An Audit of Systemic Therapy in Medullary Carcinoma Thyroid

Abstract

There is a paucity of evidence of the impact of sorafenib on MCT and it is the preferred therapy used in India. We decided to do an audit of all patients of MCT who were referred to us for systemic therapy. The objective of this exercise was to identify the treatment pattern, outcomes, and adverse events with therapy in MCT. Baseline demographics (age, gender, ECOG PS, comorbidities, habits), tumor 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, and follow-up were extracted from the rare tumor database and electronic medical records. Out of 75 patients referred for therapy for MCT, 47 (62.7%) patients were considered for immediate tyrosine kinase inhibitors as they had symptomatic status and 28 (37.3%) patients were kept on observation due to the asymptomatic nature of the disease. Out of the 28 patients, 15 (53.6%, n = 28) patients were subsequently started on TKI while in 13 (46.4%, n = 28) patients observation was continued. In the overall cohort, the median PFS was 18.9 months (95% CI 11.9–29.9) and OS was 26.6 months (95% CI 14.4–39.0). Among variables tested, only female gender had an impact on PFS (hazard ratio = 0.364 95% CI 0.148–0.895; P = 0.028) and the absence of lung metastasis had a positive impact on OS (hazard ratio = 0.443 95% CI 0.207–0.95; P = 0.037). Most commonly used TKI was sorafenib (n = 61) and sunitinib in 1 patient. The most common adverse events with TKI were palmo-plantar dysesthesia (50, 80.6%) and oral mucositis (25, 40.2%). The strategy of treating symptomatic MCT and observing in asymptomatic MCT is associated with reasonable PFS and OS. Sorafenib is the most commonly used TKI in our setup and provides similar outcomes as globally.

Background

Medullary carcinoma thyroid (MCT) is an uncommon thyroid malignancy [1]. Surgical management is the cornerstone of its management when the disease is localized or has locoregional spread [1]. Management of metastatic disease is either by active surveillance or by systemic therapy [1].

The systemic management of medullary carcinoma thyroid was largely based on antiangiogenic multi-kinase inhibitors with non-specific activity on RET, either vandetanib [2] or cabozantinib [3]. These recommendations and the United States Food and Drug Administration (FDA) approvals were based on large phase 3 randomized studies. However, recently selective RET inhibitors selpercatinib [4] and pralsetinib [5] have been approved by the FDA. These recommendations were based on non-randomized single-arm studies. Thus, a range of TKI can be used in MCT; however, in low- and middle-income countries (LMIC) due to the cost and in-availability of these agents, other options have to be used. In India, sorafenib is frequently used for the treatment of MCT. The experience of sorafenib in MCT is limited to 16 patients only from a phase 2 study [6].

There is a paucity of evidence of the impact of sorafenib on MCT and it is the preferred therapy used in India. We decided to do an audit of all patients of MCT who were referred to us for systemic therapy. The objective of this exercise was to identify the treatment pattern, outcomes, and adverse events with therapy in MCT.

Methods

Selection of Cases

The cases with carcinoma thyroid with the below-mentioned features were selected for this analysis.

1. Pathologically confirmed diagnosis of medullary carcinoma thyroid

2. Adult age (≥ 18 years)

3. The patient referred for palliative systemic therapy

4. Patients on prospective studies were excluded

All three criteria had to be satisfied for inclusion in the current audit.

Data Collection

Baseline demographics (age, gender, ECOG PS, comorbidities, habits), tumor 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, and follow-up were extracted from the rare tumor database and electronic medical records. The data were censored for analysis on 31st January 2021.

Statistical Analysis

SPSS version 16 (SPSS Inc. Released 2007; SPSS for Windows, Version 16.0. Chicago, SPSS Inc.) and R version 3.6.2 (The R Foundation for Statistical Computing Platform) were used for analysis. Descriptive statistics were performed. Progression-free survival (PFS) was calculated from the date of referral for systemic therapy to the below mentioned dates depending upon the status of systemic therapy. In patients who were started immediately on TKI, the date considered was the date of progression after the start of TKI. In patients who were asymptomatic and were started on TKI when they became symptomatic, the date considered was the date of progression after the start of TKI. In patients who were asymptomatic and were not started on TKI on becoming symptomatic, the date considered was the date of progression.

