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. 2025 Jun 19;5(1):e240062. doi: 10.1530/EO-24-0062

Real-world lenvatinib use in metastatic thyroid cancer: early dose intensity and side effect profile in an Australian centre

Monica Majumder 1,*, Shejil Kumar 1,2,*, Tony Lian 2, Venessa H M Tsang 1,2, Meredith Oatley 3, Lyndal Tacon 1, Bruce G Robinson 1,2,4, Anthony Glover 2,5,6, Roderick J Clifton-Bligh 1,2,4, Matti L Gild 1,2,4,✉
PMCID: PMC12186296  PMID: 40556750

Abstract

Objective

Lenvatinib is a multi-kinase inhibitor approved in radioiodine-refractory thyroid cancer based on results of a phase III trial. Real-world data have emphasised concerns regarding tolerability of the starting dose (24 mg/day) and frequency of dose-limiting treatment-related adverse effects (TRAEs). We aimed to assess early dose intensity, tolerability and efficacy using lenvatinib in metastatic thyroid cancer patients in an Australian centre.

Design/Methods

Retrospective medical record review was conducted of patients with advanced/metastatic differentiated, medullary and anaplastic thyroid cancer on lenvatinib at a quaternary referral centre (2014–2023).

Results

64 patients were included. Median age at lenvatinib commencement was 67 years (range 38–92). 53% were female. The most common non-nodal metastases were pulmonary (86.4%) and skeletal (50.8%). Most patients commenced lenvatinib at 24 mg/day (48/53; 90.5%), with fewer than half maintaining this dose by 8 weeks (21/45; 46.7%). Those who maintained the 24 mg dose at 8 weeks were younger at lenvatinib commencement (62 years vs 71 years, P = 0.016) and more likely to have poorly differentiated or anaplastic thyroid cancer (42 vs 22%, P = 0.018). During the median 12-month follow-up, the most common TRAEs included hypertension (n = 37), fatigue (n = 35), and nausea (n = 18). In a subgroup of 21/35 patients with differentiated thyroid cancer, median baseline and nadir serum thyroglobulin were 305 and 21.7 μg/L (median reduction 92.5% (IQR 81.1–98.0%)). In 19/35 patients with radiological response data, the majority experienced disease control as best structural response (17/19; 93.2%).

Conclusion

This real-world analysis demonstrates difficulties in maintaining early lenvatinib dose intensity, with frequent TRAEs. Greater emphasis on supportive care is needed to maximise early dose intensity and efficacy.

Keywords: radio-iodine refractory, thyroid cancer, lenvatinib, tyrosine kinase inhibitors

Introduction

The incidence of differentiated thyroid cancer (DTC) is increasing in Australia and worldwide (Albores-Saavedra et al. 2007, Blomberg et al. 2012, Lim et al. 2017, Australian Institute of Health & Welfare 2019). Although most patients with DTC have a favourable prognosis and respond well to initial surgical resection ± radioactive iodine therapy, a subset will develop more aggressive refractory disease which may be amenable to oral tyrosine kinase inhibitor (TKI) treatment (Cabanillas et al. 2019, Gild et al. 2021). Thyroid cancer cells overexpress various tyrosine kinases implicated in tumour growth, metastatic spread and angiogenesis, including the vascular endothelial growth factor receptor (VEGFR) (Gild et al. 2021). Lenvatinib is an oral multi-kinase inhibitor (including inhibition of VEGFR) approved for use in Australia in patients with radioiodine-refractory thyroid cancer at a standard initiation dose of 24 mg daily (Therapeutic Goods Administration 2020).

In a randomised placebo-controlled trial of patients with progressive radioiodine-refractory (RAIR) DTC (SELECT; n = 392), lenvatinib was associated with an improved disease response rate of 63% compared with placebo, and longer median progression-free survival by 15 months (Schlumberger et al. 2015). However, treatment-related adverse effects (TRAEs) occurred in virtually all patients treated with lenvatinib, with the most common being hypertension (∼70%), gastrointestinal disturbance (∼60%), fatigue (∼60%) and palmoplantar erythrodysesthesia (∼30%). TRAEs often prompted treatment de-escalation, including brief interruption (∼80%), dose reduction (∼70%) and in some cases, treatment cessation (∼15%). The median time to first dose reduction was 3 months, indicating that TRAEs often occurred early. Post-hoc analyses suggested that maintenance of early dose intensity may be associated with better treatment outcomes. Participants with shorter periods of treatment interruption had a greater likelihood of treatment response, and those who maintained a higher dose for the first 8 weeks had more robust early reductions in tumour size (Robinson et al. 2016, Tahara et al. 2019). A recent placebo-controlled trial also showed that patients with thyroid cancer who commenced treatment at a lower dose (18 mg/day) had worse disease response with no better safety profile (Brose et al. 2022). Hence, patients with progressive metastatic thyroid cancer who tend to have better lenvatinib treatment responses are those who commence on the maximal starting dose, maintain a higher dose during the first 8 weeks when adverse effects are most frequent, and undergo minimal treatment interruptions. However, clinicians must balance aiming for higher early dose intensity and longer duration of lenvatinib treatment for maximal anti-tumour effect with important patient-directed goals such as treatment tolerability and quality of life.

