The most widely established method of treatment of differentiated thyroid cancer (DTC) has been radioactive iodine (RAI) therapy, especially in either papillary or follicular subtypes. In most instances, such a focused-treatment approach results in remission and a positive long-term prognosis. There are, however, a bunch of patients who have a more difficult route: RAI resistance. Such patients fail to respond to the conventional treatment, hence the clinicians and patients are left to traverse the thorny path in choosing an alternate treatment.
With the development of the medics, there is a growing awareness of why some of the thyroid cancer goes refractory to RAI and how there can be different treatment alternatives that will give renewed hope.
In the present article, we investigate the pathophysiology of RAI resistance and highlight the potential options that hold the promise of shifting the therapeutic framework of thyroid cancer.
Understanding Differentiated Thyroid Cancer and RAI Therapy
Most of the thyroid cancer is differentiated and makes up over 90 per cent of all thyroid cancers, and the survival rate is most likely to be high once operated on and maintained with RAI. The RAI therapy is easy yet effective, by using the fact that the thyroid cells and thyroid cancer cells both absorb iodine, making it possible to administer radioactive iodine, and destroy any traces of cancer remaining following thyroidectomy.
Nonetheless, not every patient is benefiting from it. About 5-15 percent of differentiated thyroid cancer will become resistant to RAI; thus, they will not absorb iodine, and therefore, RAI can no longer be effective against their cancer. This raises major risks such as disease progression, metastasis, as well as higher mortality.
Why is there RAI Resistance?
Causes of RAI resistance. The causes of RAI resistance in thyroid cancer are most often cellular and molecular adaptations to modify the cancer behaviour:
- Deficiencies of iodine uptake-related mechanisms: In certain tumours, major proteins controlling the process of iodine uptake, e.g. the sodium-iodide symporter (NIS) become underexpressed or relocalized. RAI does not work when these proteins fail to work properly.
- Dedifferentiation of tumour: Differentiated cancers of the thyroid may progress towards dedifferentiation in the course of time. They also become unable to absorb iodine as they lose their thyroid-like properties.
- Genetic mutations: BRAF V600E and TERT promoter mutations, in addition to other specific genetic alterations, are related to the aggressive disease and RAI resistance. Such mutations favour tumour growth and inhibit iodine-combining genes.
Explaining these underlying causes is important towards the design of target therapies that can either revert RAI resistance or eliminate the necessity of iodine.
The Clinical Challenge of RAI-Refractory Thyroid Cancer
The RAI-refractory term includes a few clinical situations:
- No uptake of iodine in early or relapse disease
- Development of RAI-treated disease
- RAI dosage more than 600 mCi without appreciable remedy
The prognosis of patients with such categories is much worse. Survival rates may be reduced to practically 50 per cent after a metastasis of a distant nature has developed, and RAI will cease to be useful.
Clinicians have no choice but to switch gears and seek alternatives. This course of action needs to strike a balance between disease burden, symptoms, age of the patient, and quality of life, and this makes it extremely important to have good and customised alternative treatments.
Alternative Treatment Pathways
Since RAI will no longer appear as an option to certain patients, numerous therapies have been developed to replace it. There is no particular solution; however, the following approaches are becoming more and more popular and promising to patients with refractory disease.
1. Targeted Therapies
Targeted therapy has transformed the treatment of several cancers, and this has not been the exception with thyroid cancer. The drugs are molecular inhibitors against tumour proliferation and survival.
- The FDA has approved tyrosine kinase inhibitors (TKIs), sorafenib and lenvatinib, in DTC that are resistant to RAI. These drugs selectively inhibit the growth and angiogenesis of the tumour through receptors such as VEGFR, RET and FGFR.
- The RET inhibitors, such as selpercatinib and pralsetinib, are very effective in patients with RET fusion-positive cancers of the thyroid.
Although TKIs are effective in the treatment of cancer, they result in side effects such as hypertension, diarrhoea, and fatigue. They are used mostly in patients with progressive symptom onset or the metastatic phases.
2. Redifferentiation Therapies
A potential research area is regaining the tumour cell capacity to take iodine, a technique called redifferentiation. The use of agents such as MEK inhibitor (e.g. selumetinib) or BRAF inhibitor (e.g. dabrafenib) may have the potential to reinstantiate expression of the NIS to make tumours susceptible to a second course of RAI treatment.
This method, albeit still in clinical trials, can be the key to re-sensitising tumours that did not respond to RAI in the first place.
3. Immunotherapy
Immune checkpoints Goal Even though it is still in its early research phases in thyroid cancer, immunotherapy with checkpoint inhibitors (e.g., anti-PD-1 and anti-CTLA-4 antibodies) is under development, especially in combination with other drugs. Based on the promise of immunotherapy against other tumours, there is hope (tempered) that it might be useful against RAI-refractory disease, particularly the anaplastic or poorly differentiated forms.
4. External Beam Radiation Therapy (EBRT)
EBRT can be used as a non-systemic therapy to manage the symptoms and disease progression of patients whose tumours are localised and inoperable or experience painful metastases of the bone.
5. Clinical Trials and Investigational Therapies
Since thyroid cancer that is resistant to RAI is an elaborate thing in terms of its biology, trial enrollment can allow one to obtain access to advanced treatments. Trials can be of novel combinations of drugs, of genetic interventions, or of new modes of delivery, not yet widely available.
This is one of the resources that patients and health workers can refer to as they seek alternative treatment as far as head and neck cancers are concerned and this is one of the resources that are known as Eisai Oncology which has information and more resources on information of treating cancers of the head and the neck including thyroid malignancies.
Personalised Medicine: A Guiding Principle
An enhancement of personalised medicine is especially relevant to the process of RAI-resistant thyroid cancer. Tumour molecular profiling is used to discover the mutations that determine which treatments can be most productive. In this practice, patients will avoid ineffective treatments and have a better chance of getting positive results.
As an example, in patients with a BRAF mutation, a BRAF inhibitor could be used and in patients with a RET fusion, that could be a selective RET inhibitor. Individual treatment plans are effective not only in enhancing the success of treatment but also in decreasing unnecessary exposure to toxicity.
Conclusion
Though RAI is regarded as a cornerstone therapy in several patients with thyroid cancer, patients who develop resistance have no choice. Targeted therapies and redifferentiation agents, as well as molecular diagnostics, have been greatly improved, increasing the therapeutic pipeline. Proper surveillance and early management of RAI-refractory disease are important as they would enhance survival and quality of life.
Further research will only enhance the other course of receiving treatment, and thus the people who suffer RAI-resistant differentiated thyroid cancer are once again given some light of hope. It is not only what the future of care of thyroid cancer will look like, but rather what it is already doing now.
