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Diagnostic characteristics, treatment patterns, and clinical outcomes for patients with advanced/metastatic medullary thyroid cancer

Diagnostic characteristics, treatment patterns, and clinical outcomes for patients with... Background: Medullary thyroid cancer (MTC) accounts for approximately 1.6% of new cases of thyroid cancer. The objective of this study was to describe patient characteristics, biomarker testing, treatment patterns, and clinical outcomes among patients with advanced/metastatic MTC in a real-world setting in the United States and to identify potential gaps in the care of these patients. Methods: Selected oncologists retrospectively reviewed medical records of patients aged ≥ 12 years diagnosed with advanced MTC. Patients must have initiated ≥ 1 line of systemic treatment for advanced/metastatic MTC between January 2013–December 2018 to be eligible. Patient characteristics, biomarker testing, and treatment patterns were summarized descriptively; progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan– Meier method. Results: The 203 patients included in this study had a mean (SD) age of 52.2 (10.4) years; mean (SD) duration of follow-up from start of first-line treatment was 24.5 (16.0) months. Most patients (82.8%) were initially diagnosed with stage IVA, IVB, or IVC disease. Among all patients, 121 (59.6%) had testing for RET mutations, of whom 37.2% had RET- mutant MTC. The RET-mutation type was reported for 28 patients; the most common mutations reported were M918T (64.3%) and C634R (32.1%). Of the 203 patients, 75.9% received only one line of systemic treatment for advanced dis- ease, and 36% were still undergoing first-line therapy at the time of data extraction. Cabozantinib (30.0%), vandetanib (30.0%), sorafenib (17.2%), and lenvatinib (4.9%) were the most common first-line treatments. Among 49 patients who received second-line treatment, most received cabozantinib (22.4%), vandetanib (20.4%), lenvatinib (12.2%), or sunitinib (12.2%). Median PFS (95% confidence interval [CI]) from start of first- and second-line treatments was 26.6 months (20.8–60.8) and 15.3 months (6.6-not estimable [NE]), respectively. Median OS from initiation of first- and second-line treatment was 63.8 months (46.3-NE) and 22.4 months (12.4-NE), respectively. Conclusions: For the treatment of advanced/metastatic MTC, no specific preference of sequencing systemic agents was observed in the first- and second-line settings. Considering the recent approval of selective RET inhibitors for patients with RET-mutant MTC, future research should investigate how treatment patterns evolve for these patients. Keywords: RET, Medical record, Chart review, Retrospective, Observational, Real-world, United States survival *Correspondence: rparikh@rti.org RTI Health Solutions, 3040 East Cornwallis Road, Research Triangle Park, NC 27709, USA Full list of author information is available at the end of the article © The Author(s) 2022. 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The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Parikh et al. Thyroid Research (2022) 15:2 Page 2 of 14 Background Methods Medullary thyroid cancer (MTC) is a rare cancer evolving Study design overview from neural crest–derived calcitonin-producing parafol- An observational retrospective, medical record review licular C cells [1]. MTC accounts for 1.6% of all histologi- of patients who had a confirmed diagnosis of advanced/ cally confirmed incident thyroid tumors (1,562/95,669 metastatic MTC was conducted. Participating oncolo- cases) in the United States (US) [2]. A study of the US gists (medical/clinical oncologists or hematologist/oncol- Surveillance, Epidemiology, and End Results (SEER) Pro- ogists) who had treated ≥ 1 patient with advanced MTC gram for cases diagnosed in 1994–2013 found that MTC in the year before data abstraction, practiced for ≥ 3 years accounted for 8.0% of all thyroid cancer–related deaths after completion of formal training or board certifica - and 9.1% of age-adjusted thyroid cancer–related mortal- tion, and were the main decision-maker regarding treat- ity during this period [3]. MTC can be either sporadic ment for their patients with advanced MTC abstracted or hereditary, the latter occurring either with other endo- demographic and clinical data into a customized, web- crine neoplasms (multiple endocrine neoplasia [MEN] based case-report form. Oncologists were asked to select types 2A and 2B) or alone (familial MTC). Most MTC a quasi-random sample of their patients by abstracting cases are characterized by a mutation of the rearranged medical records of those whose last names began with a during transfection (RET) proto-oncogene, which can be randomly generated letter. Data abstraction occurred in either germline or somatic [4, 5]. For example, an esti- April–May 2020. Data were then compiled into an ana- mated 65%-90% of sporadic MTCs harbor somatic RET lytic data set of deidentified patient-level data. RTI Inter - mutations [5–7], and autosomal dominant inheritance national’s institutional review board (IRB) reviewed the of an activating RET mutation causes hereditary MTC study protocol and deemed the research, which was not (both MEN2 syndromes and familial MTC) [8]. considered human subjects research in accordance with Approximately half of US patients with MTC are diag- the US Code of Federal Regulations (CFR) Sect.  45 CFR nosed with local disease [9]. The primary and curative 46, to be exempt from full IRB review. treatment for most patients diagnosed with early-stage MTC comprises total thyroidectomy and neck dissec- Study population tion [10]. To treat patients with symptomatic advanced, Eligible patients had a diagnosis of histologically and/ progressive, or recurrent MTC, systemic therapies such or cytologically confirmed MTC or were initially diag - as vandetanib, cabozantinib, and, for patients with RET- nosed with or had progressed to having locally advanced mutant MTC, selpercatinib and pralsetinib are approved or metastatic MTC (collectively referred to as “advanced by the US Food and Drug Administration and included in MTC” hereafter). Patients were required to have initi- national treatment guidelines [10]. With the availability ated ≥ 1 line of systemic anticancer treatment (single of RET-targeted therapies, genetic biomarker testing to agent or combination) as their first therapy for advanced identify RET alterations should be part of the standard of MTC (i.e.,  the eligible systemic therapy) between Janu- care for patients with advanced or metastatic MTC. ary 1, 2013, and December 31, 2018, be aged ≥ 12 years at Evidence suggests that stage at diagnosis, presence that time, and have a complete medical record covering and subtype of RET mutation, levels of biomarkers such all treatments after advanced MTC diagnosis. Decisions as calcitonin and carcinoembryonic antigen (CEA), to initiate therapy were made by the treating physicians. and type of systemic treatment may affect prognosis in The date of initiation of first-line therapy for advanced advanced/metastatic MTC [11–15]. However, limited MTC was defined as the index date. Patients could be real-world evidence describes such patients in the US, living or deceased at the time of record abstraction. their diagnostic and treatment patterns, and their clinical Excluded patients had other malignant neoplasms before outcomes. This retrospective observational study evalu - the index date (except MEN2-associated pheochromo- ated the patterns of biomarker testing, treatments, and cytoma that had been resected or was documented to be clinical outcomes among patients with advanced or met- stable; nonmelanoma skin cancer; in situ cervical cancer; astatic MTC receiving routine clinical care. or other cancer from which the patient had been disease free for ≥ 5  years on the index date) or had participated in a clinical trial of an interventional drug as a first-line systemic treatment for advanced MTC. Due to the retrospective, descriptive nature of this study, the targeted sample was not based on formal sta- tistical considerations. Based on a feasibility assessment, The reported age-adjusted annual incidence-based mortality estimates per 100,000 for MTC and for all thyroid cancers were 0.04 (95% confidence a sample of approximately 200 patients across the US was interval [CI], 0.03–0.04) and 0.44 (95% CI, 0.42–0.46), respectively, and planned. 0.04/0.44 = 9.1%. P arikh et al. Thyroid Research (2022) 15:2 Page 3 of 14 Study measures n = 19 [25.3%]; Midwest, n = 12 [16.0%]; South, n = 23 In addition to patient characteristics, baseline informa- [30.7%]; and West, n = 21 [28.0%]) (Table  1). Most phy- tion extracted from medical records included tumor sicians (n = 59 [78.7%]) practiced in a cancer center or stage at initial diagnosis, testing for potential germline tertiary referral center (n = 34 [45.3%]) or a private hos- or somatic mutations of special interest, and serum CEA pital or clinic (n = 25 [33.0%]); 13  (17.3%) practiced in and calcitonin levels. Systemic therapies received before an academic or teaching hospital, and 3 (4.0%) practiced and after advanced MTC diagnosis were recorded overall in a nonteaching hospital setting. The mean (SD) num - and by line of therapy. The sequence of regimens received ber of years in practice, managing treatment of oncology for first- and second-line treatments was derived from the patients since fully qualified, was 14.7 (5.7) years. individual drug information for each line of therapy after advanced MTC diagnosis. Objective response (complete Overall cohort of patients with advanced medullary or partial response) to first- and second-line treatment thyroid cancer was reported by each patient’s oncologist. Criteria used Patient and clinical characteristics by the treating clinician to assess response could include At advanced MTC diagnosis, the mean (SD) age of physical examination, performance status, nongenomic patients included in this study was 52.2 (10.4) years; biomarker levels (calcitonin or CEA), imaging, or objec- 58.6% of patients (n = 119) were female, and 66.0% tive criteria (e.g.,  RECIST guidelines). Progression-free (n = 134) were white (Table  2). Mean (SD) duration of survival (PFS) and overall survival (OS) were estimated follow-up was 24.5 (16.0) years. Most patients (n = 168; from the start of first- and second-line therapies. Clini - 82.8%) had stage  IV MTC (including IVA, IVB, and cian-defined disease progression, initiation of subsequent IVC) at initial diagnosis. Among the 141 patients who line of treatment, and death were considered progression underwent evaluation of calcitonin level at advanced events and were used to estimate