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CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 TARGETED THERAPY FOR LOCALLY ADVANCED UNRESECTABLE OR METASTATIC MEDULLARY THYROID CARCINOMA Effective Date: November 2012 The recommendations contained in this guideline are a consensus of the Alberta Provincial Endocrine Tumour Team and are a synthesis of currently accepted approaches to management, derived from a review of relevant scientific literature. Clinicians applying these guidelines should, in consultation with the patient, use independent medical judgment in the context of individual clinical circumstances to direct care. CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 BACKGROUND Carcinoma of the thyroid gland is the eighth most common type of cancer among Canadians; an estimated 5,600 Canadians (460 Albertans) were diagnosed with thyroid carcinoma in 2012. 1 Among males and females diagnosed with cancer in 2012, the proportion diagnosed with thyroid cancer was 1.3% and 4.9%, respectively. 1 Although thyroid cancer is relatively uncommon, the incidence rate of thyroid cancer is the most rapidly increasing of all cancers (6.8% per year in males since 1998 and 6.9% per year in females since 2002). 1,2 Thyroid cancer can be classified into three subtypes: papillary or follicular, medullary, and anaplastic. Papillary or follicular are differentiated tumours and have a good prognosis, while medullary and anaplastic have a poor prognosis, due to the high rate of metastases for each. 3,4 The majority (68%) of patients are diagnosed with localized disease, which has a five-year survival rate of 99.9%. Moreover, patients diagnosed with regional disease can expect a five-year probability of survival of 97.1%. However, for the 5% of patients diagnosed with distant disease, the five-year survival rate drops to 53.9%. 2 The focus of this guideline will be medullary thyroid carcinoma (MTC), which comprises less than 10% of all thyroid cancer. 2,4,5 The five-year survival for patients with MTC is 86%; however advanced age, advanced stage, prior neck surgery, and associated multiple endocrine neoplasia 2B contributes to poorer prognosis. 6-8 American Joint Committee on Cancer Staging 9 for MTC can be found in Appendix A of this document (page 6). New drugs have been developed and tested for endocrine tumours recently, and may be efficacious in certain patients diagnosed with advanced MTC. One such drug, vandetanib, works by targeting vascular endothelial growth factor receptor (VEGFR), epidermal growth factor receptor (EGFR) and RET (rearranged during transfection) signaling. 10,11 Inhibition of VEGFR and RET signaling contributes to an antitumor effect that slows the growth of certain tumours. 12,13 The purpose of this guideline is to provide evidence-based recommendations on the use of vandetanib for MTC and to define which patients are acceptable candidates for treatment with this agent. GUIDELINE QUESTIONS • Is vandetanib more effective than placebo in delaying progression among patients with medullary thyroid carcinoma? If so, what selection criteria should be considered when identifying patients who are appropriate for treatment with vandetanib? • What is the appropriate dosing regimen for vandetanib? DEVELOPMENT This guideline was reviewed and endorsed by the Alberta Provincial Endocrine Tumour Team. Members of the Alberta Provincial Neuroendocrine Tumour Team include medical oncologists, endocrinologists, surgeons, and nurses. Evidence was selected and reviewed by a working group comprised of members from the Alberta Provincial Endocrine Tumour Team and a Knowledge Management Specialist from the Guideline Utilization Resource Unit. A detailed description of the methodology followed during the guideline development process can be found in the Guideline Utilization Resource Unit Handbook. page 2 of 7 CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 SEARCH STRATEGY The Medline database was searched (1965 through 2012 March) for relevant publications using the following search terms: vandetanib AND medullary thyroid. Results were limited to randomized controlled trials and phase II-III clinical trials. In addition, the National Guidelines Clearinghouse database was searched (2006 through 2012 March) for existing guidelines and the American Society of Clinical Oncology (ASCO) meeting abstracts database was searched (2009 through 2012 March) for relevant abstracts. Finally, chemotherapy protocols for vandetanib were searched on the Cancer Care Ontario (CCO) and British Columbia Cancer Agency (BCCA) websites. A total of three citations were returned from Medline, all of which were relevant, and one ASCO abstract was selected. Evidence is summarized in the table in Appendix B. TARGET POPULATION The recommendations in this guideline apply to patients diagnosed with locally advanced unresectable or metastatic medullary thyroid carcinoma. RECOMMENDATIONS 1. Vandetanib has been shown to slow symptomatic or anatomic progression (versus placebo) in patients with progressive medullary thyroid carcinoma. Therefore, vandetanib is recommended for patients with symptomatic or progressive medullary thyroid carcinoma with unresectable locally advanced or metastatic disease. 