[E1] Goal of management of patients with metastatic MTC: choosing when metastases require treatment. All patients with a history of cancer, especially one that is incurable and progressive, benefit from good psychological support. The ideal goal for all cancer patients would be to be free of disease without morbidity. Unfortunately, that is currently unlikely in patients with metastatic MTC because multifocal, and often multi-organ, metastases frequently develop early in the course of the disease. More realistic aims of current therapy are palliative and strategically prophylactic. The goals of managing patients with persistent or recurrent metastatic disease are to provide locoregional disease control; palliate the symptoms of hormonal excess (such as diarrhea or Cushing’s syndrome); palliate symptomatic distant metastases (such as pain); and control distant metastases that threaten to cause harm (such as impending bronchial obstruction, fracture, or spinal cord compression). The availability of new therapeutic compounds may change the management of metastatic disease in the future.
Metastases are often discovered at an early stage because detectable Ct levels lead to a compulsive search for them. When distant metastases are discovered, the initial decision is to choose which lesions require therapy. This decision must balance the usual slow rate of progressive disease and the prolonged life expectancy with good quality of life that many patients enjoy against the limited efficacy and potential toxicities of available local and systemic therapies.
- RECOMMENDATION 87
Active treatment is most often indicated in patients with lesions in critical locations such as brain metastases, impending or active central nervous system compression, airway compromise, symptomatic lesions, hormonal secretion, and impending or active fracture of a weight bearing bone. Grade: A Recommendation
[E2] Management of patients with metastatic MTC: determining tumor burden and rate of progression using sequential imaging and tumor marker DTs. Patients requiring active treatment typically include those with either a large tumor burden and/or a rapid rate of progression. Tumor burden is estimated from a complete imaging work-up (Fig. 5) (206,211,241). The progression rate can be assessed using response evaluation criteria in solid tumors (RECIST) on sequential imaging examinations or using a surrogate marker, such as Ct DT and CEA DT that are closely related to the progression rate (62,212,228,268,269). The use of tumor marker results from multiple time points helps eliminate the impact of short-term tumor marker fluctuation often seen when comparing results to only the prior values. Barbet et al. (228) studied MTC patients with abnormal Ct levels after total thyroidectomy and bilateral lymph node dissection. When the Ct DT was less than 6 months, the 5- and 10-year survivals were 25% and 8%, respectively; when 6–24 months, the 5- and 10-year survivals were 92% and 37%, whereas all patients with Ct DT greater than 2 years were alive at the end of the study. TNM stage, European Organization for Research and Treatment of Cancer score, and Ct DT were significant predictors of survival by univariate analysis, but only the Ct DT remained an independent predictor of survival by multivariate analysis. Ct DT was a better predictor than CEA DT, and Ct DT calculated using only the first four measurements was also an independent predictor of survival. Giraudet et al. (212) reported that the Ct DT and CEA DT were strongly correlated in 80% of patients, such that when they were both ≤24 or >24 months then progressive disease at 1 year was seen in 94% and 14% of cases, respectively. However, when the DTs were discordant, if only Ct DT or CEA DT was ≤24 months then progressive disease at 1 year was seen in 40% and 75% of cases, respectively, and thus determination of both DTs was recommended (212). To calculate the tumor marker DT, single exponentials are fitted to the tumor marker concentration by nonlinear least square regression. Reliable estimates are obtained using a minimum of four data points obtained over a minimum of 2 years for most patients; however, the DT of patients with DT <6 months can be reliably estimated within the first 12 months (228). To assist with these computations a tumor marker DT calculator is available on the ATA website (http://www.thyroid.org).
- RECOMMENDATION 88
Asymptomatic patients with small volume metastatic disease that is stable to slowly progressive as determined by anatomic imaging, or Ct and CEA DT >2 years, typically do not require systemic therapy, and the decision to initiate such treatment should be made with the patient only after a thorough discussion. Grade: E Recommendation
- RECOMMENDATION 89
Patients with rapidly progressive disease by anatomic imaging or biochemical DT <2 years should be considered for treatment, ideally in the context of a well-designed clinical trial. Grade: B Recommendation
[E3] Management of Ct-positive, but imaging-negative patients. Patients with detectable serum Ct levels should be imaged to detect persistent or recurrent disease as previously described (Fig. 3). In those without anatomically identified disease, long-term surveillance is indicated. The optimal timing of this follow-up has not been determined, but because the Ct and CEA DTs are predictive of tumor progression (212,228) it follows that they may be useful to determine the interval of follow-up (Fig. 5).
