Tumour markers fluctuations in patients with medullary thyroid carcinoma receiving long-term RET inhibitor therapy: ordinary lapping or alarming waves foreshadowing disease progression?
2013; Elsevier BV; Volume: 24; Issue: 9 Linguagem: Inglês
10.1093/annonc/mdt331
ISSN1569-8041
AutoresS. Postel-Vinay, Martin Schlumberger, Jean‐Charles Soria,
Tópico(s)Cancer-related Molecular Pathways
ResumoMedullary thyroid carcinoma (MTC), a rare malignancy arising from the parafollicular C cells of the thyroid gland, accounts for <5% of all thyroid cancers [1.Hundahl S.A. Fleming I.D. Fremgen A.M. et al.A National Cancer Data Base report on 53,856 cases of thyroid carcinoma treated in the US, 1985–1995.Cancer. 1998; 83: 2638-2648Crossref PubMed Scopus (1536) Google Scholar]. Virtually all patients with hereditary MTC display germline mutations in the RET (REarranged during Transfection) proto-oncogene, whereas somatic RET mutations are detected in nearly half of sporadic MTC [2.Mulligan L.M. Kwok J.B. Healey C.S. et al.Germ-line mutations of the RET proto-oncogene in multiple endocrine neoplasia type 2A.Nature. 1993; 363: 458-460Crossref PubMed Scopus (1756) Google Scholar, 3.Donis-Keller H. Dou S. Chi D. et al.Mutations in the RET proto-oncogene are associated with MEN 2A and FMTC.Hum Mol Genet. 1993; 2: 851-856Crossref PubMed Scopus (1182) Google Scholar, 4.Marsh D.J. Learoyd D.L. Andrew S.D. et al.Somatic mutations in the RET proto-oncogene in sporadic medullary thyroid carcinoma.Clin Endocrinol (Oxf). 1996; 44: 249-257Crossref PubMed Scopus (186) Google Scholar]. The key role of RET alterations in MTC launched the development of several small molecule kinase inhibitors targeting this receptor, including vandetanib (Calpresa, AstraZeneca), motesanib (AMG706, Amgen), sorafenib (Nexavar, Bayer), sunitinib (Sutent, Pfizer) and cabozantinib (Cometriq, Exelexis). The remarkable activity of these agents in patients with locally advanced or metastatic progressive or symptomatic MTC, for whom there had previously been no effective therapy, led to the approval of vandetanib and cabozantinib by the Food and Drug Administration in April 2011 (and by EMA in February 2012) and November 2012, respectively. Indeed, this represents a very low number of patients with an estimated incidence of 1 for every 1–1.5 million people per year. The approval of both drugs was based on an improvement in progression-free survival (PFS) for patients who received the drug compared with those who received placebo according to RECIST v1.0 criteria (hazard ratio [HR] = 0.35 [0.24, 0.53], P < 0.0001 for vandetanib; HR = 0.28 [0.19, 0.40], P < 0.0001 for cabozantinib) [5.Wells Jr, S.A. Gosnell J.E. Gagel R.F. et al.Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.J Clin Oncol. 2010; 28: 767-772Crossref PubMed Scopus (444) Google Scholar, 6.Schoffski P. Elisei R. Müller S. et al.An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.J Clin Oncol. 2012; (30 (Suppl), abstr 5508)Crossref Google Scholar]. The objective response rate was 45% with vandetanib, with an estimated response duration of >2 years, and 28% with cabozantinib, respectively [5.Wells Jr, S.A. Gosnell J.E. Gagel R.F. et al.Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.J Clin Oncol. 2010; 28: 767-772Crossref PubMed Scopus (444) Google Scholar, 6.Schoffski P. Elisei R. Müller S. et al.An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.J Clin Oncol. 2012; (30 (Suppl), abstr 5508)Crossref Google Scholar]. However, alternative ways of assessing treatment efficacy and tumour response have been proposed for MTC, notably the monitoring of serum calcitonin (Ct) and carcinoembryonic antigen (CEA). Ct is a small monocatenar polypeptide hormone, and elevated Ct concentrations are found in subjects with MTC or C-cell hyperplasia, but are rare in those without C-cell disease; when abnormal, Ct levels remained relatively low and do not reach levels observed in patients with MTC except in very rare cases of patients with other neuroendocrine tumours [7.Leboulleux S. Baudin E. Travagli J.P. et al.Medullary thyroid carcinoma.Clin Endocrinol (Oxf). 