J A Vallejo Casas, M Sambo 11:5 e210111 et al. RESEARCH Initial clinical and treatment patterns of advanced differentiated thyroid cancer: ERUDIT study Juan Antonio Vallejo Casas 1,*, Marcel Sambo 2,*, Carlos López López 3, Manuel Durán-Poveda4, Julio Rodríguez-Villanueva García5, Rita Joana Santos6, Marta Llanos7, Elena Navarro-González8, Javier Aller9, Virginia Pubul10, Sonsoles Guadalix11, Guillermo Crespo12, Cintia González13, Carles Zafón14, Miguel Navarro15, Javier Santamaría-Sandi16, Ángel Segura17, Pablo Gajate18, Marcelino Gómez-Balaguer19, Javier Valdivia20, Manel Puig-Domingo21, Juan Carlos Galofré22, Beatriz Castelo23, María José Villanueva24, Iñaki Argüelles25 and Lorenzo Orcajo-Rincón 5 1Department of Nuclear Medicine (UGC), Maimónides Institute of Biomedical Research of Córdoba (IMIBIC), Reina Sofía University Hospital, University of Córdoba, Córdoba, Spain 2Department of Endocrinology, Gregorio Marañón University Hospital, Madrid, Spain 3Department of Medical Oncology, Marqués de Valdecilla University Hospital, IDIVAL, Santander, Spain 4Department of General and Digestive Surgery, Rey Juan Carlos University Hospital, Madrid, Spain 5Oncology Business Group – EISAI Farmacéutica SA, Madrid, Spain 6Department of Endocrinology, Francisco Gentil Portuguese Institute of Oncology of Lisbon, Lisbon, Portugal 7Department of Medical Oncology, Hospital Universitario de Canarias, La Laguna, Santa Cruz de Tenerife, Spain 8Department of Endocrinology, Virgen del Rocío University Hospital, Seville, Spain 9Department of Endocrinology, Puerta de Hierro-Majadahonda University Hospital, Madrid, Spain 10Department of Nuclear Medicine, University Hospital and Health Research Institute of Santiago de Compostela, Santiago de Compostela, Spain 11Department of Endocrinology and Nutrition, Hospital Universitario 12 de Octubre, Madrid, Spain 12Department of Medical Oncology, Burgos University Hospital, Burgos, Spain 13Department of Endocrinology, Santa Creu i Sant Pau University Hospital, CIBER-BBN, Barcelona, Spain 14Department of Endocrinology and Nutrition, Vall Hebron University Hospital and Autonomous University of Barcelona (UAB), Barcelona, Spain 15Department of Medical Oncology, University Hospital of Salamanca, Salamanca, Spain 16Department of Endocrinology, Cruces University Hospital, Vizcaya, Spain 17Medical Oncology Unit, La Fe University Hospital, Valencia, Spain 18Department of Medical Oncology, Ramon y Cajal University Hospital, Madrid, Spain 19Department of Endocrinology, Doctor Peset University Hospital, Valencia, Spain 20Department of Oncology, University Hospital Centre Virgen de las Nieves, Granada, Spain 21Endocrine and Nutrition Service, Health Sciences Research Institute and University Hospital Germans Trias i Pujol, Badalona, Spain 22Department of Endocrinology, Clínica Universidad de Navarra, University of Navarra, Lisbon, Spain 23Department of Medical Oncology, La Paz University Hospital, Madrid, Spain 24Department of Medical Oncology, Alvaro Cunqueiro University Hospital Complex, University of Vigo, Vigo, Spain 25Department of Endocrinology and Nutrition, Son Espases University Hospital, Palma de Mallorca, Spain Correspondence should be addressed to J A Vallejo Casas or L Orcajo-Rincón: jantonio.vallejo.sspa@juntadeandalucia.es or lorenzo_orcajorincon@eisai.net *(J A Vallejo Casas and M Sambo contributed equally to this work) https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. Abstract Background: Up to 30% of differentiated thyroid cancer (DTC) will develop advanced-stage Key Words disease (aDTC) with reduced overall survival (OS). f advanced differentiated Objective: The aim of this study is to characterize initial diagnosis of aDTC, its therapeutic thyroid cancer management, and prognosis in Spain and Portugal. f relapsing differentiated thyroid cancer Methods: A multicentre, longitudinal, retrospective study of adult patients diagnosed f radioiodine-refractory with aDTC in the Iberian Peninsula was conducted between January 2007 and December differentiated thyroid 2012. Analyses of baseline characteristics and results of initial treatments, relapse- or cancer progression-free survival ((RP)FS) from first DTC diagnosis, OS, and prognostic factors f epidemiological study impacting the evolution of advanced disease were evaluated. f relapsing prognostic Results: Two hundred and thirteen patients (median age: 63 years; 57% female) were factors eligible from 23 hospitals. Advanced disease presented at first diagnosis (de novo aDTC) f survival prognostic factors included 54% of patients, while 46% had relapsed from early disease (recurrent/progressive eDTC). At initial stage, most patients received surgery (98%) and/or radioiodine (RAI) (89%), with no differences seen between median OS (95% CI) (10.4 (7.3–15.3) years) and median disease-specific-survival (95% CI) (11.1 (8.7–16.2) years; log-rank test P = 0.4737). Age at diagnosis being <55 years was associated with a lower risk of death (Wald chi-square (Wc-s) P < 0.0001), while a poor response to RAI to a higher risk of death ((Wc-s) P < 0.05). In the eDTC cohort, median (RP)FS (95% CI) was of 1.7 (1.0–2.0) years after RAI, with R0/R1 surgeries being the only common significant favourable factor for longer (RP)FS and time to aDTC ((Wc-s) P < 0.05). Conclusion: Identification of early treatment-dependent prognostic factors for an unfavourable course of advanced disease is possible. An intensified therapeutic attitude may reverse this trend and should be considered in poor-performing patients. Prospective studies are required to confirm these findings. Introduction Differentiated thyroid carcinoma (DTC) is the most In the aDTC situation, survival rates decrease markedly. frequent subtype of thyroid cancer (1). In the initial The 10-year survival rate for RAI-responder patients is disease scenario, therapeutic approach mainly relies about 56%, whereas in RR-DTC patients, this is