Introduction
Thyroid cancer is a medical condition that develops following an abnormal multiplication and growth of cells that make up thyroid glands, thereby leading to the formation of a tumor. Thyroid cancer is more predominant in women than in men and ranks fifth among cancers found in women. In women aged between 20 and 34 years, it is the most common cancer. Estimates show that about 2% of thyroid cancer cases happen in children and adolescents (Cancer.Net 2018). The current data on thyroid cancer trends show that its incidence rate in men and women grew at a steady rate of 4% annually from 2005 to 2014, making it the highest diagnosed malignancy in the United States. This observation is attributed to recent advances in healthcare that have led to the development of sensitive diagnostic tests, thus enhancing the detection of thyroid cancer in its early stages.
It is estimated that about 2,060 people will succumb to thyroid cancer in 2019, out of which 960 will be men and 1,100 will be women (Cancer.Net 2018). Overall, the likelihood of developing thyroid cancer in women is threefold higher than in men. However, mortality rates of the disorder are similar between the two genders, thereby implying that the prognosis of thyroid cancer (the likelihood of survival) is worse in men than women.
The 5-year survival rate, which is a statistic that provides information about the number of people who continue living for a minimum of 5 years following the diagnosis of cancer, is 98% for thyroid cancer (Cancer.Net 2018). Timely diagnosis of thyroid cancer facilitates effective treatment. At present, treatment options for thyroid malignancy encompass surgery, which could be full or partial, radioactive ablation, treatment with the thyroid hormone, and chemotherapy.
Surgical intervention is the most commonly used treatment form in thyroid cancer. It is commonly used to get rid of part or whole of the thyroid gland following thyroid cancer diagnosis by fine-needle aspiration (Cabanillas, McFadden & Durante 2016). However, surgery is contraindicated in certain types of thyroid cancer. Two forms of surgery are used in thyroid malignancy: lobectomy and thyroidectomy.
Lobectomy is the partial removal of the thyroid gland and is sometimes used to treat small thyroid malignancies that do not show evidence of dissemination outside the thyroid gland (Cox et al. 2018). It involves making a cut on the front part of the neck to uncover the thyroid after which the malignant lobe is excised together with the isthmus. The main advantage of this form of surgery is it eliminates the need for thyroid hormone replacement because part of the thyroid gland is left intact. Conversely, the remaining gland interferes with the accuracy of diagnostic tests meant to determine disease recurrence.
Thyroidectomy refers to the complete surgical removal of the thyroid gland. The procedure can further be classified as total, near-total or subtotal thyroidectomy depending on the extent of thyroid gland removal (Cabanillas, McFadden & Durante 2016). Daily thyroid hormone pills are usually required to continue supplying the body with the hormone following the procedure. The main advantage of thyroidectomy is the ability to monitor disease recurrence effectively using thyroglobulin blood tests and radioiodine scans. Lymph nodes containing malignant cells are usually removed during this process.
Certain complications can occur after surgery. They include short-term or permanent voice croakiness due to unintended damage to the larynx, infection of wounds, and excess bleeding. The parathyroid gland can also be damaged, thereby leading to hypocalcemia and its associated symptoms such as tingling, numbness, and muscle spasms (Papaleontiou et al. 2017).
In most cases, the first three treatments are often effective. Chemotherapy becomes necessary when other therapies have not been effective, which means that it could be the most effective therapeutic option for thyroid cancer. Then again, a few patients with thyroid cancer fail to attain optimal health outcomes following the initiation of chemotherapy, which necessitates a detailed inquiry into various chemotherapeutic agents available for this disorder. Having completed seven lab sessions about many chemistry and biology concepts, I have gained valuable skills that have helped in this research. Therefore, the aim of this dissertation is to discuss thyroid cancer chemotherapy. The mode of action, benefits, and shortcomings of this treatment approach is explained. Recent advances and prospects in the use of chemotherapy for thyroid cancer treatment are also expounded.
Mode of Action of Chemotherapy
Chemotherapy involves the use of chemical agents to annihilate malignant cells that usually divide and grow rapidly. Since this treatment results in cell death or preclusion of cell growth, it can be referred to as cytotoxic chemotherapy. Specific physiological processes that chemotherapeutic agents interfere with leading to cell death include blocking of microtubule function, protein formation, and DNA synthesis.
Chemotherapy medications may be administered orally as pills, injected, or given intravenously. This modality is a systemic treatment approach, which implies that the drugs must move through the circulatory system to reach other parts of the body. Malignant cells are predisposed to forming new cells at a faster rate than normal cells, hence making them the preferred targets for chemotherapy medications. However, the drug does not end up in sites with cancerous cells only but reaches other healthy cells. The chemical agents used in chemotherapy do not have the capacity to distinguish between healthy and malignant cells. Consequently, healthy cells can be destroyed alongside cancerous cells in patients undergoing chemotherapy. The unselective action of these drugs is responsible for the manifestation of numerous side effects associated with chemotherapy. When a physician administers chemotherapeutic agents, the point of contention is to strike a balance between the destruction of malignant cells to manage the disease and to minimize the destruction of normal cells to diminish side effects.
