The reality of treating radioactive iodine-refractory differentiated thyroid cancer: current challenges and available options
In this article, Dr Jaume Capdevila, Medical Oncologist at the Vall d´Hebron University Hospital and Vall d’Hebron Institute of Oncology (VHIO; Barcelona, Spain) discusses the challenges around treating and managing radioactive iodine-refractory differentiated thyroid cancer where there are currently few treatment options.
Over the last 30 years, the rates of thyroid cancer have significantly increased [1]. While the increase may be attributed to improved access to healthcare and detection methods, the treatment of some types of thyroid cancer can still be hugely challenging and at times disheartening, with variable prognoses among the different subtypes.
Thyroid cancer is the ninth most commonly occurring cancer globally and the most common endocrine malignancy [2,3]. Of the different types of the disease, differentiated thyroid cancer (DTC) is the most common, accounting for ~85% of thyroid malignancies [4].
Thyroid cancer can have the false perception of being a ‘less serious’ cancer
In comparison to other cancers, DTC can sometimes have the perception of being less severe than other cancers. Less than 20% of patients develop local, regional or metastatic disease and many cases reach remission when treated with the mainstay approach that includes surgery, thyroid stimulating hormone suppression and radioactive iodine I-131 (RAI) [5].
However, there is a group of underserved patients who are living in high uncertainty. Between 5–15% of DTC and 50% of metastatic DTCs are refractory to RAI treatment and for these patients the treatment options available are limited, resulting in a poorer prognosis [6]. Unfortunately, radioactive iodine-refractory (RAI-R) differentiated thyroid cancers account for the majority of thyroid cancer associated mortality [7].
For those who develop radioactive iodine treatment-refractory disease, there are limited available treatment options
RAI-R DTC is more frequent in older patients, in those with large metastases, in poorly differentiated thyroid cancer and in tumors with high 18-fluordeoxyglucose uptake on positron emission tomography/computerized tomography scan [8]. Guidelines recommend considering other systemic therapies for progressive, disseminated disease and/or symptomatic disease that is refractory to RAI.4 However, treatment of patients who are non-responsive to RAI remains a challenge. While the majority of people living with RAI-R DTC initially achieve disease control with first-line systemic therapy, most will eventually experience disease progression [9]. For these patients, there are very few further options available and unfortunately patients who are non‑responsive to RAI are expected to have a life expectancy of just 3–5 years [9].
Managing care for these patients can be daunting, making it hard to manage expectations
As a treating physician regularly seeing people living with RAI-R DTC, developing a robust care plan that has the possibility of meeting the needs of the patient is a daunting challenge. There is a clear need to manage expectations for these patients who have few viable options left. Depending on the specific nature of the patient case, most often systemic therapy is the first option we reach to, with the aim to achieve tumor control and delay progression. Endocrinologists, oncologists and nuclear medicine specialists are all involved in the care of people living with DTC and the expertise and confidence of these leading healthcare professionals can differ. In my experience, some specialities have variable levels of confidence when managing treatment selection, adverse events and dose modifications whilst maintaining efficacy when prescribing systemic therapies. It is critical that healthcare teams feel supported and have the necessary skills and experience to evaluate and proceed with the highest accuracy possible, with the best possible outcome for their patients at the heart.
The main objective is, of course, to increase the life expectancy of patients, but we must also be cognizant of a patient’s quality of life for their remaining years. These considerations need to be front of mind for healthcare teams when having conversations with patients at the time of treatment initiation, ensuring that the chosen treatment elicits maximum benefit and safety. For this, the team should be aware of which therapy to use at each timepoint and be smart in the sequential strategy of available treatments to offer patients, grounding the treatment decision-making process in evidence-based medicine where possible.