only 10% on surgery and treatment with I-131 radioiodine (RAI). (10). In this scenario, patient’s care usually involves a Overall survival (OS) rate in this population is high multidisciplinary team whose composition is variable (98.3% and 90% at 5 and 10 years, respectively) after among countries and centres (11, 12). initial diagnosis (2, 3). In this clinical context, available data in Europe are However, up to 20% of patients with DTC, excluding outdated and very limited. In response to this need, the those with microcarcinomas, present with metastasis or ERUDIT study aimed to characterize the natural evolution locally advanced disease at the time of diagnosis (4, 5, 6). of adult aDTC in Spain and Portugal. Moreover, in up to 30% of patients with initial early-stage Specifically, this communication will describe the diagnosis (eDTC), disease relapses into the advanced stage demographic and clinical characteristics, usage patterns, (aDTC), either as locoregional unresectable or metastatic and efficacy profile of upfront therapies used to treat dissemination (7). Additionally, one-third of the metastatic aDTC, either presenting at first diagnosis (de novo aDTC) or tumours will show low avidity for iodine at the time of after successive relapses (recurrent/progressive eDTC). We diagnosis and nearly two-thirds will become refractory to will also explore potential prognostic factors correlating RAI (radioiodine-refractory differentiated thyroid cancer; with disease relapse/progression from eDTC into aDTC RR-DTC) along treatment (8, 9). and death. https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. Figure 1 ERUDIT study design and evolution timeline of the aDTC patients included according to the type of their diagnosis. Type 1: de novo metastatic with resectable locoregional disease. Type 2: de novo locoregional unresectable disease. Type 3: recurrent metastatic without resectable locoregional disease. Type 4: recurrent locoregional unresectable disease, with or without distant metastases. aDTC, advanced differentiated thyroid cancer; eDTC, early stage differentiated thyroid cancer; FSR, final study report. Methods 2017, death, or lost to follow-up, whichever happened first. Patients with diagnosis of anaplastic or medullary thyroid Study design and setting cancer were excluded. Patients’ informed consent was requested. The study ERUDIT is a multicentre, observational, longitudinal, was performed in compliance with all basic principles international, and retrospective study run in 22 of the Helsinki Declaration (2013) from World Medical representative hospitals from Spain and Portugal Association (13) and applicable national regulations. (Supplementary Table 1, see section on supplementary Both accredited Research Ethics Committees of Hospital materials given at the end of this article). Clinical records Universitario Gregorio Marañón (Madrid, Spain) and from eligible patients diagnosed with aDTC from January National Ethics Committee for Clinical Research (Portugal) 2007 to December 2012, both inclusive, were retrospectively approved it. reviewed until August 2017 (expected 5–10 years follow-up) and collected from August 2017 to August 2019 (Fig. 1). Variables at initial diagnosis and clinical endpoints Patients Demographic and clinical characteristics Gender, comorbidities, initial diagnosis of DTC Patient records were considered if aDTC (papillary, (incidental post-surgery, no-incidental), diagnosis type follicular, Hürthle’s cell, or mixed or poorly differentiated) (de novo or recurrent), histology result, biochemistry at diagnosis was confirmed with first evidence of unresectable diagnosis (patients with thyroglobulin (Tg) levels and/ locally advanced and/or metastatic disease (presenting or anti-Tg positive in serum), tumour size (mm), lobes either de novo or relapsed after first treatment) being as such involved, tumour focality, tumour invasion (adjacent documented during the inclusion period. Accordingly, tissue, vascular, lymphatic nodes, absent, or no invasion), four patient types were predefined in the study protocol metastases at diagnosis by site, and type of image to account for most common situations at diagnosis: Type diagnosis were collected as variables of interest (Table 1 1, de novo metastatic with resectable locoregional disease; and Supplementary Table 2). Type 2, de novo locoregional unresectable disease; Type 3, recurrent metastatic with resectable locoregional disease; Therapeutic approach and response with/without distant metastases. Patients had to be ≥18 and Type 4, recurrent locoregional unresectable disease, (a) Surgery: neck dissection; microscopic complete resection (R0), macroscopic resection with microscopic years old at initial diagnosis and their medical records be residual tumour (R1), and gross macroscopic residual sufficiently complete to allow data analysis until 31 August tumour (R2) and histological results; (b) ablative https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. (adjuvant) I-131 radioiodine (RAI): administered dose, Clinical endpoints of interest included OS and cumulative RAI dose by intervention, RAI refractoriness disease-specific survival (DSS), which were measured from at initial diagnosis, use of human recombinant thyroid- the initial DTC diagnosis to death in the global study stimulating hormone (hrTSH) per intervention, RAI population. Relapse- or progression-free survival ((RP)FS) response according to American Thyroid Association was defined as a composite time-to-event variable (ATA) (1) criteria (excellent, structural incomplete, involving only eDTC patients that had relapsed into biochemical incomplete, and indeterminate); and (c) aDTC or died provided they were free of disease after first radiotherapy: dose and response according to the standard treatment or, alternatively, progressed into aDTC or died Response Evaluation Criteria in Solid Tumors (RECIST) having residual