Thyroid Cancer in Elderly Patients: Comparison
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Thyroid cancer is more aggressive in elderly patients due to biological causes related to age, histotype, and the advanced stage at diagnosis. In the elderly, both the diagnosis and treatment of thyroid cancer impact quality of life.

  • thyroid cancer
  • elderly
  • age

1. Introduction

Thyroid cancer (TC) is the most common endocrine cancer; according to the latest global cancer data report, TC ranks 11th among malignancies [1]. Histologically, differentiated thyroid carcinoma (DTC) arises from follicular thyroid cells, and it is further subclassified into papillary thyroid carcinoma (PTC), the most common histological type; follicular thyroid carcinoma (FTC); and Hurthle cell carcinoma (HTC). Dedifferentiated thyroid cancer progresses from poorly differentiated thyroid cancer (PDTC) to anaplastic thyroid cancer (ATC). Medullary thyroid carcinoma (MTC) arises from neuroendocrine-derived parafollicular C cells [2]. The incidence of DTC increases with age as well as thyroid cancer recurrence [3,4,5,6,7][3][4][5][6][7]. Thyroid cancer is the only malignancy for which age is a prognostic marker in most staging systems [5,7,8][5][7][8]. The therapeutic management of DTC in elderly patients remains controversial [5]. The term “elderly” generally refers to the chronological age group of the population over 65 years of age [9]. The data available in the literature regarding the results in this age group are not numerous, and the incidence analysis as well as the prognosis in elderly patients are rarely reported [3,10,11,12,13][3][10][11][12][13]. The diagnosis of cancer as well as its treatment impact a person’s quality of life (QoL). QoL and the acceptance of the disease are important in TC, since the follow-up is long thanks to good survival [14].

32. Thyroid Cancer in Elderly Patients

3.1. Peculiar Features of Thyroid Cancer in Elderly Patients

2.1. Peculiar Features of Thyroid Cancer in Elderly Patients

Some studies have reported data on peculiar features of thyroid cancer in elderly patients. In patients aged over 65 years, DTC presents itself at diagnosis with lymph node involvement [11[11][15][16][17][18][19][20],23,24,25,26,27,28], advanced-stage disease (III/IV) [11,23,24,25,27,28,29,30][11][15][16][17][19][20][21][22], distant metastases [11[11][15][16][17][19][20][22],23,24,25,27,28,30], multifocality [24[16][17],25], extracapsular extension [24[16][17][18][20],25,26,28], vascular invasion [11[11][18][21],26,29], and a low percentage of lymphocytic thyroiditis [29][21]. Regarding the histology, the follicular histotype [26][18], anaplastic carcinoma [27][19], and the undifferentiated form [11,30][11][22] are more frequent than in younger patients. Regarding these features, elderly patients have a significantly worse prognosis than younger subjects [30][22]; in addition, age has been identified as an independent risk factor for cancer-specific survival (CSS) [28][20]. Moreover, with increasing age, an increased risk of recurrence was observed together with a reduction in overall survival (OS) [26,27][18][19]. Factors that significantly increase the risk of recurrence in DTC patients >65 years old are the tumor size and lymph node metastasis (LNM) [4,31][4][23]. In a meta-analysis of 16 studies on thyroid cancer in the elderly, seven studies (7496 patients) contained data on the risk of recurrence after surgery, and the odds of recurrence increased 2.13 times (95% CI = 1.21, 3.75) [32][24]. Trimboli et al. showed that the median disease-free survival (DFS) was shorter in patients >55 years of age, and DFS decreased with advancing age. Furthermore, this group of patients had a significantly higher risk of recurrence than younger ones [33][25]. In DTC patients >60 years, cN1b, a tumor of size ≥4 cm, and extrathyroidal extension were significantly associated with the biochemical persistence of disease (BPD), and the age at surgery was associated with a thyroglobulin doubling time (Tg-DT) of <2 years independently of sex and staging [34][26].

