Preventive Surgery for Multiple Endocrine Neoplasia Type 2 Gene Carriers

Individuals with MEN 2A, 2B and FMTC are virtually certain to acquire MTC at some point in their lives (usually before age 30 years). Therefore, at-risk family members who are found to have inherited the RET gene mutation are candidates for thyroidectomy regardless of their calcitonin levels. It has been shown in several series that RET mutation carriers often harbor foci of MTC in the thyroid gland even when stimulated calcitonin levels are normal.14'18-33'34'45"47

In a series from Washington University in St. Louis reported in 1994, Wells and coauthors described the performance of preventive surgery in asymptomatic RET mutation carriers.14 Families of patients with MEN 2A were screened with genetic and biochemical testing. Thirteen children found to be asymptomatic RET mutation carriers were treated with total thyroidectomy, central lymph node dissection, and parathyroid autotransplantation (six with normal plasma calcitonin levels and seven with elevated levels). After surgery, patients received thyroid, calcium, and vitamin D supplementation. Approximately 8 weeks after the operation, the oral calcium and vitamin D were stopped. Two weeks later the serum calcium concentration was within the normal range in each patient. All patients had microscopic foci of MTC or C-cell hyperplasia. In 1996, Wells and colleagues reported an updated series including 49 patients with similar results.48 Lips and colleagues, in a series from the Netherlands reported in 1994, identified 14 young members of families affected by MEN 2A who had normal calcitonin testing but who were found to be MEN 2A gene carriers by DNA testing.18 Thyroidectomy was performed on 8 of these 14, and foci of MTC were identified in all 8.

At Washington University in St. Louis, we have performed 85 such procedures to date. All patients had central neck node dissection and parathyroidectomy with autotransplantation. Two patients were found to have nodal metastases (one despite a normal stimulated calcitonin level), and calcitonin levels remain elevated in two. Three patients continue to receive calcium supplementation. There were no recurrent laryngeal nerve injuries. Follow-up testing is being carried out in all of these patients to determine the long-term outcome of such procedures.

The finding of carcinoma in the glands of many young patients with normal stimulated calcitonin testing indicates that the operation is often therapeutic, not prophylactic. There is some urgency, therefore, to apply this genetic test to other at-risk individuals and to perform thyroidectomy on those who test positive genetically. The ideal age for performance of thyroidectomy in patients found to be genetically positive has not been determined unequivocally. We believe that 6 years of age is a reasonable time to perform surgery in patients with MEN 2A and FMTC. Patients with MEN 2B should undergo thyroidectomy during infancy because of the aggressiveness and earlier age of onset of MTC in these patients. Follow-up over the next decades will determine whether there is a significant rate of recurrence after preventive thyroidectomy. At present, it is advisable to observe these patients with stimulated plasma calcitonin levels every 1 to 2 years. These patients must also continue to be observed for the development of pheochro-mocytomas and hyperparathyroidism.

Persistent or Recurrent Hypercalcitoninemia

After primary surgery for MTC, persistent or recurrent elevation of the basal or stimulated calcitonin levels indicates the presence of residual or recurrent tumor. Although longer follow-up of reported series is needed, it is likely that thyroidectomy is curative in children with MEN 2A and FMTC in whom the diagnosis of MTC is made by genetic testing or by detection of an elevated calcitonin level after previous negative yearly testing.13,49 Patients in whom the diagnosis of hereditary MTC is made at an older age, however, when calcitonin levels are already high or a palpable tumor is present, are more likely to have residual disease after thyroidectomy. In one series, approximately 50% of these patients had persistent elevations of calcitonin levels postoperatively.35 In patients who present with a mass in the neck (this includes virtually all patients with sporadic MTC), lymph node metastases are present in more than 50%, and persistent elevation of calcitonin levels occurs in 50% to 100%.50,51 In one study of patients who presented with palpable tumors, 15 of 18 patients (83%) with hereditary disease and 11 of 20 patients (55%) with sporadic tumors had persistent disease as indicated by elevated calcitonin levels postoperatively.50