PFS. Patient and tumor MTC diagnosis, 117 (83.0%) had a known calcitonin characteristics, treatments, and clinical outcomes were level (mean [SD], 150.1 [138.9] pg/mL). Among the 108 summarized for the overall study population and for the patients who underwent CEA testing at advanced MTC subgroup of patients with RET-mutant MTC. diagnosis, 84 (77.8%) had a known CEA level (mean [SD], 30.0 [30.4] ng/mL). Among the 173 patients whose per- formance status at advanced MTC diagnosis was known, Statistical analyses 142 (82.1%) had a performance status of 0/1. All analyses were descriptive and were conducted using Most patients (n = 121; 59.6%) underwent biomarker SAS (version 9.4, SAS Institute Inc., Cary, North Caro- testing for RET mutations (Table  3). Of the 45 (37.2%) lina). Time-to-event outcomes (OS and PFS from initia- patients with known RET-mutant MTC, 25 (55.6%) had tion of first-line and second-line therapies, respectively) RET mutations first identified before advanced MTC were described using the Kaplan–Meier method. Sub- diagnosis, and 20 (44.4%) had them first identified after group analyses were conducted for patients with ger- advanced MTC diagnosis. Among patients with RET mline or somatic RET mutations. CEA and calcitonin mutations, 18 (40%) had M918T mutation, 9 (20%) had levels were evaluated at advanced MTC diagnosis and C634R mutation, 1 (2%) had C634G mutation, and the during first- and second-line treatment. A post hoc specific type of RET mutation was not known/docu- mixed-model repeated-measures analysis account- mented for 17 (38%) patients. Most patients had no ing for within-patient correlation was conducted to hereditary clinical syndromes documented (169; 83.3%); evaluate improvement or decline in calcitonin levels 15 patients (7.4%) had a diagnosis of familial MTC, 8 and CEA levels during first-line therapy [16]. Time to (3.9%) had MEN2A syndrome, and 5 (2.5%) had MEN2B. decline of ≥ 50% from the calcitonin level and CEA level The data collected did not distinguish between somatic at initiation of the treatment line (± 28  days) were each and germline biomarker testing. estimated from the mixed-model repeated-measures analysis. Treatment patterns The mean time from advanced diagnosis to initiation of Results first-line therapy was 1.9 (SD = 6.0) months (Table  4). Seventy-five physicians (40 medical/clinical oncologists Most patients (n = 154; 75.9%) received only one line of and 35 hematologist/oncologists) abstracted data from systemic anticancer therapy during the available follow- electronic medical records of a total of 203 patients with up time; 49 (24.1%) received second-line therapy, and 4 advanced MTC (per physician: mean, 2.8 patients [stand- (2.0%) received third-line therapy. Overall, 73 patients ard deviation [SD], 2.0; range, 1–6). The 75 participating (36%) were receiving ongoing first-line treatment at data physicians represented all geographic regions (Northeast, Parikh et al. Thyroid Research (2022) 15:2 Page 4 of 14 Table 1 Characteristics of Participating Physicians Total physician sample (N) 75 100.0% Number of patients treated with advanced MTC in the last 12 months Mean (SD) 26.0 (20.9) Median (IQR) 20.0 (8.0–45.0) Primary medical specialty, (n, %) Medical or clinical oncology (oncologist) 40 53.3% Hematology-oncology 35 46.7% Primary practice setting, (n, %) Cancer center/tertiary referral treatment center 34 45.3% Academic/teaching hospital 13 17.3% Other nonteaching hospital 3 4.0% Private hospital or clinic 25 33.3% Number of years in practice managing treatment of oncology patients since fully qualified Mean (SD) 14.7 (5.7) Median (IQR) 15.0 (10.0–18.0) Geographic region of practice, (n, %) Northeast 19 25.3% Midwest 12 16.0% South 23 30.7% West 21 28.0% Number of patients for whom data was provided for this study Mean (SD) 2.8 (2.0) Median (IQR) 2.0 (1.0-4.0) Min, Max 1.0 6.0 MTC medullary thyroid cancer, SD standard deviation abstraction. The mean (SD) number of lines of therapy not estimable for the 71 patients with known date of received was 1.3 (0.5); mean (SD) total duration of sys- objective response (Table 5). temic therapy was 12.0 (11.9) months. The most common first-line therapies received were cabozantinib (n = 61, Clinical outcomes 30.0%), vandetanib (n = 61, 30.0%), sorafenib (n = 35, For the overall study cohort, median PFS was 26.6 months 17.2%), and lenvatinib (n = 10, 4.9%); Table S-1 (Addi- (95% confidence interval [CI], 20.8–60.8  months) from tional file  1) presents the most common regimens overall. initiation of first-line therapy (Fig.  2A). Median OS was Figure  1 presents a Sankey chart of first- and second- 63.8  months (95%  CI, 46.3  months–not estimable) from line treatment sequences. At the end of study follow-up, initiation of first-line therapy; survival estimates at 12, 36, 40% of patients had not received a subsequent line of and 60 months were 86.9% (95% CI, 81.4%-90.9%), 63.5% treatment after discontinuing first-line treatment. Similar (54.0%-71.5%), and 60.5% (49.5%-69.7%), respectively to first-line treatment, cabozantinib and vandetanib were (Fig.  3A). Disease-specific survival at 60  months was received by similar proportions of patients in second-line 68.3% (95% CI, 58.9%-76.0%). therapy. Of the 61 patients (30%) who received cabo- zantinib in the first line, 7 (11.5%) received second-line Nongenomic biomarkers vandetanib; of the 61 patients (30%) who received van- Calcitonin and CEA levels were evaluated per routine detanib in the first line, 10 (16.4%) received second-line practice (at advanced diagnosis and/or during each cabozantinib. treatment line). A total of 109 patients had 159 calci- During first-line treatment, 129 patients (63.5%) were tonin evaluations at the initiation of first-line treat - reported to have an objective response (i.e., complete or ment (± 28  days), and 83 patients had 328 calcitonin partial response); because of ongoing responses at data evaluations during the first-line treatment; 80 patients abstraction, median duration of objective response was had 113 CEA evaluations at the initiation of first-line treatment (± 28  days), and 45 patients had 113 CEA P arikh et al. Thyroid Research (2022) 15:2 Page 5 of 14 Table 2 Characteristics of Patients With Advanced Medullary Thyroid Cancer All Patients, Patients With RET-Mutant n (%) MTC, n (%) Number of patients, N 203 100.0% 45 100.0% Age at advanced diagnosis of MTC 203 100.0% 45 100.0% Mean (SD) 52.2 (10.4) 46.6 (9.7) Median (IQR) 53 (44–59) 46 (39–54) Sex Female 119 58.6% 26 57.8% Male 84 41.4% 19 42.2% Race White 134 66.0% 24 53.3% Black/African American 45 22.2% 10 22.2% Asian, Native Hawaiian or other Pacific Islander 18 8.9% 6 13.3% Other 1 0.5% 1 2.2% Unknown or not reported 6 3.0% 4 8.9% Ethnic origin Hispanic or Latina/Latino 25 12.3% 5 11.1% Not Hispanic or Latina/Latino 163 80.3% 33 73.3% Unknown or not reported 15 7.4% 7 15.6% Total duration of follow-up, months 203 100.0% 45 100.0% Mean (SD) 24.5 (16.0) 28.8 (18.0) Median (IQR) 21.1 (15.0–28.5) 25.5 (17.9–34.5) Clinical stage at initial diagnosis Stage II 10 4.9% 0 0.0% Stage III 20 9.9% 6 13.3% Stage IVA 58 28.6% 12 26.7% Stage IVB 28 13.8% 4 8.9% Stage IVC 82 40.4% 22 48.9% Unknown or not reported 5 2.5% 1 2.2% Time from initial diagnosis to advanced diagnosis date (months), among patients 30 14.8% 6 13.3% who were initially diagnosed with stage I, II, III (n, %) Mean (SD) 26.3 (33.0) 37.5 (64.0) Median (IQR) 14.1 (8.2–28.8) 12.6 (10.1–17) Site(s) of local extension or metastasis at advanced MTC diagnosis 203 100% 25 100% Distant lymph nodes 111 54.7% 20 44.4% Bone 69 34.0% 18 40.0% Brain 14 6.9% 6 13.3% Liver 56 27.6% 19 42.2% Local structures (e.g., muscles, larynx, trachea, esophagus, or large vessels) 58 28.6% 12 26.7% Lung/pleura 81 39.9% 15 33.3% Performance status at advanced MTC diagnosis (± 30 days) 173 85.2% 42 93.3% 0 or 1 142 82.1% 36 85.7% 2–4 31 18.0% 6 14.3% Calcitonin level evaluated at advanced MTC diagnosis (± 30 days) (pg/mL) (n, %) 141 69.5% 31 68.9% Calcitonin level known (n, %) 117 83.0% 23 74.2% Mean (SD) 150.1 (138.9) 139.2 (138.6) Median (IQR) 110.0 (22.0–210.0) 100.0 (18.0–200.0) Calcitonin evaluated but level unknown or not reported (n, %) 24 17.0% 8 25.8% CEA test performed at advanced MTC diagnosis (± 30 days) (ng/mL) (n, %) 108 53.2% 26 57.8% CEA level known (n, %) 84 77.8% 14 53.8% Parikh et al. Thyroid Research (2022) 15:2 Page 6 of 14 Table 2 (continued) All Patients, Patients With RET-Mutant n (%) MTC, n (%) Number of patients, N 203 100.0% 45 100.0% Mean (SD) 30.0 (30.4) 27.5 (28.2) Median (IQR) 18.3 (3.7–50.0) 19.3 (6.8–30.0) CEA tested but level unknown or not reported (n, %) 24 22.2% 12 46.2% CEA carcinoembryonic antigen, ECOG Eastern Cooperative Oncology Group, IQR interquartile ratio, MTC medullary thyroid cancer, RET rearranged during transfection, SD standard deviation Multiple responses allowed; rows will add up to greater than 100% Reported as mixed race Length of follow-up is the duration of time between the date of initiation of first-line systemic therapy and death or end of patient record Karnofsky score were converted to the ECOG scale for 29 patients (14.3%) [17] Calcitonin normal range: < 10 pg/mL CEA test normal range: < 2.5 ng/mL Table 3 RET-Mutation Testing and Diagnosis of Hereditary Medullary Thyroid Cancer Syndromes N % Total patient sample (N) 203 100.0% Tested for germline or somatic RET mutation at any time (n, %) Yes 121 59.6% No/unknown 82 40.4% Biomarker testing at or after initial diagnosis of MTC Patients tested for potential germline and/or somatic mutations at or after initial diagnosis of MTC (n, 95 46.8% %) Patients with RET-mutant MTC (n, %) 45 37.2% RET mutation identified before initial MTC diagnosis 25 55.6% RET mutation identified after initial MTC diagnosis 20 44.4% Type of RET mutation among patients with RET-mutant MTC (n, %) 45 37.2% M918T 18 40.0% C634R 9 20.0% C634G 1 2.2% Unknown 17 37.8% Diagnosis of hereditary MTC syndromes at any time MEN2A 8 3.9% MEN2B 5 2.5% Familial MTC 15 7.4% No hereditary MTC syndrome diagnosed 169 83.3% Unknown/not reported 6 3.0% MEN2A multiple endocrine neoplasia type 2A, MEN2B MEN type 2B, MTC medullary thyroid cancer; RET rearranged during transfection The data collection form did not distinguish between germline and somatic testing evaluations during the first-line treatment. Regres - reach a decrease of ≥ 50% in CEA level occurring after sion modeling showed that calcitonin levels generally 17.7 months (Fig. 4B). decreased during first-line treatment, with an esti - mated time to reach a decrease of ≥ 50% in calcitonin Patients with RET-mutant medullary thyroid cancer level occurring 8.4  months after treatment initiation The 45 patients with RET mutations had a mean (SD) age (Fig.  4A). Similarly, CEA levels generally decreased of 46.6 (9.7) years, and most (n = 38; 84.5%) had stage IV during first-line treatment, with an estimated time to disease at advanced MTC diagnosis (Table 2). Among the P arikh et al. Thyroid Research (2022) 15:2 Page 7 of 14 Table 4 Systemic Therapy Patterns Among Patients With Advanced Medullary Thyroid Cancer All MTC Patients Patients With RET-Mutant MTC First-line Therapy Second-line Therapy First-line Therapy Second-line Therapy Number of patients initiating treatment (N, %) 203 100.0% 49 100.0% 45 100.0% 13 100.0% Performance status at start of treatment , (n, %) 138 68.0% 35 71.4% 30 66.7% 9 69.2% 0 or 1 112 81.2% 20 57.1% 25 83.3% 6 66.6% 2–4 26 18.8% 15 42.9% 5 16.7% 3 33.3% Time from advanced MTC diagnosis to first line of 203 100.0% 49 100.0% 45 100.0% 13 100.0% treatment and time between first and second line of treatment, among patients who discontinued first line of treatment (n, %) Mean (SD) 1.9 (6.0) 1.3 (2.8) 1.0 (1.4) 0.8 (0.8) Median (IQR) 0.5 (0.3–1.2) 0.5 (0.3–0.7) 0.5 (0.3–1.2) 0.5 (0.3–1.2) Total duration of therapy line, months (n) 203 49 45 13 Kaplan–Meier estimate Median (95% CI) 12.5 (9.2–18.2) 7.9 (5.8–11.2) 9.7 (6.6–23.7) NE (6.1-NE) Treatment ongoing (n, %) 73 36.0% 16 32.70% 15 33.3% 9 69.20% Number of patients who discontinued treatment 130 64.0% 33 67.3% 30 66.7% 4 30.8% (n, %) b, c Reason for discontinuation (n, %) Adverse event 3 2.3% 0 0.0% 1 3.3% 0 0.0% Patient decision 19 14.6% 5 15.2% 4 13.3% 3 75.0% Progressive disease 70 53.8% 18 54.5% 15 50.0% 1 25.0% Completion of planned course of treatment 43 33.1% 9 27.3% 11 36.7% 1 25.0% Loss to follow-up 3 2.3% 0 0.0% 0 0.0% 0 0.0% Death 9 6.9% 2 6.1% 2 6.7% 0 0.0% Other: alternative treatment 1 0.8% 0 0.0% 0 0.0% 0 0.0% Unknown 2 1.5% 1 3.0% 1 3.3% 1 25.0% Reasons for not administering additional cancer- 72 35.5% 27 55.1% 15 33.3% 3 23.1% directed systemic treatment for advanced MTC, among patients with no subsequent treat- ment and patients who were alive at the time of discontinuing last line of treatment (n, %) Patient decision 21 29.2% 6 22.2% 2 13.3% 1 33.3% Frail physical status 16 22.2% 1 3.7% 2 13.3% 0 0.0% Stable disease 23 31.9% 5 18.5% 8 53.3% 1 33.3% CI confidence interval, ECOG Eastern Cooperative Oncology Group, IQR interquartile range, MTC medullary thyroid cancer, PS performance status, Q1 first quartile, Q3 third quartile, RET rearranged during transfection, SD standard deviation Karnofsky score converted to the ECOG scale for 29 patients (14.3%) [17] Categories are not mutually exclusive. A patient may have had more than one reason/criterion assessed; thus, the column does not sum to 100% Among patients who discontinued treatment line 42 patients with known performance status at advanced treatment at data abstraction. The mean (SD) number of MTC diagnosis, 36 (85.7%) had a performance status of lines of therapy received was 1.3 (0.5); mean (SD) total 0/1. duration of systemic therapy was 9.6 (10.2) months. The Among patients with RET mutations, mean (SD) time most common first-line therapies received were vande - from advanced diagnosis to initiation of first-line ther - tanib (n = 18, 40.0%), cabozantinib (n = 14, 31.1%), and apy was 1.0 (1.4) months (Table  4). Most (n = 32; 71.1%) sorafenib (n = 5, 11.1%). During first-line treatment, 28 received only one line of therapy during the available patients (62.2%) had an objective response; the median follow-up time; 12 (26.7%) received second-line ther- duration of objective response was not estimable for the apy, and only 1 (2.2%) received third-line therapy. Fif- 12 patients with known date of objective response. teen patients (33.3%) were receiving ongoing first-line Parikh et al. Thyroid Research (2022) 15:2 Page 8 of 14 Fig. 1 Sankey Chart for Number (%) of Patients Receiving First- and Second-Line Treatment. Note: Only cabozantinib and vandetanib were approved by the US Food and Drug Administration for the treatment of advanced medullary thyroid cancer at the time of the study Median PFS for patients with RET-mutant MTC was Patients undergoing second-line therapy 47.7  months (95%  CI, 14.2  months–not estimable) from Forty-nine patients in the overall study cohort (24.1%) initiation of first-line therapy and was not estimable received second-line therapy during the available fol- from initiation of second-line therapy (Fig.  2B). Median low-up time. This subgroup had a mean (SD) age of 48.0 OS was not estimable for these patients; survival rates (10.5) years at advanced MTC diagnosis. At initiation of at 12, 36, and 60  months were 95.5% (95%  CI, 83.2%- second-line therapy, performance status was reported 98.9%), 86.8% (70.5%-94.4%), and 86.8% (70.5%-94.4%), for 35 patients, of whom 20 (57.1%) had a performance respectively. status of 0/1, and 15 (42.9%) had a performance status of 2–4. The most frequent second-line treatments were P arikh et al. Thyroid Research (2022) 15:2 Page 9 of 14 Table 5 Objective Response Rate Among Patients With Advanced Medullary Thyroid Cancer All Patients Patients With RET-Mutant MTC During First-Line During Second- During First-Line During Therapy Line Therapy Therapy Second-Line Therapy Objective response (complete or partial response) (n, %) 129 63.5% 19 38.8% 28 62.2% 8 61.5% Among those who had objective response and known date of 71 6 12 3 objective response, duration of response (n) Mean (SE) 15.4 (1.2) 16.8 (–) 8.4 (0.9) NE Median NE NE NE 95% CI 10.3 NE 16.8 4.2 NE Q1, Q3 6 NE 16.8 6.6 NE Censored (n, %) 46 64.8% 5 83.3% 7 58.3% 3 100.0% CI confidence interval, MTC medullary thyroid cancer, NE not estimable, Q1 first quartile, Q3 third quartile, RET rearranged during transfection, SE standard error Duration of objective response defined as time from complete or partial response to disease progression, death, or start of next line of treatment. Patients with treatment line ongoing or who discontinued treatment for nonprogression reasons were censored recent studies have explored patient and tumor charac- cabozantinib (n = 11, 22.4%), vandetanib (n = 10, 20.4%), teristics and treatment outcomes. Randle et  al. [9] con- lenvatinib and sunitinib (n = 6 [12.2%] for both), and ducted a population-based study evaluating survival sorafenib (n = 4, 8.2%). During second-line treatment, 19 among patients with MTC (of all stages) using 2003–2012 patients (38.8%) had an objective response; the median data from the US SEER registry. Overall 5-year disease- duration of objective response was not estimable for the specific survival was estimated to be 51% among patients 6 patients with known date of objective response. Dur- with metastatic MTC [9]. A higher 5-year disease-specific ing second-line therapy, regression modeling showed survival rate, 68.3%, was observed for the overall popula- that available calcitonin levels remained generally stable tion in the current study. This difference may be attribut - (Fig.  4C). The number of available CEA levels was insuf - able to differences in the study time frames, potentially ficient for analysis. differing prognostic factors, and the introduction of new From initiation of second-line therapy, median PFS regimens since Randle and colleagues’ analysis [9]. was 15.3  months (95%  CI, 6.6  months–not estima- In addition, a registry study conducted in a routine care ble) (Fig.  2C). Median OS was 22.4  months (95%  CI, setting in Germany enrolled 48 patients with advanced 12.4  months–not estimable), and survival estimates at MTC who were treated with the tyrosine kinase inhibi- 12, 36, and 60 months from the initiation of second-line tors (TKIs) vandetanib and/or cabozantinib [14]. This therapy were 69.1% (95% CI, 52.8%-80.8%), 42.4% (23.7%- population had a median age at diagnosis of metastatic 59.9%), and 42.4% (23.7%-59.9%), respectively (Fig. 3B). MTC of 50  years and predominantly had sporadic MTC (75% of patients) 13% had hereditary MTC, and germline Discussion RET-mutation status was not known for 13% of patients. This study retrospectively evaluated clinical character - Most patients (96%) had distant metastases. Twelve- istics, biomarkers, treatment patterns, and survival out- month survival estimates were 86% for those receiving comes among US patients with advanced MTC managed vandetanib and 70% for those receiving cabozantinib in real-world clinical settings. Of the patients evaluated, [14]. The 12-month survival rate of 87.5% observed in 37.2% had RET-mutant MTC. Cabozantinib, vande- the current study is consistent with this prior research, tanib, sorafenib, and lenvatinib were the most common and median duration of treatment was similar in the two first-line treatments. Among 49 patients who received studies (25  months in Koehler et  al. vs. 21.1  months in second-line treatment, most received cabozantinib, van- the current study). In addition, TKIs were the most com- detanib, lenvatinib, or sunitinib. For the overall popula- monly administered treatments in the current study: tion, median PFS from start of first- and second-line approximately 60% of patients received either cabozan- treatments was 26.6  months and 15.3  months; median tinib or vandetanib in the first line. The TKIs sorafenib OS from initiation of first- and second-line treatments and lenvatinib, as well as the cytotoxic drug dacarbazine, was 63.8 months and 22.4 months, respectively. were also commonly used in the first line, despite not While real-world studies in MTC have been limited, being approved by the US Food and Drug Administration particularly those evaluating treatment patterns, several Parikh et al. Thyroid Research (2022) 15:2 Page 10 of 14 Fig. 2  Progression-Free Survival A. Overall Population, First-Line Therapy. B. RET-Mutant Medullary Thyroid Cancer, First-Line Therapy. C. Overall Population, Second-Line Therapy. CI confidence interval, MTC medullary thyroid cancer, NE not estimable, PFS progression-free survival, RET rearranged during transfection, SE standard error P arikh et al. Thyroid Research (2022) 15:2 Page 11 of 14 Fig. 3 Overall Survival. A. From Initiation of First-Line Systemic Treatment. B. From Initiation of Second-Line Systemic Treatment. CI confidence interval, NE not estimable, SE standard error for the treatment of MTC. Presumably, treating phy- not harbor RET mutations [5]. In clinical practice, the sicians’ off-label use of these therapies was driven by proportion of patients undergoing testing for RET muta- evidence of clinical benefit with sorafenib [19–22], len - tions varies [26], and in the current study, 40% of patients vatinib [23], and dacarbazine [24, 25], as well as recom- were not known to have undergone testing for germline mendations in clinical guidelines that small-molecule and/or somatic RET