3.2. Surgery, Minimally Invasive Techniques (MIT), and Active Surveillance (AS)

2.2. Surgery, Minimally Invasive Techniques (MIT), and Active Surveillance (AS)

It is known that elderly patients often have more comorbidities and higher rates of surgical complications, such as length of hospital stay, intensive care unit admission, and mortality [39,40,41][27][28][29]. For patients aged >80 years, surgical mortality can occur at a rate of up to 7% [42][30]. The characteristics of elderly patients, such as frailty, functional and cognitive limits, and malnutrition, as well as comorbidities and polypharmacological therapies, can affect their ability to complete the therapeutic process and achieve full recovery after surgery [43][31]. Considering these aspects and the low proliferation rate of DTC, the surgical approaches in the elderly have been debated. The majority of the literature concerning the surgical treatment of thyroid cancer in the elderly consists of retrospective studies, lacking detailed information on the specific types of surgical treatment utilized. The studies distinguish between three different types of surgical intervention for thyroid cancer: near-thyroidectomy, thyroidectomy, and thyroidectomy with central and/or lateral nodal dissection. Additionally, comparing patients who were over 75 years of age with those who were under 75 years of age, no difference in the diagnosis of DTC or the type of surgery performed was found [27][19]. Overall postoperative morbidity was not significantly different between age groups [25][17], and no change in survival was observed between elderly patients treated with lobectomy and those treated with total thyroidectomy [30][22]. CSS was not different with respect to the type of surgery performed (lobectomy vs. total thyroidectomy) and with external beam radiation [35][32]. Patients > 85 years who underwent surgery had a better prognosis and overall cancer-specific survival (p < 0.001) than those who did not undergo surgery. For CSS, the 5-year survival and 10-year rates in surgically treated patients were 86.1% and 76.0%, while they were 47.9% and 44.9%, respectively, in unoperated patients [44][33]. In patients aged 65 or older, hospitalization days increased, with no significant change in surgical times or post-operative complications [45,46][34][35]. In patients > 70 years, there were no statistically significant differences in terms of post-surgical complications such as hypocalcemia and recurrent laryngeal nerve palsy (RLNP) compared to younger patients [24][16]. On the contrary, a study highlighted that RLNP was more common in the very elderly [46][35], and a meta-analysis confirmed the increased risk of complications (OR 1.82; 95% CI = 0.88–3.77) after thyroidectomy compared with younger patients [47][36]. Moreover, in elderly patients, the choice of the type of surgical procedure should be tailored considering the tumor and patient characteristics. No significant differences in outcomes between different types of surgery (lobectomy vs. total thyroidectomy) were found in patients with low-risk thyroid cancer, while total thyroidectomy increased the survival rate in high-risk thyroid cancer [28][20]. Comparing surgical times, complications, and hospitalization times between thyroidectomy and lobectomy, no statistically significant differences were observed, both resulting in safe operations in patients > 75 years old [7,48][7][37]. 

3.3. Hormone Replacement Therapy

2.3. Hormone Replacement Therapy

Suppressive therapy with thyroxine is used both as a replacement for thyroid gland function and as a treatment to inhibit thyroid-stimulating hormone (TSH) secretion by the pituitary gland, to prevent thyroid tumor recurrence or metastasis [72][38]. Levothyroxine suppressive therapy is independently associated with longer OS in high-risk patients, and a semi-suppressive thyroid hormone therapy led to an improvement in OS in stage II patients [73][39]. Compared to young subjects, a 20–30% lower levothyroxine dose is required in the elderly to achieve TSH suppression [74][40]. Older people, especially those >80 years, have a reduced rate of peripheral degradation of thyroxine, which is associated with an increase in negative feedback exerted by thyroxine at the pituitary level, leading to a decrease in TSH secretion. For this, despite the slight reduction in the absorption of levothyroxine due to the increased central feedback, lower doses of levothyroxine are required [74][40]. Elderly subjects may have comorbidities that make it necessary to take multiple drugs, such as phenytoin, propranolol, cholestyramine, ferrous sulfate, and warfarin [75][41], which may interfere with the absorption and/or metabolism of levothyroxine. For this reason, it is important to monitor the TSH value together with the free fractions at the beginning of the therapy and during the follow-up. One cause of failure to achieve the therapeutic target of TSH may be the patient’s poor compliance with the correct intake of levothyroxine [76][42]. Follow-up data obtained 5 years after surgery showed significant differences in the occurrence of arrhythmia, insomnia, and anxiety among several groups stratified according to TSH serum values (patients at 0.1–0.3 mIU/m and <0.1 mIU/mL compared to those at 0.3–0.5 mIU/mL) but there were no differences in recurrence and metastasis [77][43]. The bone loss and cardiac toxicity caused by thyrotoxicosis are known from the literature; therefore, it is highly recommended to monitor cardiac function and bone density in elderly patients on suppressive treatment with levothyroxine [73][39].

