Audit of Demographics, Treatment Patterns and Outcomes of Differentiated Thyroid Cancers Treated with Tyrosine Kinase Inhibitors

Abstract

The real-world patterns of TKI use in differentiated thyroid cancer (DTC) are largely governed by the accessibility and financial feasibility of the patient with more sorafenib use compared to lenvatinib. There are limited data available on the toxicity profile, safety and tolerance of sorafenib and lenvatinib in DTC. Hence, we audited our practice on DTC. This is a retrospective single-centre analysis of patients with DTC who were referred to the Department of Medical Oncology for systemic therapy. Baseline demographics (age, sex, ECOG PS, comorbidities, substance use), tumour details (site of metastasis), previous treatment details, clinical features at metastasis (symptoms), the pattern of treatment, adverse events and outcomes including progression and death were extracted. There were 67 patients with DTC referred for systemic therapy; the median age was 56 (33–81) with a male preponderance (55.6%). The most common reason to start TKI therapy was radioactive iodine (RAI) cumulative dose > 600 milliCurie, followed by low iodine uptake in the RAI low-dose scan done at progression. The most common TKI used in the first line was sorafenib in 56 (83.6%) patients followed by lenvatinib in 9 (13.4%) patients. Papillary thyroid carcinoma was the most common histology (51, 76.1%), and the rest were follicular carcinoma (16, 23.9%). With a median follow-up of 36 months, the median PFS was 13.2 months (95% CI 10.4–16.0). The median OS was 18.8 months (95% CI 10.0–27.6). Among variables tested, no factors had a significant impact on the PFS or OS. The most common adverse events were hand-foot syndrome (54, 80.5%), diarrhoea (23, 33.3%) and transaminitis (24, 34.4%). The pattern of care of patients with RAI-refractory DTC is TKI therapy, especially sorafenib and lenvatinib in the real-world settings with comparable efficacy and safety profile compared to international literature.

Background

The incidence of differentiated thyroid cancers (DTC) has increased over the past decade largely due to increased diagnostic imaging techniques and fine-needle aspiration biopsies [1]. DTCs contribute to 90% of all thyroid malignancies with papillary carcinoma being the commonest followed by follicular carcinoma [2]. For DTC, total thyroidectomy and neck node dissection followed by radioactive iodine (RAI) therapy and subsequent levothyroxine supplementation form the cornerstone of management [3]. However, the development of RAI refractoriness poses a major therapeutic challenge in 15% of the patients with DTC [4]. Recently, multi-kinase inhibitors like sorafenib [5] and lenvatinib [6] are approved for radioiodine refractory DTC. Systemic therapy with sorafenib has a clinical benefit rate (partial response and stable disease) of nearly 80% with a median progression-free survival (PFS) of 18 months for all thyroid malignancies [5, 7].

Improved PFS and overall survival (OS) were noted in patients with younger age, lung-only metastasis and RAI-avid metastatic lesions in DTC [8]. Extensive extrathyroidal extension and age were considered as poor prognostic markers for DTC [9]. Treatment compliance of DTC patients to TKI and their tolerance is largely underexplored areas which may impact the outcomes of these patients.

The real-world pattern of TKI use in DTC is largely governed by the accessibility and financial feasibility of the patient with more of sorafenib use compared to lenvatinib. There are limited data available on the toxicity profile, safety and tolerance of sorafenib and lenvatinib in DTC. The use of TKI has differential efficacy parameters across multiple malignancies. Like EGFR TKI for lung cancer, the impact varies across Asians and Caucasians. It is important to have Indian data to understand whether such differences exist in thyroid cancer. Hence, we audited our practice on DTC.

Methodology

This is a retrospective single-centre analysis of DTC patients who were referred to the Department of Medical Oncology for systemic therapy. The study was conducted according to the ethical guidelines included in the Declaration of Helsinki.

Selection of Cases

The cases with thyroid carcinoma with the following features were selected for this analysis:

1. Pathologically confirmed diagnosis of papillary or follicular carcinoma thyroid

2. Adult age (≥ 18 years)

3. Referred for palliative systemic therapy

4. Patients on prospective studies were excluded

Data Collection

Baseline demographics (age, gender, ECOG performance status (PS), comorbidities, substance use), tumour details (site of metastasis), previous treatment details, clinical features at metastasis (symptomatic or asymptomatic), the pattern of treatment, adverse events (CTCAE version 4.02), date of progression, date of death and status at last follow-up were extracted from the rare tumour database and electronic medical records. The plan of management was decided in a multidisciplinary disease management group after the baseline organ function tests like liver and renal function tests, complete blood count and biopsy confirmation of histopathology. Radiological imaging was repeated at a frequency of 3 monthly intervals. Sorafenib was started at the dose of 400 mg twice daily, lenvatinib was given at the dose of 24 mg once daily and dose reduction by 4 mg was done for the first occurrence of grade 3 toxicities. The data were censored for analysis on 31st January 2021.

