Followup and Diagnosis of Persistent Disease

After the initial therapy has been performed, serum basal and pentagastrin-stimulated calci-tonin should be measured to verify the completeness of the treatment. The first control after surgery should be done 3 months after the surgical treatment, including physical examination, neck ultrasound and measurement of serum free triiodothyronine (FT3), free thyroxine (FT4), thyroid-stimulating hormone (TSH), calcitonin, and CEA. Measurement of FT3, FT4, and TSH are requested for monitoring the levothyroxine (L-T4) replacement therapy. Serum calcitonin and CEA measurement and neck ultrasound are necessary for follow-up of the medullary thyroid disease. Due to the prolonged half-lives, if performed too early, measurement of serum calcitonin may be misleading, especially if a high serum concentration was present preoperatively [66] (Figure 21.5). If basal calcitonin is undetectable, a pentagastrin

SERUM CT \

HOURS

Figure 21.5 Disappearance rate of serum calcitonin (CT) after total thyroidectomy in two patients affected by MTC (A and B): two different half-lives of 3 and 30 hours respectively have been observed in both patients. (Modified from Fugazzola et al. [66].)

0 24 48 72

HOURS

Figure 21.5 Disappearance rate of serum calcitonin (CT) after total thyroidectomy in two patients affected by MTC (A and B): two different half-lives of 3 and 30 hours respectively have been observed in both patients. (Modified from Fugazzola et al. [66].)

stimulation test is recommended. Patients with a negative pentagastrin stimulation test should be reevaluated one year later. A large series of patients with prolonged follow-up has shown that 3.3% of patients with one postoperative negative pentagastrin tests subsequently become positive [67].Two negative pentagastrin tests on two follow-up evaluations strongly suggest that the patient is disease-free. Thus, basal serum calcitonin measurement on an annual basis is recommended, while the penta-gastrin stimulation test may be performed at longer intervals (e.g. every 5 years). In patients with undetectable levels of serum calcitonin, measurement of CEA is not necessary.

Frequently basal and/or pentagastrin-stimulated serum calcitonin is persistently elevated after initial surgery. Because serum calcitonin is a very sensitive and specific tumor marker, the finding of detectable serum levels of basal or stimulated calcitonin is an indication of persistent disease. In patients with persistent disease, serum CEA concentration should be monitored because both high and increasing levels are strongly suggestive of a progressive disease [68,69]. In the majority of cases, the challenge is to find the source of production of calcitonin and CEA. An accurate neck ultrasound is the first localization technique to be performed due to the high frequency of local recurrence and cervical node metastases. A total body CT scan and bone scintigraphy are also suggested in the workup of a patient with detectable values of serum calcitonin. Other imaging techniques such as Octreoscan, 123I-MIBG, and positron emission tomography (PET) may be useful although at present they do not appear to be particularly sensitive, especially in the presence of micrometastases [70-73]. The most accurate technique for the localization of occult metastases is probably the measurement of serum calcitonin after selective venous sampling catheterization: the presence of a gradient in the neck, in the mediastinum or in the suprahepatic veins suggests the presence of metastatic disease in the area where the higher levels of serum calcitonin have been found. It should be taken into account that this method is rather invasive and does not significantly improve the rate of cure [74-76].

About 50% of patients not cured at surgery have no evidence of metastatic disease when studied with the traditional imaging techniques (CT, MRI, PET). In this condition of "biochemical disease," characterized by the persistence of detectable levels of basal and/or pentagastrin-stimulated serum calcitonin but without evidence of metastatic lesions, the most widely accepted therapeutic strategy is that of "wait and see." A detectable serum calcitonin level is in fact compatible with long-term survival, during which calcitonin may remain stable with time or slowly increase. These patients are periodically monitored at intervals of 6 months to 1 year (Figure 21.6).

IMAGING ANALYSIS

NEGATIVE (biochemical disease)

"wait and see' ANNUAL SCREENING.

POSITIVE

"wait and see' ANNUAL SCREENING.

LOCAL DISEASE Oft SINGLE LESION:

Figure 21.6 Flow chart for the management of patients with detectable serum levels of calcitonin after total thyroidectomy.

POSITIVE

LOCAL DISEASE Oft SINGLE LESION:

SURGERY RADIOTHERAPY

PROGRESSIVE METASTATIC DISEASE

CHEMOTHERAPY

Figure 21.6 Flow chart for the management of patients with detectable serum levels of calcitonin after total thyroidectomy.

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