disease after first treatment. Finally, all v1.1 definition (objective response rate as the sum of potential prognostic factors concerning these survival complete response plus partial response; stable disease and variables were explored in the global study population progressive disease as per physician-reported best response and the recurrent/progressive eDTC cohort. to treatment) (Supplementary Table 3) (14). Medical specialities involved in initial disease management Statistical methods Department responsible for patient monitoring and the An estimated sample size of close to 300 patients was multidisciplinary committee for decision-making were originally considered representative of nearly 20% of all involved. aDTC diagnoses made in Spain and Portugal during the Potential confounding variables inclusion period based on available incidence data at the A total of 33 potential covariates were analysed using time of protocol writing. the Kaplan–Meier (K–M) method. Later, all covariates Description of baseline characteristics and were entered into the multivariate Cox model following therapeutic approaches received by patients was done significant covariates with a type I error ≤ 1. Potential both forwards addition and backwards removal of non- for the total study population and for the two mutually exclusive groups de novo aDTC (Types 1 + 2) and recurrent/ covariates included variables at initial diagnosis progressive eDTC (Types 3 + 4). Additional time-to-event described above (baseline characteristics and analyses involved other ad hoc groups like (a) patients therapeutic approaches), covariates concerning relapse with metastatic disease (Types 1 + 3) vs those with the or progression of eDTC into aDTC (type of relapse, locoregional unresectable disease (Types 2 + 4) or (b) by surgery, cumulative RAI dose, therapeutic RAI with first RAI ATA response: excellent, structural incomplete, stimulating agent (hrTSH), response to therapeutic biochemical incomplete, and indeterminate (1). Missing RAI), and variables related to the advanced disease/ data were not imputed (Fig. 2). RAI-refractory disease (RAI refractoriness (RR) criteria Data were analysed using SAS Institute Inc. Version 1, 5, 6; RR criteria 2 + 3 + 4, RR criteria 7 + 8 (15), 8.2 software (Cary, NC, USA). All data were summarised Eastern Cooperative Oncology Group score (16), using adequate descriptive statistics (mean, s.d.; watchful waiting (yes/no), watchful waiting duration median, quartiles, 95% CI; minimum and maximum (months), surgery for advanced/RAI-refractory disease, for continuous variables; and absolute and relative radiotherapy for advanced/RAI-refractory disease, use frequencies for categorical variables). Comparisons of of systemic therapy, number of lines, and reason for continuous variables were done by Wilcoxon rank-sum stopping systemic therapy). test, and categorical variables by chi-square test or Fisher’s Data were obtained from medical records resulting exact test. Parameters based on objective response followed from standard clinical practice in participating sites and the standard RECIST v1.1 definition (14) as per physician- collected in electronic case report forms as mandated reported best response to treatment. in the ERUDIT study protocol (EIS-CDT-2017-01). OS and (RP)FS survival functions were analysed and Investigators received on-site training before data entry compared using K–M and Mantel–Haenszel (log-rank) to guarantee consistency. The eCRF included a range methods. Prognostic risk factors for OS, (RP)FS, and time of filters and logical controls to reduce errors, and an to develop aDTC/RR-DTC were analysed by univariate and authorized Clinical Research Associate helped data multivariate Cox proportional risk-based regression model. entering at various sites. Non-evaluable medians in K–M curves were identified https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. Figure 2 Flow diagram of eligible patients and analysed groups with evaluable data from the initial diagnosis of differentiated thyroid cancer (DTC). The (relapse/ progression) free survival ((RP)FS) evaluation describes the time elapsed from an upfront treatment until death, relapse into advanced DTC (aDTC) in patients with available data evaluable. ∲, from 208 total patients with evaluable outcome from first surgery to death, of which, 13 patients were excluded patients who were initially free of disease, or structural progression into aDTC in patients who had initial residual disease, respectively. n, number of because of ‘metastases resection’ (n = 8) and ‘other results’ (n = 5). ∯, only 188 patients had evaluable response from the first RAI therapy to death. ∰, from 98 total patients in the cohort with initial early disease with evaluable outcome from first surgery to death or from the first RAI therapy to death, of which, 7 patients were excluded because of ‘metastases resection’ (n = 3) and ‘other results’ (n = 4). **, ATA RAI response. as NE. All P-values were nominal and when <0.05 were Demographic, clinical, and treatment characteristics considered statistically significant. of patients at initial DTC diagnosis Study population had a median (Q1–Q3) age of 63.0 Results (51.0–71.0) years, and 59% (126/213) were female. Forty- three per cent (91/213) of patients had comorbidities at A total of 213 eligible patients were identified from the the time of DTC diagnosis, being cardiovascular disease initial 254 patients diagnosed with aDTC from January in 28.6% (61/213) of them. Concerning primary tumour 2007 to December 2012 in 23 participant hospitals characteristics, median (Q1–Q3) size was 40 (25.0– (22 Spanish and 1 Portuguese). Patients were grouped 57.0) mm. Almost 60% (125/209) of patients presented according to the time and disease extension at aDTC with papillary thyroid carcinoma, 18.7% (39/209) diagnosis for the descriptive and comparative analysis with follicular thyroid