Management of differentiated thyroid cancer of the follicular epithelium

Abstract

The incidence of thyroid cancer has been increasing in many countries over the last 30 years (from 3.6/100,000 people in 1973 to 8.7/100,000 people in 2002) while mortality has been slowly decreasing (). The increase is mainly represented by papillary thyroid cancer, while follicular and anaplastic histotypes remained stable. It is a general opinion that the increase is attributable to better detection of small papillary carcinomas as a result of improved diagnostic accuracy (neck ultrasound and fine-needle aspiration cytology). Consequently, it is common experience in thyroid cancer referral centers that nearly 60%–80% of thyroid carcinomas detected nowadays are micropapillary thyroid carcinomas (less than 1 cm in size) carrying an excellent long-term prognosis. In view of this change in the presentation of the disease, the objective of thyroid cancer management should be aimed at achieving complete cure using the less aggressive diagnostic and therapeutic procedures.

• Key words:
• Radioiodine therapy
• thyroglobulin
• thyroid cancer
• tyrosine kinase inhibitors

Key messages

• The observed increase in the incidence of micropapillary thyroid cancer in the last decade has changed the clinical presentation of thyroid cancer from a potentially aggressive disease to an indolent tumor with very low risk of recurrence and mortality.

• Thus, it is of paramount importance that the management of the disease be directed towards using the less aggressive and less costly diagnostic and therapeutic procedures.

Initial treatment

Once the diagnosis of differentiated thyroid cancer (DTC) has been established, the initial treatment should be preceded by careful exploration of the neck by ultrasound to assess the status of lymph node chains. According to the American (ATA) and European (ETA) thyroid cancer guidelines (3,4) the initial treatment for DTC is total or near-total thyroidectomy whenever the diagnosis is made before surgery by fine-needle aspiration cytology, regardless of the primary tumor size. This statement is based on fair clinical evidence that total thyroidectomy is associated with better outcome, although there are reports suggesting that the extent of thyroidectomy is not a major determinant of survival, at least in papillary thyroid cancer (5–7). Nevertheless, total thyroidectomy should be preferred to less radical surgery because it facilitates the subsequent follow-up and the early discovery of metastases. Less extensive surgical procedures may be accepted in case of unifocal DTC diagnosed at final histology after surgery performed for benign thyroid disorders, provided that the tumor is small, intrathyroidal, and of favorable histological type (classical papillary or follicular variant of papillary or minimally invasive follicular). The benefit of prophylactic central node dissection in the absence of evidence of nodal disease is controversial. There is no evidence that it improves recurrence or mortality rate, but it permits an accurate staging of the disease that may guide subsequent treatment and follow-up (3,4). Compartment-oriented dissection of lymph nodes should be performed in cases of preoperatively suspected and/or intraoperatively proven lymph node metastases. In expert hands surgical complications, such as laryngeal nerve palsy and hypoparathyroidism, are extremely rare (<1%–2%) (3).

Surgery is usually followed by the administration of ¹³¹I activities aimed at ablating any remnant thyroid tissue and potentially microscopic residual tumor. This procedure decreases the risk of loco-regional recurrence and facilitates the long-term surveillance based on serum thyroglobulin (Tg) measurement and diagnostic radioiodine whole-body scan (WBS). In addition, the high activity of ¹³¹I allows a highly sensitive post-therapeutic WBS to be obtained. Despite these favorable arguments, there are also reasons for not advocating remnant ablation in all cases (8). The best compromise seems to recommend radioiodine ablation in high-risk patients and in selected low-risk patients, while there is no indication in very-low-risk patients (those with unifocal T1 tumors, less than 1 cm in size, with favorable histology, no extrathyroidal extension or lymph node metastases) (3,4). Effective thyroid ablation requires adequate stimulation by TSH. The method of choice for preparation to perform radioiodine ablation is the administration of recombinant human TSH (rhTSH) while the patient is on levo-thyroxine (LT4) therapy. A multicenter, prospective study has demonstrated that this preparation is highly effective and safe and that the rate of successful ablation is similar to that obtained with LT4 withdrawal (9). Based on these results the use of rhTSH has been approved in Europe in February 2005 by the European Medicine Agency (EMEA), and in USA in December 2007 by the FDA, as preparation for radioiodine ablation of post-surgical thyroid remnants in patients with well differentiated thyroid carcinoma without evidence of metastatic disease, using a fixed dose of 3,700 MBq (100 mCi) of ¹³¹I. However, a recent randomized prospective study has showed that in patients prepared with rhTSH, a lower dose of 1,850 MBq (50 mCi) of ¹³¹I is equally as effective as 3,700 MBq (100 mCi), even in the presence of lymph node metastases, and this further reduces radiation exposure to the whole body (10). In two recent studies (available only as conference abstracts) even lower doses of radioiodine (1,100 MBq) have been associated with effective thyroid ablation.