- RECOMMENDATION 90
Patients with detectable basal serum Ct levels postoperatively with negative imaging should have the basal Ct and CEA levels obtained approximately every 6 months initially to determine the DTs. Ongoing follow-up of these tumor markers and physical examination should occur at one fourth the shortest DT or annually, whichever is more frequent (i.e., follow the patient every 6 months if the shortest DT is 24 months). Grade: B Recommendation
- RECOMMENDATION 91
In patients with detectable basal serum Ct levels postoperatively with negative imaging, if the Ct or CEA rises substantially since the previous anatomic imaging evaluation, then a neck US should be performed. The Ct elevation required to trigger this action typically depends on the basal serum Ct and the clinical situation, but elevation by more than 20% to 100% may prompt this evaluation. If the serum Ct is >150 pg/mL then systemic imaging should be repeated as well (Fig. 5). Grade: C Recommendation
[E4] Adjunctive external beam irradiation to the neck. The benefits of EBRT are poorly evaluated and only retrospective series are available (275–281). Normalization of serum Ct after EBRT is unlikely (278). Currently, the role of EBRT in MTC is controversial; however, some evidence suggests that EBRT may improve locoregional disease control in high risk patients, although an improvement in overall survival has not been established (275,278). The morbidity of EBRT is typically greater in the elderly.
In a patient with macroscopic residual tumor in the neck after incomplete surgery, Schlumberger and colleagues (281) advocated EBRT for local disease control. Brierley et al. (279) reported in a series of MTC patients that the local=regional relapse free rate between patients that received EBRT and those that did not was no different; however, in high risk patients (microscopic residual disease, extraglandular invasion, or lymph node involvement), the local/regional relapse-free rate was 86% at 10 years with postoperative EBRT, and 52% for those with no postoperative EBRT (p=0.049). Similarly, Chow et al. (276) reported than in seven patients with lymph node metastasis, EBRT gave 100% (4/4) 10-year locoregional control compared with 33.3% (1/3) in those without EBRT.
After resection of extensive disease the use of EBRT is controversial in patients in whom surgery was macroscopically complete but who have persistently high Ct level in the absence of detectable distant metastases (278,281). The clinical dilemma is whether the residual disease is locoregional, distant, or both. In these patients, the benefits of EBRT to limit locoregional tumor recurrence may be counterbalanced by the fact that its morbidity may not be necessary, or that it may hamper any surgical procedure in case of clinical recurrence. Schlumberger and colleagues (281) studied 207 patients with MTC, 98 of who received EBRT. In 97 patients without distant metastases, EBRT was associated with decreased relapse in the neck only in patients with elevated postoperative serum Ct levels, even if surgery was macroscopically complete.
- RECOMMENDATION 92
EBRT should not be used as a substitute for surgery in patients in whom neck tumor foci can be resected without excessive morbidity. Grade: E Recommendation
- RECOMMENDATION 93
Postoperative EBRT to the neck and mediastinum may be indicated in patients who undergo a gross incomplete resection (R2 resection). Prior to initiating EBRT, physicians should ensure that optimal surgery has been performed as re-operation (other than major ablative procedures) is much more difficult, and may not be safely or technically possible, after EBRT. Grade: B Recommendation
- RECOMMENDATION 94
Postoperative adjuvant EBRT to the neck and mediastinum may be considered in patients who are found to have microscopic positive margin(s) (R1 resection) following surgery for moderate to high volume disease involving the central compartment (level VI) and one or both lateral neck compartments (levels 2A–V). EBRT may also be considered in those who appear to have undergone a margin-negative (R0) operation in the setting of moderate to high volume disease with extra-nodal soft tissue extension of tumor when the post-operative serum Ct remains detectable in the absence of distant metastases. Physicians should be sure that optimal surgery has been performed before proceeding with EBRT. (Task Force opinion was not unanimous as some questioned the benefits of EBRT in these settings) Grade: C Recommendation
- RECOMMENDATION 95
Postoperative adjuvant EBRT to the neck should not be performed in an effort to treat a persistent elevation in serum level of Ct in the absence of a gross or microscopic positive margin or moderate to high volume neck disease with extra-nodal soft tissue extension. Grade: E Recommendation
[E5] Brain metastases. Clinically apparent brain metastases from MTC are uncommon, but are probably more prevalent than has been reported due to the lack of routine CNS imaging. The possibility of brain metastases is most often considered in patients with residual or recurrent MTC and suspicious symptoms, in the setting of extensive distant metastases, and before initiation of systemic therapy (especially in the setting of a clinical trial). No randomized clinical trials exist on which to base treatment recommendations (282–284).
