Reference No: Author(s) Approval date: October committee. September Operational Date: Review:

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1 Reference No: Title: Author(s) Systemic Anti-Cancer Therapy (SACT) guidelines for Thyroid cancer Dr Fionnuala Houghton Consultant Clinical Oncologist & Dr Lois Mulholland Consultant Clinical Oncologist Ownership: Approval by: Operational Date: NICaN NICaN Drugs & Therapeutics committee October 2016 Version No. 1.2 Supercedes 1.1 Links to other policies NICaN Thyroid SACT protocols Approval date: Next Review: October 2016 September 2018 Version control for drafts: Date Version Author Comments October 2013 September 2016 October Dr L Mulholland 1.1 Dr F Houghton & Dr L Mulholland Version 1.0 completed Radioiodine ablation & lenvatinib advice updated 1.2 Dr F Houghton Lenvatinib & vandetanib are both cost per case.

2 Authorisation of Systemic Anti-Cancer Therapy (SACT) Guidelines for Thyroid Cancer These SACT guidelines are being submitted by the author on behalf of the Head & Neck oncologists group. SACT for Thyroid Malignancies V1.2 Page 1 of 14

3 Contents 1. Staging 2. Prognosis 3. DTC Treatment overview Ablation Reassessment and follow up Treatment on relapse Risk stratification 4. MTC Treatment overview Systemic therapy 5. Anaplastic thyroid cancer 6. Lymphoma of thyroid 7. References SACT for Thyroid Malignancies V1.2 Page 2 of 14

4 INTRODUCTION Thyroid cancer is the most common of the endocrine malignancies and comprises around 1% of all malignancies. There are approximately 2000 new cases of thyroid cancer diagnosed in the UK each year. Pathological subtypes include papillary, follicular, medullary, anaplastic and lymphoma. Staging TX T0 T1 T1a T1b T2 T3 T4a Primary tumor cannot be assessed. No evidence of primary tumor. Tumor 2 cm in greatest dimension limited to the thyroid. Tumor 1 cm, limited to the thyroid. Tumor >1 cm but 2 cm in greatest dimension, limited to the thyroid. Tumor >2 cm but 4 cm in greatest dimension, limited to the thyroid. 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). Moderately advanced disease. Tumor of any size extending beyond the thyroid capsule to invade subcutaneous soft tissues, larynx, trachea, esophagus, or recurrent laryngeal nerve. T4b Very advanced disease. Tumor invades prevertebral fascia or encases carotid artery or mediastinal vessels. c T4a Intrathyroidal anaplastic carcinoma. c T4b Anaplastic carcinoma with gross extrathyroid extension. NX N0 N1 N1a N1b Regional lymph nodes cannot be assessed. No regional lymph node metastasis. Regional lymph node metastasis. Metastases to Level VI (pretracheal, paratracheal, and prelaryngeal/delphian lymph nodes). Metastases to unilateral, bilateral, or contralateral cervical (Levels I, II, III, IV, or V) or retropharyngeal or superior mediastinal lymph nodes (Level VII). M0 M1 No distant metastasis. Distant metastasis. SACT for Thyroid Malignancies V1.2 Page 3 of 14

5 Anatomical stage groupings Stage T N M Papillary or follicular (differentiated) YOUNGER THAN 45 YEARS I Any T Any N M0 II Any T Any N M1 45 YEARS AND OLDER I T1 N0 M0 II T2 N0 M0 III T3 N0 M0 T1 N1a M0 T2 N1a M0 T3 N1a M0 IVA T4a N0 M0 T4a N1a M0 T1 N1b M0 T2 N1b M0 T3 N1b M0 T4a N1b M0 IVB T4b Any N M0 Stage IVC Any T Any N M1 Medullary carcinoma (all age groups) I T1 N0 M0 II T2 N0 M0 T3 N0 M0 III T1 N1a M0 T1 N1a M0 T2 N1a M0 T3 N1a M0 IVA T4a N0 M0 T4a N1a M0 T1 N1b M0 T2 N1b M0 T3 N1b M0 T4a N1b M0 Stage IVB T4b Any N IVB T4b Any N M0 IVC Any T Any N M1 Anaplastic carcinoma c IVA T4a Any N M0 IVB T4b Any N M0 IVC Any T Any N M1 SACT for Thyroid Malignancies V1.2 Page 4 of 14

