Persistent And Recurrent

Postoperative serum basal and stimulated calci-tonin measurement is a useful and an accurate marker for persistent or recurrent MTC.3738 Elevated postoperative CEA also indicates aggressive MTC.39 Over 50% of patients who present with clinically evident MTC have persistent MTC, manifested by elevated postoperative basal or stimulated calcitonin levels, even after initial "complete" surgical resection.10 Patients who have an elevated postoperative basal or stimulated calcitonin level can be grouped into two categories: those patients who had "incomplete" initial surgical resection and those patients who had an appropriate initial surgical treatment. Patients who had less than a total thyroidectomy and central neck node clearance (incomplete) usually have residual disease and should undergo cervical re-exploration with removal of all remaining thyroid tissue and bilateral modified radical (functional) neck dissection.

In patients who had apparently complete initial surgical treatment, elevated calcitonin usually indi cates occult MTC or an unidentified distant metastasis. The optimal management of patients with hyper-calcitoninemia after appropriate initial surgical treatment and without radiographic or clinical evidence of MTC remains unclear. Such patients may enjoy long-term survival without reoperation.40 Several groups using a "microdissection" surgical approach consisting of cervical and mediastinal fibrofatty and lymph node clearance in patients with persistent MTC have reported up to a 38% biochemical cure rate (normalization of basal or stimulated calcitonin) but with a short follow-up time.41-43 We found that only 10% of patients (n = 33) had normalization of their basal calcitonin using a similar approach, with a longer mean follow-up time of 7.5 years.38 More importantly, those patients who had more than a 50% decrease in the basal calcitonin after reoperation were less likely to develop distant metastases.38 Although reoperative cervical and mediastinal lymphadenectomy may provide biochemical cure in only a small subset of patients with subclinical persistent or recurrent MTC, it appears to at least decrease the likelihood of having progressive metastatic MTC. In patients with clinically evident symptomatic persistent or recurrent MTC, reoperation can also result in relief of symptoms.3844 We therefore recommend reoperation (consisting of removal of all remaining cervical and medi-astinal fibrofatty and nodal tissue) in patients who have (1) increasing calcitonin levels and had inadequate initial operations or (2) postoperative hypercal-citoninemia and a positive localizing study of locore-gional residual MTC or (3) for palliation of aggressive locoregional MTC in patients with widely metastatic MTC.

Although persistent MTC usually can be demonstrated by basal or stimulated hypercalcitoninemia, localizing the site of disease remains a challenge.3 Noninvasive imaging studies may be helpful but are imperfect (Table 3-3). The sensitivity and specificity of computed tomography, magnetic resonance imaging, and radionuclide and ultrasonographic scanning for persistent and recurrent MTC are poor and have been evaluated in only a small group of patients. Selective venous catheterization with calci-tonin measurement has been reported to have a high sensitivity in a small study but is not available at most institutions.45 Positron emission tomography often identifies one or more sites of metastatic disease, but the calcitonin levels usually remain elevated after reoperation, indicating that nonvisualized sites of metastatic MTC are present.46

Unfortunately, there is no effective standard chemotherapy regimen for patients with MTC. Most investigators have evaluated agents that had been effective against other neuroendocrine malignancies in patients with widely metastatic MTC.47-53 Dacarbazine has been used as a single agent or in combination with other agents (5-fluo-rouracil, epirubicin, cyclophosphamide, vincristine) and resulted in only partial responses in patients with advanced local MTC or metastatic MTC.3,47-51 Also, the use of interferon alfa-2a and somatostatin analogue treatment (short-term and long-term octreotide) in patients with persistent or metastatic MTC have shown no effective tumor response.54-56 Some investigators have reported that octreotide reduces the biochemical markers of MTC and relieves symptoms associated with metastatic MTC.55,56 Tachyphylaxis to long-term octreotide treatment may develop, but the dose can be escalated to relieve symptoms in patients with metasta-tic MTC. More studies are needed to better define

Table 3-3. LOCALIZING STUDIES IN PATIENTS WITH PERSISTENT OR RECURRENT MEDULLARY THYROID CANCER

Noninvasive

Anatomic Site Detected

Invasive

Anatomic Site Detected

Ultrasonography Neck

CT scan Locoregional, lung and liver metastasis

MRI Locoregional and distant metastasis to the liver and lung Bone scan Bone metastasis

Radionuclide* Neck and mediastinum and distant metastasis to the liver and lung

Venous catherization for calcitonin Laparoscopy

Local or distant disease Liver metastasis

* Several radionuclide imaging modalities have been evaluated including thalium, technetium 99m, single-photon emission computed tomography, 131I metaiodobenzylguanidine, radiolabeled anti-carcinoembryonic antigen, and, recently, positron emission tomography. CT = computed tomography; MRI = magnetic resonance imaging.

the role and agents that would be helpful in patients with unresectable MTC.

Similarly, the role of external beam radiation therapy for patients with MTC remains unclear. In small retrospective studies, several investigators have suggested some benefit in local control associated with the use of perioperative external radiation therapy.57-63 It appears that patients who benefit from radiotherapy are those with residual microscopic disease, extrathyroidal MTC invasion, or small macroscopic residual locoregional MTC. Some experts have advocated the routine use of radiotherapy in high-risk patients, defined as those with lymph node metastases and extrathyroidal invasion.64 No studies, however, have demonstrated any benefit in survival, and radiotherapy, at best, only results in partial transient tumor response or disease stabilization in a subgroup of patients. Furthermore, reoperation for locoregional persistent or recurrent MTC would be difficult after radiotherapy, and some patients with persistent or recurrent MTC have long-term survival. Lastly, cervical radiotherapy could be associated with significant side effects.65 Radiotherapy is recommended in patients who have (1) unresectable locoregional MTC, (2) incomplete tumor resection by an experienced endocrine surgeon, and (3) symptomatic bone metastasis that cannot be resected.

Because radioiodine therapy is not effective for MTC, radiolabeled anti-CEA antibody therapy has been evaluated in phase I and II radioimmunother-apy trials.66-69 These studies enrolled patients with persistent and metastatic MTC who had tumor that produced CEA. Unfortunately, the antitumor effects were modest, with a decrease in plasma cal-citonin and CEA plasma levels and symptom relief reported. Only a few patients had partial transient tumor responses. The toxicity of radiolabeled anti-CEA antibody treatment was mild. As a localizing study, radiolabeled anti-CEA antibody had a sensitivity of 91 to 100% in patients with metastatic MTC and an elevated CEA level.66-68 Unfortunately, radiolabeled anti-CEA antibody therapy thus far has limited efficacy and can be used only in patients with MTCs that produce CEA. Further studies are needed to determine its utility as a localizing study.

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