2004; 61: 299-310Crossref PubMed Scopus (270) Google Scholar]. In contrast, CEA is commonly expressed in other tumour types such as colorectal, pancreatic or breast cancer, and is therefore not specific for MTC, although MTC is the only head and neck tumour that may produce large amounts of CEA [8.Ito K. Hibi K. Ando H. et al.Usefulness of analytical CEA doubling time and half-life time for overlooked synchronous metastases in colorectal carcinoma.Jpn J Clin Oncol. 2002; 32: 54-58Crossref PubMed Scopus (33) Google Scholar]. In this issue of Annals of Oncology, Kurzrock et al. investigate fluctuations in serum markers and analyse their relationships with tumour burden (according to RECIST v1.0 criteria) in patients with MTC treated with several RET inhibitors for at least 6 months, through a retrospective analysis of 26 cases. Although nearly all patients experienced an initial decline in Ct or CEA, later transient fluctuations including spikes above baseline were observed in one-third of these patients, despite the absence of radiological progression. The absence of relationship between tumour response and biomarker fluctuations reported in this study is in line with what has previously been observed in all trials evaluating RET inhibitors that have reported data on serum markers variation, and is as such not paradigm shifting (Table 1): profound drops in Ct and CEA levels, followed by small rebounds and oscillations that usually are of much smaller magnitude than the initial decline and do not correlate with any radiological progression, have been consistently reported in patients with MTC treated with RET inhibitors [5.Wells Jr, S.A. Gosnell J.E. Gagel R.F. et al.Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.J Clin Oncol. 2010; 28: 767-772Crossref PubMed Scopus (444) Google Scholar, 6.Schoffski P. Elisei R. Müller S. et al.An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.J Clin Oncol. 2012; (30 (Suppl), abstr 5508)Crossref Google Scholar, 9.Kurzrock R. Sherman S.I. Ball D.W. et al.Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer.J Clin Oncol. 2011; 29: 2660-2666Crossref PubMed Scopus (479) Google Scholar, 10.Wells Jr, S.A. Robinson B.G. Gagel R.F. et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2012; 30: 134-141Crossref PubMed Scopus (1106) Google Scholar, 11.Schlumberger M.J. Elisei R. Bastholt L. et al.Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer.J Clin Oncol. 2009; 27: 3794-3801Crossref PubMed Scopus (314) Google Scholar, 12.Lam E.T. Ringel M.D. Kloos R.T. et al.Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer.J Clin Oncol. 2010; 28: 2323-2330Crossref PubMed Scopus (322) Google Scholar, 13.De Souza J.A. Busaidy N. Zimrin A. et al.Phase II trial of sunitinib in medullary thyroid cancer (MTC).J Clin Oncol. 2010; 28 (abst 5504)Google Scholar]. For example, an initial 90% drop (from 1000 to 100 pg/ml) can be followed by oscillations of 30% magnitude around the nadir (i.e. between 85 and 115 pg/ml), without being associated with tumour progression. Notably, Ct concentrations may fluctuate by 20%–30% at short intervals without any biological significance in any patient with MTC [7.Leboulleux S. Baudin E. Travagli J.P. et al.Medullary thyroid carcinoma.Clin Endocrinol (Oxf). 2004; 61: 299-310Crossref PubMed Scopus (270) Google Scholar, 14.Schlumberger M. Carlomagno F. Baudin E. et al.New therapeutic approaches to treat medullary thyroid carcinoma.Nat Clin Pract Endocrinol Metab. 2008; 4: 22-32Crossref PubMed Scopus (145) Google Scholar]. This retrospective study did unfortunately not include any control group of untreated patients, which makes results more difficult to interpret. Also, short-term fluctuations in serum Ct levels are often more important than that in serum CEA levels, which has been explained by differences in half-lifes and production rates. More importantly, it has been demonstrated that Ct and CEA doubling times (DTs) are more efficient tools for assessing tumour progression than their respective serum level values, and that several blood determinations have to be used to accurately perform the DT calculation [15.Giraudet A.L. Al Ghulzan A. Auperin A. et al.Progression of medullary thyroid carcinoma: assessment with calcitonin and carcinoembryonic antigen doubling times.Eur J Endocrinol. 