Practical Essentials of Intensity Modulated Radiation Therapy, 3 Ed.

10. Thyroid Carcinoma

Prashant Desai • Tony J. C. Wang • Anesa Ahamad • K. S. Clifford Chao

Thyroid Cancer – Highlights

Key Recent Clinical Studies

Though external-beam RT is now infrequently used for thyroid cancers, some initial studies show promise for treatment alternatives.

Schwartz et al. (IJROBP 2009) in a retrospective review of 131 patients treated for differentiated thyroid cancer found that IMRT was associated with less frequent severe late morbidity (2% vs 12%) as compared to 3DCRT. (PMID 19095376)

Foote et al. (Thyroid 2011) showed overall survival at 1 and 2 years of 70% and 60%, respectively, for nonmetastatic anaplastic thyroid cancer treated with surgery, IMRT, and concurrent and adjuvant chemotherapy consisting of docetaxel and doxorubicin. (PMID 21162687)

New Target Delineation Contours

FIGURE 10-11. CTV1 and CTV2 delineation in a patient with anaplastic carcinoma of the thyroid post-thyroidectomy and left modified neck dissection, pathologically T4bN1b, who received postoperative IMRT.

1. ANATOMY

• The thyroid gland lies in close proximity to the larynx and trachea, cricothyroid ligament, laryngeal nerves (external and recurrent laryngeal) and vagus nerves, common carotid artery and internal jugular vein, hypopharynx, esophagus, strap muscles, and prevertebral muscles. These critical structures in the root of the neck and thoracic inlet are at risk for direct invasion by thyroid cancer (Fig. 10-1).

• The gland consists of two lateral lobes and a central isthmus and extends from the level of C5 to T1 vertebra.

1.1. Important Anatomical Relations

• As shown in Figure 10-1, the isthmus overlies the second and third tracheal ring, and just above it is the arch of the cricoid cartilage and the cricothyroid ligament. The lobes overlie the lateral part of the cricothyroid membrane. The lateral part of this ligament has a free upper margin which is covered in mucous membrane and forms the vocal cord. The lobes surround the upper tracheal rings and esophagus as shown in the same figure.

• The lobes are related anteriorly and anteriolaterally to the strap muscles, and just posterior to the lobes are the prevertebral muscles and the inferior constrictor of the pharynx.

• The recurrent laryngeal nerves, which supply all of the intrinsic muscles of the larynx except the cricoarytenoid, may be injured during surgery or by direct tumor infiltration as it enters the larynx under the border of the inferior constrictor behind the cricothyroid joint or in the superior mediastinum.

• The most common site of injury as it crosses the inferior thyroid artery behind the lower part of the lateral lobes is the region of Berry’s ligament.1 This ligament is the thick part of the pretracheal fascia that suspends the gland from the trachea and cricoid cartilage.

• Important anatomical relations of the normal thyroid gland on CT imaging that are relevant to radiation oncology are shown in Figure 10-2, which shows transverse sections around the level of the isthmus. The spatial relation to the tracheal rings, strap muscles, prevertebral muscles, esophagus, common carotid artery, and internal jugular vein may be particularly noted. Figure 10-3 shows sections more superior, at the level of the cricoid and thyroid cartilage. The position of the thyroid gland with respect to both the cricoid and the thyroid cartilage may be noted, as also that posteriorly the gland abuts the hypopharynx.

• The direct invasion of these local structures is illustrated in Figures 10-4 and 10-5Figure 10-4 shows CT images of tumor directly invading the trachea, prevertebral muscles, and esophagus. Figure 10-5shows transverse CT images of tumor directly invading the pyriform sinus, muscles of the hypopharynx, and tracheoesophageal groove.

• Thyroid cancer recurrence posteriolaterally in the tracheoesophageal groove is a particularly challenging problem. Figure 10-6 shows examples of the typical location of these recurrences and their threat to the airway, speech, and swallowing. These images may be useful in target volume delineation. Figure 10-7 illustrates patterns of spread of thyroid cancer.

1.2. Lymph Nodes

• Regional lymph node spread is common, and the distribution of regional nodes is widespread.

• The first station nodes are the level VI nodes: pretracheal, paratracheal, paralaryngeal, and prelaryngeal (Delphian) nodes above the isthmus (Figs. 10-1 and 10-8).2

• The secondary nodes are the mid- and lower-jugular nodes, supraclavicular nodes, and less commonly upper jugular and spinal accessory nodes. Metastatic involvement of level IA (submental) and IB (submandibular) is very rare.2

• Inferiorly, the gland drains into level VII, the anterior superior mediastinal nodes.

• Superiorly, it drains as high as the parapharyngeal and retropharyngeal nodes.

• Nodal metastases from medullary thyroid cancer carry a more ominous prognosis than that of well-differentiated thyroid cancer even though pattern of spread is similar.2,3

2. NATURAL HISTORY

2.1. Pathology

• Thyroid cancer has a spectrum of histologic types of tumors according to the cells of origin. The main parenchymal cell types are follicular cells and parafollicular neuroendocrine or C cells.

• Follicular cells uptake iodine and produce the thyroid hormone. They give rise to well-differentiated cancers and anaplastic thyroid cancer.

• C cells produce calcitonin and are the cells of origin for medullary thyroid carcinoma (MTC).

• Stromal cells are responsible for sarcoma, and B or T cells give rise to lymphoma.

