New Targets in Advanced Thyroid Cancer Refractory Iodine

The majority of deaths due to thyroid cancer occur in patients with advanced DTC refractory to radioactive iodine. The spectacular advances in molecular medicine of recent years have opened new therapeutic possibilities. Currently, there is general agreement that treatment with Tyrosine Kinase Inhibitors (TKI) should only be considered in patients with differentiated thyroid carcinoma refractory to radioactive iodine, with progressive and / or symptomatic metastatic disease that can not otherwise be treated locally. Most of these "new molecules" are multichannel inhibitors with varied action, which interact on different proteins such as RET, BRAF, cKIT, MET, EGFR, MAPK, PDGFR, etc. In addition, they have the additional advantage that they markedly prevent angiogenesis by acting on VEGFR 1, 2, and 3. TKI are associated with progression-free survival but not curative. Also, causes adverse effects that can affect the quality of life.The prolongation of progression-free survival has been demonstrated with sorafenib and lenvatinib compared with placebo in two phase III trials. These two drugs have been approved by the FDA and the European Medicines Agency for use in patients refractory to radioactive iodine with metastatic disease. Based on the Phase II Trials there are other Tyrosine Kinase Inhibitors (TKI) available such as sunitinib, axitinib or pazopanib that can produce some kind of clinical benefit and therefore need further investigation.


Introduction
About One third of patients with differentiated thyroid cancer (DTC) who develop metastatic disease are refractory to radioactive iodine. [1].
Between 1975 and 1999, 15 clinical trials with cytotoxic chemotherapy were initiated. Treatment with doxorubicin and cisplatin only achieved complete remissions in 12% of patients with thyroid carcinoma of follicular origin. The combination of bleomycin, doxorubicin and cisplatin achieved an average survival of 11 months and the response to etoposide was zero. Something similar happened in patients with medullary thyroid carcinoma, in which only 25% responded to treatment partially or completely. [2].
Fortunately, today things have changed and we are witnessing a new leap in the treatment of thyroid carcinoma. The spectacular advances in molecular medicine of recent years have opened new therapeutic possibilities. [2].
New treatment strategies are needed, therefore, new strategies under investigation include targeted therapy (eg axitinib and sorafenib), vascular disrupting agents (such as combretastatin A4 phosphate, human VEGF monoclonal antibodies, eg bevacizumab, cetuximab), tumor suppressor gene therapy. Until now, none of these agents has shown good results in the treatment of anaplastic thyroid carcinoma, so further research is needed to contrast the aggressiveness of this tumor. [12].
Currently, there is general agreement that treatment with multicinase inhibitors (MKI) should only be considered in patients with differentiated thyroid carcinoma refractory to radioactive iodine, with progressive and / or symptomatic metastatic disease that can not otherwise be treated locally The reasons for such limitations arise from clinical trials. Given that the first multicentre therapeutic trial of a Tirosin Kinase Inhibitor was performed in progressed differentiated thyroid carcinoma; the evidence favored the clinical use of Tirosin Kinase Inhibitors but also revealed limitations in terms of drug toxicity and patient eligibility. [1].
Most of these "new molecules" are multichannel inhibitors with varied action, which interact (selectively or together) on various proteins such as RET, BRAF, cKIT, MET, EGFR, MAPK, PDGFR, etc. In addition, they have the additional advantage that they markedly prevent angiogenesis by acting on VEGFR 1, 2, and 3. [2].
The prolongation of progression-free survival has been demonstrated with sorafenib and lenvatinib compared with placebo in two phase III trials. These two drugs have been approved by the FDA and the European Medicines Agency for use in patients refractory to radioactive iodine with metastatic disease. [1].
It should be noted, and more in the context of thyroid carcinoma, that the use of tyrosine kinase inhibitors has been associated with the appearance of thyroid dysfunction. This effect has been seen especially after the administration of sunitinib and sorafenib. The most common dysfunction is the development of hypothyroidism, which has sometimes been described after a brief episode of thyrotoxicosis (mimicking the clinical stages of thyroiditis). [2] For this reason it is recommended to carefully and frequently evaluate the thyroid function in any patient treated with these molecules. [2].