- RECOMMENDATION 96
Patients with isolated or limited brain metastases should be considered for surgical resection. EBRT (including stereotactic radiosurgery) may be indicated for brain metastases not amenable to surgery. Grade: C Recommendation
- RECOMMENDATION 97
Patients with spinal cord compression require urgent glucocorticoid therapy, surgical evaluation, and subsequent radiation oncology consultation. Grade: C Recommendation
- RECOMMENDATION 98
Surgery is indicated in weight-bearing bone metastases with fracture or impending fracture. Grade: C Recommendation
- RECOMMENDATION 99
EBRT should be considered to treat painful bone metastases and is indicated for clinically significant lesions that are not candidates for surgery, especially if they demonstrate disease progression or may threaten adjacent structures if they progress. Grade: C Recommendation
- RECOMMENDATION 100
EBRT is indicated postoperatively for bone metastases that are incompletely resected. Grade: C Recommendation
Experience with osseous metastases from tumors other than MTC have demonstrated that percutaneous methods such as vertebroplasty (percutaneous osteoplasty/cementation) (285), radiofrequency ablation (286–289) ± cementation (290–292), cryosurgery (287,293), and arterial embolization (294–296) ± follow-up surgery (297), cementation (298), or EBRT (299) have been associated with pain reduction.
- RECOMMENDATION 101
Minimally invasive percutaneous methodologies (alone or in combination) should be considered to treat painful bone metastases, especially those that have failed or are not candidates for surgery or EBRT. Grade: C Recommendation
Asymptomatic isolated bone metastases may be surgically resected, but it is extremely uncommon for these patients to be rendered free of disease.
- RECOMMENDATION 102
Small bone metastases that are asymptomatic and are not an immediate threat may be followed. Grade: C Recommendation
Intravenous bisphosphonates have been prescribed for painful bony metastases from other primary malignancies with some success. The use of bisphosphonates to prevent progression of existing osseous metastases has been well-studied in both hematological and solid malignancies, but there is no substantial published experience in MTC (300).
- RECOMMENDATION 103
Recommend neither for nor against the use of bisphosphonates in the setting of MTC with osseous metastases. Grade: I Recommendation
[E7] Lung and mediastinal metastases. Uncommonly, dominant mediastinal lesions may be considered for surgical resection. More often, lung and mediastinal lesions are left untreated or considered for clinical trials if the lesions are progressive. Lung or mediastinal lesions causing local compression of an airway or bleeding may be considered for surgery, EBRT, or radiofrequency ablation. Lesions with central airway invasion may be amenable to the addition of photodynamic therapy or airway stenting.
- RECOMMENDATION 104
Lung or mediastinal lesions that are progressive should be considered for clinical trials, or focal therapy. Grade: C Recommendation
[E8] Hepatic metastases. The liver is a major site of MTC metastases. When liver metastases are large or progressive or are associated with symptoms such as diarrhea or pain, there is a need for treatment. Single or limited large metastases requiring therapy should be surgically resected if possible. However, liver metastases are usually multiple and disseminated throughout the liver, and are usually not amenable to surgery, percutaneous ethanol ablation (261), or radiofrequency ablation (301,302), and may be best treated with chemoembolization (261,303,304) or systemic therapy (preferably within a clinical trial).
Chemoembolization has been reported to be effective in anecdotal MTC patients; in 11 patients, symptomatic improvement was observed in all, with transient remission or stabilization in 60% (303); in 12 MTC patients, 42% had partial responses and 42% had stabilization, while diarrhea improved in 40% (304). The extent of liver involvement was the main factor that influenced the results: partial responses being observed only in patients with liver involvement<30%and when metastases were <30mm. Following a single cycle, the duration of partial responses and stabilizations was longer than 1 year. When disease progression occurred, additional therapy offered the opportunity for another partial tumor response, but of shorter duration. Despite these favorable responses, chemoembolization did not allowfor subsequent curative surgery, which is typically not possible given the frequently diffuse nature of these metastases. It is important that patients have adequate liver and renal function prior to treatment. Toxicity was mild and transient, but care must be taken to exclude the presence of a PHEO, since one death was reported in a patient with an occult PHEO who was treated by this technique (303).