2. Vandetanib should be given at a dose of 300 mg, orally, daily. DISCUSSION For localized MTC, total surgical resection of the thyroid with neck dissection, as indicated, is the standard of care and results in excellent prognosis. 2,8,14 Node dissection can also be considered. 14 In addition, EBRT may be used for disease that extends beyond the thyroid with positive margins after resection or for locally recurrent tumours. 14,15 For advanced, metastatic disease, not amenable to resection, other options may include ablation (i.e., radiofrequency, embolization, etc.) or palliative chemotherapy, or biologic therapy, such as vandetanib. 4,14 This guideline focuses on the role of vandetanib, an inhibitor of VEGFR, EGFR, and RET, in the management of unresectable MTC. Two phase II clinical trials employed vandetanib at dose of 100 mg orally per day 16 and 300 mg orally per day 17 in patients with advanced MTC. Data from these trials showed that a dose of 300 mg per day was able to achieve a better response rate than a dose of 100 mg per day; the partial response rate was 20% and 16%, respectively (there were no complete responses). Biochemically, the proportion of patients with a decrease of at least 50% in the level of in calcitonin was 80% and 16%, respectively, and the proportion of patients with a decrease of at least 50% in the level of carcinoembryonic antigen was 53% and 5%, respectively. Median progression-free survival in the 300 mg per day group (n=30) was 27.9 months. 17 A phase III trial comparing vandetanib (300 mg per day, orally) with placebo in patients with advanced MTC (n=331) demonstrated an objective response rate of 45% with vandetanib versus 13% with placebo (p<.001). Median progression-free survival for the vandetanib group was not reached at the time of page 3 of 7 CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 publication but could be approximated at 30.5 months, while that of the placebo group was 19.3 months, giving a six-month progression-free survival rate of 83% for vandetanib versus 63% for placebo (HR=0.46, 95% CI 0.31-0.69; p<.001). 18,19 To date, no randomized controlled trials, comparing vandetanib with other systemic agents, in the setting of progressive unresectable MTC, have been published and there are currently no clinical trials of this nature in progress. 20 Current work in on vandetanib in the setting of MTC focuses on comparing 300 mg per day with 150 mg per day in patients with unresectable locally advanced MTC. It will also help the investigators understand the side effects of different doses in these patients (NCT01496313). 20 In terms of toxicity, the most frequently reported adverse events (any grade) associated with vandetanib are diarrhea (56% versus 26% placebo), rash (45% vs. 11% placebo), nausea (33% versus 16% placebo), hypertension (32% versus 5% placebo), and headache (26% versus 9% placebo). The most frequent grade 3 or higher events were diarrhea (11% versus 2% placebo), hypertension (9% versus 0% placebo), and ECG QT prolonged (8% versus 1% placebo). 18,19 Patients, especially those with a history of cardiovascular disorders, for whom vandetanib is planned should be monitored closely by physicians for cardiovascular events. 21 The recent development of targeted therapies such as vandetanib has led to an increase in the expected survival for some patients with MTC. In order to predict which patients might benefit most from vandetanib, an analysis of the plasma levels of VEGFR, as a biomarker, may be useful. 