Abstract
Objective
This study aimed to describe real-world patient and physician characteristics, rearranged during transfection (RET) mutation testing and results, treatment patterns and patient-reported outcomes (PROs) in advanced or metastatic medullary thyroid cancer (aMTC) across five populous European countries.
Methods
Cross-sectional physician and patient surveys were used to collect quantitative and qualitative data in France, Germany, Italy, Spain and the UK from July to December 2020, prior to the introduction of selective RET inhibitors in Europe. Physicians completed patient record forms and a survey about their specialty and practice site. Patients were asked to provide PRO data using four validated instruments, including the EuroQol 5 Dimension (EQ-5D) questionnaire.
Results
The physician-reported sample included 275 patients with aMTC, including 79 patients with RET mutation-positive disease; median age was 60 and 56 years, respectively. Overall, 75% were tested for RET mutation (35% germline only, 21% somatic only and 44% both). Common physician-cited barriers to RET mutation testing included high cost, difficulty accessing the latest tests and time delay for results. First-line systemic therapy (most commonly vandetanib or cabozantinib) was prescribed for 69% of patients overall and 82% of the RET mutation-positive subgroup. Second-line therapy was prescribed for 12% of patients who received first-line therapy; most patients remained on first-line therapy at data capture. PROs revealed a substantial disease/treatment burden.
Conclusion
Patients with aMTC report a substantial disease/treatment burden. Outcomes could be improved by identifying patients eligible for treatment with selective RET inhibitors through more optimal RET mutation testing.
Introduction
Medullary thyroid cancer (MTC) is a rare neuroendocrine tumour derived from calcitonin-secreting parafollicular C cells (1) and accounts for approximately 2‒4% of thyroid cancers (2, 3, 4, 5) but up to 15% of thyroid-cancer-related deaths (6). Approximately 75% of MTC cases are sporadic, and 25% are hereditary (7, 8). The hereditary form of MTC can occur either with other endocrine neoplasms (multiple endocrine neoplasia (MEN) types 2A and 2B) or alone (familial MTC) (7, 8).
Most cases of MTC carry mutations in the proto-oncogene known as rearranged during transfection (RET), which can be either germline (in ≥95% of patients with hereditary MTC) or somatic (in about half of cases of sporadic MTC) (5, 8, 9, 10, 11). Germline RET mutations are present in up to 10% of patients with apparently sporadic MTCs (5, 10). European Society for Medical Oncology (ESMO) guidelines recommend that screening for RET mutations should be strongly considered in all patients with MTC for whom treatment with systemic therapy is planned (12).
Systemic therapies in advanced or metastatic MTC (aMTC) include multikinase inhibitors (MKIs) and selective RET inhibitors (12, 13). ESMO treatment guidelines from April 2022 recommend the MKIs cabozantinib and vandetanib as first-line systemic therapy, and the selective RET inhibitor selpercatinib for patients with RET mutation-positive MTC who require systemic therapy following prior treatment with cabozantinib and/or vandetanib (12). In September 2022, the European Medicines Agency extended approval of selpercatinib for the treatment of adults and adolescents (≥12 years of age) with RET mutation-positive aMTC in any line of therapy (14). Pralsetinib, another selective RET inhibitor approved by the US Food and Drug Administration for patients with RET-mutant aMTC aged ≥12 years, is currently (as of April 2023) not approved for treating thyroid cancer in Europe (15).
Clinical indicators of poor prognosis (e.g. presence of multifocal tumours, stage IV disease) appear to occur more frequently in MTC patients with RET mutations at exons 15 and 16 compared to patients with other RET mutations or those without RET mutations (16).
Real-world evidence describing clinical characteristics, RET mutation testing and treatment patterns in patients with aMTC are available from the USA (17, 18, 19, 20), although similar data from Europe, including patient-reported outcomes (PROs) for this patient population, are limited (21).
This analysis aimed to describe real-world patient and treating physician characteristics, RET mutation testing and results, systemic and supportive treatments received and health-related quality of life (HR-QoL) among patients with aMTC in five populous European countries.
Methods
Study design and data source
This study utilised data from the Adelphi Thyroid Cancer Disease Specific Programme (DSP). Adelphi DSPs are large, multinational, cross-sectional surveys that collect real-world quantitative and qualitative data from physicians and patients (22).
The survey was conducted from July to December 2020 in five populous European countries (referred to herein as EU5): France, Germany, Italy, Spain, and the UK. Participating physicians completed a survey providing information, including their specialty and workplace setting. Subsequently, physicians completed a patient record form (PRF) for each of the next five consecutive patients seen in their routine clinical practice who met the study inclusion criteria. All patients for whom a PRF was completed were invited to complete a patient self-completion form (PSC) on a voluntary basis to provide PROs. The PSC was linked to the physician-completed PRF. PSCs were completed independently by the patient and returned in a sealed envelope to ensure confidentiality.
