Current Opinion in Oncology:
ENDOCRINE TUMORS: Edited by Julie Ann Sosa
New targeted therapies and other advances in the management of anaplastic thyroid cancer
Deshpande, Hari A.a; Roman, Sanzianab; Sosa, Julie A.b
aDepartment of Medicine, Section of Medical Oncology
bDepartment of Surgery, Section of Endocrine Surgery, Yale University, New Haven, Connecticut, USA
Correspondence to Hari A. Deshpande, MD, Yale Cancer Center, Yale University, New Haven, CT 06520, USA. Tel: +1 203 737 5312; e-mail: Hari.email@example.com
Purpose of review: Anaplastic thyroid cancer is the most aggressive solid tumor known to humans. Even when found in a localized form, the prognosis is grave. For metastatic disease, there has been little effect on survival using traditional chemotherapy.
Recent findings: Over a five-decade interval, there has been little progress in the treatment of this malignancy. However, targeted agents represent a new mode of treatment, and some studies have shown encouraging preclinical results. Combretastatin has shown activity in phase 1 and phase II trials; although the registration phase III study failed to meet its accrual goals, it did appear to show some benefit, especially in younger patients.
Summary: Combinations of this compound and other targeted agents may prove to be a breakthrough in an otherwise untreatable cancer.
Anaplastic thyroid cancer (ATC) arises from the follicular cells lining the colloid follicles in the thyroid gland. These cells also give rise to the differentiated variants of thyroid cancer (papillary and follicular), which make up 90% of all thyroid cancer cases. ATC accounts for 1–2% of all thyroid cancers . The first descriptions of this rare malignancy date back to at least 1930, with more detailed pathology and clinical details emerging in the 1950s [2,3]. Even in these early reports, it was evident that Group III thyroid cancers, as they were termed at that time, were rare in patients under the age of 39 years and were highly malignant. Later reviews have evaluated prognostic factors and effect of treatment on survival. One study evaluated 100 patients with ATC treated between 1993 and 2009. The median overall survival (OS) time was 3.9 months (range 0.06–151.3 months). The overall 6-month, 1-year and 2-year survival rates were 40.4, 21.3 and 12.3%, respectively. Nineteen of the 100 patients survived for more than 1 year, and most of these underwent a complete resection as opposed to debulking, followed by adjuvant radiotherapy with or without chemotherapy [4▪▪]. Other studies have also emphasized the importance of complete resection for survival [5–7]. Radiation doses of greater than 40cGy were associated with an improvement in survival [4▪▪]. Chemotherapy is often added concurrently with radiation but appears to have a limited effect on survival in most studies [4▪▪,8▪]. Some small studies have shown favorable results with aggressive surgery, adjuvant chemoradiotherapy and further adjuvant chemotherapy [9▪]. A critical review, however, of a widely used regimen of doxorubicin and radiation yielded disappointing results [10▪▪]. New treatments are therefore needed for this highly aggressive malignancy. This review highlights some of the recent studies of new targeted agents.
Biology of anaplastic thyroid cancer
The incidence of ATC appears to have remained unchanged at about one to two cases per million over recent decades. Some studies [11▪,12,13] have suggested that there has been a decrease in incidence, but it is felt by experts that this is artifactual and may represent a more accurate diagnosis being made in these locations. In contrast, the incidence of differentiated thyroid cancer (DTC) has increased over the same time period . Both DTC and medullary thyroid cancer (MTC) have mutations in growth factor receptors or enzymes including RET (rearranged during transfection), VEGFR (vascular endothelial growth factor receptor) and BRAF (serine/threonine-protein kinase) that have allowed targeted agents to be used effectively in these diseases . Reports of mutations in ATC have raised hopes of eliciting targeted treatments for ATC as well .
Targeted agents in anaplastic thyroid cancer
Many targeted agents have been tried in the treatment of ATC patients.
Although BRAF mutations have been found in ATC patients , trials of targeted agents against this enzyme have been disappointing . The BRAF and VEGFR inhibitor sorafenib was evaluated in an open-label, phase II study in patients with biopsy-proven ATC to evaluate whether its objective response rate was greater than 20% and to further characterize its safety profile. Patients with progressive ATC who had received cytotoxic chemotherapy with or without radiation were given sorafenib on a fixed dosing schedule of 400 mg by mouth twice daily (b.i.d.) on 28-day cycles. At the time of presentation at the American Society of Clinical Oncology (ASCO) meeting in 2009, 16 patients had enrolled in the study. Two of 15 evaluable patients (13%) had a partial response (PR) and four patients (27%) had a stable disease. However, the median time to progression was 1.5 months, and the median duration of survival was 3.5 months. Grade 3 toxicities included lymphopenia (25%), rash with desquamation, weight loss and chest pain (all 12%). Grade 4 toxicities include dyspnea (6%) and lymphopenia (6%) .