Staging and risk assessment

Cancer staging is an essential and integral part of cancer management, and a predictive staging system should provide accurate prognostic information to clinicians and their patients. Several staging systems have been developed by authoritative centers. Each of them provides good risk stratification based on data available shortly after initial therapy. The most popular is the American Joint Committee on Cancer/International Union against Cancer TNM staging system based mainly on the extent of tumor and age (11). Histological subgroup, TNM staging including lymph node and distant metastases, and surgical completeness are significant prognostic factors associated with DTC outcome in several series (12). Although all staging systems are able to predict high or low risk of cancer mortality, they fail to predict the risk of recurrence and continue to have a small risk of death even in patients classified as low risk. Therefore, the addition of a postoperative clinical staging system should be used in conjunction with the American Joint Committee on Cancer (AJCC) staging system to improve prediction of risk for recurrence and to dictate the most appropriate therapy. As a proof of this, a recent Finnish report (13) has shown that the post-ablative serum Tg level is an independent predictor of recurrence in low-risk differentiated thyroid cancer. In recent guidelines, estimates of risk for recurrence and risk of disease-specific death are used to guide both initial treatment and follow-up recommendations. A European consensus report (3) defined three categories of risk to establish the indication for radioiodine ablation therapy: no indication in very-low-risk patients (unifocal T1 (< 1 cm) N0 M0, no extension beyond the thyroid capsule, favorable histology), definite indication in high-risk (any T3 and T4, or any T N1, or any M1), and probable indication in low-risk (T1 (> 1 cm), or T2 N0 M0, or multifocal T1 N0 M0, or unfavorable histology). Recently, Tuttle et al. (14) have proposed an ‘on-going risk stratification’ which takes into account the response to therapy. On this basis, patients can be classified as having an excellent, acceptable, or incomplete response to therapy. Patients with an excellent response (undetectable basal and stimulated Tg, stable Tg at the time, negative AbTg and negative neck ultrasound) have a very low risk of recurrence, and their long-term follow-up will be based on yearly physical examination and basal Tg measurements. Patients with an acceptable response (undetectable basal Tg, stimulated Tg < 10 ng/mL, declining trend of Tg, negative or declining levels of AbTg, negative neck ultrasound) require a closer follow-up, reserving additional treatments in case of evidence of disease progression. Patients with an incomplete response (detectable basal and stimulated Tg, rising trend of Tg, presence of structural disease, persistent or recurrent radioactive-iodine (RAI)-avid disease) require continued intensive follow-up with neck ultrasound, cross-sectional imaging, RAI imaging, and FDG-PET imaging. The majority of these patients will require additional therapy such as surgical resection, RAI therapy, external beam irradiation, and systemic therapies.

Follow-up

The aim of the follow-up is the early discovery and treatment of persistent or recurrent loco-regional or distant disease. The large majority of local recurrences develops and is detected in the first 5 years after diagnosis. However, in a minority of cases, local or distant recurrence may develop in later follow-up, even 20 years after initial treatment.

