Treatment of Thyroid Cancer
Because most thyroid nodules are not malignant, it is important to differentiate malignant from benign lesions to determine which patients should undergo surgery. If the cytologic result from FNA biopsy indicates that the nodule is benign, which is the case most of the time, the nodule can be safely monitored.
Malignant or indeterminate cytologic features are the main indications for surgery.
Differentiated thyroid cancer. If the cytologic result shows a malignant lesion, a total or near-total thyroidectomy should be performed if any of the following are present: a primary lesion larger than 1 cm, contralateral thyroid nodules, regional or distant metastases, personal history of radiation therapy to the head or neck, or a first-degree family history of differentiated thyroid cancer. There is significant debate in the literature regarding the extent of thyroid surgery for primary tumors confined to one lobe and for tumors that are small and of low-risk potential for recurrence. The surgical options include total lobectomy, total lobectomy with contralateral subtotal lobectomy (subtotal thyroidectomy), or total thyroidectomy. The decision about which procedure to perform should be based on the risk of local recurrence and the anticipated use of radioactive iodine(Drug information on iodine) (see section on "Radioactive I-131").
Most authorities agree that a low-risk patient (age < 45 years) with a 1-cm or smaller papillary thyroid cancer should undergo ipsilateral total lobectomy alone. Most experts also agree that total thyroidectomy (or at least subtotal thyroidectomy) is appropriate for high-risk patients with high-risk tumors. Intermediate-risk patients are treated with total lobectomy alone or total (or subtotal) thyroidectomy plus postoperative radioactive iodine. Preoperative neck imaging may be helpful in planning the surgery. Patients with radiation-induced thyroid malignancies can be treated similarly, because their cancers have a similar prognosis; however, a total thyroidectomy may be preferable in these patients because of the increased risk of multicentric tumors.
For multinodular glands with a single nodule positive for differentiated thyroid cancer, the surgical approach would include total thyroidectomy. A lobectomy may be considered in some instances if other nodules are benign or if it is the patient's preference.
The neck should be palpated intraoperatively. If positive nodes are found, a regional lymph node dissection should be performed.
Medullary carcinoma. Patients with medullary thyroid cancer should be treated with total thyroidectomy and central neck dissection. If there is involvement of the lateral neck nodes found on imaging or on clinical examination, a modified neck dissection should be performed (see section on "Lymph node dissection"). If the cancer is confined to the thyroid gland, the patient is usually cured. Postoperative adjuvant external irradiation may be used in certain circumstances (see section on "External radiation therapy").
Anaplastic carcinoma. A tracheostomy often is required in patients with anaplastic thyroid cancer because of compression of the trachea. If the tumor is confined to the local area, total thyroidectomy may be indicated to reduce local symptoms produced by the tumor mass. Radiation therapy is used to improve locoregional tumor control, often together with radiosensitizing chemotherapy.
Indeterminate or suspicious nodule
Indeterminate and suspicious FNA samples should be treated as possible cancers and should be histologically evaluated. The initial operation performed in most patients should be total lobectomy, which entails removal of the suspicious nodule, hemithyroid, and isthmus. There is no role for nodulectomy or enucleation of thyroid nodules. The specimen can be sent for frozen-section analysis during surgery. If the frozen section is clearly benign, no further resection is required.
Follicular lesion. If frozen-section biopsy results indicate a follicular lesion in a patient who is a candidate for total thyroidectomy and a decision cannot be made as to whether the lesion is benign or malignant, two options are available: (1) stop and wait for final confirmation of the diagnosis, which may require a future operation; or (2) proceed with subtotal or total thyroidectomy, which obviates the need for a later operation. The diagnosis of follicular carcinoma requires identification of vascular or capsular invasion, which may not be evident on frozen-section biopsy.
Hürthle cell carcinoma. If the nodule is diagnosed as a Hürthle cell carcinoma, total thyroidectomy is generally recommended for all large (> 4 cm) invasive lesions. Small lesions can be managed with total lobectomy. However, controversy remains over the optimal treatment approach for this cancer.
Lymph node dissection
Therapeutic dissection. Therapeutic central neck node dissection should be performed for medullary carcinomas and other thyroid neoplasms with nodal involvement by palpation or preoperative imaging. The dissection should include all the lymphatic tissue in the pretracheal area and along the recurrent laryngeal nerve and anterior mediastinum. If there are clinically palpable nodes in the lateral neck, a modified neck dissection is performed.