Given that chemotherapeutic drugs are taken into the body and allowed to permeate to the target site containing the cancerous cells, they should not be easily transformed into inactive forms or eliminated from the body. There should be sufficient time for the drug to perform its pharmacodynamic actions and in some instances, the drug should be allowed to change from its inactive state to an active metabolite that can then work on the cancerous cells.
The mechanism of chemotherapeutic agents can be classified as either direct or indirect. The sequence of events that ensue once the drug has made contact with cancerous cells in direct machinery can be grouped into three phases: adsorption, interference with metabolism, and death or destruction of the malignant cell to make it accessible to phagocytes for phagocytosis. The body recognizes cancerous cells as parasites in the presence of chemotherapeutic agents. On the other hand, an indirect mechanism occurs when the drug elicits physical alterations in its surroundings such that malignant cells cannot survive. Some of the observed changes include fluctuations in temperature and pH or the formation of immune bodies.
At present, there are hundreds of chemotherapy medications that can be used to manage cancer. These remedies can be used singly or alongside other treatment modalities. The diversity of chemotherapy drugs implies the presence of different chemical constituents, dosage instructions, specificity in treating some forms of cancer, and varying side effects. Therefore, chemotherapeutic agents can be classified based on their mode of action, chemical arrangement, and interaction with other drugs.
Cytotoxic chemotherapy drugs are directed at various stages of cell growth known as the cell cycle. Therefore, the administration of these drugs at different stages of the cell cycle leads to cell arrest at a specific point in the progression thus preventing further development (American Cancer Society 2019). A thorough understanding of the mechanism of these drugs at different phases of the cell cycle is helpful in guiding physicians to envisage drugs that can work together effectively. This knowledge also guides the dosing of drugs based on the timing of the cell cycle phases. As a result, chemotherapeutic agents can further be categorized based on the precise mechanism and phase of the cell cycle that they modify.
Alkylating Agents
Alkylating agents are chemotherapeutic agents that prevent the reproduction of cancerous cells by inflicting DNA damage. Therefore, the affected cells cannot reproduce. Alkylating agents are effective in all phases of the cell cycle and can exert their effect through three different mechanisms. Overall, these agents target guanine in DNA to which they add alkyl groups such as methyl moieties at incorrect positions. The altered structure does not permit the required base-pairing thus leading to incorrect coding of DNA. In the first reaction mechanism, the addition of alkyl groups to DNA leads to DNA destruction by repair enzymes as they try to substitute the alkylated bases.
Another machinery used by alkylating agents to initiate DNA destruction is the creation of cross-bridges, which are unwanted covalent bonds between atoms in different constituents of DNA. During the formation of cross-bridges, an alkylating agent with more than one DNA attachment site connects two bases. Cross-linking hampers the denaturation of the double-stranded DNA before the processes of replication or protein synthesis. The third mechanism results in the wrong pairing of DNA thus causing mutations.
The shortcoming of alkylating agents is that they can have negative effects on the cells that make up the bone marrow, thus inhibiting the body’s ability to make new erythrocytes. This process can cause leukemia, though the risk is very low and depends on the dose of alkylating agent administered. Cancer patients being treated with alkylating agents have a high risk of leukemia after about 10 years of therapy.
Antimetabolites
Antimetabolites hamper the development of new DNA and RNA strands by substituting the nucleotides. For example, a folic acid antagonist that bears structural similarities to folate blocks the action of the enzyme dihydrofolate reductase, which prevents the proper synthesis of thymidylate, methionine, serine, and purine nucleotides. In the absence of these building blocks, DNA, RNA, and protein synthesis cannot take place. These drugs mostly target the phase of the cell cycle when the chromosomes are being copied because this is when DNA replication occurs. Antimetabolites are usually activated intracellularly into derivatives of polyglutamate, which are retained selectively in cancer cells. Thus, they also determine the duration of action of other drugs such as methotrexate.