• The four major histopathologic types of malignant thyroid tumors are: papillary, follicular, medullary, and undifferentiated (anaplastic) carcinoma. The overwhelming majority are favorable well-differentiated tumors (Table 10-1).46

• More rare tumors include the highly lethal anaplastic or spindle cell thyroid cancer, lymphoma, squamous cell cancer, sarcoma, and metastatic tumors of the thyroid (Table 10-1).46

• Both papillary and follicular carcinomas have an excellent prognosis if they are confined to the thyroid gland with a well-defined tumor capsule, smaller than 1 cm, or are minimally invasive. Both have adverse outcomes if they are locally invasive or metastatic.7,8

• Papillary thyroid carcinoma is the most common histologic type, with a high incidence of multicentricity and lymph node metastasis. Variants of this type, which carry a poorer prognosis, are tall-cell papillary (25% 10-year mortality); columnar papillary (90% mortality); diffuse sclerosing (scirrhous), trabecular and insular variants; and tumor with anaplastic features.9

FIGURE 10-1. Endocrine layer of visceral compartment. A-1: Relations of thyroid gland with transverse section showing alimentary, respiratory, and endocrine layers. A-2: Fascia. A-3: Accessory thyroid tissue along the course of the thyroglossal duct. A-4: Approximately 50% of glands have a pyramidal lobe that extends from near the isthmus to or toward the hyoid bone; the isthmus is occasionally absent, in which case the gland is in two parts. A-5: An accessory thyroid gland can occur between the suprahyoid region and arch of the aorta.

FIGURE 10-2. Important anatomical relations of the normal thyroid gland in two separate patients on CT imaging. (A) Section at the level of the isthmus (I ). (B) Section just above the isthmus. Note that the thyroid gland (T ) overlies the tracheal ring (R) and the lobes are in direct contact with the strap muscles (S ) anteriorly and anteriolaterally. The lobes also abut the prevertebral muscles (P ) posteriorly, the esophagus (E ) posteriomedially, and the common carotid artery (A) and the internal jugular vein (V ) laterally.

FIGURE 10-3. Important anatomical relations of the normal thyroid gland above the isthmus. (A) Section at the level of the cricoid cartilage (C ). (B) Section at the inferior portion of the thyroid cartilage (Tc). Note that the thyroid gland (T ) is closely related to both these intrinsic structures of the larynx, and that posteriorly, it directly abuts the inferior constrictor muscles of the hypopharynx (H ). Note the position of the cricothyroid ligament (M ).

FIGURE 10-4. Direct invasion of adjacent structures by thyroid cancer (Tc ). (A) Trachea (B) Right prevertebral muscles (C) Esophagus.

FIGURE 10-5. Direct invasion of the adjacent structures by thyroid cancer (Tc). (A) Left pyriform sinus. (B) Right hypopharynx. (C) Right tracheoesophageal groove recurrence.

FIGURE 10-6. Recurrent tumor in the tracheoesophageal groove (TG) after total thyroidectomy. (A) Small-volume recurrence in the left tracheoesophageal groove. Despite an aggressive attempt to resect this, there remained persistent positive margins. (B) Recurrence in right tracheoesophageal groove at the level of the vocal cords which threatens the larynx and hypopharynx. (C) The same patient as in B shows tracheoesophageal groove recurrence which involves the tracheal ring (r ) and esophagus (e ), and encases the common carotid artery (a ). (D) Bulky left tracheoesophageal groove recurrence. (E) Tumor seen in D is seen here extending down along the tracheoesophageal groove into the superior mediastinum at the level of the aortic arch (Ar ). (F) Recurrence in the left tracheoesophageal groove following radiotherapy with <50 Gy given to this region.

• Follicular-variant papillary carcinoma does not have a worse prognosis. Patients with papillary thyroid carcinoma with lymphocytic thyroiditis tend to have more limited disease and better survival.10

• Follicular thyroid cancer may be more aggressive than papillary carcinoma with a higher likelihood of hematogenous spread (30%). It is typically a solitary encapsulated tumor with follicular cell invasion of the capsule or blood vessels. If capsular penetration is minimal, they are less likely to produce distant metastases or death.11

• Nonencapsulated follicular carcinomas, which extensively grow into adjacent tissues and blood vessels, are much less common. Up to 80% of these highly invasive larger cancers will metastasize, and 20% of patients will die of their tumor within a few years of diagnosis.12

FIGURE 10-7. Patterns of spread. (A) Coronal view: Note invasion of recurrent laryngeal nerve. (B) Sagittal view: Note invasion of esophagus and trachea and substernal extension. The primary cancer (thyroid) invades in various directions, which are shown as color-coded vectors (arrows) representing the stages of progression: T0, yellow; T1, green; T2, blue; T3, purple; T4a, red; and T4b, black. (From Rubin P, Hansen JT. TNM Staging Atlas with Oncoanatomy, 2nd ed. Philadelphia, PA: Lippincott Williams & Wilkins, 2012:115. Modifed from Agur AMR, Dalley AF, eds. Grant’s Atlas of Anatomy, 12th edition. Philadelphia: Lippincott Williams & Wilkins, 2009.)

• Hürthle cell tumors are included as a variant of follicular tumors in the WHO classification; however, they are an independent group.

• When oncocytic cells (also known as oxyphil or Askanazy cells) occupy most of the tumor mass, the disease is classified as Hürthle cell carcinoma. They are unpredictable and may be aggressive with a mortality rate as high as 25% in 30 years.13

• Anaplastic thyroid cancer contains giant and spindle cells. They rapidly invade local structures and lymph nodes and develop distant metastases. Small-cell anaplastic thyroid cancer has a better prognosis.

• Medullary thyroid cancer (MTC) typically presents in the upper pole because the C cells are predominantly located in the upper portion of each lobe of the gland. Approximately half of these patients present with cervical adenopathy.

