REVIEW ARTICLE

https://doi.org/10.5005/jp-journals-10088-11236
Indian Journal of Endocrine Surgery and Research
Volume 19 | Issue 1 | Year 2024

Targeted Therapy in Thyroid Cancer

Upander Kumar1https://orcid.org/0000-0002-3186-0359, Nancy Raja2, Rambhit C Dwivedi3, Ashwinee Rahalkar4, Mithun Raam5https://orcid.org/0000-0001-7766-0320, Kul R Singh6, Pooja Ramakant7, Anand Mishra8

1,2Department of Endocrine Surgery, King George’s Medical University, Rewari, Haryana, India

3Department of General Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, India

4,5Department of Endocrine and Breast Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, India

6–8Department of Endocrine Surgery, King George’s Medical University, Lucknow, Uttar Pradesh, India

Corresponding Author: Upander Kumar, Department of Endocrine Surgery, King George’s Medical University, Rewari, Haryana, India, Phone: +91 7056423286, e-mail: upkmsonuafmc@gmail.com

How to cite this article: Kumar U, Raja N, Dwivedi RC, et al. Targeted Therapy in Thyroid Cancer. Indian J Endoc Surg Res 2024;19(1):30–46.

Source of support: Nil

Conflict of interest: Dr Pooja Ramakant is associated as Editor-in-Chief of this journal and this manuscript was subjected to this journal’s standard review procedures, with this peer review handled independently of the Editor-in-Chief and his research group.

Received on: 15 April 2024; Accepted on: 15 May 2024; Published on: 17 June 2024

ABSTRACT

Personalized medicine for thyroid cancer (TC) involves tailoring treatment plans based on a patient’s specific genetic makeup and tumor characteristics. This effective treatment strategy is ultimately improving patient outcomes and quality of life. Various tyrosine kinase inhibitors, serine/threonine kinase or B-Raf proto-oncogene (BRAF) and mitogen-activated protein kinase (MAPK/MEK) inhibitors, neurotrophic tyrosine receptor kinase (NTRK) fusion inhibitors, rearranged during transfection (RET) inhibitors, vascular endothelial growth factor (VEGFR) inhibitors, redifferentiating agents, and immunotherapies have shown promising results in the last decade since their introduction for treating thyroid cancer (ThyCa). These agents may be used for radioiodine refractory (RAIR) differentiated TC (DTC), disseminated, recurrent, residual anaplastic TC (ATC), and medullary TC (MTC). They hardly have any contraindications. The knowledge of their safety profile has expanded with more and more use. They have tolerable side effects and occasionally may require treatment discontinuation or switching to other agents. The armamentarium of available drugs and new targets is rapidly increasing with the results of clinical trials. Their use in pregnancy, the risk of hematological malignancy, geographical variations in their availability and cost, definitive guidelines, and managing drug resistance are current challenges. Advances in molecular diagnosis, artificial intelligence, and molecular scissors may completely revolutionize targeted therapy in the future.

Keywords: Advanced thyroid cancer, Personalized medicine, Radioiodine refractory thyroid cancer, Redifferentiating agents, Tyrosine kinase inhibitors.

INTRODUCTION

TC is the foremost prevalent hormonal cancer. Now the proportion of aggressive and disseminated thyroid tumors is rising. RAIR TCs, poorly differentiated TC (PDTC) and ATC give worse outcomes and present serious difficulties for medical professionals. MTC with lymph nodes and/or distant metastases has a worse prognosis.1 Conventional cytotoxic chemotherapies along with radiotherapy were ineffective in improving the lives of advanced locally or disseminated TC patients. TC was only a surgical disease concept that has gone through transformation with the advances in therapeutic options.2 Advancements in disease biology, thyroid pathogenic kinases, and collaboration among endocrinologists, medical oncologists, and patients have led to a new era of targeted therapy in the past 20 years.3 The approval sequence of targeted therapy is depicted in Figure 1. Accessible and affordable tumor deoxyribonucleic acid (DNA) sequencing, an expanding list of investigational drugs, and patient demand have improved their quality and length of life.

Fig. 1: Targeted drug sequence of approval for TC

PATHOPHYSIOLOGY

Fig. 2A: Regulatory pathways for TC

Fig. 2B: Regulatory pathways for MTC

Follicular cells transform into different types of TC after undergoing certain mutations as depicted in Figure 2C. In papillary thyroid carcinoma, 30–70% have BRAF V600E mutation, and 7% have translocation of RET/PTC. 10–15% of FVPTC have RAS mutation, in follicular thyroid carcinoma, almost half of all cases have RAS mutation, and over a third have translocation of PAX8–peroxisome proliferator-activated receptor γ (PPARγ).9