Anti-Tumour Antibiotics
Contrary to conventional antibiotics, antitumor antibiotics do not target microorganisms but work by altering the DNA of malignant cells to prevent their growth and multiplication. As a result, downstream processes such as transcription and translation are also inhibited. Examples of anticancer antibiotics include anthracyclines, bleomycin, dactinomycin, mithramycin, and adriamycin. These compounds are derived from natural sources but do not have the specificity exhibited by conventional antibiotics. Therefore, the magnitude of toxicity they produce surpasses that of normal antibiotics significantly. The precise mechanisms involved include squeezing between DNA molecules (intercalation), introducing breaks to DNA strands, and inhibition of replication by modifying the action of topoisomerase II. The major concern related to the use of these antibiotics is the probability of irreversible heart damage if administered in high doses (Sakata et al. 2016). Consequently, these drugs often have a maximum limit that can be given in an individual’s lifetime.
Topoisomerase Inhibitors
Topoisomerases are a class of enzymes that influence modifications in the three-dimensional structure of DNA by mediating the disintegration and formation of phosphodiester bonds within DNA strands during the cell cycle. They lead to the uncoiling of supercoiled DNA to expose its structure to the enzymes responsible for replication and transcription. When topoisomerases are inhibited, DNA replication and transcription cannot take place due to DNA damage and the inability to rectify breaks in the DNA strands, which ultimately leads to cell death. The two major topoisomerases that are inhibited by this class of drugs are topoisomerases I and II. Therefore, these medications are further classified based on the specific topoisomerase that they affect. Doxorubicin is an example of a topoisomerase II inhibitor that is used in the treatment of thyroid cancer.
Mitotic Inhibitors
These are substances obtained from natural products, for example, plants. Their mode of action entails blocking the division of cells to form new cells. They are effective at all stages of the cell cycle because they inhibit the formation of proteins required for cell division. A shortcoming of mitotic inhibitors is the possibility of nerve damage if they are administered in excess (Nolan & Deangelis 2015). Therefore, these drugs have a maximum limit that can be given at any time.
Corticosteroids
Corticosteroids are medications whose chemical structures resemble those of natural hormones produced in the body. The use of these drugs in cancer treatment is what influences their consideration as chemotherapy medications. However, healthcare providers should conduct chemical tests before initiating their use to ascertain that they can be used safely. Furthermore, follow-up testing should be done each time the patient reports for a chemotherapy session.
Benefits of Chemotherapy in Thyroid Cancer
Chemotherapy facilitates the treatment of thyroid cancer through the various mechanisms exerted by different chemotherapy drugs as indicated in the previous section. It is sometimes used to augment the efficiency of other treatment modalities, for example, when used alongside external beam radiation therapy (EBRT) in the treatment of anaplastic cancer. Chemotherapy is also beneficial in advanced thyroid cancer that is unresponsive to other treatment modalities. Another useful application of chemotherapy is its capacity to increase the susceptibility of malignant cells in anaplastic thyroid cancer to radioactive radiations.
Shortcomings of Chemotherapy
The major disadvantages of chemotherapy are the side effects associated with its use. Chemotherapy drugs target rapidly dividing cells throughout the body but do not have the mechanism to distinguish between malignant and normal actively dividing cells. Therefore, other tissues such as the bone marrow cells, hair follicles, and cells that line the gastrointestinal tract are also affected. Consequently, chemotherapy leads to several side effects such as mouth sores, hair loss, poor appetite, queasiness and vomiting, diarrhea, increased predisposition to infections, easy bleeding, and unusual fatigue (Carr, Vissers & Cook 2014). Symptoms such as increased susceptibility to infections, easy bleeding, and unusual fatigue are associated with a decrease in leukocytes, platelets, and erythrocytes, respectively. The range and magnitude of side effects are dependent on the specific drug used, treatment duration, and mode of administration. Even though chemotherapy drugs exist for thyroid cancer, they are rarely used in the treatment of this disease because they are not often beneficial for most types of thyroid cancer.
Overcoming the Shortcomings of Chemotherapy
The side effects of thyroid cancer chemotherapy can be mitigated by using other drugs to increase the tolerability of the symptoms. The provision of supportive care services before, during, and after treatment can ease these side effects. For instance, clinicians with knowledge of natural remedies can recommend supplements to minimize queasiness. On the other hand, a mind-body therapist can provide advice on relaxation techniques to reduce anxiety during thyroid cancer chemotherapy.
Currently Used Drugs in Thyroid Cancer Chemotherapy
Doxorubicin (Adriamycin)
The most commonly used chemotherapeutic agents in thyroid cancer are doxorubicin and cisplatin (Yang et al. 2016). Doxorubicin as a single agent treatment has variable response rates ranging from 30 to 45% in some series. Consequently, combination therapies with cisplatin have been attempted without producing encouraging outcomes. However, for a local disease that cannot be eliminated via surgery and does not respond to radioiodine, combining hypofractionated radiation with doxorubicin has yielded satisfactory outcomes with response rates as high as 80% (Carling & Udelsman 2014).