Statistical Analysis

SPSS version 20 (SPSS Inc., released 2007, SPSS for Windows, version 20.0, Chicago, SPSS Inc.) and R version 3.6.2 (the R Foundation for Statistical Computing Platform) was used for analysis. Descriptive statistics were performed. PFS was calculated from the date of referral for systemic therapy to specific dates (enumerated below) depending upon the status of systemic therapy. In patients who were started immediately on TKI therapy, the date considered was the date of progression after the start of TKI. In patients who were asymptomatic and were started on a TKI when they became symptomatic, the date considered was the date of progression after the start of TKI (clinical or radiological) or death or last date of follow-up for those who are lost to follow-up.

PFS on a tyrosine kinase inhibitor (PFS-TKI) was calculated from the date of the start of systemic therapy to the date of progression. The Kaplan–Meier method was used for the estimation of PFS and PFS-TKI. The log-rank test was used for comparison. Cox regression analysis was used for the calculation of the hazard ratio. Overall survival (OS) was calculated from the date of referral for systemic therapy to the date of death or last date of follow-up for the patients who are lost to follow-up. Overall survival on tyrosine kinase inhibitors (OS-TKI) was calculated from the date of the start of systemic therapy to the date of death. The Kaplan–Meier method was used for the estimation of OS. The log-rank test was used for comparison. Cox regression analysis was used for the calculation of the hazard ratio. A p value of < 0.05 was considered significant.

Results

Baseline Characteristics

We identified 67 patients with DTC of thyroid referred for palliative systemic therapy. Figure 1 shows the patient selection, histological diagnosis and outcomes of metastatic DTC who received TKI. The baseline characteristics of these patients are given in Table 1. All patients had received previous treatment. The previous treatment received was surgery followed by RAI in 39 (58.2%), surgery followed by radiotherapy (RT) and RAI at progression in 19 (28.4%), surgery only in 2 (3.0%), surgery followed by radiation in 2 (3.0%) and palliative radiation in 2 (3.0%) patients.

Fig. 1.

The patient selection, histological diagnosis and outcomes of metastatic DTC who received TKI

Table 1.

Baseline characteristics of patients with DTC referred to medical oncology for systemic therapy (overall cohort, N = 67)

Variable	Value
Age in years
Median   Range	56 33–81
Sex, No. (%)
Male   Female	37 (55.2) 30 (44.8)
ECOG performance status, No. (%)
0–1   2   3	54 (80.6) 9 (13.4) 4 (6.0)
Comorbidity, No. (%)   Hypertension   Diabetes mellitus   Ischemic heart disease	33 (49.3) 27 (40.3) 15 (22.4) 2 (3.0)
Thyroid status, No. (%)
Hypothyroid   Euthyroid   Hyperthyroid	44 (65.7) 20 (29.9) 2 (3)
Histopathology, No. (%)
Papillary thyroid carcinoma   Follicular thyroid carcinoma	51 (76.1) 16 (23.9)
Metastasis, No. (%)
Bone   Liver   Lung   Brain	42 (62.7) 9 (13.4) 54 (80.6) 6 (9.0)

The reasons for starting TKI are highlighted in Table 2.

Table 2.

Reasons for starting TKI

	Number (%) (N = 67)
RAI cumulative dose > 600 milliCurie and progression < 1 year	18 (26.9)
Progression less than 1 year of RAI only	8 (12.0)
RAI cumulative dose > 600 milliCurie only	11 (16.4)
Low or no RAI uptake at progression	18 (26.9)
Low RAI uptake at progression and RAI > 600 milliCurie	4 (5.9)
Low RAI uptake at progression and progression less than 1 year	4 (5.9)
Unresectable/RT alone	4 (5.9)

Outcome

Overall Cohort

The median follow-up was 36 months. There were 42 events of progression. The median PFS was 13.2 months (95% CI 10.4–16.0) (Fig. 2). Among variables tested, no factors had a significant impact on PFS (Table 3).

Fig. 2.

Kaplan–Meier curve showing the PFS of patients with DTC treated with TKIs. There were 42 events of progression. The median PFS was 13.2 months (95% CI 10.4–16.0)

Table 3.