• Eighty percent of MTCs are sporadic, and the typical age of presentation is the fifth or sixth decade of life. The rest are inherited either as part of a syndrome, such as multiple endocrine neoplasia type 2A (MEN 2A), MEN 2B, or as familial medullary thyroid carcinoma (FMTC), and present in the third decade of life.

• Genetic defects have been pinpointed to mutations of the RET proto-oncogene on chromosome 10q11.14 The RET proto-oncogene codes for a cell membrane-associated tyrosine kinase receptor.

2.2. Recurrence Patterns

• Approximately one-third of patients with differentiated thyroid carcinoma have tumor recurrences after several decades.7

FIGURE 10-8. Lymphatic drainage of the thyroid gland, larynx, and trachea. The arrows indicate the direction of lymph flow. (From Moore KL, Dalley AF II. Clinically Oriented Anatomy, 4th ed. Baltimore, Lippincott Williams & Wilkins, 1999.)

• Extension into the neck is the first sign of a potentially lethal outcome.15,16

• Three-quarters of local recurrences occur in the cervical lymph nodes, and a quarter, in the thyroid bed.

• Recurrent disease in the tracheoesophageal groove is particularly challenging to resect and threatens speech, swallowing, and airway functions (Fig. 10-6).

3. DIAGNOSIS AND STAGING SYSTEMS

3.1. Signs and Symptoms

• Differentiated thyroid cancer presents most often as a solitary nodule, similar to the more common benign adenomas and cysts. They grow slowly, and therefore, diagnosis is often delayed with approximately 50% of thyroid cancers being discovered during routine examination, imaging, or surgery for presumed benign disease.7,12

• Elements of a patient’s history that should raise suspicion include

º Age <15 years or >60 years.

º Symptoms of local invasion such as hoarseness or dysphagia.

º Pain.

º Rapid growth.

º Diarrhea, symptoms of Cushing syndrome, or facial flushing due to the ability of medullary thyroid cancer to secrete hormonally active peptides (adrenocorticotrophic hormone [ACTH], calcitonin-gene related peptide [CGRP]).

º Radiation exposure.

º Positive family history of thyroid cancer.

º Medical history of diseases associated with

• MEN 2 syndromes: hyperparathyroidism, pheochromocytoma, a marfanoid habitus, or mucosal neuromas.

• Familial nonmedullary thyroid carcinoma: Gardner syndrome (a familial adenomatous polyposis with extracolonic manifestations)17; Carney complex (multiple neoplasia that affects endocrine glands or a lentiginosis syndrome)18; Cowden syndrome (multiple hamartomas); microscopic familial papillary thyroid carcinoma (more aggressive than the sporadic form)19 that often metastasizes to lymph nodes and has a high rate of recurrence and distant metastases.20

º Dense calcifications seen on imaging of the anterior neck or metastatic sites (may indicate MTC).

3.2. Physical Examination

• Complete examination of the head and neck is necessary with particular attention to the size and mobility of the mass, attachment to adjacent structures, presence of enlarged lymph nodes, quality of the voice, and presence of stridor.

• Upper airway endoscopy is used to assess vocal cord function.

• Physical findings that raise suspicion of malignancy include

º Size of >4 cm. (Nodules <1 cm in size are almost always benign, while nodules >4 cm in size have a higher risk of malignancy.)21,22

º Firm or hard consistency of nodules.

º Masses fixed to the trachea, larynx, or strap muscles.

º Presence of regional lymphadenopathy.

º Vocal cord paralysis or paresis due to invasion of the recurrent laryngeal nerve or invasion of muscles and ligaments around the larynx.

3.3. Diagnosis and Imaging

3.3.1. Preoperative

• Baseline thyroid stimulating hormone (TSH) level.

• Fine needle aspiration (FNA) of nodule and enlarged lymph nodes.

• If suspected differentiated thyroid cancer (papillary, follicular, Hürthle cell)

º Chest X-ray

º Neck ultrasound

º MRI, if suspicious for deep infiltration or extension into the mediastinum. (CT with iodine contrast is avoided.)

3.3.2. Postoperative

• Baseline radioactive iodine (RAI) scanning: Thyroid follicular cells physiologically trap and retain iodine. Four to six weeks after thyroidectomy, 3 to 5 mCi of RAI is administered orally and its gamma rays are imaged after 24 hours to produce a whole-body map of uptake. This documents any evidence of residual thyroid tissue and enables the calculation of the biologic half-life of the isotope, which is useful for deciding the doses required for ablation. It may also document metastases, although metastatic lesions are less avid and may not uptake RAI in the presence of a large competing volume of highly avid thyroid tissue.

• Follow-upScanning Postablation: Remnant thyroid tissue and tumors that uptake iodine are ablated by high-dose RAI. Diagnostic scanning is then useful for routine follow-up or diagnosis when there is an elevated thyroglobulin or other signs of recurrence.

