Endocrine DOI 10.1007/s12020-014-0448-y
RESEARCH LETTER
Second-line sunitinib as a feasible approach for iodine-refractory differentiated thyroid cancer after the failure of first-line sorafenib Vincenzo Marotta • Carolina Di Somma • Manila Rubino • Concetta Sciammarella Roberta Modica • Luigi Camera • Michela Del Prete • Francesca Marciello • Valeria Ramundo • Luisa Circelli • Pasqualina Buonomano • Annamaria Colao • Antongiulio Faggiano
•
Received: 2 September 2014 / Accepted: 4 October 2014 Ó Springer Science+Business Media New York 2014
Introduction About 5 % of patients with differentiated thyroid cancer (DTC) show RAI-refractory disease, thus having a poor prognosis [1, 2]. Tyrosine-kinase inhibitors (TKIs) has represented a revolution in the management of iodinerefractory DTC [3]. Sorafenib has been the most studied TKI in this field, showing encouraging results in several retrospective and phase II studies [4–8]. Effectiveness of sorafenib in RAI-refractory DTC has been definitely demonstrated in the phase III trial DECISION, where a significant improvement of median progression-free survival (PFS) in the treatment group, as compared with placebo, was reported (10.8 vs 5.8 months; HR 0.58, 95 % CI 0.45–0.75, p \ 0.0001) [9]. Following this finding, sorafenib has became the first TKI approved by the US Food and Drug Administration (FDA) for the treatment of RAIrefractory DTC. Given that the study cohort of the DECISION trial included only TKIs-naive patients, sorafenib V. Marotta (&) M. Rubino C. Sciammarella R. Modica M. Del Prete F. Marciello V. Ramundo P. Buonomano A. Colao A. Faggiano Department of Clinical Medicine and Surgery, Section of Endocrinology, Federico II University of Naples, Via S. Pansini 5, 80131 Naples, Italy e-mail: [email protected]
can be fully considered the first-line systemic therapy for this clinical setting. Nevertheless, sorafenib has some crucial limits. As reported for all TKIs, it is never curative and has a temporally limited effect. Furthermore, sorafenib induced the development of adverse events leading to drug withdrawal in about 20 % of patients [9]. To date, clear indications about management of RAI-refractory DTC patients after the failure of first-line sorafenib are lacking. Sunitinib is a TKI with a pharmacodynamic profile similar to sorafenib, but broader, targeting RET, c-Kit, VEGFR1, -2, PDGFR-a and -b [10]. Despite few studies have been performed so far, sunitinib seems to be effective for the treatment of RAI-refractory DTC [11–14]. Furthermore, several trials of renal cancer have showed that sunitinib was effective in achieving clinical benefit in the majority of patients who experienced the failure of first-line sorafenib [15], even inducing a longer median PFS. Hence, sunitinib may represent a feasible option as salvage treatment after sorafenib failure also in iodine-refractory DTC. Here we report clinical histories of 3 patients (followed at Federico II University, Department of Clinical Medicine and Surgery, Section of Endocrinology, Naples) with iodinerefractory DTC who were treated with sunitinib after the failure of first-line sorafenib.
Patients and methods C. Di Somma IRCCS SDN, Naples, Italy L. Camera Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy L. Circelli A. Faggiano National Cancer Institute, ‘‘Fondazione G. Pascale’’, Naples, Italy
Second-line sunitinib was offered to patients with iodinerefractory DTC who had been subjected to first-line sorafenib at our center. Inclusion criteria were as follows: (a) histological diagnosis of DTC (b) RAI-refractoriness, as indicated by the presence of at least one tumor focus without any uptake of radio-iodine or by persistence/ progression of the disease during the year after a
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Endocrine Table 1 Baseline features and clinical outcome of patients subjected to sequential treatment sorafenib-sunitinib Parameter
Patient 1
Patient 2
Patient 3
Gender
F
F
M
Age at diagnosis (years)
56
63
55
Histology
Follicular
Papillary, classic variant
Papillary, classic variant
Stage
III
IV
III
ECOG status at the beginning of treatment
2 (2)
1 (2)
1 (1)
Site of metastases before starting TKIs’ treatment
Lymph nodes (cervical and mediastinal), lung, liver, bone
Relapse in thyroid bed, cervical lymph nodes, lung
Mediastinal lymph nodes, lung
Follow-up since TKIs treatment (months)
41
38
35
Reasons for sorafenib failure
Disease progression
Disease progression
Untreatable toxicity (handfoot syndrome)
Radiological response (according to RECIST)
SD (SD)
PR (PR)
SD (SD)
9 (16)
11 (18)
14 (17)
Sorafenib (Sunitinib)
Sorafenib (Sunitinib) PFS (months) Sorafenib (Sunitinib) F female, M male, SD stable disease, ECOG eastern cooperative oncology group, PR partial response PFS progression-free survival
RAI-treatment course [16] (c) Eastern Cooperative Oncology Group performance status 0 to 2 (d) documented disease progression and/or development of untreatable toxicity under sorafenib. Treatment was performed by offlabel protocol, with approval of the institutional review board. The starting dose was 37.5 mg q.d. Dose reductions were performed if patients developed toxicities, being 25 mg q.d. the minimum allowed dosage. Sunitinib was administered with a 7-day interval after sorafenib withdrawal. Radiological response was defined by performing computed tomography (CT) scans at baseline and at 12-week intervals, in accordance to RECIST criteria version 1.1 [17]. Data were retrospectively retrieved after obtaining patients’ consent and with approval from the institutional review board.