Progression-free survival on a tyrosine kinase inhibitor (PFS-TKI) was calculated from the date of the start of systemic therapy to the date of progression. 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. Overall survival on tyrosine kinase inhibitors (OS-TKI) was calculated from the date of the start of systemic therapy to the date of death. 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.

Results

Baseline Characteristics

We identified 75 patients with medullary carcinoma thyroid referred for palliative systemic therapy. The baseline characteristics of these patients are given in Table 1. Sixty-five patients (86.7%) had received previous treatment. The previous treatment received was surgery in 24 (32%), surgery followed by radiation in 32 (42.7%), and palliative radiation in 9 (12%) patients.

Table 1.

Baseline characteristics of patients with medullary carcinoma referred to Medical Oncology for systemic therapy (overall cohort n = 75)

Variable	Value
Age in years
Median	48
Range	25–71
Gender-No. (%)
Male	56 (74.7)
Female	19 (25.3)
ECOG performance status-No. (%)
0–1	69 (92)
2	4 (5.3)
3	2 (2.7)
Comorbidity-No. (%)	12 (16)
Hypertension	4 (5.3)
Diabetes mellitus	5 (6.7)
Ischemic heart disease	2 (2.7)
Thyroid status-No. (%)
Euthyroid	50 (66.7)
Hypothyroid	25 (33.3)
Metastasis-No. (%)
Bone	44 (58.7)
Liver	30 (40)
Lung	41 (54.7)
Brain	3 (4)

ECOG Eastern Cooperative Oncology Group

Treatment Pattern

Figure 1 provides the treatment pattern. Out of 75 patients referred for therapy, 47 (62.7%) patients were considered for immediate tyrosine kinase inhibitors as they had symptomatic status and 28 (37.3%) patients were kept on observation due to the asymptomatic nature of the disease. Out of the 28 patients, 15 (53.6%, n = 28) patients were subsequently started on TKI while in 13 (46.4%, n = 28) patients, observation was continued.

Fig. 1.

Flow chart depicting the patients who were selected for the audit for medullary carcinoma, the treatment patterns, and their outcomes (immediate TKI cohort and surveillance cohort)

Outcome

Overall Cohort

The median follow-up was 38 months (95% CI 33.8–42.3). There were 45 events of progression. The median PFS was 18.9 months (95% CI 11.9–29.9). The 2-year, 3-year, and 5-year PFS were 42.3% (95% CI 29.6–54.3), 32.3% (95% CI 20.2–44.4), and 21.1% (95% CI 9.5–35.8), respectively (Fig. 2). Among variables tested, only female gender had an impact on PFS (hazard ratio = 0.364 95% CI 0.148–0.895; P = 0.028) (Table 2). The median PFS was 13.2 months (95% CI 8.9–19.5) in males versus not reached (95% CI 19.8–NA) in females.

Fig. 2.

Kaplan–Meier curve depicting the PFS in the overall cohort. There were 45 events of progression. The median PFS was 18.9 months (95% CI 11.9–29.9). The 2-year, 3-year, and 5-year PFS were 42.3% (95% CI 29.6–54.3), 32.3% (95% CI 20.2–44.4), and 21.1% (95% CI 9.5–35.8), respectively

Table 2.