Prophylactic dissection. There is no evidence that performing prophylactic neck dissection improves survival. Therefore, aside from patients with medullary thyroid cancer, who have a high incidence of involved nodes, only therapeutic neck dissection is indicated.
Removal of individual abnormal nodes. "Berry picking" is not advised when lateral neck nodes are palpable because of the likelihood of missing involved nodes and disrupting involved lymphatic channels.
Metastatic or recurrent disease
Survival rates from the time of the discovery of metastases (lung and bone) from differentiated thyroid cancer are less favorable than those associated with local recurrence (5-year survival rates of 38% and 50%, respectively). Survival also depends on whether the metastatic lesions take up I-131.
Surgery, with or without I-131 ablation (discussed below), can be useful for controlling localized sites of recurrence. Approximately half of patients who undergo surgery for recurrent disease can be rendered free of disease with a second operation.
Uses in papillary or follicular thyroid carcinoma
There are two basic uses for I-131 in patients with papillary or follicular thyroid carcinoma: ablation of normal residual thyroid tissue after thyroid surgery and treatment of thyroid cancer, either residual disease in the neck or metastasis to other sites in the body. It should be emphasized that patients with medullary (in the absence of a concomitant epithelial cell-derived differentiated thyroid cancer), anaplastic, and most Hürthle cell cancers do not benefit from I-131 therapy.
Postoperative ablation. Postoperative ablation of residual thyroid tissue should be considered in high-risk patients and patients with high-risk tumors. Ablation of residual normal thyroid tissue allows for the use of I-131 scans to monitor for future recurrence, possibly destroys microscopic foci of metastatic cancer within the remnant, and improves the accuracy of thyroglobulin monitoring.
Ablation must also be accomplished in patients with regional or metastatic disease before the use of I-131 for treatment, because the normal thyroid tissue will preferentially take up iodine compared with the cancer. Some states permit the use of I-131 for ablation and treatment on an outpatient basis, but administration is strictly governed by national guidelines, which minimize the risk of radiation exposure to the public.
Following surgery, the patient can be treated with liothyronine(Drug information on liothyronine) (Cytomel) for 2 weeks. The TSH level should be determined approximately 4 to 6 weeks after surgery; in patients who undergo total or subtotal thyroidectomy, TSH levels will generally be greater than 50 μU/mL. A postoperative iodine scan can then be performed. If this scan documents residual thyroid tissue, an ablative dose of I-131 should be given. The patient should be advised not to undergo any radiographic studies with iodine during ablation therapy and to avoid seafood and vitamins or cough syrups containing iodine. Patients are prepared with a specific diet before the I-131 therapy. Iodine-123 may also be used in the postoperative setting. It may produce a better-quality image than I-131 scans.
For patients who have contraindications for thyroid hormone withdrawal, administration of rhTSH is an alternative for preparation for radioiodine ablation of a post-surgical thyroid remnant. Currently, there are no long-term data ascertaining the maintenance of a low tumor recurrence rate using rhTSH, which may have a quality-of-life advantage compared with thyroid hormone withdrawal and is the subject of a clinical trial.
In general, doses of I-131 up to 75 to 100 mCi will ablate residual thyroid tissue within 6 months following ingestion. In some patients, it may take up to 1 year for complete ablation to occur. Patients should be monitored following ablation, and when they become hypothyroid, hormone replacement therapy should be given until they are clinically euthyroid and TSH is suppressed. Recently, lower doses have been found to be effective, and some authors have recommended doses between 25 and 50 mCi, assuming they achieve euthyroid levels with TSH suppression to less than 0.1 μU/mL.
Approximately 6 to 12 months after ablation of the thyroid remnant, a follow-up I-131 scan should be performed. Recombinant human thyrotropin alfa (Thyrogen) is now available. Patients may continue on thyroid replacement and receive two doses of thyrotropin before I-131 scanning; this approach can prevent the symptoms of hypothyroidism.
