Thyroid cancer medical therapy

Classification
Thyroid cancers can be classified according to their pathological characteristics. The following variants can be distinguished (distribution over various subtypes may show regional variation):
 * Papillary thyroid cancer (75%, incl. mixed papillary/follicular)
 * Follicular thyroid cancer (16%)
 * Medullary thyroid cancer (5-7%)
 * Anaplastic thyroid cancer (3%)
 * Lymphoma (1%)
 * Squamous cell carcinoma, sarcoma (0.5 - 2%)

Anaplastic thyroid cancer treatment
Unlike its differentiated counterparts, anaplastic thyroid cancer is highly unlikely to be curable either by surgery or by any other treatment modality, and is in fact usually unresectable due to its high propensity for invading surrounding tissues. Palliative treatment consists of radiation therapy usually combined with chemotherapy. However, with today's technology, new drugs, such as Bortezomib and TNF-Related Apoptosis Induced Ligand (TRAIL), are being introduced and trialed in clinical labs. Recent studies in Italy, have shown positive results against ATC, but more tests, outside the lab, are needed to confirm this, before it can be used in Chemotherapy. There has been some case studies where patients with aggressive Thyroid Cancer have survived outside the mean expected survival time. But the best treatment recommended at this stage is early detection and complete surgery, followed by Chemotherapy alongside Radiotherapy, for any chance of survival of ATC.

Adjuvant therapy for anaplastic thyroid cancer
Treatment of anaplastic-type carcinoma is generally palliative in its intent for a disease that is rarely cured and almost always fatal. The median survival from diagnosis ranges from 3 to 7 months, with worse prognosis associated with large tumours, distant metastases, acute obstructive symptoms, and leucocytosis. Death is attributable to upper airway obstruction and suffocation in half of patients, and to a combination of complications of local and distant disease, or therapy, or both in the remainder. In the absence of extracervical or unresectable disease, surgical excision should be followed by adjuvant radiotherapy. In the 18–24% of patients whose tumour seems both confined to the neck and grossly resectable, complete surgical resection followed by adjuvant radiotherapy and chemotherapy could yield a 75–80% survival at 2 years.

There are a number of clinical trials for anaplastic thyroid carcinoma underway or being planned.

Adjuvant therapy for medullary thyroid cancer
Unlike differentiated thyroid carcinoma, there is no role for radioiodine treatment in medullary-type disease. External beam radiotherapy should be considered for patients at high risk of regional recurrence, even after optimum surgical treatment. Brierley et al., conducted a retrospective study of the treatment given to patients with microscopic residual disease, extraglandular invasion, or lymph-node metastases and found the locoregional relapse-free rate at 10 years was 86%, compared with 52% for those patients who did not receive adjuvant therapy. Typically, 40 Gy is given in 20 fractions to the cervical, supraclavicular, and upper mediastinal lymph nodes for 4 weeks, with subsequent booster doses of 10 Gy in five fractions to the thyroid bed, especially in the setting of gross residual disease.

After a long period during which surgery and radiation therapy formed the major treatments for medullary thyroid carcinoma, clinical trials of several new tyrosine kinase inhibitors are now being studied. Preliminary results show clear evidence of response of a small percentage of patients, providing hope for future advances.

Post-operative radiotherapy for differentiated thyroid carcinoma: when and how much
The role of external beam radiotherapy (EBRT) in thyroid cancer remains controversial and there is no level I evidence to recommend it. No published randomised controlled trials have examined the addition of EBRT to standard treatment, namely surgery, radioactive iodine and medical suppression of thyroid stimulating hormones.

Imbalances in age, sex, completeness of surgical excision, histological type and stage, between patients receiving and not receiving EBRT, confound retrospective studies. Variability also exists between treatment and non-treatment groups in the use of radio-iodine and post-treatment thyroid stimulating hormone (TSH) suppression and treatment techniques between and within retrospective studies.

Farahati et al. and Philips et al. have reported statistically significant advantages for post operative EBRT, however, in both studies many confounding factors have been reported. For example, patients receiving EBRT were more likely to have node-positive disease, extracapsular extension and incomplete macroscopic excision. The differences in patient groups among these studies, and the difficulties with confounding factors, make evidence-based recommendations for the use of EBRT difficult to formulate. Tsang et al. have suggested a role for EBRT in patients with papillary cancer, with microscopic residual disease based on sub-group analysis showing a statistically significant advantage in terms of cause-specific survival (100% vs 95%; P=0.038) and local recurrence (93% vs 78%; P=0.01). Farahati et al. recommend the use of EBRT in node-positive patients over 40 years of age with papillary histology on the basis of an increase in time to local or distant failure (P=0.0009). Other indications for EBRT include high-grade tumours that do not concentrate iodine and tumours with gross local invasion where there is a high suspicion of microscopic or macroscopic residual disease.