Participating physicians and patients
Physicians were eligible to participate in the survey if they had consultations with ≥2 patients with MTC or papillary thyroid cancer in a typical 12-month period and were responsible for the management of these patients, including RET-alteration testing and treatment decisions. Patients were eligible for inclusion in the study if, at the time of data collection, they were ≥18 years of age, had a physician-confirmed diagnosis of locally aMTC, and visited the physician. Patients participating in clinical trials were not excluded.
Participating physicians were reimbursed upon survey completion according to fair market research rates; patients were not compensated for participation.
Study variables
Physicians provided information on patient demographics, clinical characteristics and current and prior treatment(s) received. Clinical characteristics included Eastern Cooperative Oncology Group (ECOG) performance status (PS), disease state (metastatic or locally advanced) and biomarker assessment.
PRFs captured individual patient data on RET alteration testing, type of test (germline/somatic) and results, MEN2A and MEN2B subtypes and whether patients with hereditary MTC received genetic counselling. The PRFs also captured data on all lines of treatments received, time from initial diagnosis to first-line treatment, duration of treatment, reason for prescribing current or most recent treatment, reason for treatment discontinuation and supportive therapies received during treatment.
PSCs captured PROs using four validated instruments: (i) the EuroQol Visual Analogue Scale (EQ-VAS), (ii) the EuroQol 5 Dimension questionnaire (EQ-5D), (iii) the Functional Assessment of Cancer Therapy‒General questionnaire (FACT-G) and (iv) the Work Productivity and Activity Impairment questionnaire (WPAI) (Table 1).
Overview of the four validated instruments used for patient-reported outcomes.
| Instrument | Description |
|---|---|
| EQ-VAS | A vertical, calibrated, line, bounded at 0 (worst imaginable health state) and at 100 (best imaginable health state) (23) |
| EQ-5D | Includes five subdomains (mobility, self-care, usual activities, pain/discomfort and anxiety/depression) and provides health utility index scores (using country-specific tariffs) that range from <0 (worse than death) to 1 (perfect health) (24) |
| FACT-G | Measures four domains of HR-QoL in cancer patients (physical, social, emotional and functional well-being), with total scores ranging from 0 (worst) to 108 (best) (25) |
| WPAI | A six-item questionnaire measuring the impact of disease on work productivity and daily activities over the past week; scores are expressed as a percentage, and higher scores indicate a larger impact (26) |
EQ-5D, EuroQol 5 Dimension questionnaire; EQ-VAS, EuroQol Visual Analogue Scale; FACT-G, Functional Assessment of Cancer Therapy‒General questionnaire; HR-QoL, health-related quality of life; WPAI, Work Productivity and Activity Impairment questionnaire.
Information about the participating physicians’ specialty and type of practice site was obtained via a physician survey.
Statistical analysis
Analyses were conducted overall for aMTC patients in all five countries combined (EU5), and for the subgroup of RET mutation-positive patients. Selected results are presented by country.
Descriptive statistics are provided for demographics and disease characteristics. Continuous variables are described as mean with s.d. and/or median with interquartile range (IQR). Categorical variables are reported as the frequency and percentage within each category.
No allowance was made for missing data through multiple imputation or other methods. Where data were missing for specific variables, they were excluded from the analysis. Therefore, the number of responses could vary between different parameters/variables.
Ethical considerations
A complete description of the methods of the survey has been previously published and validated (22, 27, 28). Patients provided informed consent for the use of their anonymised, aggregated data for research and publication in scientific journals. Neither patients nor physicians could be identified directly; all data were aggregated and de-identified before receipt.
This research obtained ethics exemption from the Western Institutional Review Board, study protocol number #AG8757.
Data collection was undertaken in line with European Pharmaceutical Marketing Research Association guidelines (29), and as such, did not require ethics committee exemption. Each survey was performed in full accordance with relevant legislation at the time of data collection, including the Health Information Technology for Economic and Clinical Health Act legislation (30).
Results
Patient demographic and clinical characteristics and physician characteristics
Demographic and clinical characteristics for all patients with aMTC (n = 275) and those with RET mutation-positive disease (n = 79) are summarised in Table 2. The largest number of patients were from France (n = 86) and Spain (n = 69), followed by Germany (n = 48), Italy (n = 40) and the UK (n = 32).
Patient demographics and clinical characteristics overall (EU5) and in patients with RET mutation-positive MTC (from PRF). Data are presented as n (%) or as median (IQR).