Xenograft studies using KTC2 (Kawasaki Thyroid cancer) ATC cells implanted into the subcutaneous tissues of nude mice were undertaken in another experiment using the multitargeted agent pazopanib, although this cell line may not truly represent ATC in humans [18▪▪]. Significantly reduced tumor growth relative to diluent was seen without affecting animal weights, thereby providing rationale for the clinical assessment of pazopanib monotherapy in human ATC. However, in the same study, 15 human patients were then treated, 11 of whom had progressed through prior systemic therapy. Enrollment was halted, triggered by a stopping rule requiring more than one confirmed Response Evaluation Criteria In Solid Tumors (RECIST) response among the first 14 of 33 potential patients. Treatment was discontinued because of disease progression (12 patients), death due to a possible treatment-related tumor hemorrhage (one patient) and intolerability (radiation recall tracheitis and uncontrolled hypertension, one patient each). Although transient disease regression was observed in several patients, there were no confirmed RECIST responses. The median time to progression was 62 days, and the median survival time was 111 days [18▪▪].
Vascular disrupting agents
The growth and development of most solid tumors require that they form their own functional vascular supply, which they do from the host normal vascular network by the process of angiogenesis. The significance of this neovasculature makes it an excellent target for treatment, and two forms of vascular targeting agents (VTAs) have evolved: those that inhibit the angiogenesis process (angiogenesis inhibitors) and those that damage the already established vessels (vascular disrupting agents, VDAs) [19,20]. Combretastatin A-4 phosphate (CA4P, fosbretabulin) was the first agent of the VDA class of compounds to enter the clinic. A phase I trial to determine the maximum tolerated dose, safety and pharmacokinetic profile of CA4P on a single-dose intravenous schedule was performed . In this study, preliminary data were obtained regarding its effect on tumor blood flow using dynamic contrast-enhanced MRI (DCE-MRI) techniques and cell adhesion molecules at the higher dose levels. Twenty-five assessable patients with advanced cancer received a total of 107 cycles over a dose escalation schema at 3-week intervals. There was no significant myelotoxicity, stomatitis or alopecia. Tumor pain was a unique side effect, which occurred in 10% of cycles, and there were four episodes of dose-limiting toxicity at dosages greater than or equal to 60 mg/m2, including two episodes of acute coronary syndrome. Pharmacokinetics revealed rapid dephosphorylation of the parent compound (CA4P) to combretastatin A4 (CA4), with a short plasma half-life (approximately 30 min). A significant (P < 0.03) decline in gradient peak tumor blood flow by DCE-MRI in six of seven patients treated at 60 mg/m2 was observed. A patient with ATC had a complete response and was alive more than 30 months after the treatment. The toxicity profile was consistent with a drug that is ‘vascularly active’ and devoid of traditional ‘cytotoxic’ side effects. Dosages less than or equal to 60 mg/m2 as a 10-min infusion defined the upper boundary of the maximum tolerated dose . On the basis of the unexpected complete response seen in the patient with ATC, a phase II study  was performed to determine the efficacy and safety of fosbretabulin in patients with advanced ATC and whether fosbretabulin altered the natural history of ATC by virtue of doubling the median survival. A secondary aim evaluated the prognostic value of serum soluble intracellular adhesion molecule-1 (sICAM). Twenty-six patients received fosbretabulin 45 mg/m2 as a 10-min intravenous infusion on days 1, 8 and 15 of a 28-day cycle. sICAM levels were obtained at baseline, over the first two cycles, and at the end of therapy. Treatment was continued until disease progression. Fosbretabulin was well tolerated; grade 3 toxicity was observed in nine patients (35%), and grade 4 toxicity in one (4%). QTc prolongation delayed treatment in four, causing one to stop treatment. Median survival was 4.7 months, with 34 and 23% alive at 6 and 12 months, respectively. Median duration of stable disease in seven patients was 12.3 months (range, 4.4–37.9 months). Baseline serum sICAM levels were measured in 24 patients, with a median level of 253.5 ng/ml. There was a significant difference in event-free survival among tertiles of baseline sICAM levels (P < 0.009). Although there were no objective responses seen with single-agent fosbretabulin as administered in this trial and a doubling of survival as the primary endpoint was not observed, it was felt that fosbretabulin