Beyond the rigours of a clinical trial with careful participant selection, protocolised assessment and high degree of support in managing TRAEs, there is increasing evidence for lenvatinib efficacy and safety outcomes in the ‘real world’. Several retrospective real-world studies of patients with metastatic thyroid cancer managed with lenvatinib have supported clinical trial evidence for its efficacy and high frequency of dose-limiting TRAEs (Kim et al. 2019, Jerkovich et al. 2020, Kish et al. 2020, Masaki et al. 2020, Rendl et al. 2020, Jiang et al. 2021, Koehler et al. 2021, Masaki et al. 2022, Peelay et al. 2023, Worden et al. 2024). However, these studies have not characterised early maintenance of lenvatinib dosing and whether early dose intensity may be associated with treatment response in a real-world cohort.

In this retrospective cohort study of patients with metastatic thyroid cancer managed with lenvatinib, we aim to primarily assess early dose intensity and tolerability of lenvatinib treatment and its efficacy in a real-world setting.

Materials and methods

Data collection

A retrospective observational study was conducted of patients (aged ≥18 years) managed with lenvatinib for progressive metastatic thyroid cancer in the outpatient Endocrinology clinics at Royal North Shore Hospital, Sydney between 1st January 2014 and 31st December 2023. Patients were included if they were diagnosed with thyroid cancer on anatomical pathology assessment of resected tumour tissue and had received at least one dose of lenvatinib. Suitable participants were identified using electronic medical record review of Endocrinology outpatient databases. Primary aims were to determine the proportion of patients maintaining maximal lenvatinib dose (24 mg/day) at 8 weeks after commencing treatment and frequency of TRAEs during follow-up. Secondary aims were to determine best structural and biochemical treatment responses after commencing lenvatinib and whether these were associated with early dose intensity.

Patients were managed with lenvatinib according to standard clinical care. Wherever feasible, oral lenvatinib was commenced at 24 mg/day (maximal daily dose) and dose adjusted as necessary according to manufacturer instructions (Eisai Pty Ltd, Australia). Patients routinely had multidisciplinary team input, which in some cases included oncology clinical nurse specialist review to assist with monitoring and treatment of TRAEs. Routine clinical care included serial clinical assessment, monitoring of blood pressure, monitoring of TRAEs and dose adjustments as necessary, monitoring of serum thyroglobulin (DTC) or calcitonin (medullary thyroid cancer (MTC)) for biochemical response, and serial CT scans (neck, chest & abdomen, ± brain) for assessing structural response. Timing and frequency of collection of these endpoints were not protocolised and were at clinician discretion.

Two investigators independently collected data by performing electronic medical record review, and any incongruence was resolved by unanimous decision. Data collated included patient demographics (age, sex), and thyroid cancer-associated variables such as histological subtype based on tumour histopathology (papillary/follicular/oncocytic advanced DTC/poorly differentiated/anaplastic/medullary), thyroid cancer stage at diagnosis, tumour size at diagnosis (mm), presence of somatic alterations on immunohistochemistry +/− sequencing (e.g. BRAF, RET, RAS), and sites of non-nodal metastases (yes/no for pulmonary, skeletal, hepatic or cerebral). Lenvatinib-associated variables included total treatment duration (months) until latest follow-up, starting dose (mg/day), dose at 8 weeks after commencement (mg/day), whether patients commenced lenvatinib at maximal dose (yes/no) and maintained maximal dose at 8 weeks (yes/no), and frequency of lenvatinib TRAEs during follow-up. TRAEs of special interest included hypertension, fatigue, palmoplantar erythrodysesthesia, nausea/vomiting, diarrhoea and proteinuria. Treatment response-associated variables included nadir value and best percentage reduction in thyroglobulin (μg/L) or calcitonin (ng/L) concentration. Best structural response was determined based on radiology reports and categorised according to RECIST v1.1 criteria as complete response (CR), partial response (PR), stable disease (SD) or progressive disease (PD) (Eisenhauer et al. 2009). Disease control rate was taken as a composite of CR, PR and SD. Time elapsed (months) between commencing lenvatinib and achieving best biochemical and structural responses was also recorded. Dates were taken as the first day of the year if month was uncertain, and the first day of the month if day was uncertain.