| Characteristics | Total EU5 (n = 275) | RET mutation positive (n = 79) |
|---|---|---|
| Age, years | ||
| Mean (s.d.) | 60.1 (11.0) | 56.0 (10.9) |
| Median (IQR) | 60.0 (53.0, 68.0) | 56.0 (50.0, 65.0) |
| Sex, n (%) | ||
| Male | 147 (53) | 42 (53) |
| Female | 128 (47) | 37 (47) |
| BMI, mean (s.d.) | 24.1 (3.0) | 23.4 (2.7) |
| Ethnic origin | ||
| White/Caucasian | 258 (94) | 73 (92) |
| Hispanic/Latino | 8 (3) | 3 (4) |
| Afro-Caribbean | 4 (1) | 2 (3) |
| Middle Eastern | 3 (1) | 0 (0) |
| Asian (Indian subcontinent) | 1 (<1) | 0 (0) |
| Southeast Asian | 1 (<1) | 1 (1) |
| Disease state at data capture | ||
| Metastatic | 217 (79) | 69 (87) |
| Locally advanced | 57 (21) | 9 (11) |
| Unknown/not assessed | 1 (<1) | 1 (1) |
| Received thyroidectomy | 141 (51) | 42 (53) |
| Family history of thyroid cancer | ||
| Yes | 31 (11) | 22 (28) |
| No | 232 (84) | 54 (68) |
| Unknown | 12 (4) | 3 (4) |
| Time between initial diagnosis and data capture, monthsa | 12.6 (5.9, 31.1) | 20.6 (7.9, 34.7) |
| ECOG PS score at initial diagnosis | ||
| 0 | 124 (45) | 43 (54) |
| 1 | 115 (42) | 30 (38) |
| ≥2 | 29 (11) | 6 (8) |
| Unknown/not assessed | 7 (3) | 0 (0) |
| ECOG PS score at data capture | ||
| 0 | 66 (24) | 17 (22) |
| 1 | 138 (50) | 44 (56) |
| ≥2 | 70 (25) | 18 (23) |
| Unknown/not assessed | 1 (<1) | 0 (0) |
| Calcitonin test performed at diagnosis | 265 (96) | 79 (100) |
| CEA test performed at diagnosis | 246 (89) | 69 (87) |
| MEN2 subtype for patients positive for germline or somatic mutation | NA | 79 |
| MEN2A | NA | 22 (28) |
| MEN2B | NA | 4 (5) |
| Familial MTC | NA | 21 (27) |
| Unknown | NA | 32 (41) |
| Genetic counselling offered for patients with family history of MTC | 31 | 22 |
| Yes | 23 (74) | 19 (86) |
| No | 5 (16) | 1 (5) |
| Unknown | 3 (10) | 2 (9) |
| Genetic counselling received for patients with family history of MTC | 31 | 22 |
| Yes | 21 (68) | 18 (82) |
| No | 2 (6) | 1 (5) |
aIn patients with known date at initial diagnosis.
BMI, body mass index; CEA, carcinoembryonic antigen; ECOG PS, European Cooperative Oncology Group performance status; EU5, France, Germany, Italy, Spain, UK; IQR, interquartile range; max, maximum; MEN2, multiple endocrine neoplasia type 2; min, minimum; MTC, medullary thyroid cancer; NA, not applicable; PRF, patient record form; RET, rearranged during transfection.
A total of 231 physicians participated (completed a physician survey and reported being able to answer on MTC patients), most of whom were medical/clinical oncologists (63%) or endocrinologists/diabetologists (26%) (Supplementary Table 1, see section on supplementary materials given at the end of this article). The greatest proportion of time spent by these physicians was in public hospitals (48%) and cancer centres (26%). In the past 12 months, the mean (s.d.) number of patients with MTC and total thyroid cancer patients (including MTC) seen was 8.8 (10.8) and 55.4 (91.8), respectively.
Median (IQR) age was 60.0 (53.0, 68.0) years in the overall patient population and 56.0 (50.0, 65.0) years in the subgroup with RET mutation-positive MTC; the proportion of male patients (53%) was the same for both groups. The majority of patients in the overall population (94%) and in patients with RET mutation-positive MTC (92%) were White/Caucasian.
The proportion of patients with metastatic disease was numerically lower in the overall MTC population than in patients with RET mutation-positive MTC (79% vs 87%). The proportion of patients with a family history of thyroid cancer (11% vs 28%) was also lower in the overall population. Overall, 87% and 74% of patients had an ECOG PS of 0‒1 at the time of initial diagnosis and data capture, respectively. Median (IQR) time from initial diagnosis to data capture was 12.6 months (5.9, 31.1). Among patients with RET mutation-positive MTC, the ECOG PS was 0‒1 in 92% at diagnosis, and 77% at data capture; median (IQR) time from initial diagnosis to data capture was 20.6 months (7.9, 34.7).
In the population with RET mutation-positive MTC, 28% had subtype MEN2A, 5% MEN2B, 27% familial MTC and 41% unknown subtype.
In the overall population and in patients with RET mutation-positive MTC, >95% had calcitonin and >85% had carcinoembryonic antigen (CEA) levels measured at initial diagnosis.
RET mutation testing patterns and results
Of the 275 patients, 207 (75%) were tested for RET mutation at any time (at or after initial diagnosis). The rate of RET mutation testing was generally similar across most countries (68‒72% for France, Germany, Italy and the UK), but was numerically higher in Spain (90%). The most common methodologies used for RET mutation testing were next-generation sequencing (46%) and reverse transcription polymerase chain reaction (35%).