Fig. 2C: Molecular mutations in TC

Anaplastic TCs typically have mutations in the p53 tumor suppressor gene (50–80%), CTNNB1 (66%), and RAS (20–40%). And 25% of MTC are hereditary form and 25% have RAS mutation. Other uncommon gene mutations in TC are TERT, NTRK fusion, PIK3A, and PTEN.9

Our immune system protects us from cancer transformation and progression. It recognizes and destroys abnormal cells before they can develop into tumors. Additionally, the immune system plays a crucial role in identifying and eliminating cancerous cells that may have formed. The mechanism is depicted in Figure 2D. The mechanisms underlying combined therapies that include immune-mediated checkpoint barriers against Pd1 or Pdl1 prevent PDL1 and PDL2 from reducing each other’s inhibiting properties in the tumor microenvironment.8 As a result, blocking the PD1 axis increases the strength of T cells’ anticancer response and the expansion of natural killers (NK).

Fig. 2D: Regulatory pathways for immune responses that impede the growth of tumors

By decreasing angiogenesis, Lenvatinib and other treatments that target the VEGF or VEGFR pathways slow the growth of tumors. It has also been demonstrated that VEGF blockade reverses immune deficiency in the cancerous milieu by encouraging the maturity of dendritic and limiting the interaction of suppressor T cells, macrophages, and suppressor cells of myeloid origin.8

Radiation therapy, BRAF and MEK inhibition, and certain RET inhibitors increase the triggering of major histocompatibility complex type I (MHCI) and/or the expression of antigens. The immune-suppressive cytokines and VEGF production can be reduced by targeting the BRAF-MAPK cascade.9

The TC is classified into subcategories according to specific epigenetic and genetic modifications caused by a variety of intrinsic factors.10 Comprehensive TC genetic and epigenetic profiling from huge databases, such as the Cancer Genome Atlas (TCGA) and the Memorial Sloan-Kettering Cancer Centre group, displayed an extensive variety of genetic and somatic variants, gene fusions, and copy number modifications that could easily differentiate WDTC from PDTC and also varies for different histological subtypes.11 Over the last decade, our understanding of molecular genetics has grown significantly, and tailored medicines for specific gene and protein abnormalities have emerged. Some of these molecular targets have been summarized in Table 1A.12

Table 1A: Molecular targets for different TC subtypes
Mutations Thyroid tumor types Approximate prevalence (%) * Influences on primary signaling routes Influence on protein and tumor activity
BRAFV600E CPTC 45 Extracellular signal-regulated kinase (ERK)/MAPK Stimulating; encouraging carcinogenesis, invasion, metastasis, recurrence, and death
  FVPTC 15
  TCPTC 80–100
  ATC 25
BRAFK601E FVPTC 4 ERK/MAPK Stimulating; possibly as BRAFV600E.
NRAS, KRAS, HRAS FTA 20–25 ERK and PI3K–AKT Stimulating; encouraging carcinogenesis, invasion, metastasis of PDTC and FTC
  FTC 30–45  
  FVPTC 30–45  
  PDTC 20–40  
  ATC 20–30    
PTEN (mutation) FTA 0 PI3K/AKT/mTOR Inhibiting the genome while stimulating the PI3K pathway increases cancer and invasiveness
  FTC 10–15  
  ATC 10–20  
  PTC 1–2  
PTEN (deletion) FTC 31 PI3K/AKT/mTOR Inhibiting the genome while stimulating the PI3K pathway increases cancer and invasiveness
PIK3CA FTA 0–5 PI3K/AKT/mTOR Stimulating; promoting tumorigenesis and invasiveness
  FTC 5–15    
  ATC 15–25    
  PTC 1–2    
AKT1 Disseminated carcinoma 16 PI3K/AKT/mTOR Uncertain; appears to promote metastasis
CTNNB1 PDTC 25 WNT–beta-catenin Stimulating; enabling the growth of tumors
  ATC 60–65    
TP53 PDTC 25 p53-dependent processes Inhibiting; enabling the growth of tumors
  ATC 70–80    
IDH1 FTC 5–25 IDH1-associated metabolic pathways Inhibiting; effect on tumors is uncertain
  FVPTC 20    
  CPTC 10    
  ATC 10–30    
ALK ATC 11 ERK and PI3K–AKT Stimulating; probably enabling the growth of tumors
EGFR CPTC 6 ERK and PI3K–AKT Stimulating; effect on tumors is uncertain
GRIM19 HCTC 14 Part of the first complex of the mitochondria oxidative pathway Probably Inhibiting; influences mitochondrial activity and demise of cells.