3.4. Radioactive Iodine I-131 (RAI) Therapy

2.4. Radioactive Iodine I-131 (RAI) Therapy

RAI therapy in thyroid cancer can be considered in an adjuvant or therapeutic setting. Age has been suggested to be related to the low prevalence of RAI avidity [79,80][44][45]. However, a survival benefit can only be expected for patients with RAI-avid lesions [81,82,83][46][47][48]. During the therapy, a period of isolation is required to limit radiation exposure after the administration of radioactive iodine to people other than the patient (according to local regulations). During isolation, patients must follow the instructions of the staff to limit exposure and maintain self-care in eating, dressing, and going to the bathroom [82][47]. RAI therapy in elderly patients with significant cognitive impairment or dependent patients may not be feasible. Because of this, brief contact with relatives to assist patients may be permitted in some cases after obtaining informed consent, according to local guidelines [84][49]. RAI therapy is usually very well tolerated. Short-term adverse effects are rare but include nausea, abdominal discomfort, salivary dryness, and dry eyes [85][50]. Over time, xerophthalmia and xerostomia tend to be the most problematic [85,86][50][51]. Serious but rare complications include bone marrow suppression and radiation pneumonitis. The development of second tumors several years later in patients with thyroid cancer treated with RAI therapy is reported in the literature [87][52]. The risk of adverse effects varies depending on the dose administered and accumulation caused by repeated RAI treatments [84][49]. Stimulation of TSH is required for the absorption and organification of radioactive iodine [88][53], which is obtained with the withdrawal of levothyroxine to achieve biochemically and clinically hypothyroid patients, with significant negative effects on quality of life [89,90][54][55]. In elderly patients, hypothyroidism, in addition to the classic symptoms, leads to several risks that must be monitored for potential cardiac effects (worsening of heart failure and water retention and angina/cardiac ischemia) [74][40]. A severe state of hypothyroidism is associated with reversible conditions of renal insufficiency [91][56], which may decrease radioactive iodine clearance and increase bodily exposure. Further deterioration may occur in patients with memory impairment [74][40]. The use of recombinant human TSH (rh-TSH) avoids the need to send the patient into hypothyroidism [92][57], simulating the hypothyroid state [93,94][58][59]. The use of rh-TSH may reduce the blood total body radiation dose through increased renal clearance in euthyroidism [95][60]; this is especially important in elderly patients, in whom renal failure may be a comorbidity. The empirical dosing strategy (150–200 mCi) often results in administered RAI activity exceeding the maximum tolerable activity (MTA), with a safety limit of 200 cGy (rads), in the blood or bone marrow in many patients with metastatic thyroid cancer.

3.5. External Beam Radiotherapy (EBRT)

2.5. External Beam Radiotherapy (EBRT)

Data on EBRT in the context of thyroid cancer in the elderly are scarce. From the available literature, it appears that radiation therapy in the neck region can be helpful as a supplementary treatment for patients above the age of 40 with inoperable large tumors or for those with remaining or recurring disease. This is particularly true when the tumor is unable to absorb radioactive iodine [35,75][32][41]. EBRT in the general population, not only in the elderly, may play a role in the treatment of DTC, either as an adjuvant therapy in selected cases or as an adjunctive therapy in patients with persistent or metastatic symptomatic disease, considering the toxicity. EBRT is often used for the treatment of patients with bone metastases and related symptoms [100][61]. The toxicity related to radiotherapy of the neck is divided into acute (in conjunction with treatment) and late (persistent). The most common acute complications are mucositis, skin erythema, desquamation associated with pain, weight loss, and the need for pain relief therapy with opioids, as well as hospitalization and sometimes tube feeding. Other types of acute toxicity include xerostomia, hoarseness, and taste perversion [101][62]. Late complications are less common and include esophageal stricture and chronic dysphagia ranging from nasogastric sores for feeding to tracheostomy placement for laryngeal stricture or edema [102][63].