Overall, for the EU5 population tested (n = 207), 35% of patients were tested for germline mutation only, 21% for somatic mutation only and 44% for both germline and somatic mutation (Fig. 1A). Positive RET mutation test results were reported for 38%, negative results were reported for 52% and results were unknown for 10%. The rate of positivity was similar in France, Italy and Spain (30‒34%), but somewhat higher in Germany (51%) and the UK (57%) (Fig. 1B). Of the 79 patients who tested positive for RET mutations, 22 (28%) were tested for germline mutation only, 19 (24%) were tested for somatic mutation only and 38 (48%) were tested for both. The mean (s.d.) time from sample acquisition to receiving test results was 20.2 (15.6) days for EU5, ranging from a mean (s.d.) of 9.6 (4.8) days in Germany to 28.4 (20.5) days in Spain.
RET mutation testing patterns (A) and results (B) (from PRF).
Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0172
In the physician survey, the most frequently cited barriers to testing for RET mutation were high cost (40%), difficulty accessing latest tests (29%), time delay for test results (27%), lack of physician educational resources (24%) and limited physician awareness of testing (24%) (n = 153).
Of the 31 patients with a family history of MTC, 22 patients (71%) had RET mutation-positive disease. Genetic counselling was offered to 23 patients (74%) and received by 21 (68%) patients with a history of MTC (Table 2).
Treatment patterns
Most patients received systemic drug treatment, including 190 of 275 patients (69%) in the overall population and 65 of 79 patients (82%) in the subgroup with RET mutation-positive MTC (Table 3). The median (IQR) time from initial diagnosis to initiation of first-line therapy was 2.8 (1.0, 22.1) months for the overall population and 7.2 (1.4, 28.7) months for patients who were RET mutation positive, indicating a skewed distribution.
Systemic drug treatment patterns (from PRF). Data are presented as n or n (%).
| Parameter | Total EU5 (n = 275) | RET mutation positive (n = 79) |
|---|---|---|
| Received first-line therapy | 190 | 65 |
| Vandetanib | 87 (46) | 37 (57) |
| Cabozantinib | 57 (30) | 20 (31) |
| Larotectinib | 3 (2) | 1 (2) |
| Any chemotherapy | 41 (22) | 9 (14) |
| Any non-cisplatin-based chemotherapy | 17 (9) | 4 (6) |
| Cisplatin-based chemotherapy | 24 (13) | 5 (8) |
| Chemotherapy regimens containing | ||
| Doxorubicin | 24 (13) | 4 (6) |
| Dacarbazine | 5 (3) | 1 (2) |
| 5-Fluorouracil | 5 (3) | 2 (3) |
| Cyclophosphamide | 3 (2) | 1 (2) |
| Clinical trial regimen | 4 (2) | 1 (2) |
| Other | 4 (2) | 1 (2) |
| Still receiving first-line therapy at data capture | 157 (83) | NA |
| Received second-line therapy | 23 | 9 |
| Vandetanib | 10 (43) | 5 (56) |
| Cabozantinib | 7 (30) | 1 (11) |
| Larotectinib | 2 (9) | 2 (22) |
| Doxorubicin | 1 (4) | 0 (0) |
| Clinical trial regimen | 1 (4) | 0 (0) |
| Other | 5 (22) | 3 (33) |
| Time from initial diagnosis to initiation of first-line therapy (months)a | 162 | 61 |
| Mean (s.d.) | 15.9 (30.4) | 22.2 (39.8) |
| Median (IQR) | 2.8 (1.0, 22.1) | 7.2 (1.4, 28.7) |
| Duration of first-line therapy (months)b | 27 | 12 |
| Mean (s.d.) | 14.7 (18.1) | 15.1 (17.7) |
| Median (IQR) | 4.6 (3.0, 20.0) | 4.8 (3.0, 23.8) |
| Reasons for discontinuing drug treatment in all patients who discontinued first-line drug treatment | 23 | 6 |
| Disease progression while receiving treatment | 14 (61) | 4 (67) |
| Switch to hospice care | 2 (9) | 0 (0) |
| Patient request to stop treatment | 1 (4) | 1 (17) |
| Switch to best supportive care only | 1 (4) | 0 (0) |
| Unacceptable tolerability | 1 (4) | 1 (17) |
| Unacceptable impact on patient’s quality of life | 1 (4) | 0 (0) |
| Other | 3 (13) | 0 (0) |
| Supportive drug therapies received at data capture in patients receiving first-line treatmentc | 107 | 37 |
| Non-opioid analgesics | 57 (53) | 18 (49) |
| Levothyroxine | 39 (36) | 16 (43) |
| Anti-emetics | 29 (27) | 11 (30) |
| Opioid analgesics | 21 (20) | 7 (19) |
| Corticosteroids | 21 (20) | 6 (16) |
| Other | 11 (10) | 3 (8) |
aAmong patients with known date at initial diagnosis; bAmong patients with known duration of first-line therapy; cAmong patients who reported receiving drug-based supportive therapies.
EU5, France, Germany, Italy, Spain, UK; IQR, interquartile range; NA, not available; PRF, patient record form; RET, rearranged during transfection.
