullary thyroid cancer (MTC).  acta medica portuguesa. 2009;  1
• 8 Kloos RT, Ringel MD, Knopp MV. et al . Phase II trial of sorafenib in metastatic thyroid cancer.  J Clin Oncol. 2009;  27 1675-1684
• 9 Kober F, Hermann M, Handler A. et al . Effect of sorafenib in symptomatic metastatic medullary thyroid cancer.  J clin Oncol. 2007;  25 14065
• 10 Chintala L, Kurzrock R, Fu S. et al . Phase 1 study of tipifarnib and sorafenib in patients with biopsiable advanced cancer (NCI protocol 7156).  J Clin Oncol. 2008;  26 3593
• 11 Lam ET, Ringel MD, Kloos RT. et al . Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer.  J Clin Oncol. 28 2323-2330
• 12 Therasse P, Arbuck SG, Eisenhauer EA. et al . New guidelines to evaluate the response to treatment in solid tumors. European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada.  J Natl Cancer Inst. 2000;  92 205-216
• 13 Laure Giraudet A, Al Ghulzan A, Auperin A. et al . Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times.  Eur J Endocrinol. 2008;  158 239-246
• 14 Akeno-Stuart N, Croyle M, Knauf JA. et al . The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells.  Cancer Res. 2007;  67 6956-6964
• 15 Carlomagno F, Anaganti S, Guida T. et al . BAY 43-9006 inhibition of oncogenic RET mutants.  J Natl Cancer Inst. 2006;  98 326-334

Correspondence