Two to three months after initial treatment thyroid function tests (FT3, FT4, TSH) should be obtained to check the adequacy of levo-thyroxine (LT4)-suppressive therapy. At 6 to 12 months the follow-up is aimed at ascertaining whether the patient is free of disease. This follow-up is based on physical examination, neck ultrasound, and rhTSH-stimulated serum Tg measurement with or without diagnostic WBS (3,4). At this time most (nearly 80%) of the patients will belong to the low-risk categories and will disclose normal neck ultrasound and undetectable (< 1.0 ng/mL) stimulated serum Tg in the absence of serum Tg antibodies. Diagnostic WBS does not add any clinical information in this setting and may be omitted. These patients may be considered in complete remission, and their rate of subsequent recurrence is very low (< 1.0% at 10 years) (15,16). Patients in remission may be shifted from suppressive to replacement LT4 therapy, with the goal of maintaining a serum TSH level within the normal range (3,4). This is particularly important in view of the possible side-effects (on heart and bone) associated with chronic TSH-suppressive therapy (17). The subsequent follow-up of these patients should be based on yearly physical examination, serum Tg measurement on replacement LT4, and neck ultrasound. Whether a second rhTSH-Tg testing should be obtained during follow-up is controversial, but available evidences suggest that an additional rhTSH stimulation test is of little clinical utility in patients who had no biochemical (undetectable basal and stimulated serum Tg) or clinical (imaging) evidence of disease at the time of their first rhTSH-Tg. (18,19). Recently, new methods for serum Tg measurement with a functional sensitivity below 0.1 ng/mL have become available. Using these systems, some authors reported a much higher sensitivity of the assay. In their experience an undetectable basal serum Tg (< 0.1 ng/mL) using ultrasensitive assays should give the same information of a stimulated Tg value, and thus the authors recommended that rhTSH-Tg testing should be abandoned (20,21). However, the higher sensitivity of these tests is at the expense of lower specificity (22).

A final issue to be considered is whether follow-up should be continued indefinitely in low-risk patients who have evidence of complete remission at 5–10 year follow-up. In these patients the risk of late recurrence is very low (probably < 1%), thus the possibility that specific follow-up may be abandoned is to be considered. However, it is important to stress that continuous monitoring (once a year) of the appropriateness of l-thyroxine replacement therapy is mandatory through the entire life.

Therapy of recurrent or persistent disease

Patients with evidence of persistent disease, or with detectable levels of serum Tg increasing with time, require imaging techniques for the localization of disease and appropriate treatment, including therapeutic doses of ¹³¹I.

Included in this category are the 5%–10% of DTC patients who presented with local or distant metastases at diagnosis and an additional 5%–10% who developed recurrent disease during follow-up. When appropriately treated, two-thirds of the patients with local disease and one-third of those with distant disease may achieve complete remission (23).

Treatment of loco-regional disease is based on the combination of surgery and radioiodine therapy. External beam radiotherapy may be indicated when complete surgical excision is not possible or when there is no significant radioiodine uptake in the tumor (3,4).

Distant metastases are more successfully cured if they take up radioiodine, are of small size, and are located in the lungs (not visible on X-rays). Lung macro-nodules may benefit from radioiodine therapy, but the definitive cure rate is very low (23). Bone metastases have the worst prognosis even when aggressively treated by combination of radioiodine therapy and external beam radiotherapy (23). Surgery for resectable bone lesions may be effective and should always be considered, particularly when a single lesion is present. When significant radioiodine uptake is visible in the majority of metastatic lesions, radioiodine therapy should be administered until proven benefit can be demonstrated, without dose limitations. Side-effects from radioiodine, although possible, are limited to the risk of developing second tumors, mainly leukemia and only after high cumulative doses. This risk is so small that it should not represent a good argument to abandon the use of radioiodine therapy. No significant increases in the rate of second cancers have been reported after a single dose of radioiodine given for thyroid ablation. Brain metastases are relatively rare and usually carry a poor prognosis. Surgical resection and external beam radiotherapy represents the therapeutic options of choice, although radioiodine treatment may be also considered in particular cases (small size, with no symptoms). Chemotherapy is no longer indicated due to lack of effective results and should be replaced by enrollment of the patients in experimental trials with tyrosine kinase inhibitor (TKI).