carcinoma, 10.0% (21/209) with (Fig. 2). Fifty-four per cent (115/213) were diagnosed Hürthle cell carcinoma, and 3.8% (8/209) with poorly with de novo aDTC and 46% (98/213) with eDTC that, differentiated carcinoma. Initial imaging techniques eventually after one or more relapses to previous showed unilateral primary involvement in 66.1% interventions, became aDTC. (119/180), extrathyroidal invasion in 26.7% (48/180), https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. Table 1 Demographic and clinical characteristics of the study population at initial disease presentation (N = 213). Global study Parameter population De novo aDTC Recurrent/progressive eDTC P-value Patient, no. (%) 213 (100) 115 (54.0) 98 (46.0) NA Age at initial diagnosis, median 63.0 (51.0–71.0) 67.0 (57.0–73.0) 56.5 (45.0–67.0) 0.0002c (Q1–Q3), years Gender, patient no. (%) Female 126 (59.2) 65 (56.5) 61 (62.2) 0.3970 Male 87 (40.8) 50 (43.5) 37 (37.8) ≥1 comorbidity Comorbidities, patient no. (%) 91 (42.7) 50 (43.5) 41 (41.8) 0.7667 Cardiovascular 61 (28.6) 33 (28.7) 28 (28.6) 0.9841 Metabolic 40 (18.8) 26 (22.6) 14 (14.3) 0.1211 Other clinically relevant 23 (10.8) 13 (11.3) 10 (10.2) 0.7965 Initial diagnosis of DTC and method, patient no. (%) Incidental post-surgery 45 (21.1) 15 (13.0) 30 (30.6) 0.0017c No incidental 168 (78.9) 100 (87.0) 68 (69.4) Echography 101 (60.1) 54 (54.0) 47 (69.1) 0.0671 Others 65 (38.7) 45 (45.0) 20 (29.4) Not available 2 (1.2) 1 (1.0) 1 (1.5) Fine needle aspiration result, 129 (60.6) 71 (61.7) 58 (59.2) 0.7037 patient no. (%) Malignant 100 (77.5) 60 (84.5) 40 (69.0) 0.0085c Indeterminate 17 (13.2) 4 (5.6) 13 (22.4) Benign 6 (4.7) 5 (7.0) 1 (1.7) Nondiagnostic 6 (4.7) 2 (2.8) 4 (6.9) Histological result, patient no. (%) 0.0497c Papillary thyroid carcinoma 125 (59.8) 67 (60.4) 58 (59.2) Follicular thyroid carcinoma 39 (18.7) 26 (23.4) 13 (13.3) Hürthle cell carcinoma 21 (10.0) 5 (4.5) 16 (16.3) Poorly differentiated 8 (3.8) 5 (4.5) 3 (3.1) Mixed carcinoma (papillary and 7 (3.3) 4 (3.6) 3 (3.1) follicular) Others 9 (4.3) 4 (3.6) 5 (5.1) Biochemistry at diagnosis, a 74 (34.7) 42 (36.5) 32 (32.7) 0.5545 patient no. (%) Diagnosis images, patient no. (%) 180 (100) 93 (51.7) 87 (48.3) 0.1120 Measurable disease, no. (%) 106 (58.9) 58 (62.4) 48 (55.2) 0.3270 Tumour size, median (mm) 40.0 (25.0–57.0) 40.0 (26.0–60.0) 38.5 (25.0–50.5) 0.3478 (Q1–Q3) Lobes involved, no. (%) 0.8248 Left or right 119 (66.1) 60 (64.5) 59 (67.8) Both 51 (28.3) 27 (29.0) 24 (27.6) Not available 10 (5.6) 6 (6.5) 4 (4.6) Tumour invasion,b no. (%) Present 48 (26.7) 34 (36.6) 14 (16.1) d Absent 34 (18.9) 12 (12.9) 22 (25.3) d Unknown 78 (43.3) 39 (41.9) 39 (44.8) d Pathological lymph nodes 37 (20.6) 24 (25.8) 13 (14.9) d Metastases by site, no. (%) Lung 66 (71.0) 66 (71.0) d Liver 5 (5.4) 5 (5.4) d Bone 33 (35.5) 33 (35.5) d Others 3 (3.2) 3 (3.2) d aRefers patients with thyroglobulin (Tg): Tg levels and/or anti-Tg positive in serum; btumour invasion refers to disease invading either adjacent tissues and structures and/or vascular spaces. Patients could be part of more than one tumour invasion category making statistical testing not feasible; cstatistically significant (P < 0.05); drecurrent/progressive eDTC patients, by definition, had no metastases at diagnosis. aDTC, advanced differentiated thyroid cancer; eDTC, early differentiated thyroid cancer. https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. and/or pathological lymph nodes in 20.6% (37/180). Time-to-event endpoints in the global Distant metastases were evidenced in 51.7% (93/180) study population of patients, mostly in lung (71.0%) and bone (35.5%) Median (Q1–Q3) study follow-up was 6.2 (4.5–9.0) years (Table 1). Baseline characteristics showed that de novo from initial DTC diagnosis and, specifically, 5.2 (3.3–7.0) aDTC patients were significantly older, the results of years from aDTC diagnosis to end of the study. No statistical tumour FNA were more likely to be malignant, and with differences were observed between median OS (mOS) and preferential follicular histology, compared to recurrent/ median DSS (mDSS) from initial DTC diagnosis to death progressive eDTC patients at initial diagnosis (Wilcoxon (mOS (95% CI): 10.4 (7.3–15.3) years and mDSS (95% CI): rank-sum test P = 0.0002, Fisher’s exact test P = 0.0085, 11.1 (8.7–16.2) years; log-rank test P = 0.4737) (Fig. 3A). and Fisher’s exact test P = 0.0497; respectively) (Table 1). mOS (95% CI) of de novo aDTC was significantly shorter Standard upfront treatments were used to manage compared to that in recurrent/progressive eDTC patients DTC after initial diagnosis (Supplementary Table 3). (6.4 (5.1–NE) vs 15.3 (10.4–17.8) years, respectively; log- Concisely, at least one surgery was given to 98.1% rank test P < 0.0001) (Fig. 3B). However, the extension of (209/213) of patients and 75.1% (157/209) of them were advance disease (metastatic vs locoregional) did not have subjected to any sort of neck dissection. Microscopic local statistical impact on mOS (10.4 (7.3–16.0) vs 8.6 (0.7–12.5) complete resection R0 was achieved in 68.4% (143/209) years, respectively; log-rank test P = 0.1869). Additionally, of cases. Eighty-nine per cent (190/213) of patients mOS (95% CI) after first surgery was 10.4 (8.1–16.0) received at least one RAI treatment, and 30% (57/190) years, being 7.8 years longer in patients with complete had a median (Q1–Q3) cumulative dose of 450.0 (400.0– macroscopic resection (R0/R1) compared to those with 500.0) mCi after three doses. Most frequent ATA response incomplete (R2) resections (12.5 (8.8–16.8) vs 4.7 (2.3– to treatment was ‘structural incomplete,’ being 61.6% 5.2) years, respectively; log-rank test P < 0.0001) (Fig. 3C). (117/190) after the first RAI dose. Ten per cent (21/213) Finally, mOS (95% CI) after first RAI treatment was 10.1 of patients received at least one course of locoregional (7.6–17.5) years, being significantly higher in