Approaches to Advanced Metastatic Disease (Stage IVC)

APPROACHES TO ADVANCED METASTATIC
DISEASE (STAGE IVC)

Figure 4 illustrates the approach to patients with metastatic disease. Establishing the overall goal, ranging from aggressive therapy to supportive care, allows the patient care team to initiate and monitor subsequent therapy in a manner understandable to the patient and family members.

Figure 4

View Larger Image

FIG. 4.  After initial evaluation and staging, patients who present with distant metastases should decide whether to pursue aggressive therapy or supportive care, which may include palliative procedures. §IMRT is preferred if possible.

Defining therapeutic goals, expected or possible adverse events, appropriate expectations, and limits of care

Patients with metastatic ATC almost uniformly have short survival and no prospects for curative outcome. Moreover, the use of aggressive approaches in metastatic ATC has never been definitively shown to improve survival. These factors combine to make it imperative that the formulation of treatment plans in patients with metastatic ATC be undertaken only after careful discussions of the expected risks and benefits of available palliative active therapies versus those expected from hospice/best supportive care approaches. In this setting, resuscitation/code status should be established and Advance Directives procured early on. Please refer to the section Establishing Treatment Goals for additional discussion of these important topics.

Timing of systemic therapies

The administration of cytotoxic and/or targeted systemic therapies in metastatic ATC has never been definitively shown to have curative potential or to improve survival or quality of life. In advanced disease, decisions related to the timing of administration of systemic therapies relative to palliative focal therapies depend greatly on the specifics of the case. In general, if a patient has symptomatic or imminently threatening focal disease that can be treated with focal measures (e.g., radiation therapy) then systemic therapy should follow, and not precede, focal therapy. If diffuse disease progression instead poses the primary threat, systemic therapy should be considered as an alternative to palliative locoregional therapies that otherwise neglect the bulk of disease and imminent global threat to the patient. Additionally, as the rate of disease progression in ATC tends to be very fast, delaying consideration of systemic therapy in ATC if desired by the patient is generally unwise because such a delay may be met with disease progression sufficient to make the patient less tolerant or unsuitable for later systemic therapy. Because inclusion criteria for clinical trials tend to be rigid, clinical trials—if suitable and desired by the patient—should be considered earlier on; however, initiation of systemic therapy if desired and suitable for a particular patient should be expeditious.

  • RECOMMENDATION 42 Palliation of symptomatic and/or imminently threatening lesions should be given high priority in comparison to treatment with systemic therapy unless the primary threat to the patient is diffuse disease progression.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

Approaches to systemic disease (cytotoxic)

There are no randomized trial data to conclusively demonstrate that survival is prolonged or quality of life improved in ATC patients in response to treatment with systemic therapy. Nonetheless, tumor regression can be induced in response to systemic therapies in some ATC patients, with anecdotal and nonrandomized study evidence supporting its use in selected patients as summarized in the following subsections. Risks and potential benefits must be carefully considered in the context of each patient in individualizing care in accord with patient directives.

Taxanes. A multicenter clinical trial conducted by Ain et al. (185) demonstrated that the taxane paclitaxel administered weekly or every 3 weeks resulted in transient disease regression in 53% of 19 evaluable patients, with anecdotal evidence suggestive that weekly therapy may be superior to 96-hour infusional therapy every 3 weeks. However, reported dosages of paclitaxel (225 mg/m2 intravenously [IV] weekly) were incorrect (personal communication from author Dr. Kenneth Ain) since paclitaxel dosages should instead be 60–90 mg/m2 IV weekly to assure safety. Moreover, criteria for response in this trial required maintenance of response for only 2 weeks, rather than the typical 4 weeks utilized in the National Cancer Institute RECIST criteria, making study results difficult to interpret in the context of studies using RECIST response criteria. Although survival data are reported, the trial was not randomized or case-controlled, so the full impact of paclitaxel therapy on survival remains difficult to accurately assess.

Anecdotal experience, however, suggests that single agent paclitaxel can have disease-modifying effects in some patients [as indicated by Ain et al. (185)] and may impact survival in a subset of treated patients. Further, a recent report indicated also that the taxane docetaxel at a dosage of 60 mg/m2 IV administered as a single agent every 3 weeks can occasionally even produce CRs—but more commonly stabilize disease for a time (188). In this study, one of seven patients had CR lasting 50 weeks, but median time to progression was only 6 weeks.