6 DIFFERENTIATED THYROID CANCER Differentiated thyroid cancer (DTC) is an umbrella term for papillary thyroid cancer (PTC) and follicular thyroid cancer (FTC) and comprises 85 % of all thyroid cancers. The current UK standard treatment for the majority of DTC includes thyroidectomy with or without lymph node dissection by a skilled thyroid surgeon followed by radioiodine remnant ablation and subsequent TSH suppression with levothyroxine. Radioiodine ablation Preparation Prior to radioiodine treatment patients can be withdrawn from thyroxine for 2-4 weeks or recombinant thyroid stimulating hormone (rtsh) can be given on the two consecutive days prior to treatment, to give a TSH level of greater than 30. Current BTA guidelines 3 recommend that rhtsh is used as the method of preparation for RRA in patients who have the following characteristics: pt1 to T3,pN0 or NX or N1, and M0 and R0 (no microscopic residual disease) Dose The standard dose of I 131 for ablation is 3.7GBq Based on the Hi-Lo and ESTIMABL data, an I 131 dose of 1.1 GBq can be considered for low-risk 4,5 disease. Patients are encouraged to follow a low-iodine diet prior to treatment. Work- up for I 131 Full blood count, Oncology profile (Specifically, calcium levels), Thyroid Function tests Baseline chest xray and ECG in selected patients Assessment of fitness to be in isolation for recommended time period Negative pregnancy test in females of child bearing potential. Routine antiemetics are given prior to the ablation and throughout their inpatient stay. Pre treating with dexamethasone should be considered for those with large volume disease particularly those with lung metastases Male patients should be offered sperm banking prior to a therapy dose. SACT for Thyroid Malignancies V1.2 Page 5 of 14

7 Written consent should be obtained by an ARSAC licence holder or delegate, to include benefits of treatment, radiation protection issues and acute and long term side effects including nausea, dry mouth, sialadenitis, lacrimal duct stenosis, fertility issues and low risk of second malignancy Patients will remain in isolation until levels of radioactivity are sufficiently low to allow discharge Patients should have a post treatment iodine scan within 7 days of ablation or treatment. Thyroid replacement should be restarted on discharge (T3 or T4). TSH Suppression Patients require TSH suppression with adequate doses of thyroxine. For low risk patients this suppression can be relaxed towards the normal range if they have a negative stimulated TG and USS at 1 year. TSH suppression can be relaxed in lower risk patients as demonstrated below. TSH <0.1 TSH TSH If patient has persistent disease Has had remnant ablation No persistent disease Intermediate or high risk disease Has not had remnant ablation Clinically disease free Tg stable USS neck normal OR Has had remnant ablation and low risk as per ATA Reassessment Patients are reassessed with either a radioiodine scan at 4-6 months or a stimulated thyroglobulin test at 9-12 months. An ultrasound scan of neck should be carried out at this time. SACT for Thyroid Malignancies V1.2 Page 6 of 14