Statistical analysis

Statistical analyses were performed using SPSS statistical software (version 28.0). Baseline characteristics were tabulated and presented as either frequency (n (%)) or distribution using mean (±SD) or median (IQR) for normative and non-normative data, respectively. Normality of data was assessed using the Shapiro-Wilk test. Changes in outcome means after lenvatinib treatment were assessed using paired samples t-test. Subgroup analyses for outcome measures were performed according to whether patients maintained the maximal lenvatinib dose at 8 weeks. Associations were assessed using Chi-squared test (for categorical variables) and independent samples t-test or Mann–Whitney U test (for normative and non-normative continuous data, respectively). A two-sided P-value of <0.05 was considered statistically significant.

Ethics statement

This study was conducted in accordance with the ethical principles stated in the Declaration of Helsinki. The protocol was approved by the Northern Sydney Local Health District Human Research Ethics Committee (2024/ETH00393), including waiver of patient consent for retrospective record review.

Results

Demographics and tumour characteristics

A total of 64 patients were included for analysis. Demographic data, thyroid cancer type, molecular classification (using immunohistochemistry ± somatic tumour sequencing) and sites of distant non-nodal metastases are summarised in Table 1. Median age at diagnosis was 59 years (range 24–90 years) and 53% were female. The most common histological subtypes were papillary (32.4%) and poorly differentiated thyroid cancer (25.0%). Majority of patients developed pulmonary (86.4%) and skeletal (50.3%) metastases.

Table 1.

Summary of all participant and disease characteristics.

Characteristics (n = total number of individuals for whom data was available) Subgroup (n = total number of individuals for whom data was available) Median (range) or n (%) Characteristics of 48 patients starting lenvatinib at 24 mg daily (n = total number of individuals for whom data was available) Subgroup (n = total number of individuals for whom data was available) Median (range) or n (%)
Age at diagnosis, years (61) 59 (24–90) Age at diagnosis, years (38) 59 (30–87)
Age at lenvatinib commencement, years (55) 67 (38–92) Age at lenvatinib commencement, years (47) 66 (39–91)
Sex (64) Male 30 (47%) Sex (48) Male 22 (46%)
Female 34 (53%) Female 26 (54%)
Histopathological subtype (64) Papillary 21 (32.4%) Diagnosis (48) Papillary 18 (38%)
Follicular 6 (9.4%) Follicular 3 (6%)
Oncocytic 6 (9.4%) Oncocytic 6 (13%)
Poorly differentiated 16 (25.0%) Poorly differentiated 11 (23%)
Anaplastic 5 (7.8%) Anaplastic 6 (13%)
Medullary 10 (15.6%) Medullary 3 (6%)
Molecular classification BRAF (23) 13 (56.5%) Molecular classification BRAF (32) 10 (31%)
RAS (15) 6 (40%) RAS (24) 3 (13%)
RET (11) 4 (36.4%) RET (24) 0 (0%)
Metastases (59) Lung 51 (86.4%) Metastases (48) Lung 37 (77%)
Skeletal 30 (50.8%) Skeletal 16 (33%)
Liver 10 (16.9%) Liver 5 (10%)
Brain 4 (6.8%) Brain 1 (2%)
Starting dose (53) 24 mg 48 (90.6%) Starting dose (48) 24 mg 48
20 mg 4 (7.5%)
10 mg 1 (1.9%)
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BRAF, v-raf murine sarcoma viral oncogene homologue B1; RAS, rat sarcoma virus; RET, rearranged during transfection.