Anthracyclines and platins. Doxorubicin, 20 mg/m2 IV weekly or 60–75 mg/m2 IV every 3 weeks has also been used in advanced ATC, and it is the only cytotoxic chemotherapy specifically approved by the U.S. Food and Drug Administration for use in ATC. Published studies of the application of doxorubicin in ATC, however, generally discuss its use in combination with surgery and radiotherapy, making assessment of response rates and impact on survival uncertain in advanced disease (166,190). However, in a trial conducted by the Eastern Cooperative Oncology Group (191) from 1976 to 1982, 84 patients with advanced progressive thyroid cancer of all histotypes (not specifically ATC) were randomized to receive doxorubicin alone (60 mg/m2 IV every 3 weeks) or doxorubicin plus cisplatin (60 mg/m2 IV doxorubicin, 40 mg/m2 cisplatin IV every 3 weeks). In 39 patients with ATC on this study, doxorubicin alone produced no CRs and one PR in 21 treated ATC patients, while doxorubicin plus cisplatin yielded three each CRs and PRs of 18 treated ATC patients (PR+CR: 5% vs. 33%; p<0.03). Median survival in ATC was only 2.7 months, but two responses to doxorubicin plus cisplatin were durable at 41.3 and 34.7 months, suggesting a possible impact on survival in select patients with ATC.

First-line therapy. At the time of the formulation of these guidelines the agents with the greatest established clinical activity in metastatic ATC are the taxanes paclitaxel or docetaxel, the anthracycline doxorubicin, and perhaps also platins. None of these agents, however, have proven ability to extend survival or quality of life in advanced ATC. Depending upon the directives of a particular patient and patient characteristics that might otherwise affect decision making, first-line therapy in advanced ATC could reasonably include these drugs as single agents or alternatively in combination. Alternatively, a clinical trial should be considered if available. Table 6 provides examples of chemotherapy regimens in advanced ATC.

TABLE 6. EXAMPLES OF CHEMOTHERAPY REGIMENS IN ADVANCED ANAPLASTIC THYROID CARCINOMA

Regimen Agents/dosages Frequency
Paclitaxel/carboplatin Paclitaxel 60–100 mg/m2, carboplatin AUC 2 mg/m2 IV Weekly
Paclitaxel/carboplatin Paclitaxel 135–175 mg/m2, carboplatin AUC 5–6 mg/m2 IV Every 3–4 weeks
Docetaxel/doxorubicin Docetaxel 60 mg/m2 IV, doxorubicin 60 mg/m2 IV (w/pegfilgrastim)
or
Every 3–4 weeks
  Docetaxel 20 mg/m2 IV, doxorubicin 20 mg/m2 IV Weekly
Paclitaxel Paclitaxel 60–90 mg/m2 IV Weekly
Paclitaxel Paclitaxel 135–200 mg/m2 IV Every 3–4 weeks
Doxorubicin Doxorubicin 60–75 mg/m2 IV Every 3 weeks
Doxorubicin Doxorubicin 20 mg/m2 IV Weekly

 

Second-line or salvage therapy. Similarly, no prospective data are available to guide decision making in choosing second-line or subsequent salvage systemic therapy in advanced ATC. Consequently, patient directives or preferences and the prior response data in a particular patient should heavily inform decision making. For instance, should a particular patient respond especially well to first-line paclitaxel therapy but progress, consideration could be given to salvage therapy using another anti-microtubule agent (e.g., ixabepilone, combretastatin/crolibulin on a clinical trial). However, since no prospective data are available to guide second-line therapy, strong consideration should be given to enrollment in clinical trials.

Approaches to systemic disease (novel or investigational)

Unfortunately, there are no systemic therapeutics (cytotoxic, novel, targeted, or otherwise) of proven benefit in terms of improved survival and/or quality of life in advanced ATC. Consequently, there is critical need to develop novel systemic therapeutic approaches, and all patients wishing an aggressive approach to their cancer who are of sufficient vigor and performance status should therefore be considered as candidates for therapeutic clinical trials. However, suitable trials may not always be available to or practical for a particular patient, justifying use of available therapeutics in the non–study setting in some circumstances.