Method
A bibliographic review on the new molecular targets in iodine-refractory thyroid cancer was carried out over the last years based on a search of globally recognized journals such as the guidelines of the American Thyroid Association (ATA), NCCN guides, Journal of Clinical Oncology, The Lancet, etc.

Result
Unfortunately, most deaths due to thyroid cancer occur in patients with advanced DTC refractory to radioactive iodine. [1].
In studies based on treatment with doxorubicin and cisplatin only achieved complete remissions in 12% of patients with thyroid carcinoma of follicular origin. The combination of bleomycin, doxorubicin and cisplatin achieved an average survival of 11 months and the response to etoposide was zero. Something similar happened in patients with medullary thyroid carcinoma, in which only 25% responded to treatment partially or completely. [2].
External beam radiation therapy has a limited role in patients with advanced differentiated thyroid carcinoma or medullary thyroid carcinoma and is not commonly used. Retrospective studies have found controversial about the use of external beam radiotherapy. The NCCN guidelines and the guidelines of the American Thyroid Association (ATA) suggest that external beam radiation therapy should be considered for patients with locally unresectable thyroid carcinoma or medullary thyroid carcinoma to optimize locoregional control. External beam radiation therapy can also be considered for patients with distant metastases such as in the brain and spinal column. [3].
In differentiated thyroid cancer, distant metastases have greater benefit if they are iodine-refractory iodine, small and localized in the lungs; otherwise, only palliation and prolongation of survival is feasible. Chemotherapy is not indicated and participation in clinical trials should be encouraged. [12].
In medullary thyroid carcinoma in advanced disease, monoor poly-chemotherapy has not shown a significant clinical benefit (<20% response rate), whereas radiotherapy is frequently used palliatively. [12].
In anaplastic carcinoma of the thyroid the most common single cytotoxic agent used against anaplastic carcinomas is doxorubicin alone or in combination with cisplatin. The results have been disappointing. The addition of bleomycin or other agents does not improve the efficacy of this combination. Recently, paclitaxel has been used in clinical trials and has shown some improvement in response rates, but not in survival. [12].
Currently, there is general agreement that treatment with Tyrosine Kinase Inhibitors (TKI) should only be considered in patients with differentiated thyroid carcinoma refractory to radioactive iodine, with progressive and / or symptomatic metastatic disease that can not otherwise be treated locally. [1].
-When considering the use of Tyrosine Kinase Inhibitors (TKI), these factors should be taken into account: -TKI are associated with progression-free survival but not curative.
TKI causes adverse effects that can affect the quality of life. The natural history of differentiated thyroid and medullary thyroid cancer with rates of disease progression ranging from a few months to a few years. [14].
Patients who are asymptomatic are not those indicated to receive TKI particularly if the adverse effects of the treatment affect the quality of life. On the other hand, if the disease progresses rapidly, they may have a greater benefit from TKI; even when adverse effects occur..
Optimal management of the adverse effects of TKI is also essential. Especially because of the adverse dermatological, hypertensive and gastrointestinal effects, since dose modification must be done, including dose reduction. [14].
In a multicentre, randomized, double-blind, placebo-controlled trial. Phase 3 study (DECISION), sorafenib (400 mg orally twice daily) was investigated in patients with cancer refractory to radioactive iodine or metastatic differentiated thyroid cancer that had progressed within the last 14 months. Adult patients (≥18 years of age) with this type of cancer were enrolled from 77 centers in 18 countries. As inclusion criteria, participants had to have at least one lesion measurable by CT or MRI according to the criteria for evaluation of response in solid tumors (RECIST), with PS 0-2; adequate functioning of bone marrow, liver and renal function; and serum thyroid stimulating hormone concentration less than 0.5 mIU / L. The primary endpoint was progression-free survival, assessed every 8 weeks. [11].
About 5% of patients develop differentiated thyroid carcinoma refractory to radioactive iodine, which generally does not respond to conventional chemotherapy, resulting in a long-term overall survival of approximately 10%. On November 22, 2013, the FDA approved sorafenib for the treatment of refractory, progressed thyroid cancer; based on the results of a randomized, placebo-controlled trial (n: 471) that demonstrated a statistically significant improvement in progression-free survival [PFS; HR, 0.59; 95% confidence interval (CI), 0.45-0.76; P <0.001, with a median PFS time of 10.8 months in the sorafenib arm and 5.8 months in the placebo arm. [4].