• Thyroglobulin (Tg), Tg antibodies, and Tg mRNA: Baseline Tg and Tg antibodies are measured postoperatively, post-RAI ablation, or upon suspicion of recurrence. The detection of circulating thyroglobulin mRNA is a more sensitive marker of residual thyroid tissue or cancer than is assay for serum Tg, particularly in patients treated with thyroid hormone or in patients with circulating antithyroglobulin antibodies; however, this test is not yet standard.23

• Recombinant Human Thyroid Stimulating Hormone (rhTSH): Both RAI scanning and measurement of serum Tg during follow-up require a raised serum TSH concentration sufficient to stimulate thyroid tissue or carcinoma to induce 131I uptake and Tg release. This can be done by withdrawing thyroid hormone, causing symptomatic hypothyroidism. Alternatively, symptomatic hypothyroidism can be avoided by administering rhTSH intramuscularly while the patient continues to receive thyroid hormone.24,25

• PET Scanning in Patients with Raised Tg and Negative RAI Scans: 2-[18F]-fluoro-2-deoxyglucose positron emission tomography (FDG-PET) is a valuable diagnostic tool for localizing residual disease in patients with thyroid cancer who have negative whole-body RAI scans and elevated Tg. The cancer cells may dedifferentiate and lose the ability to concentrate iodine. FDG-PET is approved for investigation of this group of patients. In one study of patients in this setting, PET localized occult disease in 71% of patients with elevated Tg levels, and had a positive predictive value of 92%.26

• PET scans are clinically indicated in thyroid cancer of follicular cell origin for restaging of recurrent or residual thyroid cancers in cases of

º Previous treatment by thyroidectomy and RAI ablation.

º Serum Tg of >10 ng/mL.

º Negative 131I whole-body scans.

3.3.3. Additional Investigations for MTC

• Serum calcitonin, carcinoembryonic antigen (CEA), and calcium.

• Screen for pheochromocytoma (important because this has to be managed prior to thyroid surgery).

• Screen for RET proto-oncogene. Genetic testing for RET proto-oncogene mutations should be offered to all newly diagnosed patients with clinically apparent sporadic MTC since 6% of them carry a germline mutation in RET. Children and adults in known kindreds with inherited forms of MTC should also be screened.

• Neck ultrasound.

3.4. Staging

• The American Joint Committee on Cancer issued a new edition of the TNM staging system in 2010 for tumors, including carcinoma of the thyroid. T1 tumors have been divided into two subgroups according to size and are limited to the thyroid. Also, terminology for T staging has changed. Readers are referred to the AJCC manual for details.2 Unlike for the TNM staging of other head and neck cancers, age and histology are used as criteria for staging thyroid tumors.

• The lymph node N classification is unique to this site.

• All papillary and follicular cancers are stage I or II if patients are <45 years old.

• Medullary carcinoma staging does not use age as a criterion. The staging is the same as for patients older than 45 years with papillary or follicular cancer except for T3N0 (Stage II for medullary versus Stage III for papillary and follicular).

• The difference between N1a and N1b in classification of stage III versus IV for patients with medullary cancer or patients older than 45 years with papillary or follicular cancer may be noted.

• All anaplastic carcinomas are considered T4 and thus Stage IV. Nodal metastases do not affect group staging.

• This is the most commonly used system. However, the management of a patient with thyroid cancer is dictated by the risk factors, many of which are not included in the TNM staging system.

4. PROGNOSTIC FACTORS

4.1. Differentiated Thyroid Cancer

• Ten-year relative survival rates for patients with papillary, follicular, Hürthle cell, and undifferentiated/anaplastic carcinomas were 93%, 85%, 76%, and 14%, respectively, according to an analysis of 53,856 thyroid carcinoma cases from the National Cancer Data Base (NCDB: a national electronic registry system which captures approximately 60% of incident cancers in the United States).6

• The prognostic factors of a given case are key in determining the treatment plan. Many institutions have collected and analyzed data to assign risk groups which are used to guide extent of surgery, radioactive iodine, and adjuvant radiotherapy.

• The factors that have emerged as important include

º Patient-related factors: age, gender.

º Tumor-related factors: size; histopathologic grade and variant; extrathyroidal extension in to muscles, larynx, trachea, esophagus, or recurrent laryngeal nerve; presence of lymph node or distant metastasis.

• The Mayo Clinic’s AGES classification system is based on prognostic factors such as age, grade of the tumor, extrathyroidal extension, and size of the tumor.27

• The Lahey Clinic’s AMES classification system used age, distant metastasis, extrathyroidal extension, and size.28,29

• Both the AGES and AMES systems allow patients to be classified as low-risk (long-term mortality <2%) or high-risk (mortality up to 46%).

• The University of Chicago classification system of four classes:

º I: Disease limited to the thyroid gland.

º II: Disease involving locoregional lymph nodes.

º III: Extrathyroid tumor invasion.

º IV: Distant metastasis.

• Ohio State University classification system of four stages:

º 1: Primary tumor smaller than 1.5 cm.

º 2: Primary tumor 1.5 cm to 4.4 cm or presence of cervical lymph node metastases or more than three intrathyroidal foci of tumor.

º 3: Primary tumor at least 4.5 cm or presence of extrathyroidal invasion.

º 4: Distant metastases.

• European Organization for Research and Treatment of Cancer (EORTC) also uses similar factors in risk stratification.

• While none of these predicts the high risk of recurrences that occur in patients less than 20 years old, the Memorial Sloan-Kettering Cancer Center’s GAMES system includes this factor. Their patients were divided into low-, intermediate-, and high-risk groups based on the following prognostic factors: grade, age, distant metastasis, extrathyroidal extension, and size of the tumor.30,31

º Low-risk group: below the age of 45 with low-risk tumors (99% survival).

º Intermediate-risk group: young patients with more aggres.sive tumors and older patients with less aggressive tumors than the low-risk tumors (85% survival).

º High-risk group: patients above the age of 45 with high-risk tumors (57% survival).

• The Mayo Clinic’s MACIS system adds a treatment-related factor—completeness of resection—along with distant metastasis, age, extrathyroidal tumor invasion, and size of the tumor. Completeness of resection is a major prognostic factor especially when there is extrathyroidal tumor extension.

4.2. Medullary Thyroid Cancer

• Apart from the AJCC TNM classification system, a separate though smaller set of staging approaches exist for MTC.