A number of novel agents have been preliminarily studied in ATC. Fosbretabulin, a prodrug of the investigational antimicrotuble disrupting agent combretastatin, was assessed in a phase II trial in ATC, producing no PRs or CRs in ATC patients. However, stable disease was seen in 7 of 26 patients with a median survival of 4.7 months and 23% of patients surviving 1 year (192). Its parent compound, combretastatin, has also shown preliminary activity anecdotally in a single ATC patient treated in a phase I trial of the agent (192,193), with a related compound, crolibulin, also being evaluated in ongoing clinical trials in ATC. Sorafenib, a multitargeted tyrosine kinase inhibitor that weakly inhibits the BRAF gene product and more potently inhibits angiogenesis via inhibition of vascular endothelial growth factor receptors has also been assessed in a small number of ATC patients in two recent phase II clinical trials, with no RECIST responses seen in six treated patients (194,195). Likewise, in a trial of all thyroid cancer histotypes, the tyrosine kinase inhibitor axitinib also yielded no responses in two treated ATC patients (196). Gefitinib, an epidermal growth factor receptor–targeted kinase inhibitor similarly produced no responses in five treated ATC patients although one had stable disease for 12 months (197). However, in a trial of the kinase inhibitor imatinib, two of eight evaluable patients attained a partial response, with stable disease reported in an additional four patients; 6-month progression-free survival was 36% with 6-month overall survival somewhat encouraging at 45% (198). These preliminary data suggest that novel antimicrotubule inhibitors and kinase inhibitors may ultimately find application as useful ATC therapeutics.

  • RECOMMENDATION 43 Since systemic therapy can result in transient, and occasionally more durable, disease regression or control in patients with advanced ATC and may improve survival in responders, it can reasonably be considered in patients with metastatic ATC of good performance status wishing an aggressive approach.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

  • RECOMMENDATION 44 Patients with advanced or metastatic ATC wishing an aggressive approach should be encouraged to participate in clinical trials given the rarity of ATC, lack of data in support of improved survival or quality of life from any systemic therapeutics, and the need to develop evidence-based safe and effective therapeutic approaches in advanced ATC.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

  • RECOMMENDATION 45 Combination or monotherapy including a taxane and/or an anthracycline could be considered in metastatic ATC if a suitable clinical trial is not otherwise available.
       Strength of Recommendation: Strong
       Quality of Evidence: Moderate

  • RECOMMENDATION 46 Since aggressive tumor-directed therapy may not be desired by or appropriate for all patients with metastatic ATC, consideration of best supportive care or hospice should also be prominently discussed as an alternative to systemic cancer-directed therapy.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

Systemic therapy: what is next?

As anthracyclines (doxorubicin) and taxanes (paclitaxel, docetaxel) have at least some degree of clinical activity in advanced ATC, first-line ATC therapeutic clinical trials could reasonably include one of these agents so as to assure that use of a potentially effective therapy is not withheld or delayed. In this respect, two-arm trial designs comparing doxorubicin or paclitaxel alone to paclitaxel or doxorubicin combined with another candidate ATC therapeutic (showing evidence of preclinical synergy) have particular appeal. Available but sparse preclinical data suggest that agents targeting angiogenesis, mutant p53, EGFR, aurora kinases, and PPARγ among others may represent reasonable candidate agents to consider in the salvage setting, perhaps especially when combined with cytotoxic chemotherapy.

Approaches to brain metastases

Brain metastases are relatively unusual in ATC, occurring in 1%–5% of patients clinically, but they are associated with a poor prognosis (14,15,101,199). Chiu et al. (200) studied 47 cases of all types of thyroid cancer that had been metastatic to the brain. Brain metastases were most commonly detected during the monitoring of the patient after the original diagnosis of thyroid cancer, and brain metastases were the initial manifestation of thyroid cancer in 15% of patients. Patients with brain metastases tended to be older and had more aggressive disease and accounted for 11 of the 47 patients (23%) that had ATC. Among the ATC patients with brain metastases, 56% had local regional invasion and 89% had locoregional cervical node involvement. The median time interval from the diagnosis of ATC to the diagnosis of brain metastases was 0.7 years, and the median time interval from diagnosis of brain lesions to death was 1.3 months. Disease-specific mortality was 100%. Salvati et al. (199) reported solitary brain metastases in 12 patients with thyroid cancer, five of whom had ATC. Four of five patients with ATC had lung and/or brain metastases, and median size of brain metastases in the ATC patients was 4 cm. All patients were treated with surgical removal and radiotherapy. The median survival of the five patients with ATC was 9 months (individual survival in months: 7, 8, 9, 10, 10).