Sidebar: A large, multicenter, 2-by-2, randomized, noninferiority trial that compared low-dose radioiodine (30 mCi, 1.1GBq) and high-dose radioiodine (100 mCi, 3.7 GBq) as well as thyrotropin alfa administration versus thyroid hormone withdrawal for patients with differentiated thyroid cancer (excluding extracervical metastatic disease) was recently published. Noninferiority in successful ablation, as measured by negative scan and thyrotropin level, was found, demonstrating less toxicity with the lower doses of radioiodine (Mallick U et al: N Engl J Med 366:1674–1685, 2012). At the same time, another randomized, 2-by-2 phase III trial in a similar group of differentiated thyroid cancers showed similar results (Schlumberger M et al: N Engl J Med 366:1663–1673, 2012). This also raises the issues of whether any radioiodine therapy is required for low-risk patients, as noted in the accompanying editorial (Alexander EK et al: N Engl J Med 366:1732–1733, 2012).
Treatment of residual cancer. For disease in the tumor bed or lymph nodes that was not surgically resectable, an I-131 dose of 100 to 150 mCi is given. For disease in the lungs or bone, the I-131 dose is 200 to 250 mCi. Following this therapy, the patient is again given thyroid hormone replacement, and adequate suppression is maintained by monitoring TSH levels.
Some clinicians advocate obtaining a repeat scan in 1 year, along with a chest x-ray film, and repeating this procedure yearly until a normal scan is obtained. However, the frequency of repeated scans and the dose of I-131 are rather controversial and should be guided by the individual's risk profile.
Following thyroid remnant ablation, serum Tg measurements are useful in monitoring for recurrence. Since Tg in a patient receiving thyroid hormone replacement may be suppressed, a normal test result may be incorrect about 10% of the time. In general, the presence of disease is accurately predicted by a Tg value of greater than 5 ng/mL while the patient is in the suppressed state and by a value of greater than 10 ng/mL in the hypothyroid state. However, measurable disease may not be identified in many patients. Whether or not they should be treated on the basis of the Tg value if the I-131 scan is normal is a subject of current debate. Any rise in the Tg level from the previous value should increase the suspicion of recurrent disease.
Neck ultrasonography is useful to evaluate locoregional tumor recurrence and should be performed at yearly intervals for 5 to 10 years after initial therapy, depending on the stage of disease. Continued monitoring is necessary, because late recurrence can occur. It should be pointed out that certain aggressive tumors may neither be RAI-avid nor synthesize Tg. PET scanning may contribute to localization of disease in some cases and may even carry prognostic value. PET/CT may be more useful than other imaging techniques; in a recent study, additional information was obtained with PET/CT in up to 67% of cases.
Side effects and complications
Acute effects. The acute side effects of I-131 therapy include painful swelling of the salivary glands and nausea. Ibuprofen(Drug information on ibuprofen) or other pain relievers are usually used to decrease salivary gland discomfort. Nausea may be treated with standard antiemetics.
Rarely, in patients with significant residual thyroid tissue, radioactive iodine may cause acute thyroiditis, with a rapid release of thyroid hormone. This problem can be treated with steroids and beta-blockers.
Patients must also be cautioned not to wear contact lenses for at least 3 weeks following ingestion of I-131, because the tears are radioactive and will contaminate the lenses and possibly lead to corneal ulceration.
Long-term complications. Long-term risks of are not well understood. They can include effects on the salivary glands consisting of sialadenitis and xerostomia, and possible increased risk of bladder tumors and colon cancers with repeated administrations.
Bone marrow suppression and leukemia are potential long-term complications of I-131 therapy but are poorly documented and appear to be extremely rare. Patients should have a complete blood cell count performed prior to ingestion of an I-131 dose to ensure adequate bone marrow reserve. They should also have blood counts measured yearly. Leukemia occurs rarely with doses of I-131 lower than 1,000 mCi.
Pulmonary fibrosis. Pulmonary fibrosis may be seen in patients with pulmonary metastases from papillary or follicular thyroid cancer who are treated with I-131. Those with a miliary or micronodular pattern are at greater risk, because a portion of normal lung around each lesion may receive radiation, leading to diffuse fibrosis.
Effects on fertility. Data have documented an increase in follicle-stimulating hormone (FSH) levels in one-third of male patients treated with I-131. Changes in FSH levels after one or two doses of I-131 are generally transitory, but repeated doses may lead to lasting damage to the germinal epithelium. Sperm banking should be considered in male patients likely to receive cumulative doses of I-131 higher than 500 mCi.