The MKIs vandetanib and cabozantinib were the most common first-line treatments, together accounting for 76% and 88% of prescriptions for all patients with aMTC and patients with RET mutation-positive disease, respectively. Vandetanib use was about 1.5–2 times that of cabozantinib in the first-line setting (46% vs 30% for the overall population; 57% vs 31% for patients with RET mutation-positive disease).
Chemotherapy was prescribed for some patients as first-line systemic treatment; 13% of patients in the overall population and 8% of patients with RET mutation-positive disease received cisplatin-based therapy. Non-cisplatin-based chemotherapy was prescribed as first-line systemic treatment for 9% of patients overall and 6% of patients with RET mutation-positive disease. Thus, 22% and 14% of patients in the respective groups received first-line chemotherapy (Table 3).
For patients with a known duration of first-line treatment, the median (IQR) duration of first-line therapy was 4.6 (3.0, 20.0) months for the overall population (n = 27) and 4.8 (3.0, 23.8) months for those with RET mutation-positive MTC (n = 12), indicating a skewed distribution towards more patients with shorter durations of therapy in both cohorts. However, this represents only a small proportion of the study population because 83% of patients who received first-line therapy were still receiving it at data capture.
Supportive drug therapies received during first-line treatment included non-opioid analgesics (53% of the overall group receiving first-line therapy and 49% in the subgroup with RET mutation-positive MTC), levothyroxine (36% and 43%, respectively) and anti-emetics (27% and 30%) (Table 3).
Second-line systemic drug therapy was prescribed for 12% of patients overall (23 of 190 patients who received first-line treatment) and 14% of those with RET mutation-positive MTC (9 of 65 patients). At the time of data collection, 157 (83%) of the 190 patients ever treated with first-line systemic therapy were still receiving ongoing first-line treatment. Targeted therapy with either vandetanib or cabozantinib was the most common second-line treatment, together accounting for 74% and 67% of second-line prescriptions in patients overall and in those with RET mutation-positive disease, respectively.
Details regarding first- and second-line treatment patterns by country are provided in Supplementary Table 2.
Figure 2 presents a Sankey chart of first- and second-line treatment sequences.
Sankey chart for number (%) of patients receiving first- and second-line systemic drug treatment. Of the 190 patients who received first-line therapy, 153 (83%) remained on first-line treatment at data capture.
Citation: European Thyroid Journal 13, 1; 10.1530/ETJ-23-0172
For patients who discontinued first-line systemic therapy, the most common reasons reported by physicians for discontinuing treatment in all patients with aMTC (n = 23) were disease progression while receiving treatment (61%) and switch to hospice care (9%). For patients with RET mutation-positive disease (n = 6), the most common reasons were disease progression while receiving treatment (67%), patient request to stop treatment (17%) and unacceptable tolerability (17%) (Table 3).
For patients who were receiving first-line therapy at data capture (n = 167) and reported experiencing adverse events (n = 85; 51%), the most common adverse events in the overall population were diarrhoea (42%), nausea (29%), anaemia (27%), fatigue and loss of appetite (each 24%). For patients with RET mutation-positive MTC (n = 56) who reported adverse events (n = 37; 66%), the most common were diarrhoea (49%), nausea (32%), fatigue, weight loss and hypertension (each 27%) (Table 4).
Adverse events among patients receiving first-line therapy at data capture and reported by ≥10% of patients (in either group) experiencing adverse events (from PRF). Data are presented as n (%).
| Adverse | Total EU5 (n = 167) | RET mutation-positive (n = 56) |
|---|---|---|
| Patients reporting | ||
| No adverse events | 82 (49) | 19 (34) |
| ≥1 adverse event(s) | 85 (51) | 37 (66) |
| Diarrhoea | 36 (42) | 18 (49) |
| Nausea | 25 (29) | 12 (32) |
| Anaemia | 23 (27) | 8 (22) |
| Fatigue | 20 (24) | 10 (27) |
| Loss of appetite | 20 (24) | 9 (24) |
| Weight loss | 16 (19) | 10 (27) |
| Dry skin | 15 (18) | 6 (16) |
| Hypertension | 14 (16) | 10 (27) |
| Decreased appetite | 13 (15) | 5 (14) |
| Headaches | 12 (14) | 5 (14) |
| Mouth sores | 11 (13) | 4 (11) |
| Abdominal pain | 7 (8) | 5 (14) |
EU5, France, Germany, Italy, Spain, UK; HR-QoL, health-related quality of life; PRF, patient record form; RET, rearranged during transfection.
Disease burden and HR-QoL of patients
In patients on first-line therapy at data capture, 13% of the overall population (n = 167) and 11% of patients with RET mutation-positive disease (n = 56) were asymptomatic. For patients with symptoms at data capture who were receiving first-line systemic therapy, the most frequently reported symptoms in the overall population were bone pain and weight loss (25% for each), cough (23%), swelling in the neck (21%) and tender neck (19%). In patients with RET mutation-positive MTC, the most common symptoms were bone pain (32%), weight loss (24%) and cough, voice hoarseness/change to the voice and diarrhoea (20% for each) (Table 5).
