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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.
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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
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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.
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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.
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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.
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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
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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%
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