Differentiated Thyroid Carcinoma: Risk Group Assignment and Management Controversies: Page 2 of 2
Differentiated Thyroid Carcinoma: Risk Group Assignment and Management Controversies: Page 2 of 2
There is little debate among clinicians regarding patients assigned to high-risk groups. Total thyroidectomy is optimal,[8,13,38-40] but regardless of risk group assignment, total thyroidectomy is also recommended for patients with a prior history of irradiation, those with gross pathology in both lobes at the time of operation, and those who present with distant metastases. This approach allows for maximal locoregional control and more effective treatment of distant metastases with radioactive iodine (RAI).
No prospective randomized trials have demonstrated superior survival in patients undergoing total thyroidectomies. One prospective analysis showed no difference in outcome in selected patients with differentiated thyroid carcinoma who underwent total vs hemithyroidectomy. However, most large retrospective studies indicate that this procedure increases locoregional control in high-risk disease.[40-43]
Proponents of limited thyroid resection (total lobectomy) argue that the risk of permanent hypocalcemia and recurrent nerve damage does not justify the use of total thyroidectomy in low-risk patients.[44-46] They also point out that limited thyroid resection may obviate the need for lifelong thyroid hormone replacement.
We feel that risk group assignment and surgical intervention are closely linked. However, questions can be raised regarding the benefit of risk assignment systems in the treatment of differentiated thyroid cancer:
- Do these systems provide a basis for selection of a particular therapeutic approach?
- Which patients benefit from the selection?
Within the risk group assignment systems that have only low- and high- risk categories, some patients classified in the low-risk group eventually succumb to their disease (Table 4).
The Memorial Sloan-Kettering system attempts to address this issue by assigning these patients to an intermediate-risk group. These patients represent 15% to 20% of all patients with differentiated thyroid cancer. By subdividing patients into low-, high-, and intermediate-risk groups, the low-risk group patients do not die of thyroid cancer (Table 5).
At present, the extent of surgical treatment in patients assigned to the intermediate-risk group remains controversial. Treatment recommendations for this group of patients are based on subjective selection criteria and are usually individualized, based on the available prognostic factors at the time of surgery. Currently, at Roswell Park Cancer Institute, most patients in the intermediate-risk group undergo total thyroidectomy.
In making surgical decisions regarding patients in the intermediate-risk group, it is helpful to consider the morbidity associated with total thyroidectomy vs the risks of leaving residual thyroid tissue. The reported rate of permanent recurrent laryngeal nerve injury and permanent hypoparathyroidism averages 4% and 5%, respectively.[47-49] Almost all permanent injuries occur in advanced disease and reoperative procedures. The incidence of temporary morbidity (recurrent laryngeal nerve injury, hypoparathyroidism) is much higher than permanent disability and ranges from 13% to 51%.[47-49] Although temporary injuries do not result in long-term disability, there is an associated increase in patient care cost and inconvenience.
The risks of leaving residual contralateral thyroid tissue in the face of unilateral confirmed differentiated thyroid cancer in one lobe are not clearly defined. These risks have been conjectured to include anaplastic transformation and recurrent contralateral disease. In addition, serum markers, such as thyroglobulin (TGB), cannot be used as a potential indicator of recurrent disease.
The treatment of the clinically N0 patient is somewhat controversial. Many proponents of total thyroidectomy in differentiated thyroid cancer also advocate routine dissection of the central compartment.[50,51] They point to decreased regional recurrence as the rationale to this approach.
There are no data to support the elective use of posterior-lateral neck dissection in differentiated thyroid cancer (papillary and follicular). However, faced with palpable cervical adenopathy, a modified comprehensive neck dissection should be performed, rather then selective “picking” of clinically involved nodes. This recommendation is based on clinical evidence that cervical recurrences of differentiated thyroid cancer respond poorly to radioactive iodine (RAI) treatment and therefore are best treated surgically.[8,13,43,53-55] In addition, regional control, while not proven to have an impact on survival, may be important to outcome and quality of life.
The question of how to effectively treat local, regional, and distant metastatic disease raises controversial issues regarding the use of adjuvant RAI and TSH suppression.
Radioactive iodine therapy is proposed to serve three clinical goals:(1) to ablate residual thyroid tissue preventing local recurrence; (2) to treat distant metastatic foci; and (3) to ablate local regional recurrences that are not amenable to surgical extirpation.