The effects of I-131 on female fertility have been investigated. A published article showed no significant difference in the fertility rate in women receiving RAI. Exposure to more than 100 mCi of I-131 was also not associated with increased miscarriages, congenital malformations, or thyroid disease or cancer in offspring. However, it is generally recommended to avoid pregnancy for 1 year after therapeutic I-131 administration.
Papillary or follicular thyroid cancer
There are a number of indications for external irradiation of papillary or follicular thyroid carcinoma. Surgery followed by RAI may be used for disease that extends beyond the capsule. However, if all gross disease cannot be resected, or if residual disease is not RAI-avid, external irradiation is used as part of the initial approach for locally advanced disease in older patients. The benefit of adjuvant external irradiation for cause-specific survival is inferred from institutional series. Intensity-modulated radiation therapy is associated with decreased severe late toxicities in an institutional series and provides the best target coverage in dosimetric studies.
Unresectable disease. External irradiation is useful for unresectable disease extending into the connective tissue, trachea, esophagus, great vessels, and anterior mediastinum. For unresected disease, doses of 6,000 to 6,500 cGy are recommended. The patient should then undergo I-131 scanning, and if uptake is detected, a dose of I-131 should be administered.
Recurrence after resection. External irradiation may also be used after resection of recurrent papillary or follicular thyroid carcinoma that no longer shows uptake of I-131, or for gross unresectable disease. In this situation, doses of 5,000 to 6,600 cGy are delivered to the tumor bed to prevent local recurrence. Multiple-field techniques and extensive treatment planning are necessary to deliver high doses to the target volume to minimize the risk of significant complications.
Recurrences to regional lymph nodes that are not resectable can be salvaged with regional external radiation therapy. In either situation, the radiation fields extend from cervical lymph node stations to the superior mediastinum, with esophageal stricture reported as a common long-term morbidity of treatment.
Palliation of bone metastases. External radiation therapy is useful in relieving pain from bone metastasis. If the metastasis shows evidence of I-131 uptake, the patient should be given a therapeutic dose of I-131 followed by local external radiation therapy to the lesion of up to 4,000 to 5,000 cGy. The use of intravenous bisphosphonate therapy has been shown to decrease the pain of bone metastasis and improve reported quality of life.
Anaplastic thyroid carcinoma
Anaplastic carcinoma of the thyroid is an exceptionally aggressive disease, with few long-term survivors. It often presents as a rapidly expanding mass in the neck and may not be completely resected. External irradiation to full dose (6,000 to 6,500 cGy) may slow the progress of this disease but rarely controls it.
Chemoradiation therapy. There are reports of the use of accelerated fractionation regimens of external irradiation (160 cGy twice daily to 5,700 cGy) with weekly doxorubicin(Drug information on doxorubicin) in patients with anaplastic thyroid cancer, as well as reports of the combination of doxorubicin and cisplatin(Drug information on cisplatin) with external irradiation. These regimens have improved local tumor control but at the expense of increased toxicity. Unfortunately, the majority of patients die of local and/or distant recurrence.
Medullary thyroid carcinoma
External irradiation has been used for medullary thyroid cancer in the postoperative setting, but only retrospective series are available. Therefore, this technique is controversial. However, much of the available literature has indicated that indications would include positive surgical margins, gross residual disease, or extensive lymph node metastasis. Further controversy exists in the setting of elevated postoperative calcitonin levels in patients who have undergone macroscopically complete resection, without radiographic evidence of distant disease. The recommended dose is 5,000 to 7,000 cGy in 5 to 7 weeks. Radiation is also used for palliation of different sites of metastatic disease.
Differentiated thyroid cancer
Thyroid hormone suppression. As mentioned previously, thyroid hormone is used to suppress TSH in most patients with differentiated thyroid cancer after surgery and I-131 (as appropriate) treatment. Greater TSH suppression has been associated with improved progression-free survival in patients with high-risk papillary thyroid carcinoma. Modest TSH suppression in patients with stage II disease yields similar results. Patients with stage I disease do not appear to have any change in outcomes based on the degree of TSH suppression. ATA and National Comprehensive Cancer Network (NCCN) guidelines recommend that initial TSH suppression should be below 0.1 mU/L for high-risk and intermediate-risk thyroid cancer patients, while maintenance of the TSH at or slightly below the lower limit of normal (0.1 to 0.5 mU/L) is appropriate for low-risk patients. Patients who remain disease-free for several years can probably have their TSH levels maintained within the reference range.