• One classification was proposed that characterizes stage III as extrathyroidal or extranodal extension of disease.32 These patients have significantly worse survival.33

• A third approach is used by the National Thyroid Cancer Treatment Cooperative Study Group to classify tumors into four stages.34

º I: Pre-malignant lesion C-cell hyperplasia.

º II: Primary tumor <1 cm without locoregional or distant metastasis.

º III: Tumor >1 cm or locoregional nodal metastasis.

º IV: Distant metastases.

• The important poor prognostic factors that must be considered in treatment planning include

º Age: Patients <40 years old have a 5- and 10-year disease-specific survival rate of about 95% and 75%, respectively, as compared with 65% and 50% for those older than age 40 years.33

º MEN 2B: Patients with MTC have more locally aggressive disease than that in patients with either MEN 2A or FMTC.35

º Tumors that stain poorly for calcitonin on immunostaining.36

º Rapid rise of serum CEA.37

º Persistent elevated hypercalcitonin.38

º Specific mutations in RET oncogene: Exon 16 mutation is associated with more aggressive disease.39

4.3. Anaplastic Thyroid Cancer

• Prognosis for patients with anaplastic cancer continues to remain grim. The median survival despite multimodality treatment is around 6 months with a 1-year survival of around 20%.40

• Nearly 40% of patients present with lymph node metastasis, while around 50% have distant metastasis.

• The most common site of metastasis is lung (42%) followed by bone (32%) and brain (9%).41

• In a SEER analysis of 516 patients, age <60 years and intrathyroidal tumor were found to be independent predictors of lower cause-specific mortality.40

• A multivariate analysis of 188 patients predicted age, ECOG performance status, tumor growth rate, tumor extension, and distant metastasis as independent prognostic factors for survival.42

5. GENERAL MANAGEMENT

• Multidisciplinary participation is essential in the management of thyroid cancer. While complete surgical removal of the disease is the mainstay of therapy, patients may also require radioactive remnant ablation, adjuvant radioactive iodine therapy, medical suppression of TSH by high-dose thyroxine, and/or external-beam radiation therapy.

• A detailed review of the patient and tumor characteristics with respect to the above-mentioned prognostic factors for each histologic subtype is necessary in determining the appropriate adjuvant treatment.

5.1. Surgery

• Controversy exists over the extent of initial surgery and neck dissection.4346 The extent of surgery depends on the risk of local recurrence based on the factors described in the above risk classification systems.

• The advantages of total thyroidectomy include

º Less than 2% risk of permanent hypoparathyroidism or recurrent laryngeal nerve injury.

º No risk of persistent multifocal cancer in the remnant thyroid tissue.

º Leaving residual functioning thyroid tissue hampers the detection of metastases or recurrence by radioiodine scanning or serum thyroglobulin.

• In support of this approach, one study reported that patients with papillary carcinoma considered to be low-risk (by age, metastases, extent, and size) had higher rates of local recurrence and nodal metastasis after unilateral lobectomy (14% and 19%, respectively) than after bilateral thyroid lobe resection (2% and 6%, respectively) at 20-year follow-up (P = 0.0001). However, there were no significant differences in cancer-specific mortality or distant metastasis rates between the two groups.

• Advocates of thyroid lobectomy and isthmusectomy or near total thyroidectomy argue that

º There is less risk of injury to the recurrent laryngeal nerve and permanent hypoparathyroidism.

º Occult residual foci of papillary cancer are rarely of clinical significance.

º Recurrences after conservative surgery can be managed by reoperation, and therefore, there is no survival advantage for total thyroidectomy over lobectomy for well-differentiated thyroid cancer.

• While total thyroidectomy allows for radioactive iodine dosimetry and ablation, as well as the use of serum thyroglobulin as a tumor marker in the follow-up of patients, these are generally not necessary in low risk-group patients. Although the incidence of microscopic thyroid cancer in the contralateral lobe ranges between 30% and 80%, the incidence of clinical recurrence in the opposite lobe after ipsilateral lobectomy is only 5% to 7%.47,48

• Lobectomy and isthmusectomy are appropriate for papillary cancers smaller than 1.5 cm.

• A total or near total thyroidectomy is performed for papillary cancers larger than 1.5 cm, those associated with previous radiation, gross bilateral disease, presence of adverse histopathologic features, positive margins, or follicular and Hürthle cell carcinoma.

• Central compartmental lymph node dissection is recommended. Palpable neck adenopathy or clinical suspicion of nodal metastases requires neck dissection.

• Total thyroidectomy and bilateral central neck dissection (level VI) is indicated in all patients with MTC, especially considering the high frequency of bilateral occurrence in both sporadic and familial disease.35

• Modified radical neck dissections (levels II to V) are recommended for all patients with primary tumors larger than 1 cm in diameter (0.5 cm for patients with MEN 2B) or in cases where the tumor is in the central node(s).

• Disfiguring radical neck dissections do not improve prognosis and are not indicated. In the presence of grossly invasive disease, more extended procedures with resection of involved neck structures may be appropriate. Function-preserving approaches are preferred.

• Patients with inherited disease are recommended to have total thyroidectomy by the age of 5 years. Total thyroidectomy is recommended in the first year of life or at diagnosis for MEN 2B patients with specific mutations (codon 883, 918, or 922 RET mutations). A bilateral central neck dissection (level VI) should be strongly considered for patients with MEN 2B and those identified by genetic testing.49

5.2. Adjuvant Thyroid Hormone Therapy

• Suppression of endogenous TSH is believed to deprive differentiated thyroid cancer cells of the growth promoting effect of TSH. Supraphysiologic oral thyroxine exerts a negative feedback to switch off pituitary production of TSH. Serum TSH concentration is maintained below the lower limit of the normal range (<0.1 to 0.01 mU/L). This level is less stringent in patients with low-risk disease.