mutation. Among the overall sam- kinase inhibitors may be used when preferred systemic ple, 22% of patients were known to have RET-mutation therapies are not available or appropriate [10]. positive MTC; these patients had an average age of RET-mutation positive MTC has been associated with 46.6 years. Vandetanib monotherapy was the most com- worse clinical outcomes relative to MTC tumors that do mon first-line regimen for patients with RET -mutation Parikh et al. Thyroid Research (2022) 15:2 Page 12 of 14 Fig. 4 Regression Analysis of Calcitonin and Carcinoembryonic Antigen Levels by Line of Treatment . A. Calcitonin Levels During First-Line Treatment. B. Carcinoembryonic Antigen Levels During First-Line Treatment. CEA carcinoembryonic antigen. C. Calcitonin Levels During Second-Line Treatment. CEA carcinoembryonic antigen. Note: A locally weighted polynomial regression, or LOESS, fit was estimated to smooth the a b data points and highlight the underlying trend [18]. Predicted using an unadjusted, mixed-model repeated-measures analysis. Evaluations 28 days before or after initiating treatment line were attributed to baseline (i.e., time 0). Evaluation after 28 days of treatment initiation were grouped in to 28-day intervals and have been assigned to the end of the interval positive MTC, followed by cabozantinib monotherapy. with the availability of the RET-targeted therapies selper- The PFS rate at 36  months was 55% after initiation of catinib and pralsetinib. first-line therapy for this subgroup. To date, studies eval - Previous studies have found an association between uating real-world treatment patterns for patients with elevated calcitonin and CEA levels, more rapid disease RET-mutation positive MTC have been limited, and progression, and worse survival outcomes [13, 15]. A future research should explore how treatment patterns mixed-model repeated-measures regression analysis and outcomes for patients with RET-mutant MTC evolve demonstrated that calcitonin levels decreased during P arikh et al. Thyroid Research (2022) 15:2 Page 13 of 14 Cancer Network; OS: Overall survival; PFS: Progression-free survival; RET: first-line treatment initially; appeared to trend upward Rearranged during transfection; SD: Standard deviation; SEER: Surveillance, toward the end of first-line treatment, probably related to Epidemiology, and End Results; TKI: Tyrosine kinase inhibitor; US: United States. disease progression; and remained generally stable during second-line treatment. Because the objective response Supplementary Information rate during second-line therapy (among the 49 patients The online version contains supplementary material available at https:// doi. who received it during this study) was lower (39%) than org/ 10. 1186/ s13044- 021- 00119-9. that among all patients during first-line therapy (64%), suboptimal response may potentially explain the pattern Additional file 1: Table S1. Most Common First- and Second-Line Systemic Therapies Among Patients With Advanced Medullary Thyroid of calcitonin levels during second-line therapy, empha- Cancer. sizing the need for more effective treatments. Several limitations of this study should be considered. Acknowledgements Patients selected for study inclusion represent a conveni- Kate Lothman of RTI Health Solutions provided medical writing services dur- ence sample of medical records obtained from physicians ing development of this manuscript. These services were funded by Eli Lilly willing to participate in the study and may be biased and Company. toward patients who were alive at data abstraction; study Authors’ contributions findings may not be generalizable to the overall popula - All authors made a significant contribution to the work reported, whether that tion of US patients with advanced MTC. To help mitigate is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically potential biases, physicians were recruited from a vari- reviewing the article; gave final approval of the version to be published; have ety of regions and practice types and were instructed to agreed on the journal to which the article has been submitted; and agree to select patients who were either alive or dead by a quasi- be accountable for the content of the article. random procedure. Data available for study were limited Funding to those recorded in medical records. Although internal This study was performed under a research contract between RTI Health Solu- data consistency was improved by data checks and use of tions and Eli Lilly and Company and was funded by Eli Lilly and Company. a customized data-collection form, the entered data were Availability of data and materials not validated against patients’ medical records by inde- Not applicable. pendent review. The information collected on genomic biomarker testing did not distinguish between germline Declarations and somatic mutations, and the frequency of such testing Ethics approval and consent to participate may have increased in current practice. Finally, a consid- RTI International’s institutional review board (IRB) reviewed the study protocol erable proportion of patients were undergoing treatment and deemed the research, which was not considered human subjects at the time of data abstraction, and 52% of patients were research, to be exempt from full IRB review. censored for PFS estimates; therefore, PFS estimates are Consent for publication based on immature data, and studies with longer follow- Not applicable. up are warranted in this population. Competing interests This study was performed under a research contract between RTI Health Conclusions Solutions and Eli Lilly and Company and was funded by Eli Lilly and Company. More than one-third of patients with advanced or met- RP, EE, and JAK are employees of RTI Health Solutions. LMH and NRB are employees of Eli Lilly and Company. astatic MTC were not tested for RET mutation as rec- ommended by national guidelines. For the treatment of Author details advanced/metastatic MTC, no specific preference of RTI Health Solutions, 3040 East Cornwallis Road, Research Triangle Park, NC 27709, USA. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN sequencing systemic agents was observed in the first- and 46285, USA. RTI Health Solutions, 307 Waverley Oaks Road, Waltham, MA second-line settings. The estimated OS was consistent 02452, USA. with that observed from SEER data for metastatic MTC. Received: 21 June 2021 Accepted: 9 December 2021 Considering the recent approval of selective RET inhibi- tors for patients with RET-mutant MTC, future research should investigate potential changes in these findings, particularly in the second-line setting. Evidence-based References recommendation on sequencing of systemic therapies 1. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association may benefit patients with advanced MTC. guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610. 2. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2017, National Cancer Institute. Bethesda, MD. 2020 (based Abbreviations on November 2019 SEER data submission, posted to the SEER web site, CEA: Cost-effectiveness analysis; CI: Confidence interval; IRB: Institutional review board; MTC: Medullary thyroid cancer; NCCN: National Comprehensive Parikh et al. Thyroid Research (2022) 15:2 Page 14 of 14 April 2020). Available at https:// seer. cancer. gov/ csr/ 1975_ 2017/ Accessed medullary thyroid carcinoma in Denmark 1997–2013: A nationwide 10 December 10, 2020. study. Clin Epidemiol. 2019;10:93–9. 3. Lim H, Devesa SS, Sosa JA, et al. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA. 2017;317:1338–48. Publisher’s Note 4. Moura MM, Cavaco BM, Leite V. RAS proto-oncogene in medullary thyroid Springer Nature remains neutral with regard to jurisdictional claims in pub- carcinoma. Endocr Relat Cancer. 2015;22:R235–52. lished maps and institutional affiliations. 5. Moura MM, Cavaco BM, Pinto AE, et al. Correlation of RET somatic muta- tions with clinicopathological features in sporadic medullary thyroid carcinomas. Br J Cancer. 2009;100:1777. 6. Larouche V, Akirov A, Thomas CM, et al. A primer on the genetics of medullary thyroid cancer. Curr Oncol. 2019;26:389–94. 7. Romei C, Ciampi R, Casella F, et al. RET mutation heterogeneity in primary advanced medullary thyroid cancers and their metastases. Oncotarget. 2018;9:9875. 8. Wells SA, Pacini F, Robinson BG, et al. Multiple endocrine neoplasia type 2 and familial medullary thyroid cancer: An update. J Clin Endocrinol Metab. 2013;98:3149–64. 9. Randle RW, Balentine CJ, Leverson GE, et al. Trends in the presentation, treatment, and survival of patients with medullary thyroid cancer over the past 30 years. Surgery. 2017;161:137–46. 10. National Comprehensive Cancer Network (NCCN). NCCN Clinical Practice Guidelines in Oncology (NCCN guidelines). Thyroid carcinoma, version 2. 2020. Available at https:// www. nccn. org/ store/ login/ login. aspx? Retur nURL= https:// www. nccn. org/ profe ssion als/ physi cian_ gls/ pdf/ thyro id. pdf. Accessed 2 November 2, 2020. 11. Al-Qurayshi Z, Khadra H, Chang K, et al. Risk and survival of patients with medullary thyroid cancer: National perspective. Oral Oncol. 2018;83:59–63. 12. Voss RK, Feng L, Lee JE, et al. Medullary thyroid carcinoma in MEN2A: ATA moderate- or high-risk RET mutations do not predict disease aggressive- ness. J Clin Endocrinol Metab. 2017;102:2807–13. 13. Turkdogan S, Forest VI, Hier MP, et al. Carcinoembryonic antigen levels correlated with advanced disease in medullary thyroid cancer. J Otolaryn- gol Head Neck Surg. 2018;47:55. 14. Koehler VF, Adam P, Frank-Raue K, et al. Real-world efficacy and safety of cabozantinib and vandetanib in advanced medullary thyroid cancer. Thyroid. 2021;31:459–69. 15. Kotwal A, Erickson D, Geske J, et al. Predicting outcomes in sporadic and hereditary medullary thyroid carcinoma over two decades. Thyroid. 2021;31:616–26. 16. Detry MA, Ma Y. Analyzing repeated measurements using mixed models. JAMA. 2016;315(4):407–8. 17. Ma C, Bandukwala S, Burman D, et al. Interconversion of three measures of performance status: an empirical analysis. Eur J Cancer. 2010;46:3175–83. 18. Cleveland WS, Devlin SJ. Locally weighted regression: an approach to regression analysis by local fitting. J Am Statistical Assoc. 1988;83:596–610. 19. Capdevila J, Iglesias L, Halperin I, et al. Sorafenib in metastatic thyroid cancer. Endocr Relat Cancer. 2012;19:209–16. 20. Ahmed M, Barbachano Y, Riddell A, et al. Analysis of the efficacy and toxicity of sorafenib in thyroid cancer: a phase II study in a UK based population. Eur J Endocrinol. 2011;165:315–22. 21. Lam ET, Ringel MD, Kloos RT, et al. Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer. J Clin Oncol. 2010;28:2323–30. 22. Thomas L, Lai SY, Dong W, Feng L, Dadu R, Regone RM, Cabanillas ME. Sorafenib in metastatic thyroid cancer: a systematic review. Oncologist. Re Read ady y to to submit y submit your our re researc search h ? Choose BMC and benefit fr ? Choose BMC and benefit from om: : 2014;19:251–8. 23. Schlumberger M, Jarzab B, Cabanillas ME, et al. A phase II trial of the fast, convenient online submission multitargeted tyrosine kinase inhibitor lenvatinib (E7080) in advanced thorough peer review by experienced researchers in your field medullary thyroid cancer. Clin Cancer Res. 2016;22:44–53. 24. Orlandi F, Caraci P, Berruti A, et al. Chemotherapy with dacarbazine rapid publication on acceptance and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol. support for research data, including large and complex data types 1994;5:763–5. • gold Open Access which fosters wider collaboration and increased citations 25. Schlumberger M, Abdelmoumene N, Delisle MJ, Couette JE. Treatment of advanced medullary thyroid cancer with an alternating combination of 5 maximum visibility for your research: over 100M website views per year FU-streptozocin and 5 FU-dacarbazine. The Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer. 1995;71:363–5. At BMC, research is always in progress. 26. Mathiesen JS, Kroustrup JP, Vestergaard P, et al. Danish Thyroid Cancer Learn more biomedcentral.com/submissions Group (DATHYRCA). Completeness of RET testing in patients with http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Thyroid Research Springer Journals