patients external beam radiotherapy, and 52% (11/21) showed achieving ATA ‘excellent response’ compared to those subsequent ‘stable disease’ according to RECIST v1.1 (14). with ‘incomplete biochemical’ or ‘incomplete structural’ Significant differences were observed between results response (NE (8.2–NE) vs 10.1 (6.8–NE) vs 8.3 (5.7 - 17.5) attained by de novo aDTC and recurrent/progressive years; log-rank test P = 0.0212) (Fig. 3D). eDTC, potentially favouring a better course of disease in eDTC patients (surgical results, post-RAI response, etc) (Supplementary Table 3). Time-to-event endpoints in the recurrent/progressive Multidisciplinary committees monitored initial eDTC population management in 73.2% (152/231) of the cases, the Endocrinology department being the most frequently Median (RP)FS (95% CI) after initial radical surgery was involved followed by Nuclear Medicine and Oncology 2.3 (1.7–2.9) years (n  = 90), and 1.7 (1.0 - 2.0) years (n  = 91) (Table 2). after initial RAI, being significantly higher for patients Table 2 Medical specialities involved in disease management after initial diagnosis (N = 213). Parameter De novo aDTC (N = 115) Recurrent/progressive eDTC (N = 98) Global study population (N = 213) Service responsible for patient monitoring, patient no. (%) Endocrinology 75 (65.2) 67 (68.4) 142 (66.7) Nuclear medicine 19 (16.5) 15 (15.3) 34 (16.0) Oncology 15 (13.0) 12 (12.2) 27 (12.7) Surgery 1 (0.9) 1 (1.0) 2 (0.9) Others 1 (1.1) 1 (0.5) Not availablea 5 (4.3) 2 (2.0) 7 (3.3) Presence of multidisciplinary committee, patient no. (%) No 28 (24.3) 22 (22.4) 50 (23.5) Yes 82 (71.3) 74 (75.5) 156 (73.2) Not available 5 (4.3) 2 (2.0) 7 (3.3) aRecords could not be retrieved from the electronic case report form. https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. Figure 3 Survival Kaplan–Meier curves from the initial differentiated thyroid cancer (DTC) diagnosis to death in the global study population. (A) Comparison of overall survival (OS) from initial DTC diagnosis to death by any cause (blue) vs disease-specific survival (DSS) from initial DTC diagnosis to death related to the disease (pink). No differences were found (log-rank P = 0.474). (B) Comparison of OS from initial DTC diagnosis to death by any cause according to the time of advanced DTC (aDTC) diagnosis: de novo (blue) vs recurrent/progressive (pink). The OS from the initial DTC diagnosis was a median 8.9 years shorter in patients with de novo aDTC (log-rank test P < 0.0001). (C) Comparison of OS from first surgery: complete macroscopic resection, R0/R1 (blue) vs incomplete resection, R2 (pink). The OS from initial surgery was a median 7.8 years longer in patients with R0/R1 outcome (log-rank test P < 0.0001). (D) Comparison of OS from first RAI (±surgery) according to ATA response criteria: excellent (blue) vs biochemical incomplete (pink) vs structural incomplete response (magenta) (log-rank P = 0.0212). mOS (95% CI): median OS (95% CI) years. achieving ATA ‘excellent response’ compared to those In contrast, cumulative RAI dose <600 mCi, no RAI with ‘incomplete biochemical’ or ‘incomplete structural’ treatment, and RAI-scan positivity after the initial response after this initial treatment (4.3 (0.9–9.0) vs 2.0 RAI treatment were all significantly associated with a (1.1–2.8) vs 0.6 (0.4 - 1.8) years, respectively; log-rank test higher risk of death (aHR (95% CI): 5.3 (2.3–12.0), Wald P = 0.0034) (Fig. 4). chi-square P = 0.0001; aHR (95% CI): 6.75 (2.4–18.9), Wald chi-square P = 0.0003; and aHR (95% CI): 2.4 (1.1–5.3), Wald chi-square P = 0.0307; respectively) (Table 3 and Analysis of prognostic factors Supplementary Table 4). OS In the global study population, initial DTC diagnosis under (RP)FS 55 years was confirmed as a favourable prognostic factor In the recurrent/progressive eDTC cohort, attaining R0/R1 associated with lower risk of death (adjusted hazard ratio surgical result and being eligible for rescue surgeries was (aHR): 0.39, 95% CI: 0.2–0.7; Wald chi-square P = 0.0018). associated to a longer time to disease relapse or progression https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. Figure 4 (Relapse/progression)-free survival ((RP)FS) after the first RAI treatment in patients with early disease condition stratified by ATA response (log-rank P = 0.0034). 1: excellent (blue); 2: incomplete biochemical (pink). 3: incomplete structural response (magenta). m(RP)FS (95% CI): median (95% CI) years. into aDTC/RR-DTC compared to having an R2 outcome (aHR (95% CI): 4.3 (2.0–9.2), Wald chi-square P = 0.0002 and (aHR (95% CI): 0.003 (0.00–0.05), Wald chi-square aHR (95% CI): 2.47 (1.2–5.3), Wald chi-square P = 0.0188; P = 0.0001 and aHR (95% CI): 0.003 (0.00–0.05), Wald Chi- respectively) (Table 4 and Supplementary Table 5). square P = 0.0001; respectively). Regarding RAI therapy, both cumulative RAI doses <600 mCi and use of a pre-RAI Time to aDTC/RR-DTC hrTSH were positively associated to shorter time to relapse, Additionally, we analysed prognostic factors associated progression, or death aDTC (aHR (95% CI): 2.45 (1.4–4.4), with the time of eDTC relapse or progression into aDTC Wald chi-square P = 0.0025 and aHR (95% CI): 3.78 (1.1– or RR-DTC. Same as with (RP)FS, attaining R0/R1 surgical 12.6), Wald chi-square P = 0.0304; respectively). Resulting result and being eligible for rescue surgeries was associated in ATA incomplete response (biochemical, structural, or with a longer time to relapse or progression into aDTC/ both) after the first RAI treatment was also associated with RR-DTC compared to the R2 result (aHR (95% CI): 0.002 an increased risk of earlier relapse, progression, or death (0.00–0.03), Wald chi-square P = 0.0002 and aHR (95% Table 3 Multivariate analyses for overall survival in the global study population. Overall survival (Cox proportional hazard model) Covariatesa N Adjusted hazard ratio (95% CI) Wald chi-square P-value General variables ≥55 (ref.) Age at diagnosis in years 149 <55 64 0.39 (0.214–0.703) 0.0018d Variables of initial diagnosis and first treatment ≥600 mCi (ref.) RAI cumulative dose 29 <600 mCi 160 5.32 (2.352–12.037) <0.0001d No RAI treatmentb 23 6.75 (2.406–18.946) 0.0003d RAI-scan positivity after initial RAI treatmentc No (ref.) 26 Yes 133 2.41 (1.085–5.345) 0.0307d aAll covariates were entered into a Cox regression model, bpatients not receiving RAI because of it not being clinically indicated or having tumours with negative RAI scans; crefers to 6–12 months follow-up post-treatment scans in patients that could have received surgery ± RAI as first therapeutic approach; dStatistically significant (P < 0.05). (ref.), reference category; OS, overall survival; RAI, radioactive iodine (I-131). https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. Table 4 Multivariate analyses for (relapse/progression) free survival and time to develop aDTC/RR-DTC in the eDTC cohort (N = 98). Time to develop aDTC/RR-DTC (RP)FS (Cox proportional hazard model) (Cox proportional hazard model) Adjusted hazard ratio Wald chi-square Adjusted hazard ratio Wald chi-square Covariatesa N (95% CI) P-value (95% CI) P-value Variables of initial diagnosis and first treatment Surgical outcome R2 (ref.) 1 R0/R1 90 0.003 (0.000–0.048) <0.0001f 0.002 (0.000–0.034) <0.0001f Othersb 7 0.003 (0.000–0.048) <0.0001f 0.004 (0.000–0.064) 0.0001f ≥600 mCi (ref.) RAI cumulative dose 5 <600 mCi 87 3.78 (1.13–12.60) 0.0304f No RAI treatmentc 5 2.8 (0.53–14.76) 0.2237 RAI with stimulating agent at first instanced No (ref.) 71 Yes 18 2.45 (1.37–4.38) 0.0025f 1.82 (1.02–3.26) 0.0438f RAI Response at first instance ATA criteriae Excellent (ref.) 13 Biochemistry incomplete + indeterminate 38 2.47 (1.16–5.26) 0.0188f 2.34 (1.08–5.07) 0.0315f Structural incomplete 40 4.32 (2.03–9.21) 0.0002f 3.35 (1.55–7.23) 0.0021f aAll covariates were entered into a Cox regression model; bpathological lymph node dissections or metastasectomies; cpatients not receiving RAI because of it not being clinically indicated or having tumours with negative RAI scans; dfollowing standard practice in Spain and Portugal, patients not receiving hrTSH prior to RAI, were deprived of LT4; eHaugen et al., 2016;(1) fstatistically significant (P < 0.05). (ref.), reference category; (RP)FS, relapse/progression-free survival; aDTC, advanced differentiated thyroid cancer; R0, microscopic complete resection; R1, macroscopic resection with microscopic residual tumour; R2, gross macroscopic residual tumour; RAI, radioactive Iodine (I-131); RR-DTC, radioiodine- refractory differentiated thyroid cancer. CI): 0.004 (0.00–0.06), Wald chi-square P = 0.0001; carcinoma was the most common histological type. respectively). Finally, both use of pre-RAI hrTSH (aHR Despite our study expressly selecting aDTC patients, these (95% CI: 1.8 (1.0–3.2); Wald chi-square P = 0.0438) and characteristics at initial diagnosis did not differ much incomplete response to first RAI were positively associated from those previously reported in European or North with earlier relapse or progression into aDTC/RR-DTC American series covering a wider range of population (‘incomplete biochemical’ aHR (95% CI): 2.3 (1.1–5.1), (2, 17, 18, 19, 20). Wald chi-square P = 0.0315 and ‘incomplete structural’ Half (54%) of our patients were diagnosed with de novo aHR (95% CI): 3.35 (1.5 - 7.2); Wald chi-square P = 0.0021) aDTC and, of them, 98% presented with distant metastases (Table 4). affecting mainly lungs and bones. These findings are consistent with other studies also describing half of the advanced patients present with distant metastases at first Discussion diagnosis (4, 21, 22). In addition, more recent studies reported a higher prevalence of lung metastasis (49–75%) ERUDIT is a retrospective and longitudinal study of Spanish compared to bone metastasis (17–39%) in patients with and Portuguese aDTC patients that reviewed, among aDTC at presentation regardless of the histological type others, their relevant demographic and clinical data at (23, 24, 25). The remaining 46% in our series were eDTC the time of their initial diagnosis and the therapeutic patients who progressed into aDTC stages after receiving management that ensued. Prognostic factors impacting standard therapy (surgery ± RAI). their survival as well as their relapse/progression from early Initial DTC treatment followed standard into advanced stages have been also examined. recommendations, thus relying on surgery and In total, 213 advanced DTC patients were retro­ RAI treatment (1). Consequently, different medical spectively followed for a median of 6.2 years from their specialities were involved in disease management under initial DTC diagnosis. The median age at diagnosis was a multidisciplinary team in over 73% of the cases after 63 years, being more frequent in females than males, and initial diagnosis. It is known that the implementation of with half of patients presenting at least one comorbidity, multidisciplinary teams can help to optimise therapeutic in most cases, a cardiovascular disorder. Papillary thyroid results both for patients and for the healthcare system itself https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. (11, 12) and, according to our observations, this aspiration speaking of the precocious biological aggressiveness of was already becoming the standard in the Iberian the persistent tumours identified within our series. These Peninsula even before this was established as usual clinical observations not just confirm the prognostic relevance of practice (11, 26). ERUDIT data show that Endocrinology the dynamic ATA risk stratification system (28) but also was the main responsible department followed by Nuclear provide real estimates of the expected evolution that high- Medicine and Oncology departments. risk patients may have. This, in addition, to contradict the In this study, both mOS and mDSS