- RECOMMENDATION 105
Liver metastases that are progressive, large, or associated with symptoms such as diarrhea or pain, should be considered for active treatment. The method of treatment often depends on whether the lesions requiring therapy are limited or multiple and disseminated. Grade: B Recommendation
[E9] Palliative surgery. Surgery offers effective palliative treatment for metastatic disease in several situations. First, MTC neck metastases are frequently painful, resistant to medical treatment, and their resection may offer significant pain relief. Second, mechanical effects of bulky metastases such as acute spinal cord compression, or airway and esophageal obstruction (with coughing, dyspnea, and difficulty swallowing) can be improved by palliative resection of tumor in these areas (266). Third, the diarrheal syndrome caused by large MTC tumor burden can be alleviated by surgical tumor debulking (305,306). Another method to reduce the volume of liver metastases for palliation of diarrhea and pain is chemoembolization (303,304).
- RECOMMENDATION 106
Palliative therapy, including surgery, should be considered for symptomatic lesions causing pain, mechanical compression, or hormonal secretion. Grade: C Recommendation
[E10] Chemotherapy and clinical trials. Clinical trials of chemotherapeutic regimens in patients with persistent or recurrent MTC have shown limited efficacy, with best responses of partial remission generally in the range of 10–20%, and these responses are short lived. The agents yielding the best results have been dacarbazine, fluorouracil, and doxorubicin (307–313).
‘‘Complementary’’ or ‘‘alternative’’ therapies can include a myriad of ‘‘nontraditional’’ approaches to promote a good attitude and healthy spirit; acupuncture and reflexology; herbs and vitamins; fasting, juicing, and other dietary practices; and nontraditional pharmacologic and biological therapies (314). Some cancer patients find that therapies can relieve some symptoms or side effects, ease pain, and enhance their lives during treatment. Unfortunately, there are no data that they enhance disease-specific survival or disease-free survival.
- RECOMMENDATION 107
The use of standard chemotherapeutic agents should not be considered as first-line therapy for patients with persistent or recurrent MTC given the low response rates and the advent of promising new compounds entering clinical trials and other available treatment options. Grade: D Recommendation
The experience with radio-labeled molecules delivering high radiation dose is limited, but only modest responses have been reported. Iten et al. (251) studied [90Yttrium- DOTA]-TOC in MTC patients with rising Ct levels and tumor uptake on 111In-Octreoscan. Twenty-nine percent of patients demonstrated decreasing Ct levels after therapy. Thirteen percent developed hematologic toxicities and 23% developed renal toxicities. The visual grade of 111In-Octreoscan tumor uptake was not associated with treatment response or survival.
The efficacy of pretargeted radio-immunotherapy with bispecific monoclonal antibody (BsMAb) and a 131I-labeled bivalent hapten has been evaluated (211,315,316). Patients with advanced, progressive MTC (defined by short serum Ct DT) received an anti-CEA=anti-diethylenetriamine pentaacetic acid (DTPA)–indium BsMAb, followed 4 days later by a 131Ilabeled bivalent hapten (315). Overall survival (OS) was compared with contemporaneous untreated MTC patients with comparable prognostic indicators. OS was significantly longer in high-risk, treated patients (Ct DT <2 years) than in high-risk, untreated patients (median OS, 110 v 61 months; p<0.030). Forty-seven percent of treated patients demonstrated a greater than 100% increase in Ct DT. Treated patients with bone or bone-marrow disease had a longer survival than patients without such involvement (10-year OS, 83% vs. 14%; p<0.023). Toxicity was mainly hematologic and related to bone or bone-marrow tumor spread.
Treatment with 131I-MIBG is generally regarded as ineffective for MTC, although some reports have described partial tumor remission or stability, improved symptoms and quality of life, and limited data suggesting prolonged survival (250,317–319).