had an acceptable safety profile in patients with advanced ATC. One-third of patients survived more than 6 months. Despite the small sample size, low baseline sICAM levels were predictive of event-free survival. The authors concluded that further prospective validation of sICAM as a therapeutic biomarker and exploration of combination regimens with fosbretabulin were warranted . Therefore, a multicenter, open-label, 2 : 1 randomized international trial for patients with histologically confirmed ATC was conducted. Eighty out of 180 planned patients were randomized to receive up to 6 cycles of carboplatin and paclitaxel with CA4P (CA4P arm) or without CA4P (control arm) [23▪▪]. The targeted sample size of 180 patients was not reached due to slow enrollment. After six cycles of therapy, patients on the CA4P arm without progression could continue to receive CA4P until disease progression. The primary objective of this study was OS. Secondary objectives included safety, 1-year survival and progression-free survival. Seventy-five of the 80 randomized patients received treatment with a median (min, max) follow up of 4.7 (0.1, 32.6) months. All deaths were due to disease progression except two patients whose deaths were attributed to disease-related complications. The median survival time for the CA4P arm was 5.2 months versus 4.0 months for the control arm, resulting in a hazard ratio and 95% confidence interval (CI) of 0.65 (0.38–1.10) based on the intent-to-treat analysis. This would suggest a 35% reduction in the risk of death. One-year survival was 27% on the CA4P arm versus 9% on the control arm (P = 0.065, Fisher's exact test). Grade 1–2 hypertension and Grade 3–4 neutropenia were more common on the CA4P arm. This trial, the largest prospective randomized trial ever conducted in ATC, suggested that CA4P improves OS, with a tripling of 1-year survival; however, the improvement was not statistically significant. The regimen was well tolerated, with adverse events and deaths primarily related to ATC and disease progression [23▪▪]. The primary end point of OS benefit was not reached, likely due to limited numbers of participants enrolled. The authors of the current review suggest that in order to allow optimal inclusion into new trials, future ambitious ATC phase III studies could consider having fewer cardiac and other restrictions, given the grave prognosis for these patients with standard treatment. Other trials of targeted agents have had limited numbers of patients, but some have yielded interesting results.
Imatinib is a selective tyrosine kinase inhibitor of platelet-derived growth factor receptor (PDGFR) and cABL that has been used for various types of cancer treatments . It was tested in patients with histologically confirmed ATC who had measurable disease and whose disease expressed PDGFRs by immunohistochemistry . Imatinib was administered at 400 mg orally b.i.d. without drug holiday. Response to treatment was assessed every 8 weeks. Patients with complete response, PRs or stable disease were treated until disease progression. The study was terminated early due to poor accrual. However, 11 patients were enrolled and started on treatment. At baseline, four out of 11 had locoregional disease, five out of 11 had distant metastases and two out of 11 had both. Nine of 11 had prior chemoradiation, and seven of 11 had undergone thyroidectomy. Eight of 11 were evaluable for response; four were excluded for lack of follow-up with radiologic evaluation. The overall response rates at 8 weeks were the following: complete response 0 of 8, PR 2 of 8 and stable disease 4 of 8. The median time to follow-up was 26 months (range 23–30 months). The rate of 6-month progression-free survival was 36% (95% CI, 9–65). The rate of 6-month OS was 45% (95% CI, 16–70). The most common grade 3 toxicity was edema in 25%; other grade 3 toxicities included fatigue and hyponatremia (12.5% each). There were no grade 4 toxicities or treatment-related deaths. The authors felt that imatinib appeared to have activity in advanced ATC and was well tolerated .
Combinations of targeted agents and chemotherapy
Chemotherapy has had little effect on OS of ATC as a single modality treatment. However, its use in combination with targeted agents is felt to be more promising [23▪▪]. Docetaxel has limited single-agent activity in this disease . In one study, a total of seven patients with ATC were enrolled over 30 months and received docetaxel. The treatment response was complete response in one patient, stable disease in two and progressive disease in four. The response rate was 14%, and the disease control rate (complete response along with stable disease) was 43%. The median time to progression was 6 weeks (range, 1–50 weeks) .