Systemic therapy. Eighty-five percent of patients with differentiated thyroid carcinomas are cured with surgery, , and TSH suppression. A small percentage of patients will develop or present with metastases and are more difficult to treat. When metastases have radioiodine avidity, prognosis is better and further may be used. However, when multiple doses of have been tried or the patient has non-RAI–avid disease, other options need to be considered. Although it is the most effective medical treatment for differentiated thyroid carcinoma, only about 50% to 80% of primary tumors and their metastases take up . Metastatic differentiated thyroid cancer can be stable for many years, a reason why patients with progressive or symptomatic disease should be referred for consideration of systemic treatments. Systemic therapy through a clinical trial is the treatment of choice for RAI-refractory, progressive distant metastatic disease.
Systemic cytotoxic chemotherapy. The more frequently used agent in thyroid cancer studies was doxorubicin, either alone or in combination with cisplatin. The responses were limited and only lasted a few months. Newer cytotoxic drugs (eg, taxanes, gemcitabine(Drug information on gemcitabine), and irinotecan(Drug information on irinotecan)) have not been reported in a significant number of patients with differentiated thyroid cancer. Because of toxic side effects, short duration of responses, and low response rates, cytotoxic chemotherapy agents are not recommended.
Systemic cytotoxic chemotherapy has been evaluated for widespread disease, although reproducibly effective regimens have not been identified to date.
Newer molecular-targeted therapy. Within the past decade, molecularly targeted treatments have been studied in patients with advanced thyroid carcinoma no longer responsive to and not amenable to surgery. These agents are still being investigated in clinical trials. The most promising results in clinical trials have been seen with antiangiogenic therapies.
Several phase II trials have evaluated novel treatments with good response in patients with differentiated thyroid cancer that is refractory to traditional treatments. The recognition of the presence of oncogenic mutations such as BRAF, RAS, and RET/PTC in papillary thyroid carcinoma has prognostic implications and guides therapeutic effect in patients with advanced cancer. Because the vascular endothelial growth factor receptor (VEGFR) is also up-regulated in patients with differentiated thyroid carcinoma, drugs that target VEGFR and/or inhibit BRAF are currently under investigation. According to the 2011 NCCN guidelines, patients with metastatic differentiated thyroid carcinoma that is not amenable to surgery or radioiodine therapy should be referred to a clinical trial investigating targeted therapies or considered for treatment with other small molecule tyrosine kinase inhibitors (ie, sorafenib(Drug information on sorafenib) [Nexavar], axitinib [AG-013736]. sunitinib [Sutent], or pazopanib [Votrient]) if a clinical trial is not recommended or feasible (www.nccn.org, Thyroid Carcinoma, v.2.2011). Sorafenib, sunitinib, and pazopanib are oral antiangiogenics and are commercially available and approved for other indications in the United States. These drugs have been used in phase II trials and are promising agents for patients with progressive, RAI-refractory differentiated thyroid carcinoma. Two phase II trials with sorafenib have been performed in patients with differentiated thyroid carcinoma, and both have shown favorable results. A phase III international randomized controlled trial is currently under way.
Several molecular-targeted tyrosine kinase inhibitors, such as sorafenib and sunitinib, have shown promising results for patients with RAI-resistant thyroid cancer with partial response ranging from 13% to 20%, and stable disease in 60% to 68% of treated patients.
Once differentiated thyroid carcinoma is found to be refractory to radioiodine, patients should have full staging examinations to determine the extent of disease and rate of progression. Diagnostic procedures should include neck ultrasonography; CT scan of the neck, chest, and abdomen; and CT scan or MRI of the brain. MRI of the spine and pelvis should be considered to evaluate fore bone metastases. A baseline PET scan may complete the workup. Progression rate is assessed using response evaluation criteria in solid tumors (RECIST).
Patients with RAI-refractory differentiated thyroid carcinoma enjoy a long indolent phase, when the tumor is stable or slowly progressive and asymptomatic. In such patients, the benefits of novel therapies may be outweighed by drug toxicities, and a "watchful waiting" approach is a valid strategy. Patients with measurable lesions and documented progression should be considered candidates for systemic treatment.
