TREATMENT OF DIFF THYROID CANCERS

DR SAMEER FASIH

Case 1: Papillary Thyroid Cancer

• 38 yo woman has 3 right sided thyroid nodules detected during her first pregnancy.

• US guided FNA of all 3 nodules consistent with benign colloid nodules.

• Minimal nodule growth during her second pregnancy.

• US guided FNA of 2 nodules benign colloid and one suspicious for PTC.

Case 1: PTC

• Patient was informedFNA is 97% accurate if “diagnostic” for PTC and 57% accurate if “suspicious” for PTC.

Haymart MR et al. Thyroid 18(4): 419-423, 2008.

Case 1: PTC• The patient underwent right lobectomy,

isthmusectomy, and intraoperative frozen section followed by left thyroid lobectomy completing total thyroidectomy.

• Pathology with a 1.0 x 0.8 x 0.6 cm PTC in the right thyroid lobe.

• Post-op Thyroglobulin= 0.9.

Case 2: Follicular Thyroid Cancer

• 78 yo man with a history of back pain for 5 years has an MRI revealing a 5 cm expansile L1 vertebral body mass. Follow-up CT shows an 8 cm mass at T7, invasion of the posterior wall, invasion of the adjacent thoracic vertebrae and rib, possible left neuroforaminal involvement, a second lesion at T12-L1, and hypodense nodular lesions in both lobes of the thyroid.

Case 2: FTC• He undergoes total thyroidectomy and left thoracotomy with

chest wall resection.• Pathology revealed a 2.1 x 1.4 x 1.4 cm FTC limited to the

thyroid and chest wall excision showed metastatic FTC invading skeletal muscles and rib.

Case 2: FTC• Patient receives 149 mCi I-131. Post treatment scan shows

radiotracer uptake in hyoid bone, posterior left aspect of thyroid resection bed, region of left posterior 7th rib, and patient’s L1 metastases

• Patient receives 10 doses of external beam radiation to T12-L2• Patient’s back pain improves. Patient gains weight, spirits

good • He starts Zolendronic Acid. Calcium and vitamin D monitored• Patient receives 202 mCi I-131. There is persistent uptake in

the 7th rib and L1 vertebral body

Case 2: FTC

Tumor Marker

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preop post RAI 1 post RAI 2Thyr

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Preoperative Tgb= 16,478 ng/mLPost 149 mCi I-131= 597 ng/mL,Post 202 mCi I=-131= 101.5 ng/mL

DTC• Differentiated thyroid carcinomas 94% of all

thyroid cancers• Papillary carcinoma 80% • Follicular cell carcinomas 11%• Hürthle cell carcinomas (often considered to

be a subgroup of follicular carcinoma) account for approximately 3%.

Thyroid. 2010 Jul;20(7):707-13. doi: 10.1089/thy.2010.1641.

• 10-year survival rates are 93%, 85%, and 76% for papillary, follicular, and Hürthle cell carcinomas, respectively.

Cancer. 1998 Dec 15;83(12):2638-48

• Differentiated thyroid cancers retain characteristics of normal thyroid follicular cells, including the presence of a unique sodium iodide symporter, which concentrates iodine in the cells.

• Thus, radioactive iodine (RAI) is a mainstay of the diagnosis, treatment, and management of differentiated thyroid cancers.

INITIAL TREATMENT

• Total thyroidectomy is recommended for all but a few cases of differentiated thyroid cancer.

• This surgery is often definitive, and the patient may require no further treatment.

• The surgery should include removal of all involved lymph nodes identified by preoperative neck ultrasonography, where possible.

• Radioactive iodine (RAI) should be given as part of the immediate posttreatment workup for patients with – Tumors > 4 cm, – Residual thyroid tissue– Known metastases to ablate any remnants of

carcinoma and • To improve survival.

Thyroid. 2009 Nov;19(11):1167-214. doi: 10.1089/thy.2009.0110.

• Recurrent disease and distant metastases are often associated with an increase in serum thyroglobulin.

• Serum thyroglobulin may not be reliable when an anti-thyroglobulin antibody is detected.