Diagnostic characteristics, treatment patterns, and clinical outcomes for patients with advanced/metastatic medullary thyroid cancer

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10.1186/s13044-021-00119-9
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Abstract

Background: Medullary thyroid cancer (MTC) accounts for approximately 1.6% of new cases of thyroid cancer. The objective of this study was to describe patient characteristics, biomarker testing, treatment patterns, and clinical outcomes among patients with advanced/metastatic MTC in a real-world setting in the United States and to identify potential gaps in the care of these patients. Methods: Selected oncologists retrospectively reviewed medical records of patients aged ≥ 12 years diagnosed with advanced MTC. Patients must have initiated ≥ 1 line of systemic treatment for advanced/metastatic MTC between January 2013–December 2018 to be eligible. Patient characteristics, biomarker testing, and treatment patterns were summarized descriptively; progression-free survival (PFS) and overall survival (OS) were estimated using the Kaplan– Meier method. Results: The 203 patients included in this study had a mean (SD) age of 52.2 (10.4) years; mean (SD) duration of follow-up from start of first-line treatment was 24.5 (16.0) months. Most patients (82.8%) were initially diagnosed with stage IVA, IVB, or IVC disease. Among all patients, 121 (59.6%) had testing for RET mutations, of whom 37.2% had RET- mutant MTC. The RET-mutation type was reported for 28 patients; the most common mutations reported were M918T (64.3%) and C634R (32.1%). Of the 203 patients, 75.9% received only one line of systemic treatment for advanced dis- ease, and 36% were still undergoing first-line therapy at the time of data extraction. Cabozantinib (30.0%), vandetanib (30.0%), sorafenib (17.2%), and lenvatinib (4.9%) were the most common first-line treatments. Among 49 patients who received second-line treatment, most received cabozantinib (22.4%), vandetanib (20.4%), lenvatinib (12.2%), or sunitinib (12.2%). Median PFS (95% confidence interval [CI]) from start of first- and second-line treatments was 26.6 months (20.8–60.8) and 15.3 months (6.6-not estimable [NE]), respectively. Median OS from initiation of first- and second-line treatment was 63.8 months (46.3-NE) and 22.4 months (12.4-NE), respectively. Conclusions: For the treatment of advanced/metastatic MTC, no specific preference of sequencing systemic agents was observed in the first- and second-line settings. Considering the recent approval of selective RET inhibitors for patients with RET-mutant MTC, future research should investigate how treatment patterns evolve for these patients. Keywords: RET, Medical record, Chart review, Retrospective, Observational, Real-world, United States survival *Correspondence: rparikh@rti.org RTI Health Solutions, 3040 East Cornwallis Road, Research Triangle Park, NC 27709, USA Full list of author information is available at the end of the article © The Author(s) 2022. Open Access This article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http:// creat iveco mmons. org/ licen ses/ by/4. 0/. The Creative Commons Public Domain Dedication waiver (http:// creat iveco mmons. org/ publi cdoma in/ zero/1. 0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. Parikh et al. Thyroid Research (2022) 15:2 Page 2 of 14 Background Methods Medullary thyroid cancer (MTC) is a rare cancer evolving Study design overview from neural crest–derived calcitonin-producing parafol- An observational retrospective, medical record review licular C cells [1]. MTC accounts for 1.6% of all histologi- of patients who had a confirmed diagnosis of advanced/ cally confirmed incident thyroid tumors (1,562/95,669 metastatic MTC was conducted. Participating oncolo- cases) in the United States (US) [2]. A study of the US gists (medical/clinical oncologists or hematologist/oncol- Surveillance, Epidemiology, and End Results (SEER) Pro- ogists) who had treated ≥ 1 patient with advanced MTC gram for cases diagnosed in 1994–2013 found that MTC in the year before data abstraction, practiced for ≥ 3 years accounted for 8.0% of all thyroid cancer–related deaths after completion of formal training or board certifica - and 9.1% of age-adjusted thyroid cancer–related mortal- tion, and were the main decision-maker regarding treat- ity during this period [3]. MTC can be either sporadic ment for their patients with advanced MTC abstracted or hereditary, the latter occurring either with other endo- demographic and clinical data into a customized, web- crine neoplasms (multiple endocrine neoplasia [MEN] based case-report form. Oncologists were asked to select types 2A and 2B) or alone (familial MTC). Most MTC a quasi-random sample of their patients by abstracting cases are characterized by a mutation of the rearranged medical records of those whose last names began with a during transfection (RET) proto-oncogene, which can be randomly generated letter. Data abstraction occurred in either germline or somatic [4, 5]. For example, an esti- April–May 2020. Data were then compiled into an ana- mated 65%-90% of sporadic MTCs harbor somatic RET lytic data set of deidentified patient-level data. RTI Inter - mutations [5–7], and autosomal dominant inheritance national’s institutional review board (IRB) reviewed the of an activating RET mutation causes hereditary MTC study protocol and deemed the research, which was not (both MEN2 syndromes and familial MTC) [8]. considered human subjects research in accordance with Approximately half of US patients with MTC are diag- the US Code of Federal Regulations (CFR) Sect.  45 CFR nosed with local disease [9]. The primary and curative 46, to be exempt from full IRB review. treatment for most patients diagnosed with early-stage MTC comprises total thyroidectomy and neck dissec- Study population tion [10]. To treat patients with symptomatic advanced, Eligible patients had a diagnosis of histologically and/ progressive, or recurrent MTC, systemic therapies such or cytologically confirmed MTC or were initially diag - as vandetanib, cabozantinib, and, for patients with RET- nosed with or had progressed to having locally advanced mutant MTC, selpercatinib and pralsetinib are approved or metastatic MTC (collectively referred to as “advanced by the US Food and Drug Administration and included in MTC” hereafter). Patients were required to have initi- national treatment guidelines [10]. With the availability ated ≥ 1 line of systemic anticancer treatment (single of RET-targeted therapies, genetic biomarker testing to agent or combination) as their first therapy for advanced identify RET alterations should be part of the standard of MTC (i.e.,  the eligible systemic therapy) between Janu- care for patients with advanced or metastatic MTC. ary 1, 2013, and December 31, 2018, be aged ≥ 12 years at Evidence suggests that stage at diagnosis, presence that time, and have a complete medical record covering and subtype of RET mutation, levels of biomarkers such all treatments after advanced MTC diagnosis. Decisions as calcitonin and carcinoembryonic antigen (CEA), to initiate therapy were made by the treating physicians. and type of systemic treatment may affect prognosis in The date of initiation of first-line therapy for advanced advanced/metastatic MTC [11–15]. However, limited MTC was defined as the index date. Patients could be real-world evidence describes such patients in the US, living or deceased at the time of record abstraction. their diagnostic and treatment patterns, and their clinical Excluded patients had other malignant neoplasms before outcomes. This retrospective observational study evalu - the index date (except MEN2-associated pheochromo- ated the patterns of biomarker testing, treatments, and cytoma that had been resected or was documented to be clinical outcomes among patients with advanced or met- stable; nonmelanoma skin cancer; in situ cervical cancer; astatic MTC receiving routine clinical care. or other cancer from which the patient had been disease free for ≥ 5  years on the index date) or had participated in a clinical trial of an interventional drug as a first-line systemic treatment for advanced MTC. Due to the retrospective, descriptive nature of this study, the targeted sample was not based on formal sta- tistical considerations. Based on a feasibility assessment, The reported age-adjusted annual incidence-based mortality estimates per 100,000 for MTC and for all thyroid cancers were 0.04 (95% confidence a sample of approximately 200 patients across the US was interval [CI], 0.03–0.04) and 0.44 (95% CI, 0.42–0.46), respectively, and planned. 