Multivariate analysis for PFS and OS in patients with DTC

	Hazard ratio (95%CI)	P value
Factors for PFS-Overall (n = 67)
Age	1.00(0.96–1.05)	0.885
Sex (male)	1.26 (0.59–2.67)	0.541
Comorbidity	1.11 (0.49–2.54)	0.803
Follicular thyroid carcinoma	1.342 (0.55–3.25)	0.515
Bone metastasis	1.54 (0.74–3.23)	0.249
Liver metastasis	1.31 (0.54–3.15)	0.550
Factors for OS-Overall (n = 67)
Age	0.98 (0.94–1.04)	0.611
Sex (male)	1.28(0.53–3.07)	0.579
Comorbidity	1.19 (0.46–3.10)	0.717
Follicular thyroid carcinoma	1.78 (0.58–5.55)	0.315
Bone metastasis	1.10(0.48–2.51)	0.816
Liver metastasis	1.72 (0.55–5.38)	0.349

There were 33 deaths. The median OS was 18.8 months (95% CI 10.0–27.6) (Fig. 3).

Fig. 3.

Kaplan–Meier curve showing the OS of patients with DTC treated with TKIs. There were 33 deaths. The median OS was 18.8 months (95% CI 10.0–27.6)

Table 3 shows the multivariate analysis for PFS and OS.

Treatment Compliance and Adverse Events

The most common TKI used in the first line was sorafenib in 56 (83.6%) patients followed by lenvatinib in 9 (13.4%) patients and pazopanib in 2 patients. The clinical benefit rate (complete, partial response and stable disease) was 77.6% (n = 52), and the best response was progression in 16.4%(n = 11). The response was not evaluated in 4 patients. Among the 42 patients who had progression, second-line TKI was used in 20 patients (47.6%). Lenvatinib was the most common TKI used post progression on sorafenib (11, 55%) among patients who received second-line TKI.

The adverse events related to TKI are shown in Table 4. TKI discontinuation due to toxicities occurred in 11 patients (16.4%).

Table 4.

Adverse events associated with TKI in patients with DTC according to common terminology criteria for adverse events (CTCAE)

Toxicities of TKI N = 67	Grades 1 and 2 (CTCAE) Number (%)	Grades 3 and 4 (CTCAE) Number (%)
Palmoplantar dysesthesia (hand-foot syndrome)	42 (62.6)	12 (17.9)
Proteinuria	21 (31.4)	-
Hypertension	36 (53.7)	3 (4.5)
Oral mucositis	27 (40.3)	1 (1.5)
Anaemia	25 (37.3)	-
Transaminitis	23 (34.4)	-
Diarrhoea	20 (28.8)	3 (4.4)

Discussion

RAI-refractory DTC contributes to 15% of the DTC [10] where multi-kinase TKIs like sorafenib [11, 12] and lenvatinib [10, 13] are the standard of care. Sorafenib still continues to be the most common TKI used in the real-world settings for DTC in view of the low cost [14] and manageable toxicity profile [13, 15]. This is the largest study of RAI-refractory DTC from India and one of the largest studies done in this regard in the real-world settings. Most of our patients received sorafenib at first-line progression after RAI refractoriness followed by lenvatinib at progression; however, with the recent availability of generic lenvatinib, it is being increasingly used at first-line setting among patients with DTC in view of better efficacy in PFS and OS when compared to sorafenib [16–18].

The most common cause of RAI refractoriness was crossing > 600 milliCurie of RAI therapy followed by low RAI uptake in the low-dose iodine scan at progression. The clinical benefit rate of TKI in RAI-refractory DTC of 77.6% in our study is comparable to the international meta-analysis data [19]. The PFS of TKI in our study is comparable to the international data for sorafenib [5, 20] and lenvatinib [16, 18] although individual PFS with first-line sorafenib and lenvatinib was not calculated separately in our study due to the low numbers of patients who received first-line lenvatinib (N = 9). Our study differs from a similar real-world study published on DTC [21] in that the multivariate analysis for PFS and OS did not identify any significant factors unlike the Korean study which showed that the presence of lung-only metastasis was a favourable prognostic indicator. The pattern of toxicities noted in the patients in our study mirrors that described in the DECISION trial [20] and the real-world data [21, 22] with hand-foot syndrome being the most common adverse event (60–70%) followed by gastrointestinal and constitutional symptoms leading to a TKI discontinuation rate of 15–20%.

This was a single-centre study and is of retrospective nature. However, it was done in a large academic cancer centre which attracts > 50% of its patients across India. Hence, the data are generalizable to the majority of patients in India. All consecutive patients who were willing for treatment and referred to our department for systemic therapy were included in the study. The data provide real-world evidence.

Conclusion

The pattern of care of RAI-refractory DTC is based on TKI especially sorafenib and lenvatinib in the real-world settings with comparable efficacy and safety profile compared to international literature.

Declarations

Conflict of Interest

The authors declare no competing interests.