The effect of imatinib on the antitumor activity of docetaxel in ATC cells has been investigated . Two ATC cell lines, were treated with imatinib and/or docetaxel. Cell survival assay and flow cytometry for annexin V were used to assess the induction of apoptosis. Changes of proapoptotic and antiapoptotic factors were determined by western blot. Nuclear factor-κB (NF-κB) activity was measured by DNA-binding assay. Tumor growth was also investigated in vivo. The combined treatment significantly enhanced apoptosis compared with single treatment. ATC cells expressed high levels of antiapoptotic factors, X-linked inhibitor of apoptosis (XIAP) and survivin. The treatment with docetaxel alone further increased their expressions; however, the combined treatment blocked the inductions. Although imatinib alone had no effect on NF-κB background levels, combined treatment significantly suppressed the docetaxel-induced NF-κB activation. Combined administration of the drugs also showed greater inhibitory effect on tumor growth in a mice xenograft model. The authors concluded that imatinib enhanced antitumor activity of docetaxel in ATC cells. Docetaxel seemed to induce both proapoptotic and antiapoptotic signaling pathways in ATC cells, and imatinib blocked the antiapoptotic signal. Thus, docetaxel combined with imatinib emerged as an attractive strategy for the treatment of ATC .
Histone deacetylase inhibitors with chemotherapy
Histone deacetylase inhibitors are a promising class of antineoplastic agents that induce differentiation and apoptosis. Moreover, they may enhance the cytotoxicity of drugs targeting DNA through acetylation of histones [28,29]. Using two ATC cell lines, one study  showed that valproic acid (VPA), a clinically available HDAC inhibitor, enhances the activity of doxorubicin, whose antitumor properties involve binding to DNA and inhibiting topoisomerase II. A meager 0.7 mM of VPA, which corresponds to serum concentrations in patients treated for epilepsy, increased the cytotoxicity of doxorubicin about two to three-fold. The sensitizing effect through histone acetylation involves increased apoptosis and has been demonstrated by increased caspase 3 activation and enhancement of doxorubicin-induced G2 cell cycle arrest. The authors felt these results might offer a rationale for clinical studies of a new combined therapy .
On the basis of these findings, a case report emerged of successful treatment of ATC with a combination of oral VPA, chemotherapy consisting of cisplatin and doxorubicin, external and intraoperative radiation and surgery . Tumor volume decreased by 50.7% under computed tomography measurement, and 44.6% under sonogram measurement over the course of treatment. No significant rebound in tumor size was observed between each cycle of chemotherapy. Serial cytology performed via fine needle aspiration presented a rapidly changing profile of cell types, starting with anaplastic and proceeding through increasingly well differentiated presentations. Only microscopic remnants of ATC cells were found in the histological examination of the resected thyroid. Whole body PET scan 6 months after surgery revealed no evidence of recurrence or metastasis. As of 22 November 2008, the patient was alive and disease-free 2 years after diagnosis .
Multimodality treatment (i.e. surgery, chemotherapy and radiotherapy) is generally recommended for ATC), and some studies [32,33▪,34,35] have suggested an improvement in survival for patients treated in such an aggressive manner. The role of targeted agents in this patient population has yet to be established, although some reports suggest benefit [36▪].
Targeted therapy has a role in patients with MTC and DTC. Its role in ATC has yet to be fully established, but the VDA fosbretabulin appeared to show some signal. Care needs to be taken in the design of clinical trials to include as many eligible patients as possible in this rapidly fatal disease. Other targeted agents have been less successful, including sorafenib and pazopanib, but older targeted molecules such as imatinib should be reconsidered, perhaps in combination with HDAC inhibitors based on encouraging preclinical data .
Table 1 illustrates some of the published and ongoing studies in this disease, and Fig. 1 demonstrates the proposed targets of inhibition. It is hoped that future studies will allow the establishment of some of these new medicines in the treatment profile for patients with different stages of ATC.
Conflicts of interest
REFERENCES AND RECOMMENDED READING
Papers of particular interest, published within the annual period of review, have been highlighted as:
▪ of special interest
▪▪ of outstanding interest
Additional references related to this topic can also be found in the Current World Literature section in this issue (pp. 100–101).
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anaplastic thyroid cancer; combretastatin; pazopanib
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