Symptoms among patients receiving first-line therapy at data capture and reported by ≥10% of patients (in either group) experiencing symptoms (from PRF). Data are presented as n (%).
| Symptoms | Total EU5 (n = 167) | RET mutation positive (n = 56) |
|---|---|---|
| Patients reporting | ||
| No symptom | 21 (13) | 6 (11) |
| ≥1 symptom | 146 (87) | 50 (89) |
| Bone pain | 36 (25) | 16 (32) |
| Weight loss | 36 (25) | 12 (24) |
| Cough | 33 (23) | 10 (20) |
| Swelling of the neck | 30 (21) | 5 (10) |
| Tender neck | 28 (19) | 6 (12) |
| Voice hoarseness/changes to voice | 26 (18) | 10 (20) |
| Neck pain | 26 (18) | 9 (18) |
| Dyspnoea | 21 (14) | 8 (16) |
| Diarrhoea | 21 (14) | 10 (20) |
| Lump in neck/throat | 18 (12) | 4 (8) |
| Lethargy | 16 (11) | 7 (14) |
EU5, France, Germany, Italy, Spain, UK; HR-QoL, health-related quality of life; PRF, patient record form; RET, rearranged during transfection.
Results for HR-QoL and the impact of disease on work productivity and daily activities at data capture for patients on first-line therapy are presented in Table 6. For the overall population that completed the HR-QoL questionnaires (n = 79‒80), mean (s.d.) scores were 68.4 (18.4) for EQ-VAS, 0.7 (0.2) for EQ-5D and 62.4 (16.5) for FACT-G. Using the WPAI instrument, mean (s.d.) score for percent overall work impairment (n = 16) was 27.0% (23.6), and that for percent activity impairment (n = 79) was 45.3% (27.5).
Patient-reported health outcomes at data capture for patients on first-line therapy (from PSC).
| Patient-reported outcome | Overall population | RET mutation positive | ||
|---|---|---|---|---|
| Any treatment | MKI treatmenta | Any treatment | MKI treatmenta | |
| EQ-VAS, n completed | 80 | 72 | 37 | 35 |
| Mean score (s.d.) | 68.4 (18.4) | 68.0 (18.7) | 65.3 (16.9) | 65.1 (17.2) |
| Median score (IQR) | 70.0 (60.0, 80.0) | 70.0 (60.0, 80.0) | 70.0 (52.0, 80.0) | 70.0 (50.0, 80.0) |
| EQ-5D (UK crosswalk), n completed | 79 | 71 | 46 | 34 |
| Mean score (s.d.) | 0.7 (0.2) | 0.7 (0.2) | 0.7 (0.2) | 0.7 (0.2) |
| Median score (IQR) | 0.7 (0.6, 0.8) | 0.7 (0.6, 0.8) | 0.7 (0.6, 0.8) | 0.7 (0.6, 0.8) |
| FACT-G, n completed | 80 | 72 | 37 | 35 |
| Mean score (s.d.) | 62.4 (16.5) | 63.2 (16.9) | 61.1 (15.7) | 61.5 (16.0) |
| Median score (IQR) | 60.3 (49.0, 75.0) | 61.9 (49.0, 75.8) | 59.8 (48.2, 75.5) | 60.8 (47.3, 76.0) |
| WPAI (% overall work impairment due to problem), n completed | 16 | 14 | 10 | 10 |
| Mean score (s.d.) | 27.0% (23.6) | 21.8% (19.5) | 24.5% (22.5) | 24.5 (22.5) |
| Median score (IQR) | 20.0% (10.8, 35.0) | 20.0 (10.0, 20.0) | 20.0% (12.5, 25.0) | 20.0 (12.5, 25.0) |
| WPAI (% activity impairment due to problem), n completed | 79 | 71 | 37 | 35 |
| Mean score (s.d.) | 45.3% (27.5) | 44.8% (27.6) | 46.2% (28.3) | 45.1 (28.7) |
| Median score (IQR) | 40.0% (20.0, 70.0) | 40.0 (20.0, 70.0) | 40.0% (20.0, 70.0) | 40 (20.0, 70.0) |
aMKI treatment with vandetanib or cabozantinib.
EQ-5D, EuroQol 5 Dimension questionnaire; EQ-VAS, EuroQol Visual Analogue Scale; EU5, France, Germany, Italy, Spain, UK; FACT-G, Functional Assessment of Cancer Therapy‒General questionnaire; IQR, interquartile range; MKI, multikinase inhibitor; PSC, patient self-completion form; RET, rearranged during transfection; WPAI, Work Productivity and Activity Impairment questionnaire.
For patients with RET mutation-positive disease who were on first-line therapy, EQ-VAS (n = 37), EQ-5D and FACT-G (n = 37) scores were similar to corresponding scores for the overall population (Table 6) and did not reach minimally important differences (MIDs) (31, 32). For WPAI (MIDs unavailable), percent activity impairment (n = 37) was numerically higher, and mean WPAI score for percent overall work impairment (n = 10) was numerically lower for patients with RET mutation-positive disease than in the overall population.