Brain MRI and CT scans are more sensitive in detecting lesions than PET scans, with some evidence suggesting that brain MRI is more sensitive than CT scan (199,201).

  • RECOMMENDATION 47 Patients considering therapy should have radiologic studies (MRI or CT scan) assessing the presence of brain metastases when ATC is diagnosed. Additional radiologic studies of the brain are indicated in the context of progressive disease and/or neurological abnormalities suggesting the development of a brain lesion or change in character or size of a known brain lesion.
       Strength of Recommendation: Strong
       Quality of Evidence: Moderate

Salvati et al. (199) found a statistically significant improvement in survival (p=0.03) in ATC patients undergoing total removal of brain metastases as compared with patients undergoing subtotal removal. However, the number of patients studied was small, being three for total removal (survival 9, 10, and 10 months) and two for subtotal removal (survival 7 and 8 months). Surgical treatment resulted in improvement in quality of life and improvement in neurological symptoms. Sample size was very small and selection bias may be a significant issue in this study; therefore, these data must be interpreted carefully.

There are insufficient data to make a recommendation for or against Gamma Knife therapy in patients with ATC and metastases (200). Single small solitary brain metastases can be treated with radiosurgery such as Gamma Knife or undergo surgical resection. To be considered carefully in the decision-making process, however, is whether other systemic disease is imminently threatening coupled with consideration of the goals of the patient. Multiple lesions should instead be treated with whole-brain radiation therapy.

  • RECOMMENDATION 48 Surgical removal of brain lesion(s) in selected patients and/ or radiation therapy may result in better disease control.
       Strength of Recommendation: Weak
       Quality of Evidence: Low

There is evidence that tyrosine kinase inhibitors are capable of crossing the blood–brain barrier, but there are insufficient studies to indicate that these agents are effective in treating brain metastases from ATC or whether they may be detrimental by causing increased risk of bleeding in brain metastases (202,203).

There are no prospective, randomized clinical studies assessing the role of exogenous corticosteroid administration in patients with brain metastases from ATC. Therefore, recommendations are extrapolated from studies or guidelines regarding other tumors that have metastasized to the brain.

Ryken et al. (204) published guidelines for patients with brain metastases from a variety of different tumors. They noted there was insufficient evidence to recommend that patients with asymptomatic brain metastases without mass effect receive exogenous corticosteroids routinely. However, they recommended that patients with brain metastases with mass effect causing mild symptoms receive corticosteroids to attempt to give partial relief of cranial symptoms associated with increased intracranial pressure and edema. They recommended 4–8 mg/d of dexamethasone be considered as the initial dose. Patients with moderate to severe cranial symptoms should be considered to receive 16 mg/d (generally 4 mg, 4 times daily) (204). Dexamethasone is considered the preferred corticosteroid therapy in these circumstances. Dexamethasone should be tapered slowly over 2 weeks, but there should be individualization in that longer periods of dexamethasone can be considered in patients with severe disease who remain symptomatic. It is recommended that there be discussion of the long-term issues regarding corticosteroid administration. There are insufficient studies to render specific recommendations for patients regarding metastatic ATC to the brain. However, it is presently believed that the pathophysiology, approach, and treatment of brain metastases from any cause are similar and that similar treatment recommendations would apply.

  • RECOMMENDATION 49 Neurologically asymptomatic patients with brain metastases do not routinely require exogenous corticosteroid administration. Patients with neurologic brain compressive symptoms or signs should preferably receive dexamethasone (or alternatively a glucocorticoid equivalent) at appropriate doses. Individual patient considerations should apply with regard to the initiation, dose, and duration of exogenous corticosteroid administration.
       Strength of Recommendation: Strong
       Quality of Evidence: Moderate

Mikkelsen et al. (205) provided guidelines that did not recommend routine prophylactic use of antiseizure medications for adult patients with brain metastases that have not yet had a seizure. There is a paucity of relevant controlled studies. A single underpowered randomized controlled trial did not detect a statistically significant difference in seizure activity in patients who prophylactically received antiseizure medication and those that did not (206).

