Unravelling the best combination of therapies to treat anaplastic thyroid cancer

KEYWORDS:

• Anaplastic thyroid cancer
• novel therapy
• targeted therapies
• undifferentiated thyroid cancer
• thyroid cancer

Anaplastic thyroid cancer (ATC) is rare and associated with a short life expectancy. The majority of patients have coexisting differentiated thyroid carcinoma or long standing history of goiter. All anaplastic thyroid cancer is considered as stage IV disease as patients usually present with locally advanced and metastatic disease. The American Joint Committee on Cancer (AJCC) TNM staging defines Stage IVA disease is localized to the thyroid, stage IVB disease as the tumor has spread outside of the thyroid gland but contained within the neck, and IVC with distant metastasis beyond the neck. Life expectancy is typically months with median survival of 5 months and 2 year survival of 0%. There is no effective treatment to date, and clinical trials are difficult to conduct given the short survival and aggressive nature of the disease. ATC typically has multiple genomic mutations. Single agents are ineffective in management of anaplastic thyroid cancer.

The first American Thyroid Association guideline for management of anaplastic thyroid cancer was published in 2012 [1]. Once the diagnosis of ATC is confirmed, staging and resectability of the tumor should be assessed by ultrasound and CT scan, MRI or PET scan of neck, chest and abdomen. ATC has high 18 F-fluorodeoxyglucose (FDG) uptake, so FDG-PET imaging can complement traditional imaging modalities and detect metastatic foci not readily visible otherwise. Discussion regarding prognosis with the patient is necessary as well as risks and benefit of treatment [1,2].

Multimodality treatment (combination of surgery, radiation and chemotherapy) is the most effective therapy that has been shown to improve outcome for stages IVA, and resectable stage IVB disease with a 1 year survival up to 70%, 2 year survival of 60%, and 50% living beyond 2.5 years with a median survival of 5 years [3,4]. Current treatment guidelines recommend surgical resection if possible for locoregional disease (stage IVA and resectable IVB) and stabilization of airway patency in all patients. Most experts recommend aggressive multimodality treatment in those with tumor found incidentally (i.e. small focus of incidental ATC found during surgery for differentiated thyroid cancer) [1]. Unresectable stage IVB disease may respond to aggressive therapy consisting of radiation with or without chemotherapy followed by surgery if surgery can be performed safely after reduction in burden of disease. Patients with stage IVC disease may be enrolled in clinical trials or hospice/palliative care depending on patient’s choices.

Radiotherapy in the form of intensity-modulated radiation therapy (IMRT), where multiple small photons are directed precisely to the tumor while reducing radiation to the surrounding areas, and external beam radiation therapy (EBRT) can be used. Radiation can be given alone or in combination with chemotherapy. In the SEER registry, all-cause mortality from anaplastic thyroid cancer was reduced to approximately 70% at 6 months and 81% at 1 year with combination of radiation therapy and R0/R1 resection (complete resection with no residual tumor; microscopic residual tumor presence respectively)[5]. Radiation therapy should be started as soon as possible after recovery from neck surgery, usually within 2–3 weeks. Effective chemotherapy includes the taxanes (paclitaxel or docetaxel), doxorubicin alone or a taxane with carboplatin or doxorubicin.

If the tumor is not resectable (R2 resection) but localized in the neck (stage IVB disease), then radiotherapy with >40–45 Gy IMRT or EBRT ± chemotherapy with taxane and carboplatin or doxorubicin can be given.

The majority of ATC patients present with metastatic disease (stage IVC). Currently, there is no effective therapy for stage IVC disease; however, new promising combination treatments are on the horizon. In patients who elect to proceed with aggressive therapy, locoregional radiation alone or in combination with total thyroidectomy with lymph node dissection if resectable (R0/R1) is somewhat effective for palliative treatment. Systemic chemotherapy combination of taxane/carboplatin or doxorubicin and enrollment in a clinical trial should be considered. Currently there are few clinical trials targeting genetic aberrations commonly seen in ATC.

Identifying genomic alterations will provide potential targets for new therapies. The genetic mechanisms involved in the development of anaplastic thyroid cancer are complex. Hallmarks of all cancers are self-sufficiency in growth signals and evasion of programmed cell death. Tyrosine kinase receptors/RAS/RAF/MAPK and RAS/PI3K/Akt/mTOR are the major signaling pathways involved in cell proliferation, protein synthesis and cell survival of ATC. In addition, inactivating mutations in the tumor suppressor phosphatase and tensin homolog (PTEN) and tumor protein gene (TP53) play an integral role in tumor growth, survival and cell cycle progression, differentiation, transcription and translation. Small case reports of individual patients responding to drugs that target these pathways are reported and clinical trials targeting these mutations are underway.