Results Between March 2010 and November 2013, 3 patients with metastatic iodine-refractory DTC were subjected to sequential treatment sorafenib-sunitinib (baseline features and clinical outcomes have been reported in Table 1). Patient 1 was a 56-year-old woman affected with metastatic, progressive FTC. When admitted to our center, the CT-scan demonstrated wide disease burden and neoplastic progression, as compared with the previous morphological examination (performed 5 months before): (a) multiple cervical lymph node metastases increased in number and size; (b) multiple mediastinal lymph node metastases with
123
pericardial effusion; (c) multiple pulmonary metastases increased in number and size; (d) de novo occurrence of 1 liver metastasis; (e) de novo occurrence of 1 lytic bone metastasis at the sternum. Treatment with sorafenib was started in April 2011. Best radiological response per RECIST was SD with a 18.2 % tumor shrinkage. Furthermore, the occurrence of tumor necrosis, as determined by measurement of density expressed in Hounsfield units (HU), was detected in all target lesions (shrinkage and necrosis of a mediastinal lymph node at the level of the aorto-pulmonary window is reported in Fig. 1a). Before initiation of sorafenib, Tg was 7,700 ng/ml. During such treatment, a biochemical PR was obtained, being a 77.7 % decrease of Tg levels after 4.5 months of treatment the maximum response. In January 2012, a CT scan revealed disease progression with tumor increase at lymph nodes, liver, and bone. Tg at the time of progression had almost recovered baseline levels (7,303 ng/ml). Second-line sunitinib obtained SD as best radiological response, with a 19.5 % tumor shrinkage, and tumor necrosis was detected in all target lesions (shrinkage and necrosis of a mediastinal lymph node at the level of the aorto-pulmonary window is reported in Fig. 1b). During sunitinib treatment, a biochemical PR was achieved, with a 71 % Tg reduction after 10 months of treatment. In June 2013, tumor progression was detected at lymph node, liver, and bone metastases. Combined PFS of sequential treatment sorafenib-sunitinib was 25 months (9 and 16 months, respectively). Patient 2 was a 63-year-old woman affected with metastatic, progressive classic variant PTC. When admitted to our center,
Endocrine
Fig. 1 contrast-enhanced multi-detector-CT in a 56-year-old female with DTC refractory to RAI (patient 1). A First-line sorafenib. Baseline examination (A1) shows a huge (diam. max 6.9 cm) mediastinal lymph node at the level of the aorto-pulmonary window. After 3 months of treatment (A2), considerable tumor shrinkage could be appreciated (diam. max 5.1 cm) along with associated tumor
necrosis as best tumor response. B Second-line sunitinib. Baseline examination (B1) shows a progression of the mediastinal lymph node at the level of the aorto-pulmonary window (diam. max 7.6 cm). After 3 months of treatment (B2), considerable tumor shrinkage could be appreciated (diam. max 5.9 cm) along with associated tumor necrosis as best tumor response
the CT scan demonstrated wide disease burden and neoplastic progression, as compared with the previous morphological assessment (performed 4 months before): (a) an enlarged tumor mass in the thyroid bed (b) multiple cervical lymph node metastases increased in number and size; (c) multiple pulmonary metastases increased in number and size. Treatment with sorafenib was started in July 2011. Best radiological response per RECIST was PR with a 39.6 % tumor shrinkage. Furthermore, all target lesions showed tumor necrosis. Before initiation of sorafenib, Tg was 246 ng/ml. During such treatment, a biochemical PR was obtained, being a 80.7 % decrease of Tg levels after 8 months of treatment the maximum response. In June 2012, a CT scan revealed disease progression of the locoregional relapse in the thyroid bed and of the pulmonary lesions. Tg at the time of progression had almost recovered baseline levels (218 ng/ml). After switching to sunitinib, best radiological response per RECIST was PR, with a 31.5 % tumor shrinkage. Again, tumor necrosis was detected in all target lesions. During sunitinib treatment, a biochemical PR was obtained, being a 73.3 % decrease of Tg levels after 8 months of treatment the maximum response. In December 2013, tumor progression was detected with de novo occurrence of 1 liver and 2 brain metastases. Combined PFS of sequential treatment sorafenib-sunitinib was 29 months (11 and 18 months,
respectively). Patient 3 was a 55-year-old man affected with metastatic classic variant PTC. When admitted to our center, the CT scan demonstrated a wide disease burden: (a) bilateral multiple lung metastases, the majority being more than 1 cm in size; (b) a voluminous (3 cm in size) metastatic mediastinal lymph node. Treatment with sorafenib was started in November 2011. Best radiological response per RECIST was SD with a 5.8 % tumor shrinkage. The occurrence of tumor necrosis was detected in all target lesions. During sorafenib treatment, a biochemical PR was obtained, being a 79.6 % decrease of Tg levels after 12 months of treatment the maximum response. In January 2013, the patient developed a grade 3 hand-foot syndrome which led to sorafenib withdrawal. After switching to sunitinib, a regression of the hand-foot syndrome was obtained, being grade 1 diarrhea the only reported adverse event. Best radiological response per RECIST was SD, with a 8.8 % tumor shrinkage. After initiation of sunitinib, no tumor necrosis was detected in target lesions. Sunitinib induced a biochemical SD with non-significant fluctuations of Tg levels. The CT scan performed in June 2014 demonstrated disease progression with the occurrence of a new mediastinal lymph node metastasis ([2 cm in size). Combined PFS after sequential treatment with sorafenib-sunitinib was 31 months (14 and 17 months, respectively).