Sometimes a ‘watch and wait’ strategy is adopted
A ‘watch and wait’ strategy is usually not advisable for most types of solid tumors at high risk of progression. Compounded by a distinct awareness of the lack of treatment options available for future lines of therapy as well as with a wish to avoid adding a toxicity burden to their patients, it is a difficult balance for healthcare professionals to strike. However, even though in treating RAI-R DTC a watch and wait approach is an option for some patients and recommended in guidelines, data supporting this are limited and there are no definitive biomarkers to select appropriate patients, meaning the risk of rapid progression should always be considered [10]. If there are no symptoms, healthcare professionals may adopt this strategy before systemic therapy [11].
Initiation of systemic therapy may be delayed several months or even years for the classical well-differentiated thyroid cancer that becomes refractory to iodine. This is provided the healthcare professional is comfortable with sufficient knowledge of the individual case and the disease has a slow tumor growth rate and tumor burden. Careful monitoring of disease activity is crucial when the watch and wait approach is selected to ensure that physicians don’t miss the optimal timing to start systemic therapy – at the time of potential growth and development of disease-related symptoms [11].
However, the watch and wait approach can be risky and might lead to disease progression and can also increase the risk of symptomatic metastasis [11].
Looking ahead for innovation
The unmet need for people living with RAI-R DTC is undeniable, with a distinct lack of treatment innovation entering the field for many years. The mix of emotions that a patient experiences throughout their treatment journey is vast, with evolving prognoses given at different time points in their care. For such a prevalent disease such as thyroid cancer with a high diagnosis rate, when a key backbone treatment such as RAI therapy is ineffective, we should not be in such a position where we are struggling to identify viable treatment options to deliver an effective long-term care plan.
As cancer therapies continue to evolve across the board of tumor types and multi-disciplinary teams become more experienced in their management, we are hopeful that we may also be able to deliver a more positive future for those living with RAI-R DTC.
Disclaimer: Dr Capdevila is a paid consultant of Ipsen. This article was created on the initiative of and with financial and content-related support of Ipsen. The opinions expressed in this article are those of the author and do not necessarily reflect the views of Oncology Central or Future Science Group.
References:
1. Clinical Thyroidology for the public. American Thyroid Association. Available at: https://www.thyroid.org/patient-thyroid-information/ct-for-patients/february-2017/vol-10-issue-2-p-9/. [Accessed April 2022]
2. Sung H et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA: A Cancer Journal For Clinicians. doi: 10.3322/caac.21660.
3. Pellegriti G et al. Worldwide increasing incidence of thyroid cancer: update on epidemiology and risk factors. J Cancer Epidemiol. 2013, 965212 (2013).
4. Porter and Wong. Perspectives on the Treatment of Advanced Thyroid Cancer: Approved Therapies, Resistance Mechanisms, and Future Directions. Frontiers in Oncology. 10, 592202 (2021).
5. Fleeman, N et al. A systematic review of lenvatinib and sorafenib for treating progressive, locally advanced or metastatic, differentiated thyroid cancer after treatment with radioactive iodine. BMC Cancer. 19, 1209 (2019).
6. Aashiq M. et al. Radioiodine-Refractory Thyroid Cancer: Molecular Basis of Redifferentiation Therapies, Management, and Novel Therapies. Cancers (Basel). 11(9), 1382 (2019).
7. Fullmer T. Novel Therapeutics in Radioactive Iodine-Resistant Thyroid Cancer. Front Endocrinol. (Lausanne). 12, 720723 (2021).
8. Schmidt A et al. Radioactive iodine-refractory differentiated thyroid cancer: an uncommon but challenging situation. Arch. Endocrinol. Metab. 61(1), 81-89 (2017).
9. Babu G, Kainickal CT. Update on the systemic management of radioactive iodine refractory differentiated thyroid cancer (Review). Mol. Clin. Oncol. 14(2), 35 (2021).
10. ESMO. Clinical Practice Guidelines – Thyroid cancer (esmo.org). Available: https://www.esmo.org/guidelines/endocrine-and-neuroendocrine-cancers/thyroid-cancer. [Accessed April 2022]
11. Fukuda N et al. Clinical Indications for Treatment with Multi-Kinase Inhibitors in Patients with Radioiodine-Refractory Differentiated Thyroid Cancer. Cancers (Basel). 13(9), 2279 (2021).