measured since the widely accepted evidence on the similar prognosis of these initial DTC diagnosis were around 10 years in the global two populations (biochemical incomplete and excellent study population with no statistical differences observed ATA response), should encourage second thoughts when between them. This observation implies that aDTC is the first dealing with high-risk tumours in daily practice. In leading cause of death in these patients. line with this, Sciuto et al. (19) retrospectively analysed OS analyses by groups showed that recurrent/ 1553 subjects diagnosed with DTC and highlighted the progressive eDTC patients had longer survival expectancy relevance of RAI responsiveness as the strongest predictor than those with advanced de novo aDTC diagnosis, of a good outcome in terms of survival. Several studies independently of their disease extension. As previously have described other independent predictors of disease reported, multivariate Cox model revealed that initial DTC persistence/recurrence which include male gender, diagnosis <55 years, RAI responsiveness (no evidence of diagnosis age >45, histology, high serum Tg levels, and post-RAI uptake and initial cumulative RAI (≥600 mCi)) the presence of distant metastases (19, 27, 29, 30). In our were positive independent prognostic risk factors of longer study, age at diagnosis, gender, and disease extension were OS in the global study population. Unlike other studies, statistically significant only in univariate analysis but not gender, histological type, and metastatic localizations in the adjusted multivariate Cox model, probably due to had no statistically significant impact on OS (21, 22, sample size limitations and the aggressive behaviour that 25, 27). These discrepancies might be explained by the characterize our sample selection. However, common heterogeneity of the global population analysed, our sense dictates early identification of these poor prognostic limited sample size, and the many differences found in indicators since the initial DTC diagnosis and rapid the published literature (21, 22, 25, 27). For example, implementation of commensurate therapeutic measures Schlumberger et al. (22) in a similar study with 394 could greatly change the time to relapse, progression, metastatic patients showed that age at the discovery or eventually death of these patients with aggressive of metastases and radioiodine avidity were favourable tumour profile. predictors of survival. Other studies found that older age ERUDIT study presents several limitations and at diagnosis, male sex, metastatic site (lung), and histology strengths. The main limitations involve its retrospective (follicular type) were significant factors for poor prognosis nature and limited sample size that very likely have in patients with metastases at presentation (23, 24, 25, 27). underrepresented the actual aDTC incidence in the Regarding the recurrent/progressive eDTC cohort, we Iberian Peninsula despite this being outside the scope of found an m(RP)FS of 2.3 years and an mOS of 15 years. Most the study. The reduced sample size, however, could have relevant risk factors found in univariate and multivariate affected groups’ distribution, statistical power of uni- analysis showed that R0/R1 initial surgery and being eligible and multivariate analyses, and potentially introduced a for rescue surgeries (local or metastatic) were protective selection bias mainly in the recurrent/progressive eDTC factors for death, early relapse, or progression into aDTC/ cohort. On the other hand, this study longitudinally RR-DTC. However, this observation must be taken follows for the first time relevant clinical data of European cautiously due to the small sample classified in the R2 group. aDTC patients first diagnosed de novo or as recurrent/ Additionally, poor RAI responsiveness (low cumulative RAI progressive from initial eDTC that have resulted in doses, need for use of pre-RAI hrTSH, and ATA biochemical descriptive and prognostic information useful in everyday and structural incomplete RAI responses) after initial practice decision-making. treatment was positively associated with a higher likelihood of death, premature relapse, or progression into advanced stages. Interestingly, not only patients achieving structural Conclusion incomplete (0.6 years) but even biochemical incomplete responders (2.0 years) had a shorter m(RP)FS compared to ERUDIT is the first epidemiological study that reviews those attaining excellent response (4.3 years), somewhat the natural history of aDTC in Spain and Portugal. It has https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. Downloaded from Bioscientifica.com at 07/17/2023 08:21:22AM via free access J A Vallejo Casas, M Sambo 11:5 e210111 et al. revealed interesting findings such that most aDTC tumours Gómez-Balaguer, Dr Juan Carlos Galofré, Dr Beatriz Castelo, and Dr Iñaki Argüelles have nothing to disclose. (93%) present with metastases at diagnosis of advanced disease (de novo or recurrent/progressive), patients die from their disease and not from other causes, and early disease diagnosis (eDTC) can utterly extend survival Funding compared to advanced ones (de novo aDTC). Additionally, ERUDIT study was sponsored and funded by Eisai Farmacéutica S.A. (Madrid, Spain). the study identified early poor treatment-dependent prognostic factors impacting both the pace at which early disease progresses into advanced stages and the overall survival expectancy of aDTC patients once they are as Author contribution statement such diagnosed. These observations should be promptly J A V C, C L L and M S contributed equally to methodology design, critical review of the study proposal, results and interpretation, data collection considered and translated into a proactive follow-up and an and writing of the original draft. M D P contributed to the critical review intensified therapeutic attitude in