• RAI is usually administered at treatment doses of more than 100 mCi,

• Once RAI is completed, patients start “replacement” therapy with levothyroxine, which also acts as “suppressive” therapy, because feedback inhibition of thyroid stimulating hormone by this agent, at this point, can help suppress growth of differentiated cancer.

ADVANCE DISEASE

• Recurrent or metastatic lesions either no longer take up radioactive iodine (RAI) or

• Grown in the setting of recent treatment with RAI (ie, RAI refractory)

• If the recommended lifetime dose of RAI (600 mci) has been exceeded.

• Loss of RAI uptake is often associated with the increased uptake of fluoro-deoxyglucose on positron emission tomography (PET) scanning; thus, additional sites of disease are often detected with this imaging modality.

• Once the carcinoma no longer responds to RAI therapy and is PET positive, the survival drops to an average of 2.5-3.5 years.

Robbins RJ, wan Q, grewal RK, reibke R, gonen M, strauss HW, tuttle RM, drucker W, larson SM. J clin endocrinol metab. 2006 feb;91(2):498-505. Epub 2005 nov 22.

• Exception: in rare patients, there is a solitary focus of PET-positive carcinoma that is amenable to surgery.

BRAF Mutation

• Most common mutation in papillary cancer Fugazzola, et al, Clinical Endocrinology 2004

• Codes for serine –threonine kinase• Higher incidence of extrathyroidal extension,

nodal metastases, and recurrence Xing, et al JCEM 90, 2005; Lee, et al, Cancer, 2007

• Inhibit genes involved with iodine metabolism, including NIS, AIT-B, TG, TPO Durante, et al JCEM 92, 2007

• Co-existence of BRAF and PI3K/Akt pathway mutations may facilitate progression of PTC to ATC Hou Clinical Cancer Research, 2007; Santarpia, et al, JCEM, 93, 2008

• Several tyrosine kinase inhibitors have shown activity in this setting, exploiting the vascular nature of these tumors and/or the strong association with genetic mutations that lead to aberrant intracellular signaling.

• The majority (Motesanib, Sunitinib, Sorafenib, and Pazopanib) target the mitogen-activated protein kinase and anti-angiogenic pathways.

• Eur J Endocrinol. 2011 Aug;165(2):315-22. • J Clin Endocrinol Metab. 2011 Apr;96(4):997-1005. • Clin Cancer Res. 2010 Nov 1;16(21):5260-8. • J Clin Oncol. 2010 May 10;28(14):2323-30.

Emphasis on Tyrosine Kinase Inhibitors

• Over-expression of VEGFR, EGFR, c-MET in thyroid cancer

• Sorafenib – inhibits both Raf kinase and multiple tyrosine kinase receptors (VEGF, PDGF, RET) signaling Carlomagno, et al J Natl Cancer Inst, 2006

• VEGFR over-expression in angiogenesis• VEGF blocked by Vandetinib (also blocks EGFR and

RET) Carlomagno, et al, Cancer Res 2002

• EGFR activates both MAPK and PI3K pathways, blocked by gefitinib Schiff, et al Clin Cancer Res 2004

• Imatinib inhibited cell proliferation of ATC in culture Podtcheko, et al JCEM, 2003

• In a small study (N = 17), sorafenib was associated with a partial response in 30% and stable disease in 41% of patients with RAI-refractory DTC.

Sorafenib in advanced iodine-refractory differentiated thyroid cancer: efficacy, safety and exploratory analysis of role of serum thyroglobulin and FDG-PET. Clin Endocrinol (Oxf). 2013 May;78(5):760-7

Phase III DECISION trial• (N = 417) patients treated with sorafenib.• Significantly longer median progression-free survival vs

placebo 10.8 vs 5.8 months (HR: 0.58; 95% CI: 0.45-0.75; P < .0001),

• Higher response rate (12.2% vs 0.5%; P < .0001), and stable disease ≥ 6 months (42% and 33%, respectively).

• Based on these results, the US Food and Drug Administration approved sorafenib for the treatment of locally recurrent or metastatic, progressive, DTC refractory to radioactive iodine treatment.

Phase III DECISION trial. Program and abstracts of the 2013 Annual Meeting of the American Society of Clinical Oncology; May 31 - June 4, 2013; Chicago, Illinois. Abstract 4.