Anaplastic thyroid carcinoma (ATC) is among the most belligerent and lethal forms of thyroid cancer in humans. Unfortunately, it is also among the most difficult cancers to treat. Comparative investigations have been done between ATC and well-differentiated thyroid carcinoma to reveal two notable features. It has been proposed that ATC arose through the dedifferentiation of thyroid cancer that had previously differentiated appropriately. In addition, the destructive growth model of ATC overrides all prior testimonies of a well-differentiated tumor. Similarities between the two forms of cancer insinuate that related risk factors are involved.
The distinct feature of ATC is a tangible mass with an average diameter of 9 cm as opposed to tumors of 2 to 3 cm in well-differentiated thyroid cancer. ATC tumors grow rapidly and can attain diameters of 20 cm. Furthermore, ATC tumors often invade the windpipe, voice box or the laryngeal nerve, thereby resulting in obtrusive indications, pain during swallowing, hemoptysis, and hoarseness at diagnosis. The invasion of vital structures may be so much that they warrant surgical resection. Nonetheless, the role of the surgeon may be to find a clear tissue diagnosis of the tumor, determine the disease stage, safeguard the airways and enlist the help of medical and radiation oncologists to develop appropriate analgesic procedures. The mean survival in most cases is 5 months following diagnosis because most patients succumb to disease recurrence and metastases to the liver, bone, and lungs. External radiation therapy has been attempted in the treatment of locally recurring ATC without much success. Doxorubicin is the only single chemotherapeutic agent that has demonstrated success in the treatment of ATC. The adriamycin plus platinum version of the drug exhibits higher efficacy levels than adriamycin alone (Carling & Udelsman 2014).
Sorafenib
Sorafenib is a chemotherapy agent that has received the U.S. Food and Drug Administration (FDA) approval for the treatment of radioiodine-resistant metastatic differentiated thyroid cancer (DTC) (Thomas et al. 2014). Several clinical trials have been conducted to determine its efficacy in patients with various forms of cancer. Thomas et al. (2014) appraised available evidence to determine the effectiveness of this agent in treating thyroid cancers. A systematic review conducted by the authors involved seven trials with a total of 219 patients with DTC, medullary thyroid cancer (MTC), and ATC. Complete responses to treatment were not recorded in any of the studies. Instead, an overall partial response of 21% was reported alongside stable disease state rates of 60% in the participants of the trials. Conversely, a progressive disease rate of 20% was reported. In all types of cancer, the median survival rate was one and a half years. Discontinuation of the drug was reported in 16% of patients. The reasons for withdrawing the drug included toxicity symptoms or inability to tolerate the drug. Observed side effects in more than 50% of the patients included diarrhea, hand-foot syndrome, exhaustion, loss of weight, and skin rash. About 4% of the participants succumbed to causes that were not linked to the sequel of the disease.
Thomas et al. (2014) concluded that sorafenib showed potential for the treatment of progressive DTC and MTC. Nonetheless, the drug was associated with numerous adverse events that necessitated its discontinuation. Therefore, before initiating sorafenib treatment in metastatic thyroid cancer, stringent criteria should be used to select treatment candidates. Additionally, the side effects of the drug should be managed carefully to enhance patient outcomes and improve their quality of life.
Wei, Zhang, and Luo (2018) conducted a different study to determine the appropriate dosage of sorafenib that would elicit minimal side effects among Chinese patients with thyroid cancer. The authors noted that sorafenib at a dosage of 200 mg twice daily could treat pulmonary metastases as well as cancerous pleural effusion attributed to radioiodine refractory differentiated thyroid cancer (RR-DTC). Nonetheless, there was a high incidence of adverse effects, which had a negative effect on the patients’ wellbeing.
Tyrosine Kinase Inhibitors
Using EBRT or conventional chemotherapeutic agents in the treatment of MTC has produced very disappointing outcomes. This occurrence prompted further studies to determine the potential use of tyrosine kinase inhibitors (TKIs) for the management of metastatic MTC. The approval of vandetanib by the FDA for the treatment of metastatic MTC has highlighted the potential of this drug in thyroid cancer therapy (Carling & Udelsman 2014). Tyrosine kinases are a group of enzymes that regulate mitogenic signals by catalyzing the addition or removal of phosphate groups to the intracellular proteins that take part in the signal transduction pathway. Uncontrolled cell growth is usually attributed to the augmented activity of tyrosine kinases, which is the molecular justification for using TKIs in treating thyroid cancer. Preliminary reports of a drug that could block the action of receptor tyrosine kinase and prevent the proliferation of malignant cells were made in the late 1980s. However, the first TKI was not available until 2001 when imatinib was authorized for use in the treatment of chronic myelogenous leukemia (Viola et al. 2016). Since that time, the drug has been scrutinized for the treatment of thyroid cancer.