0.04/0.44 = 9.1%. P arikh et al. Thyroid Research (2022) 15:2 Page 3 of 14 Study measures n = 19 [25.3%]; Midwest, n = 12 [16.0%]; South, n = 23 In addition to patient characteristics, baseline informa- [30.7%]; and West, n = 21 [28.0%]) (Table  1). Most phy- tion extracted from medical records included tumor sicians (n = 59 [78.7%]) practiced in a cancer center or stage at initial diagnosis, testing for potential germline tertiary referral center (n = 34 [45.3%]) or a private hos- or somatic mutations of special interest, and serum CEA pital or clinic (n = 25 [33.0%]); 13  (17.3%) practiced in and calcitonin levels. Systemic therapies received before an academic or teaching hospital, and 3 (4.0%) practiced and after advanced MTC diagnosis were recorded overall in a nonteaching hospital setting. The mean (SD) num - and by line of therapy. The sequence of regimens received ber of years in practice, managing treatment of oncology for first- and second-line treatments was derived from the patients since fully qualified, was 14.7 (5.7) years. individual drug information for each line of therapy after advanced MTC diagnosis. Objective response (complete Overall cohort of patients with advanced medullary or partial response) to first- and second-line treatment thyroid cancer was reported by each patient’s oncologist. Criteria used Patient and clinical characteristics by the treating clinician to assess response could include At advanced MTC diagnosis, the mean (SD) age of physical examination, performance status, nongenomic patients included in this study was 52.2 (10.4) years; biomarker levels (calcitonin or CEA), imaging, or objec- 58.6% of patients (n = 119) were female, and 66.0% tive criteria (e.g.,  RECIST guidelines). Progression-free (n = 134) were white (Table  2). Mean (SD) duration of survival (PFS) and overall survival (OS) were estimated follow-up was 24.5 (16.0) years. Most patients (n = 168; from the start of first- and second-line therapies. Clini - 82.8%) had stage  IV MTC (including IVA, IVB, and cian-defined disease progression, initiation of subsequent IVC) at initial diagnosis. Among the 141 patients who line of treatment, and death were considered progression underwent evaluation of calcitonin level at advanced events and were used to estimate PFS. Patient and tumor MTC diagnosis, 117 (83.0%) had a known calcitonin characteristics, treatments, and clinical outcomes were level (mean [SD], 150.1 [138.9] pg/mL). Among the 108 summarized for the overall study population and for the patients who underwent CEA testing at advanced MTC subgroup of patients with RET-mutant MTC. diagnosis, 84 (77.8%) had a known CEA level (mean [SD], 30.0 [30.4] ng/mL). Among the 173 patients whose per- formance status at advanced MTC diagnosis was known, Statistical analyses 142 (82.1%) had a performance status of 0/1. All analyses were descriptive and were conducted using Most patients (n = 121; 59.6%) underwent biomarker SAS (version 9.4, SAS Institute Inc., Cary, North Caro- testing for RET mutations (Table  3). Of the 45 (37.2%) lina). Time-to-event outcomes (OS and PFS from initia- patients with known RET-mutant MTC, 25 (55.6%) had tion of first-line and second-line therapies, respectively) RET mutations first identified before advanced MTC were described using the Kaplan–Meier method. Sub- diagnosis, and 20 (44.4%) had them first identified after group analyses were conducted for patients with ger- advanced MTC diagnosis. Among patients with RET mline or somatic RET mutations. CEA and calcitonin mutations, 18 (40%) had M918T mutation, 9 (20%) had levels were evaluated at advanced MTC diagnosis and C634R mutation, 1 (2%) had C634G mutation, and the during first- and second-line treatment. A post hoc specific type of RET mutation was not known/docu- mixed-model repeated-measures analysis account- mented for 17 (38%) patients. Most patients had no ing for within-patient correlation was conducted to hereditary clinical syndromes documented (169; 83.3%); evaluate improvement or decline in calcitonin levels 15 patients (7.4%) had a diagnosis of familial MTC, 8 and CEA levels during first-line therapy [16]. Time to (3.9%) had MEN2A syndrome, and 5 (2.5%) had MEN2B. decline of ≥ 50% from the calcitonin level and CEA level The data collected did not distinguish between somatic at initiation of the treatment line (± 28  days) were each and germline biomarker testing. estimated from the mixed-model repeated-measures analysis. Treatment patterns The mean time from advanced diagnosis to initiation of Results first-line therapy was 1.9 (SD = 6.0) months (Table  4). Seventy-five physicians (40 medical/clinical oncologists Most patients (n = 154; 75.9%) received only one line of and 35 hematologist/oncologists) abstracted data from systemic anticancer therapy during the available follow- electronic medical records of a total of 203 patients with up time; 49 (24.1%) received second-line therapy, and 4 advanced MTC (per physician: mean, 2.8 patients [stand- (2.0%) received third-line therapy. Overall, 73 patients ard deviation [SD], 2.0; range, 1–6). The 75 participating (36%) were receiving ongoing first-line treatment at data physicians represented all geographic regions (Northeast, Parikh et al. Thyroid Research (2022) 15:2 Page 4 of 14 Table 1 Characteristics of Participating Physicians Total physician sample (N) 75 100.0% Number of patients treated with advanced MTC in the last 12 months Mean (SD) 26.0 (20.9) Median (IQR) 20.0 (8.0–45.0) Primary medical specialty, (n, %) Medical or clinical oncology (oncologist) 40 53.3% Hematology-oncology 35 46.7% Primary practice setting, (n, %) Cancer center/tertiary referral treatment center 34 45.3% Academic/teaching hospital 13 17.3% Other nonteaching hospital 3 4.0% Private hospital or clinic 25 33.3% Number of years in practice managing treatment of oncology patients since fully qualified Mean (SD) 14.7 (5.7) Median (IQR) 15.0 (10.0–18.0) Geographic region of practice, (n, %) Northeast 19 25.3% Midwest 12 16.0% South 23 30.7% West 21 28.0% Number of patients for whom data was provided for this study Mean (SD) 2.8 (2.0) Median (IQR) 2.0 (1.0-4.0) Min, Max 1.0 6.0 MTC medullary thyroid cancer, SD standard deviation abstraction. The mean (SD) number of lines of therapy not estimable for the 71 patients with known date of received was 1.3 (0.5); mean (SD) total duration of sys- objective response (Table 5). temic therapy was 12.0 (11.9) months. The most common first-line therapies received were cabozantinib (n = 61, Clinical outcomes 30.0%), vandetanib (n = 61, 30.0%), sorafenib (n = 35, For the overall study cohort, median PFS was 26.6 months 17.2%), and lenvatinib (n = 10, 4.9%); Table S-1 (Addi- (95% confidence interval [CI], 20.8–60.8  months) from tional file  1) presents the most common regimens overall. initiation of first-line therapy (Fig.  2A). Median OS was Figure  1 presents a Sankey chart of first- and second- 63.8  months (95%  CI, 46.3  months–not estimable) from line treatment sequences. At the end of study follow-up, initiation of first-line therapy; survival estimates at 12, 36, 40% of patients had not received a subsequent line of and 60 months were 86.9% (95% CI, 81.4%-90.9%), 63.5% treatment after discontinuing first-line treatment. Similar (54.0%-71.5%), and 60.5% (49.5%-69.7%), respectively to first-line treatment, cabozantinib and vandetanib were (Fig.  3A). Disease-specific survival at 60  months was received by similar proportions of patients in second-line 68.3% (95% CI, 58.9%-76.0%). therapy. Of the 61 patients (30%) who received cabo- zantinib in the first line, 7 (11.5%) received second-line Nongenomic biomarkers vandetanib; of the 61 patients (30%) who received van- Calcitonin and CEA levels were evaluated per routine detanib in the first line, 10 (16.4%) received second-line practice (at advanced diagnosis and/or during each cabozantinib. treatment line). A total of 109 patients had 159 calci- During first-line treatment, 129 patients (63.5%) were tonin evaluations at the initiation of first-line treat - reported to have an objective response (i.e., complete or ment (± 28  days), and 83 patients had 328 calcitonin partial response); because of ongoing responses at data evaluations during the first-line treatment; 80 patients abstraction, median duration of objective response was had 113 CEA evaluations at the initiation of first-line treatment (± 28  days), and 45 patients had 113 CEA P arikh et al. Thyroid Research (2022) 15:2 Page 5 of 14 Table 2 Characteristics of Patients With Advanced Medullary Thyroid Cancer All Patients, Patients With RET-Mutant n (%) MTC, n (%) Number of patients, N 203 100.0% 45 100.0% Age at advanced diagnosis of MTC 203 100.0% 45 100.0% Mean (SD) 52.2 (10.4) 46.6 (9.7) Median (IQR) 53 (44–59) 46 (39–54) Sex Female 119 58.6% 26 57.8% Male 84 41.4% 19 42.2% Race White 134 66.0% 24 53.3% Black/African American 45 22.2% 10 22.2% Asian, Native Hawaiian or other Pacific Islander 18 8.9% 6 13.3% Other 1 0.5% 1 2.2% Unknown or not reported 6 3.0% 4 8.9% Ethnic origin Hispanic or Latina/Latino 25 12.3% 5 11.1% Not Hispanic or Latina/Latino 163 80.3% 33 73.3% Unknown or not reported 15 7.4% 7 15.6% Total duration of follow-up, months 203 100.0% 45 100.0% Mean (SD) 24.5 (16.0) 28.8 (18.0) Median (IQR) 21.1 (15.0–28.5) 25.5 (17.9–34.5) Clinical stage at initial diagnosis Stage II 10 4.9% 0 0.0% Stage III 20 9.9% 6 13.3% Stage IVA 58 28.6% 12 26.7% Stage IVB 28 13.8% 4 8.9% Stage IVC 82 40.4% 22 48.9% Unknown or not reported 5 2.5% 1 2.2% Time from initial diagnosis to advanced diagnosis date (months), among patients 30 14.8% 6 13.3% who were initially diagnosed with stage I, II, III (n, %) Mean (SD) 26.3 (33.0) 37.5 (64.0) Median (IQR) 14.1 (8.2–28.8) 12.6 (10.1–17) Site(s) of local extension or metastasis at advanced MTC diagnosis 203 100% 25 100% Distant lymph nodes 111 54.7% 20 44.4% Bone 69 34.0% 18 40.0% Brain 14 6.9% 6 13.3% Liver 56 27.6% 19 42.2% Local structures (e.g., muscles, larynx, trachea, esophagus, or large vessels) 58 28.6% 12 26.7% Lung/pleura 81 39.9% 15 33.3% Performance status at advanced MTC diagnosis (± 30 days) 173 85.2% 42 93.3% 0 or 1 142 82.1% 36 85.7% 2–4 31 18.0% 6 14.3% Calcitonin level evaluated at advanced MTC diagnosis (± 30 days) (pg/mL) (n, %) 141 69.5% 31 68.9% Calcitonin level known (n, %) 117 83.0% 23 74.2% Mean (SD) 150.1 (138.9) 139.2 (138.6) Median (IQR) 110.0 (22.0–210.0) 100.0 (18.0–200.0) Calcitonin evaluated but level unknown or not reported (n, %) 24 17.0% 8 25.8% CEA test performed at advanced MTC diagnosis (± 30 days) (ng/mL) (n, %) 108 53.2% 26 57.8% CEA level known (n, %) 84 77.8% 14 53.8% Parikh et al. Thyroid Research (2022) 15:2 Page 6 of 14 Table 2 (continued) All Patients, Patients With RET-Mutant n (%) MTC, n (%) Number of patients, N 203 100.0% 45 100.0% Mean (SD) 30.0 (30.4) 27.5 (28.2) Median (IQR) 18.3 (3.7–50.0) 19.3 (6.8–30.0) CEA tested but level unknown or not reported (n, %) 24 22.2% 12 46.2% CEA carcinoembryonic antigen, ECOG Eastern Cooperative Oncology Group, IQR interquartile ratio, MTC medullary thyroid cancer, RET rearranged during transfection, SD standard deviation Multiple responses allowed; rows will add up to greater than 100% Reported as mixed race Length of follow-up is the duration of time between the date of initiation of