New Development in Diagnosis and treatment of Thyroid Cancer

Ihsanullah2nd SemesterIBMS, KMU

Contents

• Cancer• Thyroid cancer• Types of TC• TNM staging• Diagnosis of Cancer• Treatment

Cancer

• Cancer is a class of diseases characterized by out-of-control cell growth.

• There are over 100 different types of cancer, and each is classified by the type of cell that is initially affected.

Why cell become Cancerous

• B/c damage to DNA.• In normal cells Damaged DNA either repair

the cell/dies.• In cancer the damaged DNA nor repair neither

dies but keep on growing abnormal cells.

Thyroid Gland

Highly vascular, brownish red gland, located anteriorly in the lower neck

Two types of cells

a) Follicular cells- use iodine from blood to make thyroid hormone which helps regulate a person metabolism.• Hyperthyroidism• Hypothyroidism• TSHb) Para follicular cells; make calcitonin, a hormone that control the Calcium.

Thyroid Cancer

• Most common endocrine neoplasm.

• Mostly occur in younger age and in women expose to radiations.

Types of Thyroid CancerMany of DNA mutation have been found in this type. having changes in specific part of RET gene, many PTC have BRAF

mutation but that is less common in children and is not mutated.

FTC Acquired changes in the RAS oncogene have a

role in causing some follicular thyroid

cancers.

IN ATC These have mutation in RAS, RET gene and often

have changes in the TP53 tumor suppressor

gene and the CTNNB1 oncogene as well.

People who have medullary thyroid carcinoma (MTC) have mutations in

different parts of the RET gene compared with papillary carcinoma patients.

TNM staging

The most common system used to describe the stages of thyroid cancer is the American Joint Committee on Cancer (AJCC) TNM system. The TNM system is based on 3 key pieces of information: • T indicates the size of the main (primary) tumor and whether

it has grown into nearby areas. • N describes the extent of spread to nearby (regional) lymph

nodes.• M indicates whether the cancer has spread (metastasized) to

other organs of the body. (The most common sites of spread of thyroid cancer are the lungs, the liver, and bones.)

Tumor Grading

Diagnosis of CancerA) Imaging Tests• Ultrasound- to check the no, and size of nodules. also helpful in determine that

nodule is solid/filled with fluid.• Radioiodine scanThey are also often used in people who have already been diagnosed with differentiated (papillary, follicular, or Hürthle cell) thyroid cancer to help show if it has spread. Hot nodules that absorb more radiations and are Not cancerous. Cold Nodule that absorb less radiations and may b benign/ malignantNote ( Radioiodine scan work well if patient have high blood levels TSH or thyrotropin.• MRI scan• Positron Emission Tomography ScanB) Blood Tests• TSH• T3 & T4 and Throglobulin

Contd

• MRI Scan• Positron emission tomography-For a PET scan, a radioactive

substance (usually a type of sugar related to glucose, known as Fluorodeoxyglucose( FDG) is injected into the blood. The amount of radioactivity used is very low.

• Because cancer cells in the body grow quickly, they absorb more of the sugar than normal cells.

• This test can be very useful if your thyroid cancer is one that doesn’t take up radioactive iodine.

Diagnosis of cancer

• Biopsy- Fine needle Aspiration therapy

For those nodules having size> 1cm. ( big enough to Be felt)

Treatment

• Surgery• Radioactive iodine treatment• Thyroid hormone therapy• External beam radiation therapy• Chemotherapy• Targeted Therapy

Surgery

• It’s the main treatment in nearly every case of thyroid cancer, Except for some Anaplastic thyroid cancers.

• If thyroid cancer is diagnosed by FNA biopsy then surgery to remove the tumor and all or part of remaining thyroid is usually recommended.

Contd

• Lobectomy

It is often sometimes used to diagnose TC if an FNA biopsy result doesn’t provide a clear diagnosis.

this operation is sometimes used to treat differentiated thyroid cancers that are small and show no signs of spread beyond the thyroid gland.

contd

• Thyroidectomy- this is most common surgery for TC.a) Total thyroidectomyb) sub- total thyroidectomy- when most of the gland is

removed.• Lymph node removal;

When the thyroid gland is removed then called total

thyroidectomy

when cancer spread to lymph node- especially important for MTC & Anaplastic cancer (where

surgery is an optional)

Radioactive Iodine

• radioactive iodine also known as I-131, is taken into the body in liquid or capsule form, it concentrates in thyroid cells.