2008; 158: 239-246Crossref PubMed Scopus (190) Google Scholar]. A recent study from Akeno-Stuart et al. [16.Akeno-Stuart N. Croyle M. Knauf J.A. et al.The RET kinase inhibitor NVP-AST487 blocks growth and calcitonin gene expression through distinct mechanisms in medullary thyroid cancer cells.Cancer Res. 2007; 67: 6956-6964Crossref PubMed Scopus (105) Google Scholar] also reported that NVP-AST487, an N,N′-diphenyl urea with an inhibitory activity of both wild-type and mutant RET kinase, could directly inhibit Ct gene transcription through a Ct promoter fragment previously reported to be activated via rat sarcoma. Consequently, early decrease of plasma Ct may only provide indirect evidence that the drug is hitting the target (and might as such be used as a pharmacodynamic biomarker), but might not necessarily correlate with any anti-tumour effect. In their original report, Akeno-Stuart et al. used multiple RET inhibitors (NVP-AST487, PP2 and vandetanib) that were evaluated in one human cell line in vitro as well as one mouse model. Consequently, although RET inhibitors used in the study from Kurzrock et al.—namely cabozantinib, sorafenib, lenvatinib and sunitinib—do not belong to the same chemical family of drugs as NVP-AST487 and might as such have a slightly different properties, we can hypothesise that the effect primarily described with NVP-AST487 can be generalised to all RET inhibitors. Given that Ct fluctuations are of limited reliability in this context, alternative biomarkers or genomic signatures that would not be directly modulated by RET inhibitors have been proposed [17.Broutin S. Ameur N. Lacroix L. et al.Identification of soluble candidate biomarkers of therapeutic response to sunitinib in medullary thyroid carcinoma in preclinical models.Clin Cancer Res. 2011; 17: 2044-2054Crossref PubMed Scopus (34) Google Scholar, 18.Bass M.B. Sherman S.I. Schlumberger M.J. et al.Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer.J Clin Endocrinol Metab. 2010; 95: 5018-5027Crossref PubMed Scopus (80) Google Scholar]. These latter were not evaluated in this study, but further investigations are warranted.Table 1Main trials of RET inhibitors in MTC that reported serum biomarker outcomesAgent/trial phaseRadiological response (% patients)Calcitonin (% patients)CEA (% patients)CorrelationRef.Cabozantinib (COMETRIQ, Exelexis)/phase IORR = 29%DCR = 68%aDCR = stable disease for >24 weeks.Any decrease = 93% More than 50% decrease from baseline = 80%Any decrease = 80% More than 50% decrease from baseline = 32%NoKurzrock et al. [9.Kurzrock R. Sherman S.I. Ball D.W. et al.Activity of XL184 (cabozantinib), an oral tyrosine kinase inhibitor, in patients with medullary thyroid cancer.J Clin Oncol. 2011; 29: 2660-2666Crossref PubMed Scopus (479) Google Scholar]Cabozantinib (COMETRIQ, Exelexis)/phase IIIORR = 28%Any decrease = 45%NRNRSchoffski et al. [6.Schoffski P. Elisei R. Müller S. et al.An international, double-blind, randomized, placebo-controlled phase III trial (EXAM) of cabozantinib (XL184) in medullary thyroid carcinoma (MTC) patients (pts) with documented RECIST progression at baseline.J Clin Oncol. 2012; (30 (Suppl), abstr 5508)Crossref Google Scholar]Vandetanib (Caprelsa, AstraZeneca)/phase IIORR = 20%DCRaDCR = stable disease for >24 weeks. = 73%BRRbBRR = normalization or >50% decrease from baseline for at least 4 weeks. = 80% (50% decrease maintained at least 4 weeks)BRRbBRR = normalization or >50% decrease from baseline for at least 4 weeks. = 53% (same)NoWells et al. [5.Wells Jr, S.A. Gosnell J.E. Gagel R.F. et al.Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.J Clin Oncol. 2010; 28: 767-772Crossref PubMed Scopus (444) Google Scholar]Vandetanib (Caprelsa, AstraZeneca)/phase IIIORR = 45%DCRaDCR = stable disease for >24 weeks. = 87%BRRbBRR = normalization or >50% decrease from baseline for at least 4 weeks. = 69%BRRbBRR = normalization or >50% decrease from baseline for at least 4 weeks. = 52%NRWells et al. [10.Wells Jr, S.A. Robinson B.G. Gagel R.F. et al.Vandetanib in patients with locally advanced or metastatic medullary thyroid cancer: a randomized, double-blind phase III trial.J Clin Oncol. 2012; 30: 134-141Crossref PubMed Scopus (1106) Google Scholar]Motesanib (AMG706, Amgen/Takeda)/phase IIORR = 2%DCRaDCR = stable disease for >24 weeks. = 48%Any decrease = 83% More than 50% decrease from baseline = 37%Any decrease = 75% More than 50% decrease from baseline = 17%NoSchlumberger et al. [11.Schlumberger M.J. Elisei R. Bastholt L. et al.Phase II study of safety and efficacy of motesanib in patients with progressive or symptomatic, advanced or metastatic medullary thyroid cancer.J Clin Oncol. 