In the past three decades, several molecular alterations have been described in tumors arising from follicular and parafollicular cells. The earliest actuated oncogene was discovered in DNA obtained from parafollicular thyroid cancer (PTC) tumor that had been irradiated and transfected into a cell line. Thereafter, subsequent studies confirmed the presence of the same oncogene in cases of PTC. Its occurrence was common in cells that had been exposed to radiation therapy. This oncogene was identified as RET. Gene mapping showed that RET was found on chromosome 10 and was responsible for encoding tyrosine kinase membrane receptors that played a role in the propagation of cells and conversion to tumor cells through the mitogen-activated protein kinase (MAPK) pathway. At present, the recurrent mutation noted in PTC is BRAFV600E, which has been reported in approximately 40% of PTC cases (Viola et al. 2016). Other aspects that stimulate thyroid cancer tumorigenesis include amplification of genes and increases in copy numbers.
Improvements in the knowledge of the molecular machinery surrounding thyroid cancer over the last decade have sparked interest in formulating novel drugs for targeted therapy. Two families of drugs consisting of small molecules have been identified: TKIs and monoclonal antibodies. Both groups of drugs can attach to one or more tyrosine kinase receptors, thereby blocking their activity. However, monoclonal antibodies cannot traverse the plasma membrane of malignant cells. Therefore, they can be effective against circulating tumor cells compared to dense tumors.
Most TKIs considered in thyroid cancer therapy are multitarget drugs except selumetinib which attaches to only one receptor. This drug is also unique in its mode of action because it inhibits tumor development by re-inducing the uptake of 131I in DTC cells that have undergone dedifferentiation. Overall, about 14 TKIs have been discovered and tested for their efficacy in thyroid cancer treatment. They include axitinib, cabozantinib, imatinib, levantinib, crizotinib, vemurafenib, vandetanib, sunitinib, sorafenib, ponatinib, intedanib, motesanib, pazopanib and BEZ235 (Viola et al. 2016). Cabozantinib has been approved by the FDA to treat MTC.
Recent Advances
The management of patients with well-differentiated thyroid cancers that progress despite current therapies presents a great challenge. During the past decade, biologic discoveries have inspired trials to evaluate new biologically directed treatments for advanced thyroid carcinomas and other complicated forms of the disease. Several novel agents are currently being tested in in vitro and clinical studies. Most clinical trials so far have focused on various TKIs. However, more work is needed to clarify patients with differentiated thyroid cancer who can benefit most from TKI treatment.
Targeted Therapies
Targeted therapies have the advantage of attacking malignant cells more precisely than conventional chemotherapy medications. These agents can be included in the main treatment or used following therapy to prevent disease recurrence. TKIs are novel targeted therapies for the treatment of resistant thyroid cancers such as radioiodine refractory (RAI-R), ATC, MTC, and poorly differentiated thyroid cancer (PDTC). In the past ten years, several TKIs have been tested for therapeutic intervention in radioactive refractive, sophisticated, and developing thyroid tumors, some of which have already been authorized for use in clinical settings (Wei, Zhang & Luo 2018). Another aspect of targeted therapy is molecular targeted treatment. Even though the prognosis of DTC is comparatively good, about 30 to 40% of patients usually build resistance to radioactive iodine treatment because of the dedifferentiation of tumors. A molecular understanding of thyroid carcinogenesis has led to the development of biologically targeted treatment drugs for RR-DTC, which has revolutionized the therapeutic situation. Detailed investigations have been conducted on sorafenib and lenvatinib to determine their safety and efficacy levels. Lenvatinib has been approved for use in China in 2017 (Wei, Zhang & Luo 2018), whereas vandetanib and cabozantinib can be used for MTC in other areas (Viola et al. 2016).
Nonetheless, the use of targeted therapy in the treatment of thyroid cancer still has many areas of uncertainty that should be clarified. Even though the efficacy of TKIs has been established through various investigations, there is a paucity of data regarding the extension of patient survival following treatment with these agents. Furthermore, these drugs have substantial levels of toxicity that take a toll on patients’ quality of life. Therefore, future studies should also investigate the most appropriate time to initiate these treatments. For example, it is unclear whether treatment should commence in the early stages of illness or after the tumor burden has increased substantially. However, in the meantime, only complicated and progressive thyroid cancers should be treated with TKIs.
Differentiating Agents
Differentiating agents are chemotherapy medications that act on malignant cells to prompt them to develop into normal cells. Notable examples include bexarotene, retinoids, arsenic trioxide, and tretinoin. All-trans retinoic acid (ATRA) is a common anti-tumor agent due to its anti-malignancy effects on several cancerous cells. However, its application in the treatment of thyroid cancer is complicated by adverse effects such as extreme fatigue and burning of the skin following systemic administration. Furthermore, pharmacological investigations reveal variable bioavailability because it is predisposed to breakdown by digestive enzymes when given orally. Therefore, there is a need to explore alternative formulations of the drug to exploit its anti-cancer properties.