  • RECOMMENDATION 50 It is not recommended that patients with brain metastases from ATC routinely receive prophylactic antiseizure medications.
      Strength of Recommendation: Weak
      Quality of Evidence: Low

Approaches to bone metastases

ATC does metastasize to bone (5%–15% of cases), usually in the presence of multiple other sites of distant metastases (14,15,101,207). Tickoo et al. (207) studied 79 patients with a variety of different types of thyroid cancer who had osseous metastases. Ten (four men, six women; mean age at bone metastasis 58.1 years) of these 79 patients had anaplastic cancer (five were solely undifferentiated and five also had a well-differentiated component). All 10 patients with ATC had died within 3.8 years of the diagnosis of osseous metastases, and 6 of the 10 patients who had ATC died within the first year. The median survival of the 10 patients with ATC was 0.55 years. Lam et al. (59) studied 38 patients with ATC (7 men, 31 women), mean age 70 years (range 15–93 years). Eighteen patients had distant metastases, five of whom had osseous metastases. The five patients with osseous metastases ranged in age from 15 to 87 years and died 1 day after admission to 10 months after diagnosis. Pittas et al. (208) retrospectively reviewed 146 patients with thyroid cancer and bone metastases. Ten of these patients had undifferentiated cancer; their median survival was less than a year, and 3-year survival was 20%.

Given the paucity of studies regarding the diagnosis and treatment of osseous metastases in patients with ATC, it is reasonable to consider relevant recommendations in patients with cancers with more frequent osseous metastases. In this regard, there are three primary issues: (i) how to best treat symptomatic and/or threatening bony metastases, (ii) how to optimally undertake surveillance for additional metastases, and (iii) the role of systemic agents in preventing or slowing bony metastases.

With regard to therapy for symptomatic or threatening bony metastases, surgery or radiotherapy can be considered depending upon the situation. In general, radiation therapy is preferred in ATC unless surgery is absolutely required to preserve function (e.g., imminently threatening spinal cord compression, pathological long bone fracture). The generally dire prognosis for ATC lessens enthusiasm for aggressive surgical palliation, if avoidable. Newer approaches to palliation of bony metastases such as cryoablation may have a role also, but have been largely unexplored to date.

With regard to systemic therapy related to bony metastases, there are no available data specific to ATC. Nonetheless, Aapro et al. (209) reported the recommendation of an international committee related to systemic therapy for bony metastases for solid tumors in general. They reviewed the literature and noted that bisphosphonates are effective in preventing, inhibiting, and delaying cancer-associated skeletal complications. In summary, the committee recommended intravenous zolendronic acid therapy for patients with osseous metastases from solid tumors. Intravenous as opposed to oral bisphosphonates are preferred because data are largely unavailable on the roles of oral bisphosphonates in bone metastases. Patients must have recent (e.g., within 2–3 days) renal function and calcium assessments and routine initial and monitoring dental examinations with consideration of osteonecrosis as an infrequent adverse effect. Hortobagyi et al. (210) demonstrated that monthly IV infusion of pamidronate in patients with osseous metastases from breast cancer increased the time to the initial skeletal complication and decreased the percentage of patients with skeletal complications. Zolendronic acid was associated with decreased skeletal complications in six patients with osseous metastases from thyroid cancer (209). The mechanisms of bone metastases occurring and propagating are complex but may be similar in different diseases (211,212).

Bisphosphonates, especially given intravenously, have potential side effects that include an acute-phase reaction and posttherapy bony pains, hypocalcemia, and rarely osteonecrosis of the jaw. There is also a risk of atypical femoral fractures (213), but this risk is small compared to benefits in patients with bony metastases. Bisphosphonates should be administered cautiously to patients with renal disease and should not be administered to patients with a creatinine clearance 35 mL/min or less or to patients with hypocalcemia, vitamin D deficiency, or a history of allergy to bisphosphonates (213). Bisphosphonate dosage should also be corrected based upon renal function and dosages held for hypocalcemia.

Denosumab, an inhibitor of receptor activator of nuclear factor B ligand (RANK ligand) is also effective in decreasing skeletal events in patients with osseous metastatic cancer and in some settings is more effective than intravenous bisphosphonates (214). Complications of the two classes of agents are relatively similar (214). At present, there are insufficient published studies specifically regarding ATC to substantiate its use in this disease, but the mechanisms of bone metastasis development and progression may be similar in various diseases.