2009; 27: 3794-3801Crossref PubMed Scopus (314) Google Scholar]Sorafenib (Nexavar, Bayer)/phase IIORR = 6%DCR = 52%aDCR = stable disease for >24 weeks.Any decrease = 80% More than 50% decrease from baseline = 45%Any decrease = 60% More than 50% decrease from baseline = 5%NoLam et al. [12.Lam E.T. Ringel M.D. Kloos R.T. et al.Phase II clinical trial of sorafenib in metastatic medullary thyroid cancer.J Clin Oncol. 2010; 28: 2323-2330Crossref PubMed Scopus (322) Google Scholar]Sunitinib (Sutent, Pfizer)/phase IIORR = 35% SD = 57% (median duration 32 weeks)More than 30% decrease from baseline = 40%NRNRDe Souza et al. [13.De Souza J.A. Busaidy N. Zimrin A. et al.Phase II trial of sunitinib in medullary thyroid cancer (MTC).J Clin Oncol. 2010; 28 (abst 5504)Google Scholar]ORR: overall response rate; CDR: disease control rate; SD: stable disease; BCR: biochemical response rate; CEA: carcinoembryonic antigen; Ref: reference; NR: not reported.a DCR = stable disease for >24 weeks.b BRR = normalization or >50% decrease from baseline for at least 4 weeks. Open table in a new tab ORR: overall response rate; CDR: disease control rate; SD: stable disease; BCR: biochemical response rate; CEA: carcinoembryonic antigen; Ref: reference; NR: not reported. Whether drug holidays or dose reductions could have influenced the fluctuations in serum biomarkers may also need consideration. Compared with imaging measurements, serum tumour markers fluctuate more rapidly and are therefore more markedly influenced by treatment interruptions. Ct and CEA half-lives are reported to be ∼3–30 h and 3–13 days [8.Ito K. Hibi K. Ando H. et al.Usefulness of analytical CEA doubling time and half-life time for overlooked synchronous metastases in colorectal carcinoma.Jpn J Clin Oncol. 2002; 32: 54-58Crossref PubMed Scopus (33) Google Scholar, 19.Fugazzola L. Pinchera A. Luchetti F. et al.Disappearance rate of serum calcitonin after total thyroidectomy for medullary thyroid carcinoma.Int J Biol Markers. 1994; 9: 21-24Crossref PubMed Scopus (55) Google Scholar], respectively, whereas cabozantinib, sorafenib, lenvatinib and sunitinib half-lives are about 8 days, 36 h, 30 h and 1 day, respectively. In the light of that information, even a short drug holiday could have influenced the results and favoured serum markers oscillations, notably through a potential direct release of inhibition of the Ct gene transcription. Similarly, some patients treated with long-term tyrosine kinase inhibitors may have faced disabling side-effects requiring temporary drug holidays or dose reductions that could have influenced the results. We can therefore regret that the patient's dose intensity per cycle—expressed as a percentage of the theoretical dose to be administered, should there not be any drug holiday or dose reduction—was not reported in the present study; it would have been particularly interesting to evaluate whether oscillations in tumour markers did correlate with the half-life of each drug, or with the patient's dose intensity per cycle. On the other hand, similar fluctuations of serum Ct level have been observed during the treatment of MTC patients with vandetanib—that has a long half-life of 19 days in the serum— making drug holiday a poorly likely explanation [5.Wells Jr, S.A. Gosnell J.E. Gagel R.F. et al.Vandetanib for the treatment of patients with locally advanced or metastatic hereditary medullary thyroid cancer.J Clin Oncol. 2010; 28: 767-772Crossref PubMed Scopus (444) Google Scholar]. Moreover, and beyond drug holidays planned in accordance with the physician, this also highlights the importance of thoroughly recording treatment adherence, as non-observance (secondary to drug side-effects) occurs more frequently than expected with targeted agents of chronic administration [20.Jabbour E.J. Kantarjian H. Eliasson L. et al.Patient adherence to tyrosine kinase inhibitor therapy in chronic myeloid leukemia.Am J Hematol. 