Cristiano et al. (2017) investigated the anti-cancer activity of liposomes laden with ATRA on human thyroid cancer cells. Liposomes with an average breadth of approximately 0.2 micrometers with negatively charged surfaces were made and used to convey ATRA. Their effects on the propagation and development of thyroid cancer cell lines in vitro were investigated side by side with the free drug. The precise cell lines were PTC-1, FRO and B-CPAP. It was noted that the liposomes safeguarded ATRA against destruction by light and enhanced its antiproliferative potential because of improved uptake by the cells. Cristiano et al. (2017) concluded that ATRA-loaded liposomes were useful formulations for the management of ATC.
In a separate study, Lan et al. (2016) investigated whether ATRA could enhance the uptake of iodine by inhibiting the transcriptional potential of β-catenin in thyroid cancer cells. Undifferentiated thyroid cancer cell lines from humans were used (SW1736). These cells were subjected to three treatments: transfection of β-catenin shRNA, alcohol, and ATRA. The outcome measures were the production of β-catenin, sodium iodide symporter (NIS) and epithelial-mesenchymal transition (EMT)-phenotype (Lan et al. 2016). The proteins linked with the incursion and metastasis were also evaluated. Thereafter, the effect of ATRA on the production of NIS, capacity to take in iodine, growth parameters and treatment outcomes following radioactive iodine therapy were investigated under laboratory and physiological conditions.
The authors noted that the transcriptional activity of β-catenin declined following treatment with ATRA. This reduction was attributed to the inhibited phosphorylation of specific amino acid residues in the protein. Furthermore, ATRA promoted the expression of NIS and overturned the EMT phenotype in cells that received alcohol treatment. Overall, the expression of oncogenic proteins such as cytokeratin 18, vimentin, urinary plasminogen activator and fibronectin reduced (Lan et al. 2016). There was a substantial decline in the proliferation of malignant cells when ATRA treated cells were compared to alcohol treated cell lines. Additionally, the in vitro intake of iodine increased by 350%, leading to the inhibition of tumour growth following treatment with radioactive iodine in animal models. The authors concluded that ATRA could promote the production of NIS by impeding the transcriptional activities of β-catenin and lead to the enhancement of isotope responsiveness to radio-iodine during the treatment of undifferentiated thyroid cancer in humans.
Bulk tumour cells and rare cancer stem cells (CSCs) pose challenges in the treatment of many malignancies due to their high self-renewal potential. The concurrent delivery of multiple drugs with nanoparticles is gaining momentum as a novel cancer therapy with high efficacy levels. Sun et al. (2015) attempted a combination treatment involving doxorubicin and ATRA in the elimination of bulk tumour cells and CSCs. ATRA and doxorubicin were compressed in the same nanoparticle concurrently using a single emulsion technique. The authors observed that the simultaneous administration of these drugs led to the effective delivery of the medications to CSCs and other cells as well as the precise differentiation of the two types of cells and the destruction of the CSCs. The transformation of CSCs into non-CSCs lowered their self-regeneration potential and rendered them susceptible to chemotherapy. The combined treatment enhanced the anti-cancer effect of the treatment. The authors concluded that this combinational drug delivery system enhanced drug accumulation in malignant cells and cancer stem cells, thus suppressing tumor growth tremendously while lowering the incidence of CSC (Sun et al. 2015).
A recent challenge in thyroid cancer treatment in the management of RR-DTC is its poor prognosis, which is attributed to cancer stem cells that are resistant to radiotherapy. Mei et al. (2017) conducted in vivo studies to investigate the effect of ATRA on CD133-positive cells. Various assays were used in this study, including cell cycle, colony formation, apoptosis, Cell Counting Kit-8, and ethynyl deoxyuridine. The stem cell features of CD133-positive cells were inhibited by ATRA, which prompted the differentiation of these cells to CD133-negative cells as well as programmed cell death of the CD133-positive cells. Mei et al. (2017) concluded that ATRA could suppress the cancerous attributes of CD133-positive cell even though the mechanism involved was unknown. This study provided a novel perspective on the treatment of RAI-R DTC by targeting CD133-positive cells and stimulating the expression of NIS.