REDIFFERENTIATION OF RADIOIODINE-RESISTANT THYROID CARCINOMA

Iodine is transported to follicular cells with the help of sodium iodide symporter (NIS). As TC undergoes subsequent mutations may disrupt this symporter and the tumor becomes radioiodine resistant. Pathways involved in making tumor radioiodine resistant and targeting intermediaries for redifferentiation are depicted in Figure 3A. Amplification of NIS’s basolateral trafficking proteins results from the abnormal MAPK signaling process, impairing NIS’s ability to function. NIS is inhibited when the PI3K-AKT cascade is triggered. The mTOR route inhibits NIS protein transcription factors. Thus, PPI3K, AKT, mTOR, and MAPK inhibitors aid in redifferentiation. Other potential agents used are modulating transcription of the NIS pathway (retinoic acid, HDAC, and PPARγ inhibitors), demethylating agents, and telomerase inhibitors elaborated in Table 1B.13–23

Table 1B: Agents used for redifferentiation of refractory TC
Class Drug Study Response
BRAF and MEK inhibitors13,14 Dabrafenib (150 mg twice a day BD) Phase II clinical trial 6/10 patients increased radioiodine uptake
MEK inhibitors15 Selumetinib (25 mg/m2 BD) Phase II clinical trial 12/20 patients increased radioiodine uptake
HDAC inhibitors Romidepsin 7 mg/m2 during a 21-day cycle on days 1, 3, and 5 × 3 cycle   10% response rate
PPARγ inhibitors Rosiglitazone 8 mg once a day OD for 6 weeks Kebebew et al. 25% response rate
Retinoic acid 13 cis Retinoic acid    
PDGFRα Crenolanib 100 mg TDS Phase II clinical trial  
Her 3 Lapatinib (750–1500 mg escalating dose) NCT01947023 is a phase I trial (Dabrafenib + Lapatinib) 60% response rate with a median PFS of 15 months
mTOR inhibitors Everolimus (10 mg OD) NCT02244463 1/1 patient in 2 trails
PFS: 15.2 months
Telomerase inhibitor Curcumin (0.2–12 gm over 3 months) Schwertheim et al.  
TKIs16–18 Lenvatinib 24 mg/
Sorafenib 400 mg/Cabozantinib 60–140 mg once a day		 Multicenter Phase II/III trails PFS/OS 10.8/-, 20.2/-, 8.9/14.4 months, respectively

Fig. 3A: Redifferentiation mechanism pathways and its target agents

ATC AND PDTC

The most successful targeted medication for treating ATC patients with a mutant BRAF V600E is dabrafenib with trametinib. The other BRAF/MEKi, vemurafenib, and NTRKi, in ATC, exhibit an inadequate therapeutic response. Lenvatinib’s efficacy could not be as good as expected, and other tyrosine kinase inhibitors (TKIs) that target angiogenesis might not work at all when taken individually. However, the therapeutic effect rate rises substantially when combined with chemotherapeutic or anti-PD1/PD-L1 medications. According to fundamental research discoveries RETi, mTORi, CDK4/6i, and CA4P may be promising targeted therapeutic options for ATC patients.24 Different therapeutic agents for anaplastic and poorly differentiated TC mechanisms have been depicted in Figure 3B and summarized in Table 1C.25–30

Table 1C: Therapeutic agents for anaplastic TC24
Class Drug Study Response
Multitarget tyrosine-kinase inhibitor (TKI) Lenvatinib (24 mg daily)
Sorafenib (400 mg daily)		 Accepted at the 2019 Annual Meeting of the Japanese Society of Medical Oncology One year after initiating Lenvatinib, the ORR was 45%, the progression-free control rate was 76.4%, and the median survival rate was 18.4%
BRAF and MEK antagonist25 Dabrafenib (150 mg BD + Trametinib (2 mg OD) European Society of Medical Oncology 2018 OS 86 weeks, PFS 60 weeks
Immunotherapy Spartalizumab (400 mg IV/28 days)
Pembrolizumab 200 mg IV		 Underway trials (NCT03181100; NCT03122496; NCT02239900; NCT02404441) RR 19% (phase 2 trial)
OS 5.9 months, 40% @ 1 year
NTRK inhibitors Larotrectinib26 and Entrectinib Ongoing trials (e.g., NCT02576431, NCT02122913, NCT02568267, NCT02650401)  
RET Selpercatinib Phase ½ trial (2 ATC patients) 18 months (1 patient)
ALK fusions Crizotinib (250 mg OD) One case report 90% of all pulmonary lesions disappeared accessed @ 6 months
Antiangiogenic drugs Lenvatinib (24 mg OD continuous cycles) Prospective clinical trial, Japan (2000 to 2012) 24% responded, OS 10.6 months
Anti-EGFR molecules Gefitinib (250 mg daily) open-label phase II trial 1/5 had stable diseases for 1 year
mTOR inhibitors Everolimus (10 mg OD) NCT02244463) 1/1 patient in 2 trails
PFS: 15.2 months
Vascular disrupting agents Fosbretabulin (45 mg/m2 IV fusion, D1,8,15 of 28day cycle) Phase II trial 7/26 patients had stable disease
CDK 4/6 inhibitors Palbociclib (125 mg daily) In vitro testing Rb-positive ATC cells exhibit dose-dependent suppression of growth