Sidebar: A study of cabozantinib, an oral, potent inhibitor of MET, VEGFR2, and RET enrolled 15 patients with metastatic differentiated thyroid cancer. Participants were required to have RAI-refractory disease, to have progressed on standard therapies, and to have measurable disease. Eight of the 15 patients (53%) had confirmed partial responses (PRs), including 1 patient with marked improvement of a bone infiltrating lesion. Six patients (40%) had stable disease (SD); all 14 patients who had 1 or more post-baseline scans experienced tumor regression (range: -9% to -55%). The disease control rate (PR + SD) was 80% at 16 weeks. Ten of the 15 patients (67%) remain on cabozantinib with a median follow-up of 7.3 months. Median progression-free survival and overall survival have not been reached. Most common grade 3/4 adverse effects were diarrhea (20%), elevated lipase level (20%), hypertension (13%), and palmar-plantar erythrodyesthesia (13%); one related grade 5 event reported was hemoptysis due to aorto-tracheal fistula in a patient with a history of prior mediastinal radiation therapy and extensive neck surgeries (J Clin Oncol 30(s), abstract 5547, 2012).
Sidebar: In a recent study of selumetinib (AZD6244, ARRY-142866), an MEK1/2 inhibitor, changes in tumor iodine uptake and RECIST response after RAI therapy were evaluated. In this study, 24 patients were enrolled, 22 were eligible, and 20 were evaluable. For the 20 evaluable patients, median age was 61 (range: 44 to 77 years) and 11 were men. Nineteen patients had tumors analyzed for BRAF and N-,K- RAS mutations. Eight patients had BRAF mutant (MUT) and 11 had BRAF wild-type tumors; 1 patient was to be analyzed. Selumetinib increased I-124 uptake in 12 of the 20 patients (4 of 8 with BRAF MUT; 8 of the 12 other patients). Eight of the 12 patients who achieved sufficient iodine avidity to warrant RAI therapy included all 5 patients known to be NRAS MUT to date and 1 BRAF MUT patient. Of the 7 patients who have received RAI, 5 had PRs; 2 had SD. Mean percent reduction in thyroglobulin level in this group (pre-RAI vs 2 months post-RAI) was 91%. No Common Terminology Criteria for Adverse Events toxicities greater than grade 2 attributable to selumetinib were observed. One patient received a diagnosis of myelodysplastic syndrome more than 51 weeks after RAI (unrelated to selumetinib; J Clin Oncol 30(s), abstract 5509, 2012).
Medullary thyroid carcinoma
In patients with medullary thyroid carcinoma, the usual treatment is surgery. Various oral, small molecule tyrosine kinase inhibitors have been investigated in patients with locally advanced, metastatic, or progressive hereditary and sporadic medullary thyroid carcinomas. The responses have been variable among agents and have consisted of partial response as the best outcome. However, the development of these novel agents and others offers much promise in the targeted treatment of metastatic medullary thyroid carcinoma, which currently has no cure. In patients with hereditary medullary carcinoma who have a coexisting pheochromocytoma, appropriate control of catecholamine hypersecretion should precede thyroid surgery.
In April 2011, the FDA approved vandetanib for treatment of medullary thyroid carcinoma in patients with progressive locoregional and metastatic disease under a restricted prescription program, REMS. Approval was based on two pivotal trials of vandetanib. An open-label phase II trial of patients with locally advanced or metastatic hereditary medullary thyroid carcinoma showed partial response in 20%, stable disease at 24 weeks or more in 53%, calcitonin levels decreased by 50% in 80%, and CEA levels decreased by 50% in 53%. In addition, vandetanib exhibited a significant objective response rate compared with placebo. Vandetanib's safety and efficacy were established in an international phase III randomized, double-blind, placebo-controlled study that showed median progression-free survival of 16.4 months in the placebo group vs 22.6 months in the vandetanib arm (HR = 0.35). In clinical trials of vandetanib, QT interval prolongation, torsade de pointes, and sudden death have been reported; thus, prescribers must be properly educated about these risks and should participate in the REMS program.