Retinoic acid (RA) is another differentiating agent that has been used to stimulate the redifferentiation of thyroid malignancies boosting their intake of I131 and effectiveness to radioactive therapy. However, its impact on ATCs was uncertain. Similarly, resveratrol prompted cancer redifferentiation but its effect on ATC was not known. Li et al. (2018) addressed this knowledge gap by testing the effects of these two drugs on three human ATC cell lines using several experimental assays. The specific cells used were THJ-11T, THJ-16T and THJ-21T. The authors observed that retinoic acid wielded a small inhibitory effect on these cells. There was a significant decline in the number of cells treated with resveratrol as well as a reduction in cyclin D1 immuno-labelling, susceptibility to apoptosis, and initiation of caspase-3. Resveratrol did not prevent the growth of the cancer cells but increased their sensitivity to RA. The findings revealed the possible use of resveratrol on its own or together with RA in the treatment of ATCs. Using resveratrol was beneficial in circumventing resistance to RA in ATC cells. The redifferentiating capacity of resveratrol in ATC cells was also demonstrated (Li et al. 2018), an observation that was corroborated by Shin et al. (2016) in a meta-analysis involving 16 studies and 348 patients. The authors showed that treatment using RA in RAI-R was partially effective in this form of cancer.
Klopper et al. (2015) reported that between 5 and 10% of patients with thyroid cancer had a belligerent type of DTC that was unresponsive to traditional therapy, chemotherapy, and radiation therapy. They demonstrated that about 20% of human thyroid cancers produced a retinoid X receptor (RXR) protein, which could be exploited as a possible target for the management of advanced thyroid cancers using bexarotene. This drug has been previously used for the treatment of T-cell lymphoma with approval from the FDA. In vitro studies have demonstrated that bexarotene inhibits cell growth, whereas in vivo studies have proven that the drug reduces the growth of malignant cells, which is associated with the availability of an RXR isotype (RXRγ). Therefore, Klopper et al. (2015) performed a clinical trial to ascertain tumor response to bexarotene. Secondary measures in the trial involved checking the capacity of iodine concentration in confirmed radioiodine-resistant thyroid cancer following bexarotene treatment as well as finding the relationship between tumor response and the production of RXRγ receptors. Bexarotene was administered at dosages of 300 mg/m2/day following a fourteen-day intake of large quantities of fish oil. The purpose of the fish oil pre-treatment was to avoid hypertriglyceridemia, a common side effect in patients treated with bexarotene. Immunohistochemistry assays of primary tumor tissues were conducted to investigate the expression of the RXRγ protein. However, the trial did not yield satisfactory outcomes.
Later, Shen et al. (2018) investigated the potential role of bexarotene in the preclusion and treatment of drug-resistant cancers. Bexarotene has been used successfully in the chemoprevention and management of several malignancies. Combining it with other cell-killing agents or targeted therapies improves treatment efficacy while alleviating toxicity because its side effects do not overlap with those noted in other drugs. The only shortcoming was that only a small fraction of patients who were treated with bexarotene benefitted from it. It was proposed that the concentration of RXR could be useful as a biomarker to predict bexarotene response in several malignancies including thyroid cancer. Solving this puzzle could pave way for personalised clinical use of bexarotene in the treatment of thyroid cancer.
Immunotherapy
Enhanced comprehension of the operations of the human immune system and the development of immune alteration methods have paved the way for a new era in cancer treatment. Thus, the notion of exploiting the body’s own biology to treat cancer is a ground-breaking field of oncology. Humans have developed special biomolecules known as checkpoint proteins to guarantee that the immune system does not injure the host while mounting an immune response to foreign antigens. These checkpoint proteins stop immune responses before further damage can occur. Nonetheless, as much as cancer cells behave like parasites and can be attacked by the immune system, they have developed numerous machinery to escape the human immune system. One such mechanism is the capacity to restrict immune reactions via immune checkpoints. Novel cancer treatments exploit the knowledge of immune modulation and checkpoints such as “cytotoxic T-lymphocyte antigen 4 (CTLA4) and the programmed cell death 1 (PD1) pathway” (Byun et al. 2017, p. 195).
These new drugs control immune checkpoint proteins such as CTLA4 and PD1, which are receptors formed on stimulated T cells. The development of antibodies that can block these receptors has led to their routine clinical use. Blocking immune checkpoints also causes inflammatory side effects known as immune-related adverse events (IRAEs) (Byun et al. 2017). The symptoms of IRAEs mimic those seen in autoimmune diseases.