Fig. 3B: Targets for anaplastic TC

MTC

RET gene-mutated kinases were initially discovered as point mutations in MTC and rearrangement defects in PTCs. RET gene kinase structure resembles VEGFR2, making it suitable for anti-angiogenic drugs. The early phase 1 trial of motesanib diphosphate inhibited RET kinase at a concentration 20 times higher than VEGFR2, suggesting potential use in treating RET-driven cancers. Sorafenib was the first approved drug in 2013 for progressive, RAIR DTC enhanced cancer-free survival. [5.8–10.8 months (m)]. Lenvatinib further improved to 18.3 months.31 Sorafenib and lenvatinib have been compared in Table 1D.

Table 1D: Sorafenib and lenvatinib comparison
  Decision trial Select trial
Patient (n) 416 392
Arms Sorafenib vs placebo Lenvatinib vs placebo
Median age 63 years 64 years
Histopathological variant of DTC [n (%)] 118 (57%) 132 (50%)
PTC 50 (24.2%) 101 (38.7%)
FTC 24 (11.6%) 28 (10.7%)
PDTC
mPFS (months)
10.8 vs 5.8
18.3 vs 3.6
ORR 12.2 vs 0.4%, p < 0.0001 64.7 vs 1.4%, p < 0.0001
OR HR 0.80 (95% CI: 0.55–1.17) HR 0.72 (95% CI: 0.51–1.08)
  p = 0.13 p = 0.11
Incidence AE (%)
(All grades)		 98.6% 97.3%
Death-related therapy (n) 1 6
Reference (27, 28) (29)

In MTC, Vandetanib which inhibits VEGFR2, RET, and EGFR kinases was approved in 2011 improved progression free survival (PFS) from 19.3 (placebo) to 30.5 m. Cabozantinib was used in metastatic progressive MTC that had tripled the PFS. Improvement in PFS did not translate into improving overall survival (OS). It might be due to further mutation leading to accelerated progression, or there are other important hidden pathways with more clinical implications. Cabozantinib’s response to the RET M918T mutation led to an improvement in PFS and an increase in OS from 18.9 to 44.3 m. It led to the new concept of targeting oncogenic drivers.29

Pralsetinib and selpercatinib are specific drugs intended for those with RET-altered MTC. Its potency for wild RET mutation is 8–28 times greater than that of standard drugs like vandetanib and cabozantinib.32 MTC targets and drugs have been summarized in Figure 3C and Table 1E.33

Table 1E: Therapeutic agents for medullary TC
Drug/Dose Targets Study Approval Outcome
Cabozantinib 140 mg/day MET, RET and VEGFR-2 EXAM trial (Phase III) 2012 (FDA)
2013 (EMA)		 PFS: 11.3 months compared with 4.1 months (placebo)
HR: 0.29; 95% CI: 0.20–0.41; p < 0.0001
Vandetanib 300 mg/day RET, VEGFR-2 and EGFR ZETA trial (Phase III) 2012 (FDA)
2012 (EMA)		 PFS: 30.4 months compared with 19.2 months (placebo)
Selpercatinib 160 mg twice a day RET LIBRETTO trial (Phase I/II) 2020 (FDA)
2021 (EMA)		 HR: 0.45; 95% CI: 0.30–0.70; p < 0.0001
Pralsetinib 300 mg/day RET ARROW trial (Phase I/II) 2020 (FDA)
NA (EMA)		 HR: 0.70; 95% CI: 0.49–0.90; p < 0.0001
EMA, European Medicines Agency; FDA, Food and Drug Administration

Fig. 3C: Targets for medullary TC

GENETIC MARKERS EVALUATION32

NGS is a promising method for identifying and treating indeterminate thyroid nodules and cancer, as it provides precise genetic information.34,35 Its evolution is depicted in Figure 4. Afirma XA ThyroSeq V3, TheGenNEXT, and ThyraMIR are new targeted mutation detection approaches for thyroid neoplasm that offer a higher NPV and a better PPV than conventional genetic tests36 have been compared in Table 2. Determining mutational updates can help with prognosis and personalized treatment, but whether this will enhance overall outcomes is unknown. NGS shows potential for customized treatment and diagnosing TC.37