22,23 However, these potential biomarkers have only been studies in lung cancer, not MTC. Future research will need to focus on finding predictive markers to help determine which MTC patients can benefit from vandetanib and other promising biologic agents. GLOSSARY OF ABBREVIATIONS Acronym EBRT EGFR MTC NETs RET VEGFR Description external beam radiotherapy epidermal growth factor receptor medullary thyroid carcinoma neuroendocrine tumours rearranged during transfection vascular endothelial growth factor receptor DISSEMINATION • • • Present the guideline at the local and provincial tumour team meetings and weekly rounds. Post the guideline on the Alberta Health Services website. Send an electronic notification of the new guideline to all members of CancerControl Alberta. MAINTENANCE A formal review of the guideline will be conducted at the Annual Provincial Meeting in 2013. If critical new evidence is brought forward before that time, however, the guideline working group members will revise and update the document accordingly. page 4 of 7 CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 CONFLICT OF INTEREST Participation of members of the Alberta Provincial Endocrine Tumour Team in the development of this guideline has been voluntary and the authors have not been remunerated for their contributions. There was no direct industry involvement in the development or dissemination of this guideline. CancerControl Alberta recognizes that although industry support of research, education and other areas is necessary in order to advance patient care, such support may lead to potential conflicts of interest. Some members of the Alberta Provincial Endocrine Tumour Team are involved in research funded by industry or have other such potential conflicts of interest. However the developers of this guideline are satisfied it was developed in an unbiased manner. REFERENCES 1. Canadian Cancer Society’s Steering Committee on Cancer Statistics. Canadian Cancer Statistics 2012. Toronto, ON: Canadian Cancer Society; 2012. May, 2009. Available from: http://www.cancer.ca/Canadawide/About%20cancer/Cancer%20statistics.aspx Cited: July 19, 2012. 2. Howlader N, Noone AM, Krapcho M, Neyman N, Aminou R, Waldron W, Altekruse SF, Kosary CL, Ruhl J, Tatalovich Z, Cho H, Mariotto A, Eisner MP, Lewis DR, Chen HS, Feuer EJ, Cronin KA (eds). SEER Cancer Statistics Review, 1975-2009 (Vintage 2009 Populations), National Cancer Institute. Bethesda, MD, http://seer.cancer.gov/csr/1975_2009_pops09/, based on November 2011 SEER data submission, posted to the SEER web site, April 2012. 3. Hundahl SA, Fleming ID, Fremgen AM, et al.: A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the U.S., 1985-1995 [see comments] Cancer 83 (12): 2638-48, 1998. 4. National Cancer Institute. Thyroid Cancer Treatment (PDQ). Available from http://www.cancer.gov/cancertopics/pdq/treatment/thyroid/HealthProfessional Cited: July 17, 2012 5. Schlumberger M, Carlomagno F, Baudin E, Bidart JM, Santoro M. 2008 New therapeutic approaches to treat medullary thyroid carcinoma. Nat Clin Pract Endocrinol Metab 4:22–32 6. Saad MF, Ordonez NG, Rashid RK, et al.: Medullary carcinoma of the thyroid. A study of the clinical features and prognostic factors in 161 patients. Medicine (Baltimore) 63 (6): 319-42, 1984. 7. Bergholm U, Bergström R, Ekbom A: Long-term follow-up of patients with medullary carcinoma of the thyroid. Cancer 79 (1): 132-8, 1997. 8. Roman S, Lin R, Sosa JA 2006 Prognosis of medullary thyroid carcinoma: demographic, clinical, and pathologic predictors of survival in 1252 cases. Cancer 107:2134–2142 9. Thyroid. In: Edge SB, Byrd DR, Compton CC, et al., eds.: AJCC Cancer Staging Manual. 7th ed. New York, NY: Springer, 2010, pp 87-96. 10. Carlomagno F, Vitagliano D, Guida T, Ciardiello F, Tortora G, Vecchio G, Ryan AJ, Fontanini G, Fusco A, Santoro M 2002 ZD6474, an orally available inhibitor of KDR tyrosine kinase activity, efficiently blocks oncogenic RET kinases. Cancer Res 62: 7284–7290. 11. Wedge SR, Ogilvie DJ, Dukes M, Kendrew J, Chester R, Jackson JA, Boffey SJ, Valentine PJ, Curwen JO, Musgrove HL, Graham GA, Hughes GD, Thomas AP, Stokes ES, Curry B, Richmond GH, Wadsworth PF, Bigley AL, Hennequin LF 2002 ZD6474 inhibits vascular endothelial growth factor signaling, angiogenesis, and tumor growth following oral administration. Cancer Res 62:4645–4655. 12. Bunone G, Vigneri P, Mariani L, Buto´ S, Collini P, Pilotti S, Pierotti MA, Bongarzone I. 1999 Expression of angiogenesis stimulators and inhibitors in human thyroid tumors and correlation with clinical pathological features. Am J Pathol 155:1967–1976. page 5 of 7 CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 13. Wang W, Johansson HE, Bergholm UI, Westermark KM, Grimelius LE. 1997 Expression of c-Myc, TGF- and EGF-receptor in sporadic medullary thyroid carcinoma. Acta Oncol 36:407–411 14. National Comprehensive Cancer Network. Clinical Practice Guidelines in Oncology: Thyroid Carcinoma. Available at www.nccn.org Cited: July 19, 2012. 15. Brierley JD, Tsang RW: External radiation therapy in the treatment of thyroid malignancy. Endocrinol Metab Clin North Am 25 (1): 141-57, 1996. 16. Robinson BG, Paz-Ares L, Krebs A, Vasselli J, Haddad R. Vandetanib (100 mg) in patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Endocrinol Metab. 