2012; 87: 687-691Crossref PubMed Scopus (60) Google Scholar]. This study also highlights the current limitations of RECIST criteria for assessing response to small tyrosine kinase inhibitors. It has been extensively described that such criteria may not be the most accurate way to assess response to such agents. In the particular case of MTC, finding the best tool for evaluating response is even more challenging, as (i) multiple metastatic lesions are common and variability among the selection of target lesion may lead in discrepancies regarding tumour response; (ii) anti-tumour effects might not necessarily results in changes in tumour size, given the sometimes fibrous, amyloid, sclerotic, necrotic or calcified nature of the disease; (iii) many patients have slow growing diseases, for which the sensitivity of RECIST criteria is limited [14.Schlumberger M. Carlomagno F. Baudin E. et al.New therapeutic approaches to treat medullary thyroid carcinoma.Nat Clin Pract Endocrinol Metab. 2008; 4: 22-32Crossref PubMed Scopus (145) Google Scholar]. Very interestingly, the study from Kurzrock et al. reported fluctuations according to RECIST criteria in 30% of the patients, with no impact on the long-term disease outcome when treatment was continued at the same dose and schedule. This has direct implications for clinical practice, as premature removal of these patients from treatment would have been harmful. However, one should keep in mind that this study only reports findings on 26 patients who did not progress after 6 months of RET inhibitor therapy, out of an initial 39 enrolled patients. Therefore, tumours of all these 26 patients unavoidably display some degree of RET-oncogene addiction, and findings may not be applicable to all patients with MTC. It would have been interesting to report in parallel whether the absence of correlation between tumour markers and radiological assessments variations was also observed in the population of patients who progressed within the first 6 months. Should this not be the case, this would add another degree of complexity into the evaluation of tumour response, suggesting that criteria that should be used for defining early progression (and stopping early an inefficient treatment) might potentially differ from rules that should be used for long-term responders, in order to avoid stopping prematurely a beneficial drug. Having more details about the morphological examinations that were carried out, their reproducibility as well as the choice and nature of target lesions, would have brought meaningful added value to this study and provided essential insights to better interpret the results. Which proportion of patients presented liver metastases as target lesions? Was liver magnetic resonance imaging (MRI) carried out, or how were liver metastases assessed? Were any dissociated responses observed? These data are currently crucially lacking and dissociated responses or suboptimal imaging (such as the use of computed tomography [CT] scan instead of MRI to assess liver metastases) could explain most of the observed inconsistencies [21.Dromain C. de Baere T. Lumbroso J. et al.Detection of liver metastases from endocrine tumors: a prospective comparison of somatostatin receptor scintigraphy, computed tomography, and magnetic resonance imaging.J Clin Oncol. 2005; 23: 70-78Crossref PubMed Scopus (298) Google Scholar]. Alternative imaging techniques that could be used to assess treatment efficacy in MTC include MRI or ultrasonography with contrast injection [14.Schlumberger M. Carlomagno F. Baudin E. et al.New therapeutic approaches to treat medullary thyroid carcinoma.Nat Clin Pract Endocrinol Metab. 2008; 4: 22-32Crossref PubMed Scopus (145) Google Scholar]. Other methods, such as fludeoxyglucose-positon emission tomography scanning, have not demonstrated any benefit when compared with conventional CT scan—mainly because the baseline uptake of FDG is low in most of the patients with MTC [22.Giraudet A.L. Vanel D. Leboulleux S. et al.Imaging medullary thyroid carcinoma with persistent elevated calcitonin levels.J Clin Endocrinol Metab. 