Lenvatinib dosing

Majority of patients commenced lenvatinib at the standard dose of 24 mg daily (48/53; 90.6%), while the starting dose was unable to be confirmed in 17% (11/64) of the cohort. Less than half of patients (21/45; 46.7%) remained on 24 mg daily after 8 weeks, at which point six patients had ceased lenvatinib, including three due to treatment intolerance (Table 2, Fig. 1). Patients who maintained the 24 mg/day dose at 8 weeks were younger (62.4 ± 13.0 vs 71.1 ± 9.8 years, P = 0.016) and more likely to have poorly differentiated or anaplastic thyroid cancer (42.3 vs 21.7%, P = 0.018), with no difference in sex distribution or sites of metastases. Median duration of lenvatinib treatment until latest follow-up, cessation or death was 12 months (n = 25).

Table 2.

Summary of 8-week dose in patients who commenced lenvatinib at 24 mg daily.

Dose at 8 weeks n = 45
24 mg 21
20 mg 9
18 mg 2
14 mg 5
10 mg 1
Ceased 6
Deceased 1
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This analysis included 45 patients after excluding three individuals who commenced lenvatinib at 24 mg daily but whose 8-week dose was unable to be confirmed.

Figure 1.

Figure 1

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Bar graph of 8-week lenvatinib dose distribution in patients who commenced lenvatinib 24 mg daily. Adv-DTC, advanced differentiated thyroid cancer; PDTC, poorly differentiated thyroid cancer; PTC, papillary thyroid cancer; FTC, follicular thyroid cancer.

Treatment related adverse effects

TRAEs occurred frequently during overall follow-up, including hypertension (n = 37), fatigue (n = 35), nausea (n = 18), proteinuria (n = 11), palmar-plantar erythrodysesthesia (n = 10) and diarrhoea (n = 8).

Best biochemical response

In a subset of patients with DTC, 21 patients had analysable baseline and follow-up Tg concentrations. Patients were excluded if Tg concentrations were undetectable or low before commencing lenvatinib despite metastatic disease (e.g. due to poorly differentiated or anaplastic disease or assay interference by positive anti-Tg antibodies). Median baseline Tg was 305 μg/L (IQR 46.1–792.3) and median nadir Tg 21.7 μg/L (IQR 5.4–161.5), representing a median best relative reduction of 92.5% (IQR 81.1–98.0%) which occurred at a median 4 months from commencing lenvatinib.

Best structural response

Data regarding best structural disease response during lenvatinib treatment were available for 19 patients. Of these, ten (34.5%) achieved PR, 17 (58.7%) had SD, two (6.9%) had PD and no patients experienced CR, indicating a disease control rate of 93.2% (17/19), which occurred at a median 3 months from commencing lenvatinib. Insufficient data were available to assess associations between best biochemical and structural disease responses and early lenvatinib dose intensity.

Discussion

Lenvatinib is a well-established treatment for managing patients with progressive metastatic thyroid cancer resistant to radioiodine therapy. Real-world data are increasingly being leveraged to inform clinical management of patients on lenvatinib, with a focus on balancing sustained anti-tumour efficacy with optimising tolerability, safety and quality of life. This retrospective analysis is the first Australian study examining real-world outcomes using lenvatinib and characterisation of dosing intensity, TRAEs and disease response. This cohort experienced frequent TRAEs consistent with phase III randomised controlled trial (RCT) data and other real-world analyses. The maximal dose (24 mg/day) was not maintained in over half the patients after 8 weeks of treatment although majority overall experienced favourable early treatment responses.

In our cohort, best biochemical response occurred at a median 4 months and best structural disease response (with a disease control rate of 93.2%) was achieved at a median 3 months from starting lenvatinib. Such favourable early treatment responses to lenvatinib were also shown in the SELECT study. An extended post-hoc analysis of SELECT found median time to first objective response was 3.5 months with a median duration of response of 30 months (Gianoukakis et al. 2018). Early tumour shrinkage, defined as a reduction in size greater than 10%, has also been achieved in another analysis in 81.3% of patients by 8 weeks after commencing lenvatinib (Masaki et al. 2017). This is in keeping with a post-hoc SELECT analysis demonstrating that the most rapid anti-tumour effect occurs within the first 8 weeks of starting lenvatinib (Robinson et al. 2016). Early treatment response also predicted more favourable long-term outcomes (prolonged progression-free survival), which remained marginally significant (P = 0.06) after multivariate adjustment (Schlumberger et al. 2015). Hence, based on available RCT and real-world data, it appears the extent of anti-tumour response is maximal within the first few months of commencing lenvatinib, after which maintenance of response likely facilitates favourable survival outcomes.