2010 Jun;95(6):2664-71. 17. Wells SA Jr, Gosnell JE, Gagel RF, Moley J, Pfister D, Sosa JA, Skinner M, Krebs A, Vasselli J, Schlumberger M. Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer. J Clin Oncol. 2010 Feb 10;28(5):767-72. 18. Wells SA Jr, Robinson BG, Gagel RF, Dralle H, Fagin JA, Santoro M, Baudin E, Elisei R, Jarzab B, Vasselli JR, Read J, Langmuir P, Ryan AJ, Schlumberger MJ. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol. 2012 Jan 10;30(2):134-41. 19. Wells SA, Robinson BG, Gagel RF, et al. Vandetanib (VAN) in locally advanced or metastatic medullary thyroid cancer (MTC): A randomized, double-blind phase III trial (ZETA). 2010 ASCO Annual Meeting. J Clin Oncol 28:15s, 2010 (suppl; abstr 5503). 20. U.S. National Institutes of Health. Clinical Trials Registry. Available from http://clinicaltrials.gov/ct2/search Cited July 18, 2012. 21. (vandetanib) Prescribing Information. Available from http://www1.astrazeneca-us.com/pi/vandetanib.pdf Cited July 19, 2012. 22. Hanrahan EO, Ryan AJ, Mann H, et al. Baseline Vascular Endothelial Growth Factor Concentration as a Potential Predictive Marker of Benefit from Vandetanib in Non–Small Cell Lung Cancer. Clin Cancer Res May 15, 2009 15; 3600. 23. Hanrahan EO, Lin HY, Du DZ, et al. Correlative analyses of plasma cytokine/angiogenic factor (C/AF) profile, gender and outcome in a randomized, three-arm, phase II trial of first-line vandetanib (VAN) and/or carboplatin plus paclitaxel (CP) for advanced non-small cell lung cancer (NSCLC). J Clin Oncol 2007;25(18) suppl:7593. page 6 of 7 CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 APPENDIX A: AMERICAN JOINT COMMITTEE ON CANCER STAGING SYSTEM (7th EDITION, 2010) 7 FOR THYROID CANCER Primary Tumor (T) TX: Primary tumor cannot be assessed. T0: No evidence of primary tumor. T1: Tumor ≤2 cm in greatest dimension limited to the thyroid. T1a: Tumor ≤1 cm, limited to the thyroid. T1b: Tumor >1 cm but ≤2 cm in greatest dimension, limited to the thyroid. T2: Tumor >2 cm but ≤4 cm in greatest dimension, limited to the thyroid. T3: Tumor >4 cm in greatest dimension limited to the thyroid or any tumor with minimal extrathyroid extension (e.g., extension to sternothyroid muscle or perithyroid soft tissues). T4a: Moderately advanced disease. Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. Intrathyroidal anaplastic carcinoma. T4b: Very advanced disease. Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels. Anaplastic carcinoma with gross extrathyroid extension. Regional Lymph Nodes (N) NX: Regional lymph nodes cannot be assessed. N0: No regional lymph node metastasis. N1: Regional lymph node metastasis. N1a: Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/Delphian lymph nodes). N1b: Metastases to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII). Distant Metastasis (M) M0: No distant metastasis. M1: Distant metastasis. Anatomic Staging for Medullary Thyroid Carcinoma Stage I: T1, N0, M0 Stage II: T2-3, N0, M0 Stage III: T1-3, N1a, M0 Stage IVA: T4a, N0-1a, M0 and T1-4a, N1b, M0 Stage IVB: T4b, Any N, M0 Stage IVC: Any T, Any N, M1 page 7 of 7 CLINICAL PRACTICE GUIDELINE ENDO-002 Version 1 APPENDIX B: CLINICAL STUDIES USING VANDETANIB IN PATIENTS WITH MEDULLARY THYROID CANCER Author (trial) Wells SA Jr. 2012 (JCO article + ASCO abstract) Design phase III Treatments 1. vandetanib 300 mg/d PO 2. placebo Patients (n) advanced medullary thyroid carcinoma (n=331) Response objective response 45% vandetanib 13% placebo (p<.001) Survival PFS (med): not reached (~30.5 mos) V vs. 19.3 mos P Adverse events (vandetanib) Any grade: diarrhea (56% vs. 26%); rash (45% vs. 11%); nausea (33% vs. 16%); hypertension (32% vs. 5%); PFS (6-mos): 83% V vs. 63% P headache (26% vs. 9%) HR 0.46 (95% CI 0.31-0.69) Grade 3+ (≥2% pts): diarrhea (11% vandetanib vs. placebo; p<.001 vs. 2%); hypertension (9% vs. 0%); ECG QT prolonged (8% vs. 1%) Robinson BG. 2010 phase II vandetanib 100 mg/d PO advanced medullary thyroid cancer (n=19) CR: 0% n/a PR: 16% (n=3) SD (>24 wk): 53% calcitonin ↓50%: 16% (n=3) Wells SA Jr. 2010 phase II open label vandetanib 300 mg/d PO locally advanced or metastatic medullary thyroid carcinoma (n=30) carcinoembryonic antigen ↓50%: 5% (n=1) PR: 20% (n=6) PFS (med): 27.9 mos med dur 10.2 mos SD (>24 wk): 53% calcitonin ↓50%: 80% (n=24) carcinoembryonic antigen ↓50%: 53% (n=16) Mostly grade 1-2: diarrhea 47% (n=9); fatigue 42% (n=8); rash 26% (n=5); constipation 21% (n=4); anorexia 16% (n=3); back pain 16% (n=3); nausea 16% (n=3); photosens. rxn 16% (n=3) Mostly grade 1-2: diarrhea 70% rash 67% fatigue 63% nausea 63% headache 47% anorexia 43% vomiting 40% page 7 of 7