8 A stimulated thyroglobulin is carried out by giving recombinant TSH 0.9mg on days 1 and 2 with a thyroglobulin level taken on day 5. If this is normal the patient is considered to be low risk and can be considered for annual review. A raised thyroglobulin under stimulation is suggestive of persistent or metastatic disease and further I 131 should be considered Follow up The purpose of regular, routine follow up of patients with DTC is to - detect recurrent disease - detect and manage toxicities from treatment with I ensure patients are on the appropriate dose of levothyroxine to maintain the appropriate level of TSH suppression - manage other associated problems including hypocalcaemia and monitoring of bone density Patients should be reviewed 2-3 months post ablation. This should comprise: Discussion of post treatment scan Thyroid function tests, thyroglobulin levels and serum calcium Review of toxicities post ablation Physical examination of thyroid bed and lymph nodes and thyroid status Review of thyroxine dose Follow up should be life long as the disease has a long natural history and late recurrences are not uncommon. Patients should be reviewed at least annually (more often for high risk disease) with physical examination, history, TFTs and thyroglobulin levels measured at each visit. For low and intermediate risk patients, frequency of follow up thereafter is usually 3-6 monthly for the first two years, 6-12 monthly years 3-5 and annually thereafter. Follow up of high risk patients is individualised to their needs. SACT for Thyroid Malignancies V1.2 Page 7 of 14

9 Very low risk patients who do not require long term TSH suppression can be discharged from specialist care after 5 to 10 years to community based follow up. Risk stratification The risk of recurrence of DTC can be stratified into low, intermediate and high. Designation to one of these risk groups will guide the intensity of follow up and level of TSH suppression that is required This is a dynamic process and level of risk may change for an individual with time as more information about their disease becomes available. ATA risk stratification Low risk Intermediate risk High risk No local or distant metastases Microscopic invasion of tumour Macroscopic tumour invasion into perithyroidal soft tissues at initial surgery All macroscopic tumour has been Cervical lymph node metastases or I131 Incomplete tumour resection resected uptake outside the thyroid bed on the post therapeutic WBS No tumour invasion Tumour with Distant metastases of locoregional tissues or structures aggressive histology or vascular invasion No aggressive histology or vascular invasion Thyroglobulinaemia out of proportion to what is seen on the postablative scan If I131 was given, no I131 uptake outside the thyroid bed on the post therapeutic WBS SACT for Thyroid Malignancies V1.2 Page 8 of 14

10 Treatment on relapse Locally recurrent disease should be treated surgically if possible. External beam radiotherapy is indicated when disease is unresectable and does not concentrate iodine sufficiently. Whilst disease remains iodine avid, repeated therapy doses of radioiodine may be used as local or systemic treatment. Metastatic disease should be treated with therapy doses of 5-7GBq. There is no evidence for use of recombinant TSH in this setting and patients should be withdrawn from thyroxine prior to treatment. Pre treating with dexamethasone should be considered for those with large volume disease particularly those with lung metastases. Patients should have a post treatment scan to assess for iodine uptake. The challenge in treating these patients arises when disease becomes refractory to iodine, usually as a consequence of the disease becoming less differentiated, which confers a very poor prognosis. First line treatment should be with a tyrosine kinase inhibitor, of which Lenvatanib has shown the biggest clinical benefit. A phase 3 trial showed PFS 18.3 months on levatanib versus 3.6 months on placebo. 6 Regime: Lenvatanib 24mg od D1-28 The tyrosine kinase inhibitor Sorafenib should be considered second line. A phase 3 trial showed PFS of 10.8 months on sorafenib versus 5.8 months on placebo. 7 Regime: Sorafenib 400 mg bd PO d1-28. No NICE guidance is currently available for targeted therapies, however there is positive SMC guidance and therefore funding is available on a cost per case basis. The SMC advice takes account of the benefits of a Patient Access Scheme (PAS) that improves the cost-effectiveness of sorafenib and lenvatinib. This advice is contingent upon the continuing availability of the PAS or a list price that is equivalent or lower. SACT for Thyroid Malignancies V1.2 Page 9 of 14