first-line systemic therapy and death or end of patient record Karnofsky score were converted to the ECOG scale for 29 patients (14.3%) [17] Calcitonin normal range: < 10 pg/mL CEA test normal range: < 2.5 ng/mL Table 3 RET-Mutation Testing and Diagnosis of Hereditary Medullary Thyroid Cancer Syndromes N % Total patient sample (N) 203 100.0% Tested for germline or somatic RET mutation at any time (n, %) Yes 121 59.6% No/unknown 82 40.4% Biomarker testing at or after initial diagnosis of MTC Patients tested for potential germline and/or somatic mutations at or after initial diagnosis of MTC (n, 95 46.8% %) Patients with RET-mutant MTC (n, %) 45 37.2% RET mutation identified before initial MTC diagnosis 25 55.6% RET mutation identified after initial MTC diagnosis 20 44.4% Type of RET mutation among patients with RET-mutant MTC (n, %) 45 37.2% M918T 18 40.0% C634R 9 20.0% C634G 1 2.2% Unknown 17 37.8% Diagnosis of hereditary MTC syndromes at any time MEN2A 8 3.9% MEN2B 5 2.5% Familial MTC 15 7.4% No hereditary MTC syndrome diagnosed 169 83.3% Unknown/not reported 6 3.0% MEN2A multiple endocrine neoplasia type 2A, MEN2B MEN type 2B, MTC medullary thyroid cancer; RET rearranged during transfection The data collection form did not distinguish between germline and somatic testing evaluations during the first-line treatment. Regres - reach a decrease of ≥ 50% in CEA level occurring after sion modeling showed that calcitonin levels generally 17.7 months (Fig. 4B). decreased during first-line treatment, with an esti - mated time to reach a decrease of ≥ 50% in calcitonin Patients with RET-mutant medullary thyroid cancer level occurring 8.4  months after treatment initiation The 45 patients with RET mutations had a mean (SD) age (Fig.  4A). Similarly, CEA levels generally decreased of 46.6 (9.7) years, and most (n = 38; 84.5%) had stage IV during first-line treatment, with an estimated time to disease at advanced MTC diagnosis (Table 2). Among the P arikh et al. Thyroid Research (2022) 15:2 Page 7 of 14 Table 4 Systemic Therapy Patterns Among Patients With Advanced Medullary Thyroid Cancer All MTC Patients Patients With RET-Mutant MTC First-line Therapy Second-line Therapy First-line Therapy Second-line Therapy Number of patients initiating treatment (N, %) 203 100.0% 49 100.0% 45 100.0% 13 100.0% Performance status at start of treatment , (n, %) 138 68.0% 35 71.4% 30 66.7% 9 69.2% 0 or 1 112 81.2% 20 57.1% 25 83.3% 6 66.6% 2–4 26 18.8% 15 42.9% 5 16.7% 3 33.3% Time from advanced MTC diagnosis to first line of 203 100.0% 49 100.0% 45 100.0% 13 100.0% treatment and time between first and second line of treatment, among patients who discontinued first line of treatment (n, %) Mean (SD) 1.9 (6.0) 1.3 (2.8) 1.0 (1.4) 0.8 (0.8) Median (IQR) 0.5 (0.3–1.2) 0.5 (0.3–0.7) 0.5 (0.3–1.2) 0.5 (0.3–1.2) Total duration of therapy line, months (n) 203 49 45 13 Kaplan–Meier estimate Median (95% CI) 12.5 (9.2–18.2) 7.9 (5.8–11.2) 9.7 (6.6–23.7) NE (6.1-NE) Treatment ongoing (n, %) 73 36.0% 16 32.70% 15 33.3% 9 69.20% Number of patients who discontinued treatment 130 64.0% 33 67.3% 30 66.7% 4 30.8% (n, %) b, c Reason for discontinuation (n, %) Adverse event 3 2.3% 0 0.0% 1 3.3% 0 0.0% Patient decision 19 14.6% 5 15.2% 4 13.3% 3 75.0% Progressive disease 70 53.8% 18 54.5% 15 50.0% 1 25.0% Completion of planned course of treatment 43 33.1% 9 27.3% 11 36.7% 1 25.0% Loss to follow-up 3 2.3% 0 0.0% 0 0.0% 0 0.0% Death 9 6.9% 2 6.1% 2 6.7% 0 0.0% Other: alternative treatment 1 0.8% 0 0.0% 0 0.0% 0 0.0% Unknown 2 1.5% 1 3.0% 1 3.3% 1 25.0% Reasons for not administering additional cancer- 72 35.5% 27 55.1% 15 33.3% 3 23.1% directed systemic treatment for advanced MTC, among patients with no subsequent treat- ment and patients who were alive at the time of discontinuing last line of treatment (n, %) Patient decision 21 29.2% 6 22.2% 2 13.3% 1 33.3% Frail physical status 16 22.2% 1 3.7% 2 13.3% 0 0.0% Stable disease 23 31.9% 5 18.5% 8 53.3% 1 33.3% CI confidence interval, ECOG Eastern Cooperative Oncology Group, IQR interquartile range, MTC medullary thyroid cancer, PS performance status, Q1 first quartile, Q3 third quartile, RET rearranged during transfection, SD standard deviation Karnofsky score converted to the ECOG scale for 29 patients (14.3%) [17] Categories are not mutually exclusive. A patient may have had more than one reason/criterion assessed; thus, the column does not sum to 100% Among patients who discontinued treatment line 42 patients with known performance status at advanced treatment at data abstraction. The mean (SD) number of MTC diagnosis, 36 (85.7%) had a performance status of lines of therapy received was 1.3 (0.5); mean (SD) total 0/1. duration of systemic therapy was 9.6 (10.2) months. The Among patients with RET mutations, mean (SD) time most common first-line therapies received were vande - from advanced diagnosis to initiation of first-line ther - tanib (n = 18, 40.0%), cabozantinib (n = 14, 31.1%), and apy was 1.0 (1.4) months (Table  4). Most (n = 32; 71.1%) sorafenib (n = 5, 11.1%). During first-line treatment, 28 received only one line of therapy during the available patients (62.2%) had an objective response; the median follow-up time; 12 (26.7%) received second-line ther- duration of objective response was not estimable for the apy, and only 1 (2.2%) received third-line therapy. Fif- 12 patients with known date of objective response. teen patients (33.3%) were receiving ongoing first-line Parikh et al. Thyroid Research (2022) 15:2 Page 8 of 14 Fig. 1 Sankey Chart for Number (%) of Patients Receiving First- and Second-Line Treatment. Note: Only cabozantinib and vandetanib were approved by the US Food and Drug Administration for the treatment of advanced medullary thyroid cancer at the time of the study Median PFS for patients with RET-mutant MTC was Patients undergoing second-line therapy 47.7  months (95%  CI, 14.2  months–not estimable) from Forty-nine patients in the overall study cohort (24.1%) initiation of first-line therapy and was not estimable received second-line therapy during the available fol- from initiation of second-line therapy (Fig.  2B). Median low-up time. This subgroup had a mean (SD) age of 48.0 OS was not estimable for these patients; survival rates (10.5) years at advanced MTC diagnosis. At initiation of at 12, 36, and 60  months were 95.5% (95%  CI, 83.2%- second-line therapy, performance status was reported 98.9%), 86.8% (70.5%-94.4%), and 86.8% (70.5%-94.4%), for 35 patients, of whom 20 (57.1%) had a performance respectively. status of 0/1, and 15 (42.9%) had a performance status of 2–4. The most frequent second-line treatments were P arikh et al. Thyroid Research (2022) 15:2 Page 9 of 14 Table 5 Objective Response Rate Among Patients With Advanced Medullary Thyroid Cancer All Patients Patients With RET-Mutant MTC During First-Line During Second- During First-Line During Therapy Line Therapy Therapy Second-Line Therapy Objective response (complete or partial response) (n, %) 129 63.5% 19 38.8% 28 62.2% 8 61.5% Among those who had objective response and known date of 71 6 12 3 objective response, duration of response (n) Mean (SE) 15.4 (1.2) 16.8 (–) 8.4 (0.9) NE Median NE NE NE 95% CI 10.3 NE 16.8 4.2 NE Q1, Q3 6 NE 16.8 6.6 NE Censored (n, %) 46 64.8% 5 83.3% 7 58.3% 3 100.0% CI confidence interval, MTC medullary thyroid cancer, NE not estimable, Q1 first quartile, Q3 third quartile, RET rearranged during transfection, SE standard error Duration of objective response defined as time from complete or partial response to disease progression, death, or start of next line of treatment. Patients with treatment line ongoing or who discontinued treatment for nonprogression reasons were censored recent studies have explored patient and tumor charac- cabozantinib (n = 11, 22.4%), vandetanib (n = 10, 20.4%), teristics and treatment outcomes. Randle et  al. [9] con- lenvatinib and sunitinib (n = 6 [12.2%] for both), and ducted a population-based study evaluating survival sorafenib (n = 4, 8.2%). During second-line treatment, 19 among patients with MTC (of all stages) using 2003–2012 patients (38.8%) had an objective response; the median data from the US SEER registry. Overall 5-year disease- duration of objective response was not estimable for the specific survival was estimated to be 51% among patients 6 patients with known date of objective response. Dur- with metastatic MTC [9]. A higher 5-year disease-specific ing second-line therapy, regression modeling showed survival rate, 68.3%, was observed for the overall popula- that available calcitonin levels remained generally stable tion in the current study. This difference may be attribut - (Fig.  4C). The number of available CEA levels was insuf - able to differences in the study time frames, potentially ficient for analysis. differing prognostic factors, and the introduction of new From initiation of second-line therapy, median PFS regimens since Randle and colleagues’ analysis [9]. was 15.3  months (95%  CI, 6.6  months–not estima- In addition, a registry study conducted in a routine care ble) (Fig.  2C). Median OS was 22.4  months (95%  CI, setting in Germany enrolled 48 patients with advanced 12.4  months–not estimable), and survival estimates at MTC who were treated with the tyrosine kinase inhibi- 12, 36, and 60 months from the initiation of second-line tors (TKIs) vandetanib and/or cabozantinib [14]. This therapy were 69.1% (95% CI, 52.8%-80.8%), 42.4% (23.7%- population had a median age at diagnosis of metastatic 59.9%), and 42.4% (23.7%-59.9%), respectively (Fig. 3B). MTC of 50  years and predominantly had sporadic MTC (75% of patients) 13% had hereditary MTC, and germline Discussion RET-mutation status was not known for 13% of patients. This study retrospectively evaluated clinical character - Most patients (96%) had distant metastases. Twelve- istics, biomarkers, treatment patterns, and survival out- month survival estimates were 86% for those receiving comes among US patients with advanced MTC managed vandetanib and 70% for those receiving cabozantinib in real-world clinical settings. Of the patients evaluated, [14]. The 12-month survival rate of 87.5% observed in 37.2% had RET-mutant MTC. Cabozantinib, vande- the current study is consistent with this prior research, tanib, sorafenib, and lenvatinib were the most common and median duration of treatment was similar in the two first-line treatments. Among 49 patients who received studies (25  months in Koehler et  al. vs. 21.1  months in second-line treatment, most received cabozantinib, van- the current study). In addition, TKIs were the most com- detanib, lenvatinib, or sunitinib. For the overall popula- monly administered treatments in the current study: tion, median PFS from start of first- and