Once bony metastases are noted, surveillance for additional metastases becomes important. Priority should be given to detection of threatening lesions where they can do the greatest harm—most often spine, long bones, and related areas (e.g., acetabulum). Imaging techniques are constantly evolving, and the most sensitive and specific method to diagnose osseous metastases will vary with the individual tumor involved, the osseous site of metastases, whether the patient is symptomatic and if a specific area is being considered, or whether the purpose of the study is for screening the skeleton in a patient with a high likelihood of osseous metastases (208,215–217). Given these caveats, a skeletal survey with plain radiographs to include long bones may be used to screen the skeleton. ATC osseous lesions are mainly osteolytic in nature. Since 99mTc methylene diphosphonate mainly detects osteoblastic lesions, this technique has less sensitivity and specificity than other available radiologic techniques (217). MRI and CT scans are excellent for identifying bone lesions in a specific site but are less useful for general skeletal screening, although whole body MRI is a newer technique (215). CT scans combined with 18FDG PET scans are very helpful in identifying osseous lesions and screening the skeleton but are expensive (215).

Bone metastases causing pain can be effectively alleviated with a course of palliative radiotherapy, typically performed over 1–2 weeks with 5–10 equal daily fractions of 300–400 cGy to a total dose of 2000–3000 cGy. A single fractionation of 800 cGy may also be appropriate. In the setting of metastases involving weight-bearing bones, orthopedic fixation of fracture due to metastasis should be considered. Long bone fractures most commonly involve the femur and humerus and are typically first internally fixed by intramedullary devices that control impaction, distraction, and stress by the use of proximal and distal interlocking fixation devices (218,219). These techniques allow weight-bearing ambulation. Palliative radiotherapy can be administered after orthopedic fixation to further promote pain relief without the fear of exacerbating the fracture. A similar concept is also seen with decompressive surgical intervention in the setting of spinal cord compression caused by metastatic cancer. A recent randomized trial has shown that direct decompressive surgery plus postoperative radiotherapy is superior to radiotherapy alone in the treatment of spinal cord compression secondary to metastatic disease (218,219).

  • RECOMMENDATION 51 Patients with ATC who during the course of monitoring and treatment have skeletal symptoms, such as pain or pathologic fracture, should have radiologic evaluation of the specific area of concern. If there is proven osseous metastasis at a single specific site, radiologic evaluation of the skeleton may be performed to identify other sites of bony metastases.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

  • RECOMMENDATION 52 It is reasonable to treat osseous metastases from ATC in a comparable manner to patients with other aggressive tumors causing osseous metastases with emphasis on radiotherapy and/or surgery. Metastatic lesions to the bone should be considered for palliative radiotherapy. If the lesions are in a weight-bearing region, orthopedic fixation should be considered prior to initiation of palliative radiotherapy.
       Strength of Recommendation: Strong
       Quality of Evidence: Low

  • RECOMMENDATION 53 Patients with known osseous metastases from ATC should be considered for periodic intravenous bisphosphonate infusions or subcutaneous RANK ligand inhibitor. Given the lack of data, it is not possible to make a definitive recommendation regarding the frequency and duration of these treatments.
       Strength of Recommendation: Weak
       Quality of Evidence: Low

Approaches to other sites of metastases

Thyroid cancers including ATC can metastasize to any site, and therapy needs to be individualized to metastatic locations, much as would be the case for other malignancies. Several additional "special cases" related to metastatic sites also deserve comment, including lung, liver, and skin.

Lung metastases are quite common in advanced ATC. Unfortunately, most patients with lung metastases have numerous metastases that cannot be effectively resected or treated with stereotactic radiation approaches. However, some patients develop symptomatic metastases to pleura or chest wall that can be palliated using radiotherapy. Occasionally, central mediastinal nodal metastases arise that compress bronchi and threaten postobstructive pneumonia. Under such circumstances, palliative radiotherapy should be considered. Endobronchial lesions causing hemoptysis can be palliated using endobronchial therapy such as laser or by radiotherapy.

Liver metastases in ATC are often numerous, similarly making directed therapy impractical in most patients. In rare situations, however, patients can develop a few liver metastases in the absence of other threatening systemic disease. As in other cancers metastatic to liver, focal palliation with radiofrequency ablation or stereotactic body radiosurgery can be considered in such patients.