Certain immunotherapeutic treatments enhance the body’s capacity to identify and mount responses against malignant cells, thus boosting host anti-tumor immunity. These drugs can prompt lasting responses in specific groups of patients and across several tumor types. Kollipara et al. (2017) reported the excellent performance of immunotherapy in the treatment of a patient with anaplastic thyroid cancer (ATC). The respondent was a 62‐year‐old male with a diagnosis of ATC and had received prior treatment involving a thyroidectomy, lymph node dissection, and chemotherapy. The sequencing of DNA samples from the patient showed a mutation in the BRAF V600E gene and the overexpression of mRNA responsible for the formation of three proteins namely survivin, tubulin beta 3, and thymidine phosphorylase. BRAF forms part of the MAPK signaling pathway that triggers cancer development, whereas the V600E mutation observed in the patient was a widespread BRAF mutation noted in many cancers (Kollipara et al. 2017). Immunohistochemical analyses showed that the tumor produced proteins and antibodies associated with PD‐L1. The patient’s treatment was informed by DNA sequencing data, leading to the decision to use vemurafenib and nivolumab. This treatment resulted in a significant reduction of tumor nodules. The authors concluded that genomic sequencing‐based methods were beneficial in augmenting the immunotherapeutic management of thyroid cancer.
Immunotherapy has been applied in the post-surgical treatment of thyroid cancer in the light of personalized medicine. Wei, Zhang, and Luo (2018) proposed the feasibility of immunotherapy in the management of DTC following surgery due to the capacity to obstruct PD-1, an immune checkpoint receptor in addition to its ligand (PD-L1). Even though there are limited studies exploring the application of immune checkpoint blockers in managing patients with DTC, immunotherapy widens the scope of treatments that may be available for the management of DTC, especially RR-DTC. BRAF and MEK inhibitors are reported to have brief action times and drug resistance. Therefore, combining various inhibitors of small molecules with PD-L1/PD-1 antibodies could enhance the efficiency of thyroid cancer therapy. These new treatments have been proposed, but their preclinical testing in China is constricted by the unavailability of dependable, authentic murine thyroid cancer cell lines and steady animal models.
Opportunities for Future Research
Overall, chemotherapy denotes the use of chemical compounds to stimulate recovery by invigorating the body’s natural defence mechanism, reducing toxic indications, and revoking the negative effects of malignant cells. Chemotherapy drugs may also boost host cell resistance to the adverse effects of cancer cells. Nevertheless, significant outcomes in thyroid cancer chemotherapy have only been realized with substances that can prevent the development of malignant cells or annihilate them. Therefore, there is a need to explore the development of chemical substances that can exploit other aspects of chemotherapy.
The biggest problem observed in the treatment of thyroid cancer is caring for patients who exhibit advanced forms of the disease, for example, those with well-differentiated thyroid cancer that persist even with the use of conventional treatment modalities. Advanced MTC and ATC also present challenges in their management. However, with innovative genetic and genomic expertise, the molecular pathogenesis of thyroid cancer can be studied in greater detail to help in the recognition of genes and reactions that play a role in thyroid cancer advancement, particularly in the initial stages. Having such an insight will provide valuable knowledge to facilitate preclusion, enhanced diagnosis, classification and treatment. Making sense of the molecular pathogenesis of thyroid cancer can promote personalised medical and surgical interventions for patients with complicated thyroid cancers.
Comparative and chronological clinical studies can be performed to provide information regarding the most appropriate treatment strategy at a given disease stage as well as the correct order of treatments in cases requiring more than one treatment approach. The effectiveness of single and combined targeted therapies can also be ascertained alongside the most appropriate dosages to decrease toxicity without compromising their efficacy. The escape phenomenon occurs when previously susceptible tumors become unresponsive to chemotherapy drugs. In such cases, it may be necessary to attempt new drugs. To circumvent this phenomenon, there is a need for comprehensive molecular investigations of metastatic and development of cancerous tissues in the course of therapy.
Most patients with resistant thyroid cancer have reduced quality of life because of side effects associated with using multiple thyroid cancer chemotherapy agents. Therefore, there is a need for cross-resistance studies between drugs to prevent unwarranted, redundant, and destructive treatments. Preclinical exemplars and clinical trials need to be done to determine the connections between different TKIs, new cancer drugs, EBRT, and conventional cytotoxic chemotherapy. A deeper comprehension of the molecular basis of cancer development, incursion, metastasis, and mechanism of resistance develops could shed light on the development of novel, directed drugs that could selectively destroy malignant cells while sparing normal cells. This achievement can lower drug toxicity to improve the quality of life for cancer patients.
Conclusion
Chemotherapy is not used as the first line treatment for thyroid cancer. However, it is a viable option for the management of cancers that do not respond to conventional therapies, including partial and complete surgical interventions. Several chemotherapeutic drugs have been developed and approved for use by the FDA. However, cross-resistance continues to challenge the use of chemotherapy in thyroid cancer management. Furthermore, the adverse side effects associated with some drugs limit their use even though the drugs can eliminate malignant cells effectively. Therefore, there is a need for investigations to understand the molecular mechanism of thyroid cancer development, invasion, metastasis, and resistance. Furthermore, the development of selective chemotherapy agents can minimize the side effects of chemotherapy and enhance patient wellbeing while undergoing treatment.
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