The clinical course of patients with MTC who have positive nodes has been addressed in several studies. MTC can be a very indolent disease. Many patients with persistently high levels of calcitonin after thyroidectomy and node dissection continue to do well without evidence of disease for many years. In a study of 18 patients, 16 of whom had persistently elevated calcitonin levels after "adequate surgery," Block and coworkers found that calcitonin levels remained stable for up to 6 years and recommended observation in the absence of overt clinical disease.52 These observations and this approach have been supported by other groups.51,53 Other studies have indicated a poorer outcome in these patients. In a Norwegian study of 84 cases of MTC, it was noted that more than 50% of patients who presented with cervical node metastases eventually died of the disease.19 In a series of 139 patients operated on for MTC at Mayo Clinic, it was found that 59% of the patients with positive cervical lymph nodes experienced progression of disease.53 In a subsequent report from Mayo Clinic, 66% of node-positive patients with hereditary MTC died, and none of the patients with positive nodes had normal calcitonin levels after a median follow-up of 15.7 years.35 The variable outcome of patients with positive lymph nodes is explained by differences in the biologic virulence of the tumor, the extent of spread at the time of treatment, and the adequacy of surgical extirpation.

Nonsurgical Treatment of the Patient with Persistent or Recurrent Medullary Thyroid Carcinoma

Radiation Therapy

The thyroid C cells do not concentrate iodine, and reports of radioactive iodine treatment of metastatic MTC have indicated a lack of significant effect.54 Several reports have advocated the use of external beam radiation therapy for MTC.55"58 These retrospective studies involved small numbers of patients, and it is difficult to determine whether or not radiation treatment had a significant effect. Other studies have not supported the use of radiation therapy in MTC.23,24,59 In the report by Samaan and colleagues, 202 patients were studied retrospectively. Even though the authors believed that the characteristics of the two groups were comparable, it was found that the patients who received external beam radiation therapy had a worse outcome those who did not.24 A study from France in 1992 reported a series of 59 patients with MTC, all of whom received external beam radiation therapy to the neck and upper mediastinum after surgery.60 Of these 59 patients, 44 had positive nodes and 11 had residual tumor after surgery. After radiation therapy to a mean dose of 54 Gy, 18 patients (30%) experienced clinically evident local recurrences. Thirty-five patients were still alive (median follow-up, 65 months), and 24 had no clinical evidence of disease, although calcitonin levels were not available for all patients. These data indicate a high rate of clinically significant local recurrence, and without post-treatment calcitonin levels it is impossible to determine the actual response rate. Postradiation scarring, fibrosis, and vasculitis make further surgery for removal of metastatic deposits much more difficult and dangerous in the radiated patient. Further studies are needed to define the role of radiation therapy in this disease.

Chemotherapy

In patients with advanced or metastatic MTC, chemothera-peutic regimens have not been extensively studied because of the relative rarity of the disease. Existing reports, however, have not shown any consistent benefit from either singleagent or combination chemotherapy regimens. Doxorubicin (Adriamycin) as a single agent was not noted to alter the progression of MTC.61 A study of combination chemotherapy, using doxorubicin, cisplatin, and vindesine, resulted in one partial remission and three minor responses of 20 patients treated.62 Another study used a combination of dacarbazine (dimethyl triazeno imidazole carboxamide, DTIC) and 5-fluorouracil (5-FU).61 In the five patients treated, there were three partial responses that lasted less than a year.63 In a study by Schlumberger and coworkers, combinations of 5-FU and streptozocin and 5-FU and dacarbazine were given alternately to 20 patients with metastatic MTC. Three partial responses and 11 long-term stabilizations were observed.64

The use of low-dose interferon-a was reported in two patients with MTC.64-65 Both of these patients showed improvement in symptoms and in calcitonin level after treatment. Neither had a complete response.

Juweid and colleagues reported the results of a phase 1 clinical trial in which 12 patients were treated with highdose l31I-MN-14F(ab)2 anti-CEA monoclonal antibody combined with autologous hematopoietic stem cell rescue (AHSCR).66 Toxicity was acceptable, and one partial response was reported. Schott and coauthors reported treatment of seven patients with MTC by immunotherapy with calcitonin-pulsed dendritic cells.67 One significant response was seen in this preliminary study. Chemoembolization of liver metastases from patients with MTC has been effective in reducing the size of lesions and in ameliorating symptoms (author, unpublished data).

Studies with tyrosine kinase inhibitors have shown in vitro activity, and clinical trials to test these agents are under way.68"70

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