this subpopulation. This of results and interpretation. L O R and J R V G the conceived the idea, could, at least potentially, reverse its doomed prognosis methodology design, coordination, execution of the research, and provided the financial support leading to this publication. J A V C and L O and positively impact disease evolution in many cases. R contributed as corresponding authors on behave of the ERUDIT Study Group of Co-authors. R J S, M L, E N G, J A, V P, S G, G C, C G, C Z, M N, J S S, A S, P G, M G B, J V, M P D, J C G, B C, M J V and I A contributed to data collection and final draft review. All the above authors confirm that the study was performed in compliance with all basic principles of the Helsinki Supplementary materials Declaration (2013) and applicable national regulations. Both accredited This is linked to the online version of the paper at https://doi.org/10.1530/ Research Ethics Committees of Hospital Universitario Gregorio Marañón ETJ-21-0111. (Madrid, Spain) and National Ethics Committee for Clinical Research (Portugal) approved it. Declaration of interest This article is the authors’ own work, and not an official position of the Acknowledgements institutions or funder. Dr Juan Antonio Vallejo Casas reports grants, The authors of the ERUDIT Study Group thank Eisai Farmacéutica S.A. consultant fees and non-financial support from Eisai, during the conduct (Madrid, Spain) for funding the study support, to Lidesec S. L. (Madrid, of the study; consultant fees and non-financial support from Sanofi, Spain) for the operational management, to Medicxact S. L. (Madrid, Spain) consultant fees from Bayer, consultant fees and non-financial support for the statistical analysed support and Cristina Gil Roda Medical Writing from Novartis, outside the submitted work; Dr Marcel Sambo reports (Barcelona, Spain) for the editorial assistance. grants and consultant fees from Eisai, during the conduct of the study; Dr Carlos López López reports grants and consultant fees from Bayer, grants and consultant fees from Eisai, grants and consultant fees from Pfizer, grants and consultant fees from Ipsen, grants and consultant fees from Novartis, grants and consultant fees from Lilly, during the conduct of the study; Dr Lorenzo Orcajo Rincón and Dr Julio Rodríguez-Villanueva García References report employees from Eisai, with interests outside the submitted work; 1 Haugen BR, Alexander EK, Bible KC, Doherty GM, Mandel SJ, Dr Marta Llanos reports consultant fees from Roche, consultant fees from Nikiforov YE, Pacini F, Randolph GW, Sawka AM, Schlumberger M, Amgen, consultant fees from Eisai, consultant fees from Ipsen, consultant et al. 2015 American Thyroid Association management guidelines for fees from Servier, consultant fees from Lilly, consultant fees from Merck, adult patients with thyroid nodules and differentiated thyroid cancer: outside the submitted work; Dr Elena Navarro-González reports consultant the American Thyroid Association guidelines task force on thyroid fees from Eisai, during the conduct of the study; Dr Javier Aller reports nodules and differentiated thyroid cancer. Thyroid 2016 26 1–133. consultant fees and non-financial support from Eisai, during the conduct (https://doi.org/10.1089/thy.2015.0020) of the study; consultant fees from Eisai, consultant fees and non-financial 2 Dal Maso L, Tavilla A, Pacini F, Serraino D, van Dijk BAC, support from Ipsen, outside the submitted work; Dr Guillermo Crespo Chirlaque MD, Capocaccia R, Larrañaga N, Colonna M, Agius D, et al. reports grants from Ipsen, grants from Roche, grants from BMS, grants from Survival of 86,690 patients with thyroid cancer: a population-based Eisai, grants from Sanofi, grants from Janssen, grants from Eusa Pharma, study in 29 European countries from EUROCARE-5. European Journal of grants from Pierre Fabre, outside the submitted work; Dr Cintia González Cancer 2017 77 140–152. (https://doi.org/10.1016/j.ejca.2017.02.023) reports other from Hospital Santa Creu i Sant Pau, during the conduct of 3 Surveillance, Epidemiology and End Results (SEER) Program, National the study; Dr Miguel Navarro reports consultant fees and non-financial Institutes of Health. Cancer stat facts: thyroid cancer, 2017. (available support from Ipsen, non-financial support from Novartis, consultant at: https://seer.cancer.gov/statfacts/html/thyro.html) fees and non-financial support from Bayer, outside the submitted work; 4 Haugen BR & Sherman SI. Evolving approaches to patients with Dr Javier Valdivia reports consultant fees from Novartis, MSD, Roche and advanced differentiated thyroid cancer. Endocrine Reviews 2013 34 Eisai during the conduct of the study; Dr Manel Puig-Domingo reports non- 439–455. (https://doi.org/10.1210/er.2012-1038) financial support from Eisai during the conduct of the study and, Dr María 5 Kebebew E & Clark OH. 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(available at: https://www.encr.eu/) doi.org/10.1002/jso.24740) 18 Lee YK, Hong N, Park SH, Shin DY, Lee CR, Kang SW, Lee J, Jeong JJ, 30 Kim Y, Roh JL, Song D, Cho KJ, Choi SH, Nam SY & Kim SY. Predictors Nam KH, Chung WY, et al. The relationship of comorbidities to of recurrence after total thyroidectomy plus neck dissection and mortality and cause of death in patients with differentiated thyroid radioactive iodine ablation for high-risk papillary thyroid carcinoma. carcinoma. Scientific Reports 2019 9 11435. (https://doi.org/10.1038/ Journal of Surgical Oncology 2020 122 906–913. (https://doi. s41598-019-47898-8) org/10.1002/jso.26090) Received in final form 13 June 2022 Accepted 30 June 2022 Accepted Manuscript published online 1 July 2022 https://etj.bioscientifica.com © 2022 The authors This work is licensed under a Creative Commons https://doi.org/10.1530/ETJ-21-0111 Published by Bioscientifica Ltd. Attribution-NonCommercial 4.0 International License. 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