There are several tyrosine kinase receptors which can be targeted. One patient with ATC treated with vemurafenib (PLX4032), a BRAF inhibitor, showed a drastic resolution of metastatic pulmonary lesions in 38 days [6]. On the other hand, one patient treated with another BRAF inhibitor, dabrafenib, showed progression of disease despite treatment [7]. Efficacy of an ALK (anaplastic lymphoma kinase) inhibitor, crizotinib, in 1/1 patient with metastatic ATC has been reported. This patient had more than 90% improvement of pulmonary lesions by RECIST criteria at 6 months [8].

Platelet derived growth factor receptor (PDGFR) can be inhibited with imatinib. Eleven patients were treated with Imatinib. At a median of 32.7 months follow-up, 0/8 had complete response, 2/8 partial response and 4/8 had stable disease [9]. Epidermal growth factor receptor (EGFR) inhibitor, pazopanib is not effective as a monotherapy [10] but treatment with CUDC-101, a combination of EGFR, HER2 and histone deacetylase (HDAC) inhibitor, shows promising results [11]. In addition, a combination of pazopanib with paclitaxel reduced tumor volume significantly in vitro and in one patient with anaplastic thyroid cancer. This is thought to be due to an ‘off target’ effect of pazopanib on inhibition of Aurora A kinase, a critical step in mitotic cell spindle formation, stabilization and separation during cell cycle [12]. RET and RET/PTC targeted agents (sorafenib, sunitinib, vandetanib) have also shown some success [13–17].

The PI3K/AKT/mTOR pathway is an intracellular signaling pathway important in regulating the cell cycle. Everolimus, an mTOR inhibitor, has been a target for ATC patients carrying an mTOR mutation. One patient with ATC treated with everolimus had a reduction in tumor size in the first 18 months but progressed due to resistance to the treatment [18].

Microtubules are extremely important in the process of cell mitosis, and are therefore a potential target for anticancer therapy. Fosbretabulin is a microtubule inhibitor that has shown significant activity against ATC. In a large study of 80 patients recruited from 11 countries and treated with fosbretabulin in combination with carboplatin/paclitaxel, 26% survived at 1 year where the majority of patients had stage IVC disease [19]. Peroxisome proliferator-activated receptor (PPAR-gamma), which regulates transcription of various genes in ATC, has also been targeted, with a PPAR-gamma agonist, efatutazone, with some success. Smallridge et al. showed in 15 patients treated with efatutazone and paclitaxel, that 1/15 patients had a partial response and 7/15 had stable disease [20]. In addition, a potential future target is a transcriptional activating mutation in the promoter region of the telomerase reverse transcriptase (TERT) gene. TERT mutation has been reported in high frequency in anaplastic thyroid cancer [21] and thus may serve as a potential target in (V600E) mutant tumors.

The future of ATC management will likely depend on individualized targeted therapy, by studying the molecular profiling of genomic alterations detected in each individual patient. One of these currently available resources is a Foundation One analysis. So far three patients from our institution with confirmed anaplastic thyroid cancer have had molecular profiling. All three patients carried four to seven different mutations. Profiling requires 2–4 weeks and may identify possible combination therapies.

To date there are no US FDA approved therapies for anaplastic thyroid carcinoma. However, clinical trials are in progress targeting these potential molecular markers. Individual patients with anaplastic cancer have wide variability in the types of genomic alterations; thus ‘a one size fits all approach’ will not be effective. In addition, the length of time required for molecular profiling needs to be truncated due to the aggressive nature of the disease.

Current clinical trials targeting these potential sites include MLN0128 (an mTOR inhibitor), paclitaxel ± efatutazone, adalimumab, crozotinib (Alk mutation), IMRT + paclitaxel ± pazopanib, and dabrafenib and trametinib (in BRAF mutant tumors).

In summary, anaplastic thyroid cancer remains one of the deadliest diseases in the world. Over the last decade, progress has been made from preclinical studies and several drugs are now in phase II clinical trials. Although there is no effective therapy to date, new therapies targeting multiple mutations in individual patients will likely be the future for this tumor.

Declaration of interest

R.C. Smallridge is the Principal Investigator of a phase 2 clinical trial supported by The Alliance for Clinical Trials in Oncology, The National Cancer Institute (CTEP), and Daiichi-Sankyo. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.