Future perspective

The molecular basis of DTC is well characterized, and the critical genetic pathways involved in the development of specific tumor histotypes have been elucidated. Most of them act through the RTK–RAS–RAF–MAPK pathway or the phosphatidylinositol 3-kinase (PI3K)–AKT pathway (24), and all of them confer constitutive activation to the transformed cells. In addition, mutations of tumor suppressor genes have been discovered and associated with progression toward a more aggressive phenotype. As in several other human malignancies, the knowledge of the molecular alterations has prompted the search for new agents able to inhibit the function of specific oncoproteins, aiming to shut down the uncontrolled growth of neoplastic cells and, hopefully, to reduce toxicity in normal cells, the so-called ‘targeted therapy’. In thyroid cancer several molecules have been developed, blocking the RTK–MAPK and the PI3K–AKT pathways, those activated by RET-PTC, RAS, and BRAF (24) mutations. In addition, the action of some experimental drugs is not restricted to one single protein, but is also directed against non-thyroid-specific genes that play a critical role in tumor cell growth and metastasis, such as angiogenesis regulatory genes. Of the identified pro-angiogenic factors, vascular endothelial growth factor (VEGF) is key, binding to two tyrosine kinase receptors, VEGF receptor (VEGFR)-1 and VEGFR-2 that also trigger MAPK signaling (25). In papillary thyroid cancer, the intensity of VEGF expression correlates with a higher risk of metastasis and recurrence, and a shorter disease-free survival. Inhibiting VEGFR blocks the growth of the tumor's endothelial cells, and inhibiting EGFR may deprive the tumor of one important growth factor sustaining an aggressive phenotype. After extensive in-vitro experiments showing that several compounds are effective, some are currently being tested in phase I–II–III clinical trials, including motesanib diphosphate, axitinib, gefitinib, sorafenib, and sunitinib. None of these is specific for one oncogene protein, but they target several TK receptors and pro-angiogenic growth factors. The results of phase II–III clinical trials conducted so far are promising.

Administration of motesanib diphosphate, an agent that targets VEGFR, PDGFR, KIT, and RET RTKs, in a single-arm multicenter phase II trial, resulted in partial response (PR) and stable disease (SD) rates of 14% and 67% in 93 subjects with DTC with tolerable and manageable toxicities (26). Axitinib, an agent that targets all VEGF receptors, PDGFR-beta, and KIT, was evaluated in a single-arm study of 60 subjects with advanced thyroid cancer and reported PR and SD rates in 13 patients (22%) and in 30 patients (50%), respectively (27). Gefitinib, a small molecule inhibitor of the EGFR tyrosine kinase, was used to treat 27 patients with radioiodine-refractory, locally advanced, or metastatic thyroid cancer of different histotypes, including papillary, follicular, medullary, and Hurthle cell carcinoma. No objective responses were observed, although tumor reduction that did not meet the criteria for partial response was achieved in 32% of the patients and five patients with stable disease had a decrease in thyroglobulin to <90% of base-line. In addition, stabilization of the disease was obtained in 48%, 24%, and 12% of the patients after 3, 6, and 12 months of treatment, respectively. The authors interpreted these results as modest but still suggestive of a biological effect of the drug (28). Administration of sorafenib (an agent that inhibits a variety of kinases including Raf kinase, vascular endothelial growth factor receptors, platelet-derived growth factor receptors, and RET tyrosine kinases) in 30 patients with metastatic, iodine-refractory thyroid carcinoma determined a partial response in 7 patients (23%), stable disease in 16 patients (53%), with an overall clinical benefit rate (partial response + stable disease) of 77%, a median progression-free survival of 79 weeks, and an overall acceptable safety profile (29). Sunitinib is an inhibitor of VEGFR-1, VEGFR-2, fetal liver tyrosine kinase receptor 3 (FLT3), KIT, PDGFR in both biochemical and cellular assays, but the response rate in clinical trials is still being evaluated. Altogether, the preliminary results of these trials are promising and indicate that targeted therapy might become the first-line treatment of metastatic refractory thyroid cancer patients in the near future (30).

Declaration of interest: The author state no conflict of interest and have received no payment in preparation of this manuscript.