Cabozantinib, also known as XL-184 (a c-MET, VEGFR2, and RET kinase inhibitor), has shown robust antiangiogenic and antitumor effects in patients with medullary thyroid cancer in phase I trials. A phase I dose escalation study of XL-184 that included 37 patients with medullary thyroid cancer showed partial response in 68% of patients, stable disease in 41% of patients, and tumor shrinkage of 30% or more in 49% of patients. Dose-limiting toxicities included grade 3 palmar-plantar erythrodysesthesia, mucositis, and elevations in liver enyzme levels.
Sidebar: Cabozantinib is an oral inhibitor of MET, VEGFR2, and RET. A phase III randomized study of cabozantinib vs placebo in 330 patients with progressive, unresectable, locally advanced or metastatic medullary thyroid cancer is under way. The median patient age is 55 years; 67% are male; 96% have measurable disease. RET mutation status is positive in 48%, negative in 12%, and unknown 39%. Prior exposure to tyrosine kinase inhibitor was found in 21%; 78% had no prior exposure, and in 2% exposure history is unknown). As of June 15, 2011, 44.7% of patients receiving cabozantinib and 13.5% receiving placebo remained on the study treatment. Statistically significant progression-free survival prolongation of 7.2 months was observed; median progression-free survival for cabozantinib was 11.2 months vs 4 months for placebo (HR = 0.28; 95% CI, 0.19–0.40; P < .001). Progression-free survival results favored the cabozantinib group across subset analyses, including RET status and prior tyrosine kinase inhibitor use. Overall response rate was 28% for cabozantinib vs 0% for placebo (P < .001). An interim analysis of overall survival (44% of the 217 required events) did not show a difference between cabozantinib and placebo. The most frequent grade 3 or higher adverse events (cabozantinib vs placebo) were diarrhea (15.9% vs 1.8%), palmar-plantar erythrodysesthesia (12.6% vs 0%), fatigue (9.3% vs 2.8%), hypocalcemia (9.3% vs 0%), and hypertension (7.9% vs 0%; J Clin Oncol 30(s), abstract 5508, 2012).
Sidebar: Fifty-nine patients were enrolled in a phase II trial of lenvatinib, an oral tyrosine kinase inhibitor targeting VEGFR1-3, FGFR1-4, RET, KIT, and PDGFRβ. A dose reduction for management of toxicity was needed in 54% of patients, and 22% were withdrawn from therapy because of toxicity. The most common treatment-related adverse events were proteinuria (58%), diarrhea (56%), hypertension (48%), fatigue (44%), decreased appetite (41%), nausea (34%), and decreased weight (32%). Independent imaging review (IIR) confirmed partial responses in 21 patients (relative risk [RR] = 36%; 95% CI, 24–49) and investigator assessment confirmed partial responses in 29 patients (RR = 49%; 95% CI, 36–62). For patients who received prior VEGFR-directed treatment (n = 26), RR was 35% (IIR); with no prior VEGFR-directed treatment (n = 33), RR was 36% (IIR). Median progression-free survival by IIR was 9 months (95% CI, 7; based on minimum 8 months' follow-up, 46% events observed). There was no clear difference in treatment response between RET-mutant and RET–wild type patients. Low baseline levels of angioprotein-2, sTie-2, hepatocyte growth factor, and interleukin-8 were associated with greater tumor shrinkage and prolonged progression-free survival, whereas high baseline levels of VEGF and sVEGFR3 were associated with greater tumor shrinkage (J Clin Oncol 30(s), abstract 5591, 2012).
Anaplastic thyroid carcinoma
As mentioned previously, the usual treatment for patients with resectable or localized anaplastic thyroid cancer is surgery. Like radiotherapy, chemotherapy is an important alternative approach, but further evaluation is needed to optimize its effectiveness. Patients with unresectable local tumors should be referred to clinical trials, treated with radiotherapy and chemotherapy, or maintained with best supportive care. Imatinib(Drug information on imatinib) (Gleevec, a Bcr-Abl and PDGF inhibitor) and sorafenib (Nexavar) are currently being studied in phase II trials in patients with anaplastic thyroid carcinoma, with preliminary data showing partial response in 13% to 25%, and stable disease in 27% to 50% of patients. Further investigation is needed to identify better therapeutic options for patients with this aggressive form of thyroid carcionma.