Fig. 4: Molecular diagnostic evolution timeline

Table 2: Comparison of Afirma XA, Thyroseq V3, and ThyGeNEXT/ThyraMIR
Afirma XA ThyroSeq V3 ThyGeNEXT/ThyraMIR
Whole transcriptome RNA next-generation sequencing Customized RNA and DNA next-generation sequencing Customized RNA and DNA next-generation sequencing + miRNA expression
Sensitivity 68% Sensitivity 82% Sensitivity 90%
Specificity 91% Specificity 94% Specificity 93%
Negative prediction ability 96% Negative prediction ability 97% Negative prediction ability 95%
Positive prediction ability 47% Positive prediction ability 66% Positive prediction ability 74%
Rule out malignancy Rule out and rule in malignancy Rule out and rule in malignancy
Two dedicated FNA pass One dedicated FNA pass It may be performed on routine stained smears, enabling the selection of adequate representative slide
Only accredited laboratory performs and requires a centralized morphology review It may be performed at the local Institute It may be performed at the local Institute
Indeterminate (Bethesda 3–4) and malicious/cancerous nodules (Bethesda 5–6) Indeterminate (Bethesda 3–4) and malicious/cancerous nodules (Bethesda 5–6) Indeterminate (Bethesda 3–4)

INDICATIONS for TARGETED THERAPY IN TC

CONTRAINDICATIONS43

There are very few absolute contraindications of targeted therapy and can be given with dose modifications. They have been summarized in Table 3A.

Table 3A: Contraindications of targeted therapy
Targeted agents Absolute contraindications Relative contraindications
TKI Pregnancy Hypertension, interstitial lung disease, and long-QT syndrome
Immunotherapy Failure to communicate, pregnancy ahead of the initiation of immunotherapy, uncontrolled/unstable asthma, children less than 2 years and elderly patients >65 years, start during pregnancy, concomitant lymphoid malignancies, AIDS patients, Consecutive immune system decline in primary and secondary immunodeficiency syndromes Cardiovascular diseases, treatment with beta-blockers, angiotensin-converting enzyme (ACE) inhibitors, selective serotonin reuptake inhibitors (SSRI), monoamine oxidase inhibitors (MAO), persistent infections, autoimmune illnesses, and uses of immune-suppressing drugs
Selective RET inhibitors   Anemia, thrombocytopenia, neutropenia, uncontrolled diabetes, Hypertension, hypertriglyceridemia, and hypercholesterolemia
Antiangiogenic agents Chronic kidney diseases Crcl <30 mg/dL, Child-Pugh class B& C Hypertension, Chronic kidney diseases Crcl 30–60 mg/dL, Child-Pugh class A, colitis, hypocalcemia, neutropenia, thrombocytopenia, acne, photosensitivity, QT prolongation > 500 ms, heart failure, stroke, angina, gangrene, interstitial lung diseases, bleeding disorders, reversible posterior leukoencephalopathy syndrome
ALK fusion (Crizotinib) QT prolongation > 500 ms Hypersensitivity
mTOR inhibitors Systemic fungal infection, taking antiseizure medications, and severe infection, pneumonitis Hypersensitivity, galactose intolerance, hematological impairment (anemia, thrombocytopenia, neutropenia), uncontrolled diabetes, hypertriglyceridemia, and hypercholesterolemia
NTRK inhibitors (larotrectinib and entrectinib), Anti-EGFR, CDK 4/6 inhibitors (palbociclib), BRAF and MEK inhibitors There are no listed contraindications. Hypersensitivity and other side effect may need dose modifications  
CrCl, creatinine clearance; ms, milliseconds

Advantages

  • Potentially less damage to healthy cells.

  • Potentially less adverse effects.

  • Higher efficiency (more than 50% response rate vs 30% compared with conventional chemotherapies).44

  • Better standard of living.

Adverse Events (AEs)

AEs related to TKI therapy can be classified as “on-target,” referring to the target’s elevated effect, or “off-target,” referring to the alteration of additional targets that may be physiologically or entirely unrelated to the target. Liver dysfunction, issues with digestion, elevated blood pressure, proteinuria, and restlessness are the most frequent complications. These AEs, which usually happen 2–3 weeks after therapy, have an impact on patient adherence and present new difficulties in terms of controlling side effects and enhancing patients’ quality of life. Compared with other multiple kinase inhibitors (MKIs), approved TKIs including Selpercatinib and pralsetinib had lower rates of dose reductions and discontinuations owing to AEs related to treatment and improved toxicity characteristics.45

TKI-induced hepatotoxicity typically occurs within 2 months of treatment, with symptoms like fatigue, nausea, and dark urine. Biochemical markers include elevated alanine aminotransferase (ALT), aspartate aminotransferase (AST), alkaline phosphatase (ALP), bilirubin, and globulin and decreased albumin synthesis.4

TKIs can cause gastrointestinal toxicities, such as diarrhea, nausea, vomiting, and pancreatic atrophy. Nausea rates range from 23–58%, with the most common being lenvatinib, cabozantinib, and selpercatinib. Vomiting rates range from 10 to 48%, with pazopanib being the lowest.4

Diarrhea was reported in 30–79% of patients, most commonly with vandetanib. Treatments include loperamide, antibiotic therapy, hydration, octreotide administration, and dose reduction if antidiarrheal therapies are insufficient.4