Multivariate analysis for PFS and OS in the overall cohort and immediate TKI start cohort

	Hazard ratio (95%CI)	P value
Factors for PFS-overall (n = 75)
Age	1.02 (0.99–1.05)	0.166
Gender (female)	0.36 (0.15–0.89)	0.028
Bone metastasis	1.23 (0.63–2.43)	0.524
Liver metastasis	1.33 (0.73–2.43)	0.344
Lung metastasis	1.81 (0.91–3.57)	0.088
Factors for OS-overall (n = 75)
Age	1.01 (0.98–1.03)	0.568
Gender (female)	0.54 (0.22–1.33)	0.178
Bone metastasis	1.33 (0.65–2.75)	0.437
Liver metastasis	1.276 (0.67–2.43)	0.462
Lung metastasis	2.26 (1.05–4.83)	0.037
Factors for PFS-TKI in immediate TKI cohort (n = 47)
Age	1.01 (0.98–1.04)	0.514
Gender (female)	0.778 (0.22–2.70)	0.692
Bone metastasis	1.792 (0.81–3.96)	0.148
Liver metastasis	1.45 (0.66–3.16)	0.351
Lung metastasis	1.78 (0.84–3.80)	0.134
Factors for OS-TKI in immediate TKI cohort (n = 47)
Age	1.01 (0.97–1.04)	0.637
Gender	0.62 (0.20–1.92)	0.410
Bone metastasis	1.49 (0.65–3.44)	0.340
Liver metastasis	1.19 (0.51–2.75)	0.684
Lung metastasis	1.98 (0.90–4.37)	0.089

There were 40 deaths. The median OS was 26.6 months (95% CI 14.4–39.0). The 2-year, 3-year, and 5-year OS were 50.1% (95% CI 37–61.8), 42.3% (95% CI 29.5–54.5), and 30% (95% CI 17.2–43.9), respectively (Fig. 3). Among variables tested, only the absence of lung metastasis had a positive impact on OS (hazard ratio = 0.443 95% CI 0.207–0.95; P = 0.037) (Table 2). The median OS was 15.5 months (95% CI 12.5–21.4) in presence of lung metastasis versus not reached (95% CI 38–NA) in absence of lung metastasis. Table 2 shows the multivariate analysis for PFS and OS.

Fig. 3.

Kaplan–Meier curve depicting the OS in the overall cohort. There were 40 deaths. The median OS was 26.6 months (95% CI 14.4–39.0). The 2-year, 3-year, and 5-year OS were 50.1% (95% CI 37–61.8), 42.3% (95% CI 29.5–54.5), and 30% (95% CI 17.2–43.9), respectively

Immediate Started on TKI Cohort

Out of 47 patients, progression events were observed in 33 patients. The median PFS-TKI was 9.47 months (95% CI 7.4–15.67). The 1-year and 2-year PFS-TKI were 44.2% (95% 28.5–58.9) and 14.4% (95% CI 4.8–28.9) (Fig. 4). Among tested factors, none of the factors impacted PFS-TKI (Table 2). There were 32 deaths leading to a median OS of 13.63 months (95% CI 9.93–18.2). The 1-year, 2-year, and 3-year OS-TKI were 59.1% (95% CI 42.5–72.4), 26.2% (95% CI 13–41.5), and 19.1% (95% CI 7.8–34.2) (Fig. 5). Among tested factors, none of the factors impacted OS-TKI (Table 2).

Fig. 4.

Kaplan–Meier curve depicting the PFS in the immediate TKI start cohort. Out of 47 patients, progression events were observed in 33 patients. The median PFS-TKI was 9.47 months (95% CI 7.4–15.67). The 1-year and 2-year PFS-TKI were 44.2% (95% 28.5–58.9) and 14.4% (95% CI 4.8–28.9)

Fig. 5.

Kaplan–Meier curve depicting the OS in the immediate TKI cohort. There were 32 deaths leading to a median OS of 13.63 months (95% CI 9.93–18.2). The 1-year, 2-year, and 3-years OS-TKI were 59.1% (95% 42.5–72.4), 26.2% (95% CI 13–41.5), and 19.1% (95% CI 7.8–34.2)

Asymptomatic Cohort

Out of 28 patients, 12 had progression events for PFS. The median PFS was 45.3 months (95% CI 25.2–NA). The 2-year PFS and 5-year PFS were 79.9% (95% CI 58–91.1) and 34.3% (95% CI 11–59.6). There were 8 deaths and the median OS was not reached (95% 39–NA). The 2-year OS and 5-year OS were 84.2% (95% CI 63–93.8) and 56.1% (95% CI 26.8–77.6).