• The radiation can destroy the thyroid gland and any other thyroid cells (including cancer cells) that take up iodine, with little effect on the rest of your body.

• This treatment can be used to ablate (destroy) any thyroid tissue not removed by surgery or to treat some types of thyroid cancer that have spread to lymph nodes and other parts of the body.

• Note( we have to increase the level of TSH)

• Note ( In this case we have to raise the TSH level)

Thyroid hormone therapy

Taking daily pills of thyroid hormone (thyroid hormone therapy) can serve 2 purposes:• It can help maintain the body’s normal metabolism (by

replacing missing thyroid hormone after surgery). • It can help stop any remaining cancer cells from growing (by

lowering TSH levels). After a thyroidectomy, the body can no longer make the thyroid hormone it needs, so patients must take thyroid hormone (levothyroxine) pills to replace the loss of the natural hormone.

External beam radiation therapy

• External beam radiation therapy uses high-energy rays (or particles) to destroy cancer cells or slow their growth.

• It is more often used as part of the treatment for medullary thyroid cancer and anaplastic thyroid cancer.

Note ( It is used for those cancer cells which can’t take iodine)

Chemotherapy

• thyroid cancers do not respond well to chemotherapy. But exciting data are emerging about some newer targeted drugs.

• Targeted therapies; Unlike standard chemotherapy drugs, which work by attacking rapidly growing cells (including cancer cells), these drugs attack specific targets on cancer cells.Tyrosine kinase inhibitors: as tyrosine kinase inhibitors (TKIs) may help treat thyroid cancer cells with mutations in certain genes, such as BRAF and RET/PTC. Many of these drugs also affect tumor blood vessel growth (see

• In Papillary TC, cells have changes in BRAF gene which help them Grow.

• Drugs that target cells with BRAF gene changes.• TKIs that have shown early promise against thyroid cancer in

clinical trials .

vemurafenib (Zelboraf®), dabrafenib,

and selumetinib, sorafenib (Nexavar®),

sunitinib (Sutent®), pazopanib (Votrient®),

cabozantinib (Cometriq), motesanib (AMG 706),

axitinib (Inlyta®), vandetanib (Caprelsa®).

contd

• TK’s inhibitors shown to be helpful in the treatment of medullary thyroid cancer (MTC) in clinical trials, and are now approved for use against advanced forms of the disease.

• Others TKI’s already approved to treatOther types of cancer and might be useful Against MTC & DTC if other drugs are not Working.

Vandetanib and cabozantinib

sunitinib, sorafenib, pazopanib

ADR’s of TKI’s

Mitogen activated protein kinases(MAPK)

• MAPK target specific oncologic Pathway in DTC progression• Low Toxicity Profile• many of the targeted MAPK drugs block the Raf kinases in

patients with RET or BRAF mutations.• Sorafenib stabilize disease Progression and lower Serum TGLevel.

Sorafenib

Anti angiogenesis drugs

• Anti-angiogenesis drugs work by disrupting these new blood vessels. TKIs l such as

• axitinib,• motesanib,• sunitinib, • sorafenib,• pazopanib,• cabozantinib,

Histone deacetylation Inhibitors

• Histone acetylation results in a more open chromatin configuration and gene transcription. Many different types of cancer cells have been found to have deregulated histone acetyltransferase or histone deacetylase enzymes.

• Several histone deacetylate Inhibitors.• Valporic acid increase expression of the sodium-iodide symporter and radioiodine uptake

vorinostat, depsipeptide, valproic acid

FDA Approved novel therapy

• Vandetanib. Vandetanib (AZD6474/ZD6474,Zactima) is an orally bioavailable inhibitor of RET, VEGFR-2 and epidermal growth factor receptor (EGFR) [Carlomagno et al. 2002;Wedgeet al.2002].

Investigational therapies

Drug targets Refrence Dosage DTC MTC ATC

Axitinib VEGFR1-3, PDGFR,KIT

Cohenet al. [2008b]

300 mg daily

77% 18% 3%

Motesanib

VEGFR1-3, PDGFR,KIT, RE

Shermanet al.[2008

125 mg daily

100%

Pazopanib VEGFR1-3, PDGFR,KIT

Bibleet al. [2010]

800 mg daily

100%

Tipifarnib sorafenib

Farnesyltransferas

Honget al. [2011]

MTD 200mg (+600mg)

63% 37%

Gefitinib EGFR Pennellet al. [2008]

250 mg daily

67% 15% 19%