• Postoperative thyroid hormone therapy is indicated in MTC, but TSH suppression is not appropriate because C cells lack TSH receptors.

5.3. Radioactive Iodine Remnant Ablation (RRA)

• It is not likely that all thyroid tissue will be removed by routine surgery. It is often necessary to ablate the thyroid remnant with 131I. This is not the same as RAI therapy, which is the administration of larger doses to destroy neck disease or metastases.

• RRA is the destruction of residual microscopic thyroid tissue post-thyroidectomy. 131I is concentrated in thyroid cells and emits short-range beta irradiation, which destroys remnant microscopic tumor cells with a relatively low dose to adjacent organs. This achieves the following:

º Thyroid tissue often must be ablated before optimally concentrating in cervical or pulmonary metastatic deposits, which may be less avid than the normal thyroid itself.

º Elimination of thyroid remnants allows rendering of a hypothyroid state to achieve a high circulating TSH level necessary for diagnostic RAI scanning.

º Viable normal Tg-producing thyroid cells are ablated, and serum Tg measurement becomes a sensitive test for follow-up. (Thyroid tissue is the only physiologic source of Tg.)

• RRA is done after an initial diagnostic RAI scan at 4 to 6 weeks. When the amount of tissue is small, 30 mCi is often used. If it demonstrates a significant thyroid remnant or the initial scan shows metastasis tumor, 75 to 150 mCi of RAI is administered to ablate this tissue.

5.4. Radioactive Iodine Therapy

• Following remnant ablation, if RAI imaging demonstrates the presence of RAI-avid tumor, RAI therapy is given and repeated at intervals of 6 to 12 months until there is no longer evidence of functioning disease.

• The therapeutic dose of RAI has empirically varied between 100 and 200 mCi, depending upon the extent of local and metastatic disease.

• The total lifetime dose of RAI is between 800 and 1,000 mCi.

• Complications of RAI include self-limiting thyroiditis and parotitis. Bone marrow depression and pulmonary fibrosis are rare and seen only after very high cumulative doses of RAI.

• Undifferentiated tumors and medullary carcinomas do not concentrate iodine and, therefore, are not amenable to RAI therapy. Older patients, those with Hürthle cell or poorly differentiated tumors, and those with bone metastases may also fail to adequately concentrate RAI.

5.5. Adjuvant External-Beam Radiotherapy

• Aggressive thyroid cancer is frequently treated with adjuvant external-beam radiotherapy (EBRT) following thyroidectomy or resection of recurrent disease to reduce the risk of local recurrence, which can threaten the airway, speech, and swallowing.

• Although there is no consensus on what the indications are for EBRT, and no data from randomized trials are available, retrospective analysis suggests that it is effective in reducing local recurrence.

• For example, one review from the Princess Margaret Hospital/University of Toronto studied the impact of EBRT as part of the initial management of differentiated thyroid carcinoma in 382 patients with a median follow-up of 10.8 years. Age >60 years, tumor size >4 cm, multifocality, postoperative residuum, lymph node involvement, less extensive surgery (less than near-total thyroidectomy), and the lack of use of radioiodine were significant with regard to locoregional failure. Although the use of EBRT was associated with more advanced local disease, there were no statistically significant differences in local control between patients who received RT and those who did not, even after adjustment for the identified prognostic factors. In the subgroup of 155 patients with papillary histology and microscopic residuum, both 10-year cause-specific survival (100% vs 95%, P = 0.038) and local relapse-free rate (93% vs 78%, P = 0.01) were higher for patients given RT than for those not given RT. There were 33 patients with macroscopic residual disease who received postoperative RT. Their 5-year local relapse-free rate was 62% and cause-specific survival was 65%.50

• Other reports also observed that postoperative EBRT lowers the locoregional recurrence rate of thyroid cancer when used to treat patients who had undergone complete resection but were at high risk for local failure.5155

• The favorable effects of RT in patients with advanced medullary thyroid cancer and residual microscopic disease after surgery or those with disease spread to local lymph nodes have also been reported by studies of large thyroid cancer databases in the United Kingdom, France, and Canada.5659 The present data show a significantly reduced local relapse in patients with medullary carcinoma on prolonged follow-up.

• The following are some of the indications for EBRT:

º In differentiated thyroid cancer,

• High-risk patient with high-risk tumor.

• Extrathyroidal extension and microscopic residual tumor.

• Gross residual tumor.

• After resection of recurrent tumor at primary site especially in the tracheoesophageal groove.

º Poorly differentiated thyroid cancer with extensive invasion of central compartment structures, such as muscles, nerves, trachea, esophagus.

º MTC with

• Extensive nodal (moderate- to high-volume disease with extra nodal extension) or mediastinal disease.

• Persistently elevated calcitonin without distant metastases.

• Residual disease (microscopic and gross).

• Extrathyroidal invasion.

º Anaplastic thyroid cancer.

º Distant metastatic deposits, such as in bone, lung, or brain.

5.6. Treatment of Anaplastic Cancer

• A multidisciplinary approach to treatment is essential for the management of anaplastic cancer.

• Complete surgical resection followed by combined chemotherapy and radiation offers the best chance of survival.

• SEER studies have shown that combination of surgery and radiation improves survival.40,60

• Doxorubicin-based radiosensitization has been historically used but there is an increasing interest in taxane-based therapy.