The use of EBRT is controversial for those patients with microscopic residual disease. All reports on the use of EBRT have been retrospective, with varying criteria for patient selection, resulting in contradictory conclusions. Several studies have described either no or deleterious effects for EBRT, but many others have described benefit. In a study from Toronto, Brierley et al. found superior local control and improved survival in patients who received EBRT for microscopic residual disease (10-year local relapse-free rate 93% compared with 83% for patients not receiving EBRT, P = 0.01; and cause-specific survival 99% compared with 93%; P = 0.04). “Total thyroidectomy with adjuvant 131I, followed by TSH suppression is considered standard therapy for differentiated thyroid carcinoma”. In the absence of randomised data, there is credible evidence from retrospective studies (Level II-III) to recommend EBRT in addition to standard therapy in high-risk patients.

The apparent difference in outcomes related to the dose of radiotherapy is subject to the confounding factors in all retrospective studies of EBRT as outlined above. However, there are few published data that define the dose to be used. In one retrospective study, 114 patients with macroscopically resected, well-differentiated thyroid cancer were treated with EBRT and an ‘adequate’ total dose was defined as >45 Gy. Patients receiving an ‘adequate’ dose had a significantly improved local regional relapse-free survival (P<0.001). However, only three of the 114 patients in this study also received radio-iodine, and therefore the role of EBRT in addition to standard management was not examined. A total dose of 50–60 Gy was used in the two studies, which showed a reduction in local failure where EBRT was used in addition to radio-iodine (Farahatti et al., and Phillip et al.). Others have treated patients with gross residual disease with 50 Gy in 20 fractions or its equivalent and 40 Gy in 15 fractions or its equivalent in the presence of microscopic residual disease. If the decision is made to treat a large volume, including the cervical nodes for instance, or if there is extracapsular extension and local invasion of cervical nodes, fractionation is changed to 2 Gy fractions. Currently, recommended doses are 50 to 60 Gy in 25 to 30 fractions over 5 to 6 weeks.

To treat the thyroid bed, a clinical target volume from the hyoid to suprasternal notch is determined. A simple technique is to use two antero-lateral oblique wedged fields, or direct electron beams. When using oblique fields the posterior border is placed to exclude the spinal cord. If it is determined that the clinical target volume should include the cervical and superior mediastinal lymph nodes, as well as the thyroid bed, a two-phase technique is commonly used. The initial volume (phase I) includes the regional lymph nodes from the mastoid tip to the carina, including the thyroid bed. The phase I volume may consist of parallel opposing antero-posterior/postero-anterior fields to 40–46 Gy. The phase II volume should include the tissues considered at highest risk of relapse, aiming to boost the high-risk area to a total dose of 14 Gy (cumulative total dose of 60 Gy). For the boost to the thyroid bed alone, several techniques can used, such as, a direct anterior electron beam, antero-lateral oblique wedge fields, or a lateral pair of angled-down oblique fields, achieved with a couch rotation of 10–20 degrees, aiming inferiorly to avoid the shoulders, off the spinal cord. Since the thyroid bed target volume is wrapped around many critical structures in the neck and it is often necessary to include regional lymph nodes, treatment planning of this difficult volume is ideal for conformal radiotherapy, or intensity-modulated radiation therapy. A conformal plan may be used either to treat the thyroid bed alone or to include the cervical nodes.

Recommended indications for the use of EBRT are:


 * 1) High Grade tumors that do not concentrate radio-iodine.
 * 2) Recommendations for EBRT after 131I therapy include high-risk patients defined as; older (>45 years) with potential microscopic residual disease, after resection of gross extrathyroid extension (i.e. UICC 6th edition category T4a or T4b but not T3), or multiple lymph-node involvement.
 * 3) Bulky tumors with superior mediastinal / retro-sternal extension.
 * 4) Gross evidence of local invasion at surgery and presumed to have significant macro or microscopic residual disease, particularly if there is residual tumour that fails to concentrate 131I and is apparent only by raised thyroglobulin.
 * 5) For locally advanced tumors which are inoperable for a variety of lesions it can be used for palliation along with TSH suppression.
 * 6) For recurrent disease in the neck which is not amenable to radio-iodine therapy or further surgery.
 * 7) For palliation of recurrent disease or metastatic disease in bone, cerebrum, spine and other areas.