Among the 15 patients who were started on TKI, 10 had progressed on TKI and the median PFS-TKI was 19.6 months (95% CI 6.3–21.2). The 2-year PFS was 20.8% (95% CI 3.4–48.3). There were 6 deaths in this cohort and the median OS was 24.1 month (95% CI 7.8–NA). The 2-year OS was 57.3% (95% CI 24.5–80.2).

Treatment Compliance and Adverse Events

The adverse events related to TKI are shown in Table 3. TKI stoppage due to toxicities occurred in 9 patients (14.5%).

Table 3.

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

Toxicities of TKI N = 62	Grade 1 and 2 (CTCAE) Number (%)	Grade 3 and 4 (CTCAE) Number (%)
Palmoplantar dysesthesia (hand foot syndrome)	41 (66.1)	9 (14.5)
Proteinuria	15 (24.1)	-
Hypertension	17 (27.4)	1 (1.6)
Oral mucositis	23 (37.0)	2 (3.2)
Anemia	12 (19.3)	-
Transaminitis	16 (25.8)	-

Discussion

To the best of our knowledge, this is the largest experience published in the real-world setting on systemic management of advanced and/or metastatic medullary carcinoma thyroid. A unique pattern of treatment was seen in the study. Nearly $\raisebox{1ex}{$1$}\!\left/ \!\raisebox{-1ex}{$3$}\right.$ of patients only were kept on surveillance in spite of having disease on imaging. This was done as these patients had asymptomatic disease. Nearly 50% of these patients only required treatment, thus, attesting to the safety of this approach and the judgment of treating medical oncologists. The excellent PFS and OS in this cohort further provides confidence in this approach. This approach differs from NCCN guidelines which would suggest asymptomatic and imaging negative patients to be kept on observation. We feel that this approach of ours, avoids adverse events of TKI and the financial cost of TKI and its complications without impacting the outcomes.

The current study shows important differences in treatment between high-income countries and low-middle-income countries. The choice of treatment in the current study was largely dictated by availability and cost. Both vandetenib and cabozantinib during the period of this study were not available in India and hence the choice of treatment. Sorafenib was the most favored TKI (98.4%). This was based on the available phase 2 results of sorafenib by Lam et al. In the 16 patients, phase 2 study response rate of 6.3% and a median PFS of 17.9 months was observed [6]. The median PFS-TKI observed in patients with immediate start of TKI cohort was 9.0 months. This is lower than the PFS reported in multiple studies [7–10]. The reason being most of these studies have included only ECOG PS 0–1 patients and have treated asymptomatic patients too [7–10]. As we restricted our treatments in symptomatic patients, we feel that the median PFS was lower. However, this is in concurrence to international data from Brazil by Castroneves et al. In this study of progressive metastatic medullary carcinoma, the median PFS of sorafenib was 9 months [11].

The drug stoppage due to adverse events in our study was 14.5% and grade 3–4 HFS was seen in 14.5% of our patients. The literature reported that drug permanent discontinuation rate was 5–25% while the grade 3–4 HFS rate was 8–28% [7–10]. Our data is similar to this data thus suggesting that adverse events in Indians are similar to that seen worldwide.

This was a single-center study and is of retrospective nature. However, it was done in a large academic cancer center which drains > 50% of its patients across India. Hence, the data is generalizable for India. All consecutive patients who were willing for treatment and referred were captured. The data provides real-world evidence.

Conclusion

The strategy of treating symptomatic MCT and observing in asymptomatic MCT is associated with reasonable PFS and OS. Sorafenib is the most commonly used TKI in our setup and provides similar outcomes as globally.

Declarations

Conflict of Interest

The authors declare no competing interests.