second-line approximately 60% of patients received either cabozan- treatments was 26.6  months and 15.3  months; median tinib or vandetanib in the first line. The TKIs sorafenib OS from initiation of first- and second-line treatments and lenvatinib, as well as the cytotoxic drug dacarbazine, was 63.8 months and 22.4 months, respectively. were also commonly used in the first line, despite not While real-world studies in MTC have been limited, being approved by the US Food and Drug Administration particularly those evaluating treatment patterns, several Parikh et al. Thyroid Research (2022) 15:2 Page 10 of 14 Fig. 2  Progression-Free Survival A. Overall Population, First-Line Therapy. B. RET-Mutant Medullary Thyroid Cancer, First-Line Therapy. C. Overall Population, Second-Line Therapy. CI confidence interval, MTC medullary thyroid cancer, NE not estimable, PFS progression-free survival, RET rearranged during transfection, SE standard error P arikh et al. Thyroid Research (2022) 15:2 Page 11 of 14 Fig. 3 Overall Survival. A. From Initiation of First-Line Systemic Treatment. B. From Initiation of Second-Line Systemic Treatment. CI confidence interval, NE not estimable, SE standard error for the treatment of MTC. Presumably, treating phy- not harbor RET mutations [5]. In clinical practice, the sicians’ off-label use of these therapies was driven by proportion of patients undergoing testing for RET muta- evidence of clinical benefit with sorafenib [19–22], len - tions varies [26], and in the current study, 40% of patients vatinib [23], and dacarbazine [24, 25], as well as recom- were not known to have undergone testing for germline mendations in clinical guidelines that small-molecule and/or somatic RET mutation. Among the overall sam- kinase inhibitors may be used when preferred systemic ple, 22% of patients were known to have RET-mutation therapies are not available or appropriate [10]. positive MTC; these patients had an average age of RET-mutation positive MTC has been associated with 46.6 years. Vandetanib monotherapy was the most com- worse clinical outcomes relative to MTC tumors that do mon first-line regimen for patients with RET -mutation Parikh et al. Thyroid Research (2022) 15:2 Page 12 of 14 Fig. 4 Regression Analysis of Calcitonin and Carcinoembryonic Antigen Levels by Line of Treatment . A. Calcitonin Levels During First-Line Treatment. B. Carcinoembryonic Antigen Levels During First-Line Treatment. CEA carcinoembryonic antigen. C. Calcitonin Levels During Second-Line Treatment. CEA carcinoembryonic antigen. Note: A locally weighted polynomial regression, or LOESS, fit was estimated to smooth the a b data points and highlight the underlying trend [18]. Predicted using an unadjusted, mixed-model repeated-measures analysis. Evaluations 28 days before or after initiating treatment line were attributed to baseline (i.e., time 0). Evaluation after 28 days of treatment initiation were grouped in to 28-day intervals and have been assigned to the end of the interval positive MTC, followed by cabozantinib monotherapy. with the availability of the RET-targeted therapies selper- The PFS rate at 36  months was 55% after initiation of catinib and pralsetinib. first-line therapy for this subgroup. To date, studies eval - Previous studies have found an association between uating real-world treatment patterns for patients with elevated calcitonin and CEA levels, more rapid disease RET-mutation positive MTC have been limited, and progression, and worse survival outcomes [13, 15]. A future research should explore how treatment patterns mixed-model repeated-measures regression analysis and outcomes for patients with RET-mutant MTC evolve demonstrated that calcitonin levels decreased during P arikh et al. Thyroid Research (2022) 15:2 Page 13 of 14 Cancer Network; OS: Overall survival; PFS: Progression-free survival; RET: first-line treatment initially; appeared to trend upward Rearranged during transfection; SD: Standard deviation; SEER: Surveillance, toward the end of first-line treatment, probably related to Epidemiology, and End Results; TKI: Tyrosine kinase inhibitor; US: United States. disease progression; and remained generally stable during second-line treatment. Because the objective response Supplementary Information rate during second-line therapy (among the 49 patients The online version contains supplementary material available at https:// doi. who received it during this study) was lower (39%) than org/ 10. 1186/ s13044- 021- 00119-9. that among all patients during first-line therapy (64%), suboptimal response may potentially explain the pattern Additional file 1: Table S1. Most Common First- and Second-Line Systemic Therapies Among Patients With Advanced Medullary Thyroid of calcitonin levels during second-line therapy, empha- Cancer. sizing the need for more effective treatments. Several limitations of this study should be considered. Acknowledgements Patients selected for study inclusion represent a conveni- Kate Lothman of RTI Health Solutions provided medical writing services dur- ence sample of medical records obtained from physicians ing development of this manuscript. These services were funded by Eli Lilly willing to participate in the study and may be biased and Company. toward patients who were alive at data abstraction; study Authors’ contributions findings may not be generalizable to the overall popula - All authors made a significant contribution to the work reported, whether that tion of US patients with advanced MTC. To help mitigate is in the conception, study design, execution, acquisition of data, analysis and interpretation, or in all these areas; took part in drafting, revising, or critically potential biases, physicians were recruited from a vari- reviewing the article; gave final approval of the version to be published; have ety of regions and practice types and were instructed to agreed on the journal to which the article has been submitted; and agree to select patients who were either alive or dead by a quasi- be accountable for the content of the article. random procedure. Data available for study were limited Funding to those recorded in medical records. Although internal This study was performed under a research contract between RTI Health Solu- data consistency was improved by data checks and use of tions and Eli Lilly and Company and was funded by Eli Lilly and Company. a customized data-collection form, the entered data were Availability of data and materials not validated against patients’ medical records by inde- Not applicable. pendent review. The information collected on genomic biomarker testing did not distinguish between germline Declarations and somatic mutations, and the frequency of such testing Ethics approval and consent to participate may have increased in current practice. Finally, a consid- RTI International’s institutional review board (IRB) reviewed the study protocol erable proportion of patients were undergoing treatment and deemed the research, which was not considered human subjects at the time of data abstraction, and 52% of patients were research, to be exempt from full IRB review. censored for PFS estimates; therefore, PFS estimates are Consent for publication based on immature data, and studies with longer follow- Not applicable. up are warranted in this population. Competing interests This study was performed under a research contract between RTI Health Conclusions Solutions and Eli Lilly and Company and was funded by Eli Lilly and Company. More than one-third of patients with advanced or met- RP, EE, and JAK are employees of RTI Health Solutions. LMH and NRB are employees of Eli Lilly and Company. astatic MTC were not tested for RET mutation as rec- ommended by national guidelines. For the treatment of Author details advanced/metastatic MTC, no specific preference of RTI Health Solutions, 3040 East Cornwallis Road, Research Triangle Park, NC 27709, USA. Eli Lilly and Company, Lilly Corporate Center, Indianapolis, IN sequencing systemic agents was observed in the first- and 46285, USA. RTI Health Solutions, 307 Waverley Oaks Road, Waltham, MA second-line settings. The estimated OS was consistent 02452, USA. with that observed from SEER data for metastatic MTC. Received: 21 June 2021 Accepted: 9 December 2021 Considering the recent approval of selective RET inhibi- tors for patients with RET-mutant MTC, future research should investigate potential changes in these findings, particularly in the second-line setting. Evidence-based References recommendation on sequencing of systemic therapies 1. Wells SA Jr, Asa SL, Dralle H, et al. Revised American Thyroid Association may benefit patients with advanced MTC. guidelines for the management of medullary thyroid carcinoma. Thyroid. 2015;25:567–610. 2. Howlader N, Noone AM, Krapcho M, et al. (eds). SEER Cancer Statistics Review, 1975–2017, National Cancer Institute. Bethesda, MD. 2020 (based Abbreviations on November 2019 SEER data submission, posted to the SEER web site, CEA: Cost-effectiveness analysis; CI: Confidence interval; IRB: Institutional review board; MTC: Medullary thyroid cancer; NCCN: National Comprehensive Parikh et al. Thyroid Research (2022) 15:2 Page 14 of 14 April 2020). Available at https:// seer. cancer. gov/ csr/ 1975_ 2017/ Accessed medullary thyroid carcinoma in Denmark 1997–2013: A nationwide 10 December 10, 2020. study. Clin Epidemiol. 2019;10:93–9. 3. Lim H, Devesa SS, Sosa JA, et al. Trends in thyroid cancer incidence and mortality in the United States, 1974–2013. JAMA. 2017;317:1338–48. Publisher’s Note 4. Moura MM, Cavaco BM, Leite V. 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Chemotherapy with dacarbazine rapid publication on acceptance and 5-fluorouracil in advanced medullary thyroid cancer. Ann Oncol. support for research data, including large and complex data types 1994;5:763–5. • gold Open Access which fosters wider collaboration and increased citations 25. Schlumberger M, Abdelmoumene N, Delisle MJ, Couette JE. Treatment of advanced medullary thyroid cancer with an alternating combination of 5 maximum visibility for your research: over 100M website views per year FU-streptozocin and 5 FU-dacarbazine. The Groupe d’Etude des Tumeurs a Calcitonine (GETC). Br J Cancer. 1995;71:363–5. At BMC, research is always in progress. 26. Mathiesen JS, Kroustrup JP, Vestergaard P, et al. Danish Thyroid Cancer Learn more biomedcentral.com/submissions Group (DATHYRCA). Completeness of RET testing in patients with

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Thyroid ResearchSpringer Journals

Published: Feb 12, 2022

Keywords: RET; Medical record; Chart review; Retrospective; Observational; Real-world; United States survival

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