TKIs are linked to cardiovascular damage due to the role of TK-R in proper cellular homeostasis. Major heart ailments include hypertension, decreased ventricular ejection fraction, coronary artery disease, and QT lengthening.45

Adverse events related to targeted therapy have been summarized in Table 3B9 and the mechanism of TKI-induced hypertension has been depicted in Figure 5.46

Table 3B: Adverse events associated with targeted therapy in TC
Adverse events Sorafenib Lenvatinib Vandetanib Entrectinib Cabozantinib Larotrectinib Pralsetinib Selpercatinib
(All grade) (%) (%) (%) (%) (%) (%) (%) (%)
Fatigue 51 58 25 47 40 36 37 37
Diarrhea 68 58 55 36 62 23 35 37
Hypertension 40 69 33 NR 32 12 41 44
Anorexia 31 48 22 12 45 14 16 NR
Weight loss 48 47 11 NR 47 NR NR NR
Nausea 21 40 34 33 44 30 16 34
Hand-foot syndrome 75 33 NR NR 49 NR NR NR
Skin rash 51 16 44 12 17 NR 25 NR
QT prolongation NR 7 15 3.3 NR NR NR 18
Weight gain NR NR NR 24 NR 14 NR 24
Increased alanine aminotransferase levels 25 0.4 NR 37 88 46 44 50
Increased aspartate
aminotransferase levels		 22 0.4 NR 43 87 46 68 56
NR, not reported

Fig. 5: TKIs induced hypertension mechanism

Treatment Planning

Treatment planned by medical oncologists is based on disease pathology and molecular biology, patient performance status, comorbidities, side effects, cost, availability, and response to treatment. Customized treatment and patient stratification are aided by a broader genetic classification. Generally, RAS-like tumors react better to differentiation therapy than BRAF-like tumors. This could be because of variances in the way that each tumor behaves to multikinase inhibitors or because RAS-like tumors have more basal differentiation. Each patient needs personalized treatment and needs to be discussed in MDT before planning therapy. BRAF and TERT mutation are very important in TC prognosis and outcome.47 The most used first-line agent is sorafenib followed by sunitinib/lenvatinib as the second-line agent followed by pazopanib as the third-line agent.29,48 Initial treatment can be started with nonselective MKI inhibitors affecting the diverse types of tyrosine kinase receptors such as sorafenib and lenvatinib. More selective agents are better where the specific mutation is known. These selective agents should be preferred for having side effects and comorbidities such as hypertension because of their fewer side effects. Antiangiogenetic drugs with immune checkpoint blocking agents are indicated for the treatment of advanced TCs due to biological reasons, and a randomized controlled trial is presently being conducted to evaluate the efficacy of lenvatinib with pembrolizumab in this regard. BRAF V600E mutated DTCs and ATC do not respond similarly to BRAF and MEK inhibitors. These agents have excellent responses [ORR (overall response rate) 58 vs 33%] in high mutation burden and high MAPK output ATC compared with DTCs that have low mutation burden and low MAPK output.15,49 Also, immunotherapy along with BRAF inhibitors has a better response [ORR 10 vs 65%] in ATC compared with immunotherapy alone.50,51 DTC has a low mutation burden and a slow-growing tumor. BRAF inhibitors alone can lead to activation of alternate Her 2/3 pathway. So, the combination of BRAF with Her 2/3 inhibitors (lapatinib) can avoid resistance and have a better response in DTC.52 Combination therapy prevents resistance which should be preferred in rapidly growing and poorly differentiated tumors, such as BRAF and MEK inhibitors, using immunotherapy and vascular disrupting agents along with TKIs. It checks different mutation populations of cells and dose reduction improves the side effect profile. Treatment planning and sequencing have been summarized in Figures 6A and B respectively.

Fig. 6A: Targeted therapy choices in TC

Fig. 6B: Treatment sequencing

Guidelines for Targeted Therapies in TC53

  1. Discussing individualized treatment plans and exploring the role of genetic testing in determining tumor mutations and gene expression profiles in the most effective personalized treatment.

  2. Active surveillance may be an option with timely monitoring meanwhile the patient’s general condition improves to restart targeted therapy or become fit for surgery.

  3. Local therapies like surgery, embolization, and radiotherapy may delay the need for systemic therapy in otherwise elsewhere stable diseases.

  4. In progressive diseases, multikinase inhibitors are used as the initial line of therapy, followed by the utilization of RET inhibitors as a second-line option, and subsequently NTRK inhibitors as a third-line treatment.

  5. Ongoing research should aim at developing novel therapies targeting alteration for improved outcomes in TC patients.

Patient Education

These drugs target the alterations within cells by interfering with specific proteins that aid in the growth and metastasis of malignancies throughout the body. They have distinct kinds of side effects and differ from conventional chemotherapy. Patients are encouraged to follow a healthy lifestyle exercising regularly, taking nutritious food, avoiding junk foods containing trans-fat and sugar, limiting smoking and alcohol, and managing stress. These activities rebuild their strength and energy levels. These improve the targeted therapy’s hepatic, gastrointestinal, and cardiovascular side effects.