3.6. Target Therapy

2.6. Target Therapy

The definition of radioiodine refractory DTC (RR-DTC) according to the 2015 ATA guidelines is as follows: (1) the primary and/or metastatic lesions do not absorb 131I out of 131I-WBS; (2) the primary and/or metastatic lesions do not demonstrate the ability to concentrate 131I, whereas, before, they were avid for 131I; (3) 131I is concentrated differently in some lesions at the 131I-WBS but not in others; and (4) primary and/or metastatic lesions show progressive disease (PD) within 1 year of 131I treatment despite sustained 131I concentrations [50][64]. Conventional chemotherapy is not associated with lasting responses, while it has significant toxicity [103][65]. Tyrosine kinase inhibitors (TKIs) have been shown to be a treatment for thyroid cancer patients with metastatic or locally advanced RR-DTC. TKIs are administered orally and their mechanism of action is by blocking the tyrosine kinase receptor at various levels (VEGFR 1–3, FGFR 1–4, PDGFR-alpha, RET, and KIT), thereby inhibiting the proliferation signal [104][66]. Evidence has shown that TKIs lead to an antitumor response even at lower than optimal dosages; therefore, patients continue treatment at the lowest tolerated doses [105,106][67][68]. In consideration of comorbidities and polypharmacological therapies in the elderly, it must be kept in mind that that TKIs are metabolized via cytochromeP450 system 3A4 [107][69]. Drug inhibitors of this cytochrome include common drugs such as amiodarone and verapamil, and antibiotics such as macrolides and azole antifungals. Enzyme inducers include dexamethasone, rifampicin, St. John’s wort (herbal remedy for depression), and pioglitazone. In Italy, the two TKIs approved and reimbursed by the National Health System for the treatment of DTC are lenvatinib (first line) and cabozantinib (second and/or third line). In the SELECT study, lenvatinib led to a significantly longer median progression-free survival (PFS) of 18.3 months, compared to 3.6 months in the placebo group, for patients in the treatment arm [108][70].

3.7. Quality of Life

2.7. Quality of Life

DTC in the majority of cases has a very good prognosis, with an overall long-term survival rate of more than 90%. At present, it is known that the diagnosis and cancer management impact various aspects of a patient’s quality of life (QoL), and monitoring these changes is critical. In addition to mortality, cancer can cause significant morbidity, not only from the disease but also from the treatment. This is especially true for DTC patients, who mostly have a long survival period. The Short-Form Health Survey 36 (SF-36) is a generic QoL tool; it is divided into 36 questions that can be self-administered to estimate a health profile that includes eight domains. QoL analysis was severely impaired in 67% and 6% of unoperated and operated patients > 75 years old, respectively, suggesting that surgery for DTC increases the survival rate and promotes the quality of life of patients [56][71]. Physical functioning was worse in thyroid cancer survivors aged ≥ 50 and those with a lower educational level, who needed more follow-up attention [15][72]. When comparing the quality of life test results between thyroid cancer survivors and age- and sex-matched controls, thyroid cancer survivors were observed to more often have >2 comorbid conditions and lower educational levels. No differences were found between elderly thyroid cancer survivors and an elderly normative sample on the EORTC-QLQ-C30 functioning scales [16,117,118][73][74][75].

43. Conclusions

More aggressive forms of DTC occur often in the elderly, presenting with larger tumors, local extension, and/or distant metastases at diagnosis. Survival rates decline with advancing age, regardless of the degree of differentiation of thyroid cancer. The main negative prognostic factors in elderly patients with DTC are more aggressive histological types, the presence of comorbidities and disabilities, and often a delayed diagnosis. The existing literature is ambivalent concerning the significance of patient age in terms of surgical versus nonsurgical treatment outcomes for low-risk thyroid cancer; for this reason, surgery, MIT, or active surveillance can be taken into consideration in the elderly. Compared to young subjects, a 20–30% lower levothyroxine dose is required in the elderly to achieve TSH suppression, and attention may be paid to bone loss and cardiac toxicity. RAI therapy in the elderly is often administrated with rhTSH to avoid the complications of hypothyroidism. In the elderly, reduced iodine uptake by the lesions can be observed, and it seems that this depends on the reduced expression of the sodium iodide symporter (NIS), which is also observed in the elderly or in large-diameter tumors. EBRT must be taken into consideration regarding the patient and the malignancy’s characteristics, as the therapeutic benefits may not always outweigh the risk, especially in elderly patients. In elderly patients becoming metastatic with RR-DTC-resistant disease, tyrosine kinase inhibitors such as lenvatinib and cabozantinib led to longer median progression-free survival. New target therapies such as selpercatinib/pralsetinib or larotrectinib are age- and tumor-agnostic therapies with a good safety and efficacy profile. As regards the elderly, in addition to cancer and its treatment, a major factor that affects the quality of life is advanced age; therefore, attention must be paid to this age group, in terms of both diagnosis and disease treatment.

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