Early dose intensity is crucial in optimising initial response to lenvatinib, especially during these early months of therapy when maximal structural response can be achieved. This was demonstrated in a post-hoc analysis of SELECT whereby early dose intensity (measured as area under the curve) is associated with greater tumour size reduction (Robinson et al. 2016). However, this seemingly critical early phase of treatment is also the highest-risk period for onset of dose-limiting TRAEs (Haddad et al. 2017). Of note, in our cohort, although the vast majority commenced lenvatinib at the maximal recommended dose (24 mg/day), less than half were able to persist with this dose by 8 weeks in the setting of frequent TRAEs. We found that younger age and more aggressive subtypes of thyroid cancer (poorly differentiated or anaplastic) were associated with greater likelihood of early dose maintenance. This is a novel finding and may reflect clinician preference to treat such cases more aggressively or reduced tolerability of higher doses in older patients. Based on other real-world analyses, various factors may limit early lenvatinib dose intensity. Patients may not be commenced on the maximal dose, for example, due to presence of comorbidities, concerns regarding risk of devastating complications in treating tumours in high-risk locations, e.g. trachea-oesophageal fistula, and prior intolerance to TKIs (Locati et al. 2019, Jerkovich et al. 2020, Hamidi et al. 2022). Other real-world studies have attributed the occurrence of TRAEs as the main precipitant for reducing or ceasing lenvatinib doses (Kim et al. 2019, Kish et al. 2020, Rendl et al. 2020, Masaki et al. 2022, Peelay et al. 2023, Worden et al. 2024). Other reasons cited included progression of disease, inadequate response, functional decline or patient desire to cease treatment. Rates of discontinuation or dose reduction varied significantly between different studies, which may be related to heterogeneity in cohort selection and average starting doses. Use of lenvatinib in the setting of MTC is not routine, however is supported by phase II clinical trial data demonstrating favourable outcomes for overall response rates and disease control rates as well as in real-world analyses (Schlumberger et al. 2016, Matrone et al. 2021).

The high frequency of TRAEs experienced in our cohort was consistent with those observed in the phase III RCT and other retrospective studies. Hypertension and diarrhoea are two of the most common lenvatinib-associated TRAEs and the most common precipitants for dose interruptions (Cabanillas et al. 2019). Further complicating the picture, post-hoc analyses of SELECT demonstrated that occurrence of hypertension and diarrhoea may predict more favourable survival outcomes, however it is unclear whether this relationship is mediated by dose intensity (Haddad et al. 2017, Wirth et al. 2018). In SELECT, prespecified management plans were in place for hypertension, including frequent measurement of blood pressure and early initiation of antihypertensive treatment (Wirth et al. 2018). Despite highly prevalent TRAEs, the frequency of treatment discontinuation was comparatively low (15%) indicating that TRAEs can mostly be managed by careful dose de-escalation in a highly supported clinical environment. Close monitoring and supportive therapy are often required to proactively and adequately manage TRAEs to help minimise treatment de-escalation (Cabanillas & Takahashi 2019). A multidisciplinary approach including endocrinologists, endocrine surgeons, medical and radiation oncologists, specialised nursing staff and allied health are likely required to optimise patient outcomes (Capdevila et al. 2023, Mallick & Harmer 2023). Patients should be adequately counselled regarding potential TRAEs with lenvatinib and the need for close monitoring, particularly during the early treatment phase, preferably with specialised oncology nursing involvement where available.

Our cohort’s disease control rate was greater than 90% in individuals with available radiological response data, comparable with those seen in the phase III RCT (∼85%) and a recent real-world Italian cohort (89%) both of which used RECIST criteria (Schlumberger et al. 2015, Marotta et al. 2024). Best structural responses have varied widely in other real-world studies, potentially explained by heterogeneity in classification systems used, including RECIST, PERCIST or physician-reported responses (Locati et al. 2019, Jerkovich et al. 2020, Kish et al. 2020, Hamidi et al. 2022, Masaki et al. 2022, Worden et al. 2024). Regarding biochemical response, our cohort demonstrated a best median relative Tg reduction of 92.5% at median 4-month, similar to the maximal reductions of 86–98% seen in other real-world studies (Werner et al. 2016, Masaki et al. 2020, Rendl et al. 2020, Marotta et al. 2024). However, concerns over utility of Tg assessment as a marker of treatment response to lenvatinib have been raised due to an often lack of correlation with structural disease and limited interpretation in patients with positive Tg antibodies (Masaki et al. 2017, Rendl et al. 2020). More comprehensive assessment of structural and biochemical responses in our cohort was limited due to incomplete data availability.