Evaluation

The patient is assessed for any significant medical history (hypertension, diabetes, asthma, medication review, etc.), and blood work [Complete blood count (CBC), liver and renal function test, coagulation profile, random blood sugar, thyroid function test (TFT), ECG, and echocardiogram] are taken. Also, head, neck, thorax, abdomen, and pelvis imaging using contrast-enhanced computed tomography (CECT) to assess metastatic disease.45,53

The patient monitoring, treating drug-induced hypertension, and potential drug interaction of targeted therapy have been summarized in Table 3C-1 to 3C-3, respectively.53

Table 3C-1: The suggested timeline for clinical assessment of patients undergoing targeted treatments for metastatic thyroid carcinoma
Days Clinical examination CBC, LFT, RFT, BP, ECG, urinalysis Imaging
7 Yes Yes –
14 Yes Yes –
28 Yes Yes –
42 If required If required –
56 Yes Yes –
84 Yes Yes Yes
Table 3C-2: The suggested therapy course for hypertension in patients undergoing targeted treatments for metastatic thyroid carcinoma
Phase Drug group Dose
1 ACE antagonist, for example, Captopril 12.5–25 mg
2 Nicardipine 10–60 mg
3 Consult a cardiologist  
Table 3C-3: Combined pharmaceuticals could lengthen the QTc duration
Antibiotics Macrolides, Fluoroquinolone, Metronidazole, Penicillin derivatives, Ceftriaxone
Antifungals Itraconazole
Antihistamines Mizolastine
Antivirals Lopinavir/Ritonavir
Antimalarials Piperaquine, Mefloquine, Mefloquine
Anesthetics Halogenated volatile anesthetics
Antiarrhythmics Amiodarone, Sotalol, Quinidine,
  Procainamide
Antidepressants Tricyclene antidepressant
  Serotonin–Norepinephrine reuptake inhibitors
Antipsychotics Fluphenazine, Risperidone
  Clozapine, Haloperidol
  Pimozide, Ziprasidone
Other Cisapride

Prognosis and Cost

Until recently, patients with progressive TC refractory to 131I therapy (RAI-R), as well as ATC and MTC patients had a dire outcome, with OS after 10 years under 15%.

Comprehending the etiology of malignant neoplasms has enabled the discovery of innovative targeted treatments to enhance the results. Since 2011, five single medications (sorafenib, lenvatinib, vandetanib, cabozantinib, and selpercatinib) and one combination therapy (dabrafenib with trametinib) have been approved by the regulatory agencies, all demonstrating increases in progression-free survival or high response rates.45 For a month of treatment, all medications are available within the range of 5000 rupees except selpercatinib, BRAF and MEK inhibitors. When patents expire, the cost of these products will decrease and they will become more affordable. At least in preliminary human trials, more focused targeting of mutant oncogenic kinases is producing greater efficacy with fewer toxicities. Though it seemed impractical only 15 years ago, endocrinologists, medical oncologists, and patients were working together to make progress possible. Tumor gene sequencing is becoming more and more affordable, and this, along with a growing portfolio of investigational drugs and patient demand for better treatment options, will surely result in new and more effective targeted therapies that improve our patients’ quality and longevity of life.

Healthcare Team Outcome

Aggressive metastatic TCs can be treated exclusively with continuous monitoring. As a result, managing these patients requires a highly personalized approach that considers the patient’s chance of recurrence as well as specific needs. The collaboration of all multidisciplinary team members, which includes but is not restricted to the thyroid surgeon, pathologist, radiologist, endocrinologist, and maybe oncologist, is essential in delivering the best care for the patient while eliminating unnecessary therapy.

The nursing team must make sure that the patient feels included comfortably at all stages of treatment, including preparing for therapy, medicine therapy, and monitoring response and AEs. A dedicated oncology is a valuable complement to a multidisciplinary team during targeted therapy. Interprofessional teamwork is dependent on open communication among the entire team and meticulous record-keeping to make sure that all experts working on the case have access to the latest patient details and can contact one another if whatever needs to be addressed. This sort of interprofessional supervision of care, paired with free data sharing, will produce the most favorable patient outcomes.