2007; 92: 4185-4190Crossref PubMed Scopus (190) Google Scholar, 23.Ong S.C. Schoder H. Patel S.G. et al.Diagnostic accuracy of 18F-FDG PET in restaging patients with medullary thyroid carcinoma and elevated calcitonin levels.J Nucl Med. 2007; 48: 501-507Crossref PubMed Scopus (130) Google Scholar]. In a nutshell, assessing therapeutic efficacy in MTC faces three major challenges, namely the suboptimal imaging techniques, the frequent dissociated responses and the slow evolution of the tumour (both in the case progression in the absence of treatment and for response to treatment). In this context, PFS may probably be a better efficacy outcome than overall response rate (ORR). Moreover and whatever the outcome chosen to evaluate treatment efficacy (such as ORR, PFS, time-to-progression, etc.), the determination of the target lesions alongside with the choice of the most sensitive and reproducible morphological examination technique is key in the follow-up of MTC patients. Finally, one has to keep in mind that RET inhibitors should only be administered to patients having a documented progression by RECIST within the previous 12 months, and that patients only displaying Ct or CEA elevations (without any radiological progression) are not eligible for such therapies. In these latter patients, Ct or CEA DTs are not only insufficient to document progression, they are also irrelevant and useless to assess therapeutic efficacy. We must acknowledge that meaningful evaluation of tumour response to targeted agents of chronic administration is more complex than initially anticipated, and that the ‘one-size fits all’ criteria have obvious limitations. Distinct patterns of response have been observed with novel targeted agents or immune therapy, either challenging the use of RECIST criteria or the reliability of tumour markers [24.Choi H. Charnsangavej C. Faria S.C. et al.Correlation of computed tomography and positron emission tomography in patients with metastatic gastrointestinal stromal tumor treated at a single institution with imatinib mesylate: proposal of new computed tomography response criteria.J Clin Oncol. 2007; 25: 1753-1759Crossref PubMed Scopus (1236) Google Scholar, 25.Wolchok J.D. Hoos A. O'Day S. et al.Guidelines for the evaluation of immune therapy activity in solid tumors: immune-related response criteria.Clin Cancer Res. 2009; 15: 7412-7420Crossref PubMed Scopus (2599) Google Scholar]. Notably, the classification as ‘Progressive Disease’ may not follow the same rules for immediate primary resistance and for acquired resistance of long-term responsive tumours. Distinguishing true progression from labile biomarker or imaging fluctuations in long-term responders is crucial to avoid stopping prematurely a beneficial drug, and efforts should be put on developing appropriate tools for meaningful tumour evaluation in such particular contexts. Further, the eventuality of a direct interaction between a targeted therapy and a tumour marker might need to be more broadly evaluated, especially when the use of biomarkers has direct therapeutic implications. The use of genomic signatures, evaluating simultaneously several relevant pathways and biomarkers, could also represent a meaningful alternative to single biomarkers to monitor response in metastatic MTC patients [17.Broutin S. Ameur N. Lacroix L. et al.Identification of soluble candidate biomarkers of therapeutic response to sunitinib in medullary thyroid carcinoma in preclinical models.Clin Cancer Res. 2011; 17: 2044-2054Crossref PubMed Scopus (34) Google Scholar, 18.Bass M.B. Sherman S.I. Schlumberger M.J. et al.Biomarkers as predictors of response to treatment with motesanib in patients with progressive advanced thyroid cancer.J Clin Endocrinol Metab. 2010; 95: 5018-5027Crossref PubMed Scopus (80) Google Scholar]. The possibility of building a specific MTC composite score for response, which would combine imaging data, tumour marker measurements and clinical benefit, may also be considered. With the recent approval of RET inhibitors for advanced MTC, more comprehensive retrospective studies, reporting clinical, serum biomarkers and imaging data from several techniques pre- and per-treatment, are warranted to better understand the assessment of long-term response to such therapies and to generate hypothesis that would be prospectively validated in independent cohorts. Even if assessing tumour markers of patients treated with RET inhibitors could bring interesting information, this should only be limited to exploratory studies and not drive therapeutic decisions: RECIST criteria, using optimal imaging techniques according to the patient's disease localisation, should still remain the gold standard for assessing treatment efficacy. The authors have declared no conflicts of interest.
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