Our study possesses several limitations. This was a retrospective analysis of real-world clinical experience in adults with advanced/metastatic thyroid cancer managed with lenvatinib. This study represents a single institution experience of standard clinical care using lenvatinib and may not be reflective of specialised management in other centres. There was heterogeneity in timing of outcome assessments, given frequency of clinical follow-up and assessment of treatment response were not protocolised and at the clinician’s discretion. Completeness of data for safety and efficacy endpoints was limited, including reporting of TRAE grades and use of prior or concurrent treatments (e.g. radioactive iodine, chemotherapy, radiotherapy or other TKIs), as this depended on reporting in clinical documentation. Data were not recorded regarding dietary interventions, nutritionist involvement and use of ancillary exercise programmes, which may have influenced dose tolerability. Various pathology and radiology providers were utilised across a wide geographic distribution with further limited data availability, given Royal North Shore Hospital is a quaternary referral centre for advanced thyroid cancer patients. Interpretation of radiological response at times relied on investigator interpretation of historical radiology reports. Association between lenvatinib disease response and presence of molecular alterations was unable to be assessed, given results of this testing (e.g. BRAFV600E IHC, which is routinely performed at our institution) were not available for all patients. Furthermore, there was no centralised criterion for commencing lenvatinib, which was largely based on the individual clinician’s discretion. Most patients were commenced based on Australian government subsidisation criteria (advanced/metastatic RAIR-DTC); however current practice is for all patients considering TKI treatment to be discussed at a multidisciplinary meeting. Assessment of early dose intensity would have been strengthened by characterisation of dosage area under the curve, however we utilised the 8-week dose as a practical alternative measure given dosing over this period has been associated with treatment response (Robinson et al. 2016). Finally, due to missing data, particularly in patients with ATC and MTC, we were unable to achieve one of our aims to quantitatively assess associations between early dose intensity with biochemical and structural treatment responses. Despite this, we have analysed a relatively large cohort of patients with metastatic thyroid cancer in a real-world setting with comprehensive data regarding TRAEs. The limited number of patients at full dose at 8 weeks despite data describing the value of increasing the area under curve (AUC) during this period shows the practical challenges in a real-world setting. Validity of our data is supported by similarity in safety and efficacy outcomes in comparison with the phase III RCT and other real-world analyses. This study represents the first real-world focused assessment of early lenvatinib dose intensity in thyroid cancer. This is an important clinically relevant outcome which may predict early treatment response and longer survival, and this warrants further interrogation in a real-world setting.

In this retrospective single-centre cohort study, safety and efficacy of lenvatinib in patients with metastatic thyroid cancer were consistent with the pivotal phase III RCT and other real-world analyses. Although early dose intensity is associated with better treatment outcomes in the pivotal RCT, our cohort demonstrates the difficulties in achieving this in a real-world setting, as less than half of patients maintained the 24 mg dose at 8 weeks in the setting of frequent TRAEs. Protocolised, proactive multidisciplinary management of TRAEs should be utilised in such clinical settings and may facilitate higher early dose intensity and tolerability of treatment. Future real-world studies should assess early lenvatinib dose intensity and its association with treatment response and survival to further inform early clinical treatment goals.

Declaration of interest

Monica Majumder, Shejil Kumar, Tony Lian, Meredith Oatley, Lyndal Tacon, Anthony Glover and Matti L Gild have no disclosures. Venessa H Tsang has received honorarium from Eisai. Bruce G Robinson has received honoraria for advisory board participation from Eisai, Lilly and Ipsen. Roderick J Clifton-Bligh has received honorarium from Eisai and for advisory board participation from Ipsen.

Funding

This work did not receive any specific grant from any funding agency in the public, commercial or not-for-profit sector.

Author contribution statement

MM: conceptualization; formal analysis (equal); investigation (equal); writing – original draft preparation (equal). SK conceptualization; formal analysis (equal); investigation (equal); writing – original draft preparation (equal). TL: formal analysis; investigation; writing – original draft preparation. VHT: conceptualization; writing – review & editing. MO: writing – review & editing. LT: conceptualization; writing – review & editing. BGR: conceptualization; writing – review & editing. AG: conceptualization; writing – review & editing. RJC: conceptualization; writing – review & editing. MLG: conceptualization (lead); writing – review & editing (lead).

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