No study has prospectively compared a population treated with adjuvant RAI with a matched population treated with surgery alone. Only two recent retrospective studies have demonstrated a significant reduction in recurrences using adjuvant RAI.[56,57] In addition, one study reported a survival advantage in patients treated with RAI, while several other studies showed no survival advantage of adjuvant RAI treatment.[8,58-60]
Some of the differences in clinical outcome seen with adjuvant RAI may be due to differences in dosage and treatment timing paradigms.[42,61,62] The side effects of RAI should not be minimized; these include radiation thyroiditis, sialoadenitis, radiation cystitis, and potential carcinogenic risk.[63,64] We presently support the use of RAI in all high-risk patients and in selected intermediate-risk patients.
RAI for Distant Metastases
Radioactive iodine remains the mainstay of the treatment of distant metastases. Distant metastases are seen more frequently in older patients (more than 45 years) both at initial presentation and after prior surgical therapy. The uptake of RAI in this cohort of patients is poorer then that seen in the younger population, 50% vs 70% overall.[43,55]
Although it is generally accepted that RAI is effective in the treatment of distant metastases, a recent study in patients with distant disease questions the positive impact of RAI therapy on overall survival. Moreover, the same study showed no difference in survival when distant foci were treated at the time of detection by RAI scan vs detection by conventional radiography. This multivariate analysis concluded that age and involvement of multiple organs were the only significant prognostic factors affecting survival in patients treated with RAI for distant metastases. The evidence from this single study needs to be confirmed. We recommend detecting distant foci as early as possible using an RAI scan.
Role of TSH Suppression
The role of TSH suppression is less controversial. Several studies have demonstrated the beneficial effect of TSH suppression on survival and recurrence in patients with differentiated thyroid cancer.[31,60,63,66] We presently advise all patients with differentiated thyroid cancer to receive suppressive therapy. A TSH level below normal but detectable has been shown to be as effective as nondetectable TSH levels in suppressing serum TGB levels.
In differentiated thyroid cancer, the two most common sites of failure are the neck (62%) and the lung (56%). Locoregional recurrences to the neck and mediastinum as well as distant metastases are responsible for most deaths.[56,68,69] Multiple surgeries improve survival and aggressive surgical attempts are essential in regaining local-regional control.[68,70] In patients with unresectable recurrent disease, external-beam therapy is effective and provides reasonable local control (50%). Interestingly, two independent studies found that the extent of initial surgery did not significantly affect survival in advanced disease.[56,68]
Up to 5% of all treatment failures (locoregional and distant) occur after 20 years or more. There are two reported cases of death from local and regional relapse of DTC more then 40 years after initial therapy. Interestingly, both patients received total thyroidectomies as initial therapy.
In conclusion, an apparently benign course over 20 to 30 years does not preclude a fatal relapse; repeated aggressive attempts at surgical locoregional control seem justified; and external-beam radiation offers an effective tool in the control of locoregional disease that is not amenable to surgery.
Patients treated for differentiated thyroid cancer require long-term follow-up. No single modality is completely effective in detecting all recurrences. A combination of clinical examination, serum TGB measurements, repeat FNA, and chest radiog- raphy are recommended. The frequency of RAI scanning after initial evaluation is a matter of clinical debate.
At present, we prefer to perform an initial RAI scan and to follow these patients with a repeat RAI scan at 3- to 5-year intervals. Thyroglobulin is a very sensitive marker of recurrence, but its specificity is low in the presence of residual thyroid tissue. A rise in TBG above 3 ng/mL is suggestive of recurrent disease.
Our current practice is to clinically follow patients on at least a yearly basis indefinitely. Since most recurrences occur in the first 4 to 5 years, more frequent examinations during this period would be considered safe practice.
Based on prognostic factors and risk group analysis, treatment of the majority of patients with differentiated thyroid cancer follows generally accepted guidelines. These are outlined in a consensus conference that included proponents of both total thyroidectomy and hemithyroidectomy. Total lobectomy (lobectomy including isthmus), and near-total or total thyroidectomy are all reasonable therapeutic options for differentiated thyroid cancer. For a papillary carcinoma less than 2 cm, confined to one lobe, without extrathyroidal extension, and in the absence of distant metastases or contralateral cervical lymph node metastases, total lobectomy can be considered. It is also an accepted treatment for a follicular cancer confined to one lobe with low-grade histology (microinvasive) and in the absence of regional and distant metastases, particularly if the diagnosis of follicular cancer is obtained only after surgical intervention.
Total thyroidectomy and RAI ablation is recommended in all other patients. However, in selected inter- mediate-risk patients, morbidity and oncologic benefit should be carefully weighed. The impact of initial surgery and adjuvant RAI therapy on recurrence and death still needs to be clearly defined by conclusive clinical studies.
It is hoped that the study of molecular mechanisms in differentiated hyroid cancer may reveal specific prognostic markers of progression and recurrence and help resolve some of the shortcomings of the current risk assignment systems.
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