Physician and patient perspectives on systemic anti-cancer therapy
The most frequently cited reasons for prescribing vandetanib or cabozantinib in the overall patient population (n = 149) were progression-free survival (PFS) benefit (60%), overall survival (OS) benefit (44%) and being recommended by national guidelines (42% for EU5, ranging from 32% in the UK to 50% in Italy and Germany) (Supplementary Table 3). Results were similar for patients with RET mutation-positive MTC (n = 57).
The most frequently reported areas for improvement of MKI therapy in the overall population (n = 142) were OS benefit (22%), PFS benefit (16%), a high response rate (14%) and a manageable side effect profile (13%) (Supplementary Table 4). Similar needs for improvement were reported in patients with RET mutation-positive disease (n = 54), with a somewhat higher frequency reported for OS benefit (31%).
The most frequently reported goals of therapy for the overall population (n = 275) and for those with RET mutation-positive MTC (n = 79) were to improve quality of life (29% and 32%, respectively) and increase OS benefit (22% and 25%, respectively) (Supplementary Table 5).
The most important treatment goals were to improve survival (30% and 36%) and improve quality of life (25% and 29%) as self-reported by all patients with aMTC and patients with RET mutation-positive MTC (n = 56 and n = 28), respectively (Supplementary Table 5).
Discussion
This study presents real-world data from five populous European countries on the clinical profile, RET mutation testing, treatment patterns and PROs for aMTC patients, prior to the commercial availability of selective RET inhibitors in Europe, including a subgroup of patients with RET mutation-positive disease. Data provide insight into the rationale for prescribing anti-tumour systemic therapy and barriers to RET mutation testing.
At the time of data collection, patients with RET mutation-positive aMTC had a numerically higher rate of metastatic disease compared to the overall population (87% vs 79%), which appears to be consistent with prior evidence suggesting that patients with RET mutation-positive MTC have more aggressive disease (16).
Three-quarters of the overall patient population were tested for RET mutations, of whom 38% tested positive. The lack of testing in one-quarter of patients with MTC is at variance with ESMO guidelines at the time of data capture (33), which recommended that all MTC patients be tested for germline RET mutations, and that testing for somatic RET mutations be conducted if selective RET inhibitor therapy is planned. It is reasonable to expect that the rate of testing could increase over time (as this was a point-in-time study) and could increase in future with European regulatory approval of the first selective RET inhibitor in 2021. Previously reported real-world data from the USA by Parikh et al. (17) in 203 patients with MTC showed a somewhat lower RET-alteration testing rate of 60% but a very similar rate of RET mutation-positive MTC (37%). The most frequently cited barriers to RET mutation testing in our physician survey were cost, difficulty accessing latest tests and time delay for test results. The proportion of physicians citing time delay for test results as a barrier was highest in Spain (34), which was also the country with the longest turn-around time to receive test results, suggesting that shortening the time delay could reduce this as a barrier to testing.
The MKIs vandetanib and cabozantinib were the most common first-line treatments. Vandetanib was used more frequently than cabozantinib, possibly because of its earlier regulatory approval and therefore greater physician familiarity with the drug in Europe. In addition, a large proportion of patients came from France and Spain (56% combined), which are the only two countries in the study where cabozantinib is not reimbursed. Conversely, the UK contributed the fewest number of patients (12%) and provides reimbursement for cabozantinib but not vandetanib. First-line MKI use observed in our study is in line with ESMO guidelines (12, 33) and consistent with the study by Parikh et al. (17). In patients with RET mutation-positive disease, these drugs accounted for 88% of prescriptions in the first-line setting compared with 76% in the overall population. This difference may be related to the higher frequency of metastatic disease we observed in patients with RET mutation-positive MTC and may suggest that physicians consider a patient with a positive RET mutation test result more suitable for treatment with an MKI than for patients with RET mutation-negative MTC or untested patients. This concept was supported by a large proportion of physicians reporting ‘suitable for patients with RET gene mutation/fusion’ as a reason to prescribe MKIs to RET mutation-positive patients. The most common reasons for prescribing MKIs in the overall population were PFS/OS benefits, recommended by national guidelines, and high response rate.
A small proportion of patients received chemotherapy as first-line treatment, despite ESMO guidelines not recommending such therapy (12, 33). We observed that 36% of patients receiving first-line drug treatment who received supportive drug therapy in the overall EU5 population were prescribed levothyroxine at data capture. This may have been related to the low rate of patients reported to have received thyroidectomy (51%), classification on the PRF of levothyroxine as a line of therapy rather than supportive treatment, and a potentially significant lag time between the initiation of levothyroxine and systemic anticancer therapy. Patients who did not receive thyroidectomy may have had unresectable MTC at the time of their initial diagnosis, which is supported by the short median time (2.8 months) from initial diagnosis to first-line systemic treatment. These data highlight the need for timely diagnosis and initiation of treatment to provide locoregional control of the disease.