• In one study of 30 patients, hyperfractionation to a total dose of 40 Gy in 1.25 Gy bid with neoadjuvant and adjuvant doxorubicin-based chemotherapy was well tolerated with a 3-year survival of 27%.61Twice-daily fractionation, as compared to daily fractionation, may confer survival benefits.62

• A more recent study by Foote et al. of 10 patients with nonmetastatic anaplastic cancer treated with concurrent and adjuvant doxorubicin/taxane chemotherapy and radiation showed overall survival of 70% and 60% at 1 and 2 years, respectively.63

6. INTENSITY-MODULATED RADIATION THERAPY FOR THYROID CARCINOMA

6.1. Rationale

• The thyroid gland itself is closely apposed to the cricoid, larynx, cricothyroid ligament, prevertebral muscles, esophagus and hypopharynx, and common carotid arteries.

• The draining lymph nodes extend from the high cervical level II nodes to central paratracheal level VI nodes and superior mediastinal level VII nodes.

• The target volume therefore extends from the high neck to well below the shoulder. This poses a technical challenge in administering 50 to 60 Gy to such an extensive concave target, particularly without exceeding the limits of the spinal cord.

• During the early investigation of beam intensity modulation, it was recognized that IMRT could efficiently spare the spinal cord and deliver higher doses than delivered by conventional techniques.

• Nutting et al. compared 3DCRT with IMRT and found that IMRT improved PTV coverage and reduced spinal cord dose. IMRT using the simultaneous integrated boost technique yielded the best dose distribution.64

• With early clinical experience, it is now evident that IMRT presents significant advantages in the treatment of this disease: it affords adequate coverage of the high-risk volume with sparing of the spinal cord, level II nodes, and parotid glands to avoid significant xerostomia.

6.2. Target Volume Determination

• The clinical target volumes (CTVs) can be divided as follows for descriptive purposes: CTV1 (boost volume), CTV2 (primary-risk volume), CTV3 (low-risk volume).

• CTV1 (boost volume) is a boost subvolume of high priority that covers small regions where a higher dose may be delivered such as sites of positive margins, gross macroscopic residual tumor, or in the case of multiple recurrent cancer, the site of recurrence, such as the tracheoesophageal groove. The goal of this CTV is usually to give 63 to 66 Gy in 30 fractions.

• CTV2 (primary-risk volume) covers the primary tumor bed, initial thyroid gland volume, the central compartment and immediately adjacent lymph nodes in level VI, and adjacent tissues in the anterior portion of the supraclavicular fossa. The CTV2 is usually prescribed 60 Gy in 30 fractions.

• The following six sources of information provide useful guidelines in determining the CTV2:

(1) Knowledge of the anatomical location within the neck at various levels on the transverse CT images. Specifically, the relation of the thyroid gland to normal tissues as illustrated in Figures 10-1 to 10-6.

(2) Detailed review of the preoperative physical examination findings. Ideally, the treating oncologist should examine the patients preoperatively in order to establish the extent and location of palpable or visible masses. This is not usually the case because many of the indications for radiotherapy are only discovered intraoperatively or based on pathologic findings, and the first time that the radiation oncologist encounters the patient is following definitive surgery.

(3) Review of available preoperative imaging. Preoperative CT scans are rarely available to aid in localizing the preoperative thyroid gland and tumor volume, as shown in Figures 10-4 to 10-6. Most patients would not have had CT scans because the administration of iodine contrast interferes with postoperative RAI scans by impairment of the cellular uptake of radioactive iodine. For this reason, MR imaging should be performed if patients are seen preoperatively and if it is likely that they will require postoperative radiotherapy.

(4) Review of operative notes with particular attention to the following findings

º The extent of tumor in all directions and planes; the structures invaded such as larynx, trachea, esophagus, strap muscles, and prevertebral muscles.

º The location of adherent tumor which was removed piecemeal or shaved off.

º The locations where the surgeon felt that residual tumor may have been left in situ.

(5) Pathology report with particular attention to location of positive margins, confirmation of structures invaded, and the location of positive nodes.

(6) Findings on planning CT scan. Although it is not a diagnostic scan, and contrast is not usually given, a planning CT scan image may occasionally show gross residual lymphadenopathy, and it is useful to review such images with a diagnostic radiologist. In such cases, a boost volume may be customized.

• Nodal CTV2 is the nodal CTV that covers the regions containing pathologically involved positive nodes plus a margin to include the adjacent nodal levels superiorly and inferiorly. This is usually subjected to 60 Gy in 30 fractions.

• Although this dose is the same goal dose as that of the primaryCTV2, it may be preferable to delineate it separately for the purpose of prioritizing targets for inverse planning. The primary CTV2 is assigned a higher priority.

• CTV3 is the elective nodal volume that covers the nodal levels beyond nodal CTV2 or the nodal regions of the contralateral neck. This is usually subjected to 54 to 56 Gy in 30 fractions. (The elective dose to undissected elective nodal regions using non-IMRT conventional 3D conformal radiotherapy is 50 Gy in 25 fractions in 5 weeks. The target dose is 54 to 56 Gy in 30 fractions in 6 weeks to take into account the longer overall treatment time of this region over the 6 weeks with IMRT).

• At the level of the supraclavicular fossa in patients with positive paratracheal level VI nodes, the posterior supraclavicular fossa nodal regions may be included in the CTV3. The advantage of this is that it avoids irradiating the brachial plexus to >60 Gy, which may occur if hot spots arise in the posterior part of this volume.

• In some cases, nodal CTVs may not be necessary.

• The superior mediastinal nodal region is part of CTV3 and is usually subjected to a goal dose of 54 to 56 Gy in 30 fractions.