11 Third line, Chemotherapy Palliative chemotherapy has largely been superseded by targeted therapies (see above). It can however be considered in good performance status patients with rapidly progressive, symptomatic, 131I refractory, locally advanced or metastatic disease when targeted therapies are unavailable or have proved unsuccessful. The agents used are doxorubicin and cisplatin, but durable responses are uncommon. 3 MEDULLARY THYROID CANCER Medullary thyroid cancer (MTC) accounts for 5-10% of all thyroid cancers and 25% of these will be familial in origin. Standard management includes total thyroidectomy and central compartment node dissection, with selective bilateral neck dissection for those with T2-4 disease or clinically apparent nodes. 2 Radioiodine is not used in the management of MTC. For recurrent or metastatic disease, chemotherapy has essentially been ineffective. Radiolabelled Meta-Iodo-Benzyl_Guanadine (MIBG) or somatostatin analogues (eg Octreotide) have been used but not widely evaluated. Prognosis for these patients is limited, with 5 year survival rates of 25% and 10% of patients alive at 10 years. Tyrosine Kinase Inhibitors Vandetanib is currently the only drug with a European licence for use in advanced or metastatic medullary thyroid cancer and has demonstrated activity in Phase II trials. 7 Regime: Vandetanib 300 mg PO d1-30. (Available by IFR) SACT for Thyroid Malignancies V1.2 Page 10 of 14

12 ANAPLASTIC THYROID CANCER This is the least common and most aggressive subtype of thyroid cancer. Most patients present with advanced disease. Surgery is rarely indicated. These tumours do not take up radioiodine. External beam radiotherapy is the treatment of choice and treatment is often palliative. Radical Treatment Surgery is very rarely indicated as disease is usually advanced at presentation but thyroidectomy is carried out if possible followed by chemotherapy/radiotherapy as indicated. Palliative treatment Short courses of palliative radiotherapy may be useful for symptom control in locally advanced disease. Palliative chemotherapy: commonly used regimes include single agent doxorubicin or epirubicin, doxorubicin and cisplatin, paclitaxel and paclitaxel and carboplatin. 3 LYMPHOMA OF THYROID These cancers are usually managed by the lymphoma team and details of treatment can be found in the NICC lymphoma guidelines. Systemic therapy summary DTC Iodine sensitive disease- radioactive iodine Iodine resistant disease (palliative intent)- First line lenvatanib (IFR), Second line sorafenib (IFR), Third line doxorubicin 75mg/m2. MTC For progressive and symptomatic disease: SACT for Thyroid Malignancies V1.2 Page 11 of 14

13 Use of tyrosine kinase inhibitor within trial setting or Vandetanib (IFR). Anaplastic thyroid cancer Palliative: Doxorubicin 75mg/m 2 SACT for Thyroid Malignancies V1.2 Page 12 of 14

14 References 1. AJCC Cancer Staging Handbook, 7 th Ed 2. British Thyroid Association Guidelines, 2 nd Ed, British Thyroid Association Guidelines, 3 rd Ed, Ablation with Low-Dose Radioiodine and Thyrotropin Alfa in Thyroid Cancer, Mallick et al, N Engl J Med 2012;366: Strategies of Radioiodine Ablation in Patients with Low-Risk Thyroid Cancer, Schlumberger et al, N Engl J Med 2012; 366: Schlumberger M, et al. et al. Lenvatanib versus placebo in radioiodinerefractory patient s thyroid cancer: NEJM 372, 2015 (No.7). 7. Sorafenib in locally advanced or metastatic patients with radioactive iodine-refractory differentiated thyroid cancer: The phase III DECISION trial. J Clin Oncol 31, 2013 (suppl; abstr 4) 8. Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial. J Clin Oncol Jan 10;30(2): doi: /JCO Epub 2011 Oct Shimaoka K, Schoenfeld DA, Dewys WD, Creech RH, De Conti R. A randomized trial of doxorubicin versus doxorubicin plus cisplatin in patients with advanced thyroid cancer. Cancer 1985;56: Williams SD, Birch R, Einhorn LH. Phase II evaluation of doxorubicin plus cisplatin in advanced thyroid cancer: a Southeastern Cancer Study Group Trial. Cancer Treat Rep 1986;70: Hoskin PJ, Harmer CL. Chemotherapy for thyroid cancer. Radiother Oncol 1987;10: SACT for Thyroid Malignancies V1.2 Page 13 of 14