Sorafenib has clinically relevant antitumor activity in patients with metastatic refractory thyroid carcinoma, resistant to iodine, with a general clinical benefit rate of 77%, a median PFS of 79 weeks and a generally acceptable safety profile. These results represent a significant advance over chemotherapy in both the response rate and the PFS. [10].
Sorafenib significantly improved progression-free survival compared to placebo in patients with differentiated iodine-refractory thyroid cancer. These results suggest that sorafenib is a new treatment option for patients with thyroid cancer refractory iodine. [11]. Lenvatinib is approved for thyroid cancer differentiated by the FDA, but has also been studied in medullary thyroid cancer. [15].
Lenvatinib is an oral tyrosine kinase inhibitor, which inhibits the kinase activities of the VEGF receptors VEGFR1 (FLT1), VEGFR2 (KDR), VEGFR3 (FLT4), FGFR1, 2, 3 and 4, the derived growth factor receptor of alpha platelets (PDGFRa), KIT and RET. A single randomized controlled trial [E7080-G000303 or SELECT (here in after referred to as Study 303)] together with a safety database of 1,108 patients who were exposed to lenvatinib in several clinical trials was submitted to support approval in the United States. [4].
Lenvatinib demonstrated antitumor activity in phase I studies against several solid tumors, including advanced medullary thyroid cancer. This phase II study demonstrated an objective response rate (ORR) for lenvatinib of 36% in patients with progressive medullary thyroid carcinoma. The ORR was similar between patients with (35%) and without previous treatment with anti-VEGF (36%). It is associated with greater tumor reduction and prolonged progression-free survival. These findings support the continued investigation of lenvatinib for the management of medullary thyroid carcinoma. [5].
In 2012, the FDA approved cabozantinib for the same indication based on the efficacy of XL184 (Cabozantinib) in the advanced medullary thyroid cancer (EXAM) trial. [8] Which is a double-blind phase III trial comparing oral cabozantinib at 140 mg per day with a placebo in 330 patients with documented radiographic progression of metastatic medullary thyroid carcinoma. The main end point is PFS. Other end points are the response rate, overall survival and safety. This study also used a 2: 1 randomization scheme, but unlike the ZETA trial, the EXAM study did not allow the active drug to cross. The study reached its main endpoint of PFS prolongation: 11.2 months for the use of cabozantinib and 4 months for the placebo (hazard ratio, 0.28, 95% CI, 0.19 to 0.4; P <.001). Objective rates of tumor response and biochemical responses were also significantly improved with cabozantinib. [8].
The frequent occurrence of weakness, arterial hypertension, gastrointestinal discomfort (abdominal pain, diarrhea, constipation, vomiting and anorexia), skin lesions (erythema palmo plantar or hand-foot syndrome) or fatigue have been described. Patients may also report paresthesias in the hands and feet, hypopigmentation, instability, blurred vision, alteration in the sense of taste or flu-like symptoms. The appearance of anemia, leukopenia or decreased platelet count has been seen, with an increased risk of bleeding. Rarely (less than 10% of cases) there may be alterations in liver or kidney function tests, changes in the ionogram or appearance of severe hemorrhage. Usually, the adverse effects are dose-dependent, so they tend to be reduced by temporarily stopping the drug or decreasing the dose. [2].
Currently, the nonrandomized phase I / II trial of the combination of vandetanib plus bortezomib is recruiting patients with solid tumors (including medullary thyroid carcinoma). [7]. Cabozantinib and vandetanib are approved by the FDA for the treatment of advanced medullary thyroid carcinoma. [3].
On April 6, 2011, the FDA approved vandetanib [6], which is an oral inhibitor of RET kinase, PDGFR and EGFR [13]; for the treatment of advanced thyroid cancer in patients with unresectable, locally advanced disease or metastatic disease [6] based on the ZETA study. [8].