• For patients with positive mediastinal nodes, the inferior extent of the mediastinal nodal CTV3 is taken at the carina.

• For patients without mediastinal nodal involvement, the inferior limit may be considered above this and is usually taken down to the level of the aortic arch. The advantage of a higher inferior limit here is that it avoids radiation of the lungs.

6.3. Target Volume Delineation

• CTV1, CTV2, and CTV3 delineation in a patient with pathological T3N1b (AJCC 2010) papillary thyroid carcinoma, with the tumor extending into mediastinum with positive margins on the right side, receiving IMRT is shown in Figure 10-9.

• Figure 10-10 shows CTV1, CTV2 and CTV3 delineation in a 62-year-old male with papillary thyroid carcinoma, status pT4aN1a post total thyroidectomy and 131I treatment. He presented with a soft tissue recurrence adjacent to the larynx and right neck, status post re-resection.

• Target volume delineation for a 69-year-old man is shown in Figure 10-11. The patient had anaplastic carcinoma of the thyroid, status pT4bN1b post total thyroidectomy and left modified neck dissection. He underwent postoperative radiation therapy to the tumor bed and neck nodes.

FIGURE 10-9. CTV1, CTV2, and CTV3 delineation in a patient with pathological T3N1b (AJCC 2010) papillary thyroid carcinoma, with the tumor extending into mediastinum with positive margins on the right side, receiving IMRT.

FIGURE 10-10. CTV1 and CTV2 delineation in a 62-year-old male with papillary thyroid carcinoma, status pT4aN1a post total thyroidectomy and 131I treatment.

6.4. Normal Tissue Delineation

6.4.1. Critical Organs

The critical avoidance structures that should be outlined are

• Spinal Cord. Traditionally, the dose limit to the spinal cord is set at 45 Gy. Extra caution is also exercised because thyroid cancer patients have a high likelihood of long-term survival and therefore higher chances of developing complications.

• Parotid Glands. See Chapter 4Table 4-14.

• Lungs. The entire lung should be scanned so that a dose volume histogram (DVH) for the lung can be generated. Although the lung is not usually outlined in head and neck radiotherapy, this is highly recommended for thyroid cancer where the nodal CTV includes part of the mediastinum. In cases where there are positive nodes in the superior mediastinum, the nodal CTV usually extends to the carina. Failure to generate and inspect the lung DVHs and isodose lines encompassing the lung may easily lead to neglecting that the volume of lung being irradiated is above tolerance. The constraints set should be more stringent than the usual levels used in lung cancer patients (V20 < 35%) because thyroid cancer patients have a high likelihood of long-term survival and therefore a higher chance of manifesting pulmonary dysfunction. They may also develop lung metastases, with which also they can survive for a long time, and this may further exacerbate symptomatic pulmonary inadequacy.

• Submandibular Salivary Glands. In many cases, these glands can be spared the high dose volume. The mean dose should be kept <39 Gy.65

• Pharyngeal Constrictors. There is evidence to indicate that sparing pharyngeal constrictors may decrease dysphagia and aspiration. We recommend keeping the mean dose to the constrictors to <50 Gy and V60 < 30%. See Chapter 4.

• Brain and Brainstem. Portions of these structures that lie at the same level of the target volume should be outlined and avoided. The constraint is usually set at around 54 Gy, and the dose received is usually well below this.

FIGURE 10-11. Target delineation for a 69-year-old man with anaplastic carcinoma of the thyroid, status pT4bN1b post total thyroidectomy and left modified neck dissection.

6.4.2. Nonspecific Avoidance Regions

• Avoidance structures can be used to assist in optimization. These are not specific organs but regions within tissue that when specified for avoidance will generally attract penalties during optimization, facilitating a final plan that gives hot spots well away from the specified region. These include

º Oral Cavity Avoidance Volume to reduce the dose to the mucosa of the structures of the oral cavity, the mandible, and the lips. Lowering the dose to the mucosa reduces acute mucositis, late xerostomia, and dysphasia. Limits of 30 to 40 Gy can usually be achieved without sacrificing CTV coverage even with high level II nodal CTVs.

º Posterior spinal cord avoidance volume to aid in reducing the dose to the spinal cord.

º Supraglottic avoidance includes the suprahyoid epiglottis and aryepiglottic fold. This volume should be kept anteriorly since the lateral lobes of the thyroid gland ascend superiorly along the posteriolateral aspect of the thyroid cartilage. It should be well superior to the insertion of the cricothyroid ligament (Fig. 10-1).

º Posterior brachial plexus avoidance volume in the lower half of neck to reduce the dose to the brachial plexus. This region is at the level of the CTVprimary60 where small hot spots within the 60 Gy volume may occur in the brachial plexus. For example, a 10% hot spot would give 66 Gy, which is above the tolerance for this group of patients who are expected to live for a longer period of time.

6.5. IMRT Results

• In a study from MSKCC, 20 patients with non-anaplastic cancer underwent IMRT treatment and had a 2-year local progression-free rate of 85% and overall survival of 60%. The patients had manageable acute toxicities, and there were no significant radiation-related late effects.66

• In a retrospective review of 131 consecutive patients with differentiated thyroid cancer at M.D. Anderson, Schwartz et al. found that IMRT was associated with less frequent severe late morbidity (2% vs 12%) as compared to 3DCRT though survival outcomes were not impacted.67

• Another study from M.D. Anderson compared outcomes for anaplastic thyroid cancer treated with 3DCRT versus IMRT and found no difference in survival outcomes. Long-term chronic toxicity could not be assessed due to short median survival times.68

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