- RECOMMENDATION 108
Treatment with radio-labeled molecules may be considered in selected patients, ideally in the setting of a well-designed clinical trial. Grade: C Recommendation
Recently, a number of promising agents have been studied in phase I and phase II clinical trials with results presented at national scientific meetings (320–324). Several of these agents have demonstrated significant partial response rates in the range of 20–50% with a larger number of patients demonstrating stable disease. Thus, while these cytostatic agents are unlikely to demonstrate a complete remission, they have the potential to provide high rates of disease control with durable responses and relatively low toxicity. Improved quality of life, such as diminished diarrhea, is also possible. However, it is difficult to make a specific recommendation regarding their use in patients with advanced MTC, since there is little peer reviewed published data and most of these compounds have not been approved by the U.S. Food and Drug Administration. Further, long-term toxicity of these compounds needs to be investigated. Additionally, it is possible that combination therapy with two or more of these targeted agents, or a combination of a targeted agent with conventional cytotoxic chemotherapy will eventually prove more efficacious than a single targeted therapy alone.
- RECOMMENDATION 109
Given the absence of an established effective systemic therapy for patients with advanced MTC, physicians should give high priority to facilitating enrollment of their patients into well-designed clinical trials. Grade: C Recommendation
[E11] Symptoms, evaluation, and treatment of hormonally active metastases. Diarrhea, ectopic corticotropin-releasing hormone (CRH), and ectopic adrenocorticotropic hormone (ACTH) are the main hormonally mediated complications of MTC. Other rare situations include the ectopic production of PTH-related peptide, insulin, and glucagon.
Diarrhea occurs most frequently in the setting of advanced disease, frequently in patients with hepatic metastases. The diarrhea may be hypersecretory (325), or due to enhanced gastrointestinal motility (326), or a combination of both. The diarrhea can be debilitating both in terms of quality of life and nutrition. Therapy with antimotility agents (such as loperamide or codeine) is first-line therapy due to their lowside effects and ease of administration. Treatment with somatostatin analogues and debulking of large tumor deposits have also been employed. Somatostatin analogue therapy for diarrhea hasmostly been reported in this setting in small nonrandomized cohort studies with variable results that may suggest modestly improved symptoms in some patients (327–330). The combination of somatostatin analogs with interferon alpha has been reported in single center studies to improve symptoms of flushing and diarrhea in the majority of patients (331,332), although these findings have not been confirmed by others. Local treatment of large hepatic metastases using selective artery chemoembolization has also been reported in nonrandomized studies (303,304). Fromigue et al. (304) reported that five of their patients had diarrhea, but only two had an objective response. By contrast, Lorenz et al. (303) reported that all six of their patients with diarrhea had improvement.
- RECOMMENDATION 110
Therapy to reduce the frequency and amount of diarrhea in the setting of MTC should be employed. Initial therapy should include antimotility agents. Alternative therapies may include treatment with somatostatin analogues and local therapies such as surgery or chemoembolization in selected cases. Grade: C Recommendation
MTCs can occasionally secrete high levels of bioactive hormones other than Ct that rarely cause clinical manifestations; typically in the setting of metastatic disease that frequently includes large hepatic metastases. The most common of these additional hormonal secretions is ACTH or CRH that can result in Cushing syndrome, which may present with hypokalemia. MTC is reported to account for up to 2–6% of all cases of ectopic Cushing syndrome (333,334). Control of cortisol levels (or action) and clinical manifestations may be achieved by debulking of large hepatic metastases (surgery or chemoembolization), by medical therapy using ketoconazole, mifepristone, aminoglutethimide (335), metyrapone (335), or mitotane (336), and=or by bilateral adrenalectomy (333,334,337–339). Treatment with somatostatin analogs is ineffective. Overall, based on individual case reports or small clinical series, the development of Cushing syndrome from MTC is associated with poor patient survival due to the progressive MTC; however, because Cushing syndrome can be severe and debilitating, treatment should be considered even in the setting of widely metastatic MTC.
- RECOMMENDATION 111
Clinicians should maintain a heightened vigilance for Cushing syndrome due to tumoral production of ACTH and/or CRH from MTC. Grade: C Recommendation
- RECOMMENDATION 112
While MTC patients with Cushing syndrome typically have a poor prognosis, treatment should be considered even in the setting of widely metastatic MTC because the syndrome can be severe and debilitating. Grade: C Recommendation
- RECOMMENDATION 113
Cushing syndrome from MTC may be treated in a multimodality manner with therapy directed towards the tumor and medical therapy directed towards the Cushing Syndrome, or bilateral adrenalectomy. The choice of therapy may depend on multiple factors including the severity and the stability of the MTC and the response of the Cushing Syndrome to medical therapy. However, expert opinion of the Task Force generally favored bilateral adrenalectomy. Grade: C Recommendation