Patients were randomized 2: 1 with vandetanib, 300 mg / d orally (n = 231), or placebo (n = 100). The main objective was the demonstration of improvement in progression-free survival (PFS) with vandetanib compared with placebo. Another approach was to evaluate the global survival and the objective response rate. The analysis of PFS randomized to vandetanib (hazard ratio: 0.35, 95% confidence interval: 0.24 to 0.53, p <0.0001). The objective response rate for the vandetanib arm was 44% compared to 1% for the placebo arm. The most frequent grade 3 and 4 toxicities (> 5%) were diarrhea and / or colitis, hypertension, fatigue, hypocalcemia, skin rash and prolongation of the QT interval. This approval was based on a statistically significant and clinically significant improvement in the PFS. [6].

Discussion
Based on the Phase II Trials there are other Multicinase Inhibitors available such as sunitinib, axitinib, cabozantinib or pazopanib that may produce some kind of clinical benefit but only phase III results with vandetanib are expected in the near future. [1].
Axitinib is a potent selective inhibitor of VEGFR 1, 2 Y 3 and 10 times less potent to inhibit PDGFR and C-kit. A phase I trial of 36 patients with advanced solid tumors took axitinib 5 mg twice daily. It was shown that axitinib was rapidly absorbed, with peak plasma concentrations from 2 to 6 hours after administration. Based on the recognized importance of thyroid cancer angiogenesis and preliminary evidence of antitumor activity, the activity of this drug was investigated in a Phase II Trial. [9].
Axitinib has significant antitumor activity in all histological subtypes of thyroid cancer, as evidenced by the high response rate, the prolonged duration of response and overall survival. The modulation of VEGFR-2 and VEGFR-3 by axitinib demonstrates the selectivity of this oral inhibitor against VEGFRs. These results also validate the therapeutic efficacy of VEGFR inhibition in patients with advanced thyroid cancer. [9].
Pazopanib is another targeted agent that has shown promising activity in patients with differentiated thyroid cancer and in preclinical studies of anaplastic thyroid cancer. These results led to a phase II study (N = 16) of pazopanib in patients with advanced anaplastic thyroid cancer. However, the data from this trial showed minimal activity with pazopanib in this context; no confirmed RECIST responses were observed. [15] Motesanib  CMT  91  II  2  81  48  48  CDT  93  II  14  67  35  40   Sunitinib   CMT  23  II  35  57   28  CMT  6  II  83  CMT  15  II  33  27  CDT  31  II  14  68   Vandetanib   CMT  30  II  20  73  53  CMT  19  II  16  64  53  CMT  331  III  45  42  83

Conclusions
The present study concludes the importance of the new molecular targets for the treatment of advanced thyroid cancer, refractory iodine, since around one third of patients with differentiated thyroid cancer (DTC) develop metastatic disease. New treatment strategies have been developed which include targeted therapy (eg, axitinib and sorafenib), vascular disrupting agents (such as combretastatin A4 phosphate, human VEGF monoclonal antibodies, eg bevacizumab, cetuximab), tumor suppressor gene therapy.
Currently, there is general agreement that treatment with Tyrosine Kinase Inhibitors (TKI) should only be considered in patients with differentiated thyroid carcinoma refractory to radioactive iodine, with progressive and / or symptomatic metastatic disease that can not otherwise be treated locally.
Patients who are asymptomatic are not those indicated to receive TKI particularly if the adverse effects of the treatment affect the quality of life. On the other hand, if the disease progresses rapidly, they may have a greater benefit from TKI; even when adverse effects occur.
The prolongation of progression-free survival has been demonstrated with sorafenib and lenvatinib compared with placebo in two phase III trials. These two drugs have been approved by the FDA and the European Medicines Agency for use in patients refractory to radioactive iodine with metastatic disease.
fenib has clinically relevant antitumor activity in patients with metastatic refractory thyroid carcinoma, resistant to iodine, with a general clinical benefit rate of 77%, a median PFS of 79 weeks and a generally acceptable safety profile. These results represent a significant advance over chemotherapy in both the response rate and the PFS.
Lenvatinib is approved for thyroid cancer differentiated by the FDA, but has also been studied in medullary thyroid cancer.
Cabozantinib and vandetanib are approved by the FDA for the treatment of advanced medullary thyroid carcinoma.
Based on the Phase II Trials there are other Tyrosine Kinase Inhibitors (TKI) available such as sunitinib, axitinib or pazopanib that can produce some kind of clinical benefit and therefore need further investigation.