In patients who had received first-line systemic drug therapy, 83% were still on first-line therapy at data capture; second-line treatment was prescribed for 12% of patients overall and 14% of those with RET mutation-positive disease. Targeted therapy with MKIs was the most common second-line treatment. There was no off-label use of lenvatinib or sorafenib in our study, which contrasts with the Parikh et al. study (17) conducted in the USA, where this was common (22% in first-line, 5% in second-line therapy).
ECOG PS seemed to deteriorate over time, as the proportion of patients with scores of 0‒1 decreased from the time of initial diagnosis to the time of data capture in both overall and RET mutation-positive groups. Results showed a substantial disease/treatment burden, with >85% of patients symptomatic while receiving first-line therapy at data capture. Results of the EQ-5D index score and WPAI indicated that HR-QoL, work productivity and activities of daily living were impaired in the overall population and among patients with RET mutation-positive disease. Mean (s.d.) EQ-5D utility values were 0.7 (0.2) for the overall EU5 population and in the subgroup with RET mutation-positive MTC. These scores are lower (less favourable) than mean utility scores reported for the general population in the UK (0.856) or for the general population aged 55‒64 years in the UK (0.804) (35). They are also lower than mean utility scores reported for the general population of several other European countries (35, 36, 37), and our findings are consistent with results of a study in the UK in which EQ-5D utility scores in patients with thyroid cancer were significantly lower than the average UK population (38). PROs from EQ-VAS (overall EU5 mean score 68.4 on a scale of 0‒100) and FACT-G (overall EU5 mean score 62.4 on a scale of 0‒108) instruments in our study also showed impairment compared with general/healthy population data (35, 37, 39, 40). For example, population norms across 20 countries, most of which are in Europe, showed that mean EQ-VAS scores varied from 70.4 to 83.3 in the total population across all ages/genders (35). Normative data of a Swedish general population (GP) sample showed a mean FACT-GP score of 77.7 (40). Mean (s.d.) WPAI scores for the overall EU5 population showed a 45.3% (27.5) impairment in work productivity and a 27.0% (23.6) impairment in daily activities that were due to the disease and/or treatment (‘due to problem’); similar results were reported by patients with RET mutation-positive MTC.
Results on first-line systemic therapy from our study are generally in line with findings from the Parikh et al. study (17), which showed that approximately three-quarters of patients received only one line of systemic therapy; 36% were still receiving first-line therapy at the time of data extraction, and the most common first-line agents were vandetanib or cabozantinib. However, a higher proportion of patients in our study were still receiving first-line therapy at the time of data collection. Our study also corresponded well with findings from the study by Parikh et al. (17), and several other smaller real-world studies (in Germany (21), Japan (41) and South Korea (42)), for the proportion of patients with metastatic disease and median age, respectively. However, in the US study (17), the median ages of patients overall (53 years) and for those with RET mutation-positive MTC (46 years) were younger than in our study (60 and 56 years, respectively).
Study limitations include the selection of consecutive patients, which may have resulted in the over-representation of patients who consult more frequently, and the relatively small number of patients for some variables (e.g. physicians’ reasons for discontinuing first-line systemic therapy). In addition, since this is a point-in-time study, it is not feasible to determine cause and effect. Evaluation of OS was not possible because all patients were alive at data capture.
Conclusion
This study, conducted in five populous European countries prior to the availability of selective RET inhibitor therapy in Europe, highlights the substantial burden of disease and/or treatment in patients with MTC and the need for improved therapy. Identifying patients who are eligible for treatment with selective RET inhibitors can be achieved through increasing rates of RET alteration testing in routine practice. RET testing can be optimised by increasing the testing rate for germline RET mutations followed by somatic RET mutation testing in patients with negative germline testing results.
Supplementary materials
This is linked to the online version of the paper at https://doi.org/10.1530/ETJ-23-0172.
Declaration of interest
Grace Segall, Urpo Kiiskinen, Min-Hua Jen and Ravinder Singh are employees and minor shareholders of Eli Lilly and Company. Isaac Sanderson, Alex Rider and Katie Lewis are employees of Adelphi Real World Ltd. The authors have no other relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript apart from those disclosed.
Funding
This study was supported by Eli Lilly and Company.
Author contribution statement
GS was involved with the interpretation of data for the work and with the drafting and critical revision of the work. UK was involved with the conception of the work, the design of the work, the interpretation of data for the work and the critical revision of the work. M-HJ was involved with the conception of the work, the interpretation of data for the work and the critical revision of the work. RS was involved with the interpretation of data for the work and with the critical revision of the work. IS was involved with the design of the work, the acquisition and analysis of data for the work and the critical revision of the work. AR and KL were involved with the design of the work, the acquisition of data for the work and the critical revision of the work. All named authors meet the International Committee of Medical Journal Editors (ICMJE) criteria for authorship for this article, take responsibility for the integrity of the work as a whole, and have given their approval for the version to be published.
Acknowledgements
The authors would like to acknowledge Greg Plosker and Marie Cheeseman (Rx Communications, Mold, UK) for medical writing assistance with the preparation of this manuscript, funded by Eli Lilly and Company.
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