PEARLS AND OTHER ISSUES

Pretreatment biopsy investigation identifies immunohistochemistry that may distinguish ATC, lymphoma, or pleomorphic sarcoma and aids in the design of targeted therapy depending on the mutation profile. ATC’s genetic study should include TERT promoter mutations that are linked to RAS or BRAF alterations, as well as targetable aberrations. Lenvatinib and sorafenib could be considered regular initial therapies for RAI-resistant DTC.54 Recently, the FDA and EMA licensed larotrectinib for all the TRK gene fusion proteins exhibiting malignancies in adults and children.54 Prior MKI therapy is not a barrier to future use of these drugs. MKIs must be taken until the patient requests to stop receiving treatment, the condition worsens, or the toxicities become unacceptable. Locoregional therapy (e.g., EBRT, embolization, percutaneous interventional approaches) can be used for local management in cases of single-site advancement that does not stop MKIs.23 Highly selective medicines have improved safety identities, such as larotrectinib for TRK overexpressing malignancies and RET antagonists (e.g., BLU 667, LOXO 292). Due to the adverse effect of MKI inhibitors on the thyroid gland, TSH may rise. so, it should be monitored every month to make sure that suppression remains intact. Patients should have skin lesion surveillance and early treatment because they might get a second malignancy, such as a skin or hematological malignancy. Because MKIs can be lethal if given to a pregnant woman and can diminish fertility in both sexes, conservation of fertility strategies should be explored before therapy begins.

Present Gap in the Treatment Options

TKI use is insufficient during pregnancy. Some studies are possible due to advanced maternal-age pregnancies and increased cancers. While some studies report the successful administration of imatinib, erlotinib, and nilotinib studies related to TC-specific agents are lacking. However, AEs and concern for teratogenic effects persist. Most pregnancy data on TKI use is inconclusive, leading to the co-prescription of TKIs with an effective contraception method during therapy and several weeks after discontinuation.

Other concerns are the severe AEs of TKIs. These AEs lead to insufficient dosing, defaults, and discontinuation of therapy. Also, AEs of TKIs limit their use in patients with comorbidities, such as hypertension, interstitial lung disease, and long-QT syndrome.

Cancer-targeted therapy still faces a big challenge from TKIs that have developed resistance through a variety of methods. There is a lack of effective therapies for patients with advanced or disseminated TC who do not have specific genetic mutations that can be targeted by TKIs. Current shortcomings include resistance to targeted therapies and limited treatment options for patients with advanced diseases. MKIs yet improves PFS but none translates into improving OS.

Although TKIs have shown success in the therapy of TC, more effective and personalized therapeutic options are still needed.

Additionally, developing new resistance mechanisms and lacking predictive biomarkers further complicate the management of TC patients receiving tyrosine kinase therapy.

Treatment of diseases beyond progression is a critical aspect of medical care. It involves exploring alternative treatment options when the initial treatment is no longer effective. This can include experimental therapies, clinical trials, or palliative care to manage symptoms and improve quality of life.

Barriers to Treatment of Patients Driven by Genomics

Resistant to personalized treatments: development of genetic mutations in RAS by BRAF600E facilitated tumors after BRAF antagonist therapy.

Most non-actionable DNA alterations are implicated in the advancement of TC.

The chronological and geographic diversity of tumors.

Access to genome sequencing and/or innovative therapies varies by country, location, and healthcare situation.55,56

Current Debate

The effectiveness of molecular testing in indeterminate lesions in the early phase of the application. Not all mutation translates into malignancy. Even the same mutation can be identified in benign conditions. The very high cost of molecular testing limits its uniform application in management and therefore does not translate into proportion benefit. The vast majority of TKIs are non-specific inhibitors of numerous proteins in the primarily activated MAPK pathway. Even resistance to these drugs can develop quickly. Further treatment guidelines are not clear about the effectiveness of other TKIs of the same or different groups. The ideal MKI sequence in RAI-refractory DTC is also not defined presently. Recommendations for dosage and substitutes in the event of serious adverse effects are also limited.

Future

Molecular markers offer the potential for diagnosing malignant lesions on fine needle aspiration (FNA) biopsy, distinguishing aggressive and indolent disease, gaining knowledge affecting clinical decision-making on a large scale, and opening new options for possible therapeutic targets.36

Artificial intelligence (AI) technology has boosted the success rate and precision of diagnosis and treatment of various tumors. AI provides novel approaches to ultrasound and histopathological examination by merging a tumor’s morphological, textural, and molecular characteristics and surroundings. This will open the path for a TC at the personal level, improving medical data acquisition and analysis.7,57

Molecular scissors will be deployed in somatic cells to correct the mutation changes. More clinical trials will be conducted to explore various therapeutic options and find the optimal combination of drugs to maximize patient outcomes.58 Gene therapy may be a potential treatment for RAIR TCs.13,21

CONCLUSION

Targeted therapy is now regarded as an exciting strategy in customized TC management. It targets specific genetic mutations or biomarkers, improving treatment outcomes, redifferentiating radioiodine-resistant tumors, and reducing side effects while minimizing harm to the patient’s body. The whole treatment plan has been summarized in Figure 6C.

Fig. 6C: Treatment summary

ORCID

Upander Kumar https://orcid.org/0000-0002-3186-0359

Mithun Raam https://orcid.org/0000-0001-7766-0320

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