Thyroid cancer metastases to skin are rare. Dahl et al. (220) reported 43 patients with skin metastases from thyroid cancer (all types). Papillary thyroid cancer accounted for 41%, follicular cancer 28%, ATC 15%, and MTC 15%. Given its rarity compared to the other types, it would appear that ATC has a greater tendency to metastasize to cutaneous sites than the other types of thyroid cancer. The scalp was the most common site of cutaneous metastases (220). The vast majority of patients with cutaneous metastases had known disseminated thyroid cancer. Capezzone et al. (221) reported a single patient that had cutaneous metastases from ATC 4 months after thyroidectomy, and these cutaneous metastases were the first sign of distant disease.

Cutaneous metastases should be approached in the customary manner by FNA, core biopsy, or preferably excisional biopsy or removal if feasible with appropriate histologic examination and stains. All patients with ATC should have a periodic skin examination with special attention to areas of patient concerns. The treatment of cutaneous metastases depends on the clinical situation. If the cutaneous abnormality occurs in the setting of known widespread metastases, it may not be necessary to biopsy or remove the lesion. If the lesion represents an initial presentation or initial recurrence, a biopsy is required for a diagnosis. Excisional biopsy of the lesion is usually considered adequate treatment for the cutaneous manifestation.

Utility of cryoablation and selective embolization

Cryoablation is the application of low temperatures to a specific area of abnormal or cancerous tissue. There are insufficient reports to allow a definitive conclusion as to the role of cryoablation, radiofrequency ablation, and embolization in patients with ATC. Dedecjus et al. (222) and Tazbir et al. (223) reported the utility of selective embolization of thyroid arteries in a total of 20 patients with thyroid cancer, seven of whom had ATC. Embolization was considered for patients with inoperable local disease with symptoms. Six patients with ATC had improvement in respiration, four had decreased local discomfort, two had disappearance of stridor, and two patients had decreased local tumor bleeding.

  • RECOMMENDATION 54 A definitive recommendation regarding cryoablation, radiofrequency ablation, and selective embolization in patients with ATC cannot be made.
       Strength of Recommendation: Weak
       Quality of Evidence: Insufficient

Approach to thrombosis and/or tumor invasion into vasculature

Seo et al. (224) studied 84 patients with 86 malignant thyroid tumors (of all types), each of whom had extracapsular extension. CT evaluation was able to identify invasion of the common carotid with a sensitivity of 75% and accuracy of 98.8% and of invasion of the internal jugular vein with a sensitivity and accuracy of 33.3% and 97.1%, respectively. Panzironi et al. (225) used ultrasound to diagnose bilateral jugular vein thrombosis in a patient with ATC who had superior vena cava syndrome. Sugimoto et al. (226) also reported a patient with ATC that extended locally as well as into the left internal jugular vein, bilateral brachiocephalic veins, superior vena cava, and right atrium. CT and MRI demonstrated these abnormalities. Intra-atrial extension via the superior vena cava is rare, being reported in about 13 cases. Surgical removal of the tumor thrombus was attempted in six cases, generally with poor outcomes.

  • RECOMMENDATION 55 Tumor invasion into cervical veins can be diagnosed by CT, MRI, or venogram in the appropriate clinical context. There are insufficient data available to recommend either monitoring or a specific therapy such as surgery or radiation therapy for vascular tumor invasion.
       Strength of Recommendation: Weak
       Quality of Evidence: Low

In general, patients with various cancers are at higher risk for thrombosis (227). Relative indications for prophylactic anticoagulation include prolonged surgery, chemotherapy, long-term in-dwelling central venous lines, or prolonged immobility (227). The American Society of Clinical Oncology Guidelines (227) do not recommend prophylactic anticoagulation routinely in cancer patients who are ambulatory, with the notable exception of patients receiving thalidomide or lenalidomide. Hospitalization is considered an indication for prophylaxis for venous thromboembolism if the patient does not have active bleeding or other relevant contraindications. Major surgery is thought to be an indication for pharmacologic thromboprophylaxis. Patients with established venous thromboembolism should generally be treated with low molecular weight heparin with consideration of the individual context (227). There are inadequate studies assessing systemic anticoagulation in patients with ATC to form specific conclusions.

  • RECOMMENDATION 56 Consider prophylactic anticoagulation in patients who are at high risk for thromboembolic disease such as major surgery or receiving pertinent chemotherapy (specifically including thalidomide or lenalidomide).
       Strength of Recommendation: Strong
      Quality of Evidence: Moderate

  • RECOMMENDATION 57 Patients with documented venous thromboembolism should generally be treated with low molecular weight heparin with specific consideration of the individual context.
       Strength of Recommendation: Strong
       Quality of Evidence: High