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Endocrine
Discussion
References
To date, only few cases of second-line sunitinib after sorafenib failure are available in the literature, but clinical description was not so detailed as patients were included in larger trials having different objectives [7, 11, 12, 18]. In patient 1 and 2 who discontinued sorafenib because of disease progression, sunitinib achieved durable clinical benefit lasting more than that observed with sorafenib. This restoration of anti-neoplastic activity was further confirmed by the biochemical PR and the detection of tumor necrosis, which is a recognized marker of response to targeted therapies [19]. The regain of tumor sensibility obtained by second-line sunitinib may be explained by its more pronounced anti-angiogenic action, with lower IC50 for the angiogenic receptor kinases, as compared with sorafenib. Indeed, upregulation of plasma VEGF and other angiogenic factors seems to be the main mechanism leading to resistance to single-agent anti-angiogenic therapy [20]. This hypothesis is further empowered by several studies on renal cancer, where the sequence sorafenib-sunitinib obtained longer median PFS, as compared with the reverse regimen sunitinib-sorafenib [15]. In patient 3, failure of initial sorafenib was due to grade 3 hand-foot syndrome, which developed while the patient was still responsive to treatment, both at the morphological and the biochemical level. Switching from sorafenib to sunitinib allowed a regression of dermatological toxicity, without any other moderate/severe adverse events occurring during the whole treatment period. Furthermore, sunitinib perfectly replaced sorafenib in its anti-tumor effect by obtaining a durable morphological stability and by prolonging the biochemical response. In iodine-refractory DTC, hand-foot syndrome is the most common adverse event related to sorafenib, representing the major reason for drug interruptions, reductions, and withdrawal [9]. The VEGFblockage seems to play a minor role in the pathogenesis of this toxicity, being the inhibition of non-angiogenic tyrosinekinases, particularly c-kit and Raf, the key pathogenetic event [21]. Importantly, sunitinib has a stronger anti-angiogenic action, as compared with sorafenib, but elicits a weaker inhibiton of c-kit and Raf. Given this pharmacodynamic profile, sunitinib may allow to overcome hand-foot syndrome related to sorafenib. In conclusion, we showed that sunitinib may be a feasible tool for overcoming failure of first-line sorafenib in iodine-refractory DTC, both with the occurrence of disease progression and untreatable toxicity. Nevertheless, dedicated and larger studies are needed to better address this issue.
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Conflict of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Nothing to declare about financial disclosure.
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RESEARCH LETTER
Second-line sunitinib as a feasible approach for iodine-refractory differentiated thyroid cancer after the failure of first-line sorafenib Vincenzo Marotta • Carolina Di Somma • Manila Rubino • Concetta Sciammarella Roberta Modica • Luigi Camera • Michela Del Prete • Francesca Marciello • Valeria Ramundo • Luisa Circelli • Pasqualina Buonomano • Annamaria Colao • Antongiulio Faggiano
•
Received: 2 September 2014 / Accepted: 4 October 2014 Ó Springer Science+Business Media New York 2014
Introduction About 5 % of patients with differentiated thyroid cancer (DTC) show RAI-refractory disease, thus having a poor prognosis [1, 2]. Tyrosine-kinase inhibitors (TKIs) has represented a revolution in the management of iodinerefractory DTC [3]. Sorafenib has been the most studied TKI in this field, showing encouraging results in several retrospective and phase II studies [4–8]. Effectiveness of sorafenib in RAI-refractory DTC has been definitely demonstrated in the phase III trial DECISION, where a significant improvement of median progression-free survival (PFS) in the treatment group, as compared with placebo, was reported (10.8 vs 5.8 months; HR 0.58, 95 % CI 0.45–0.75, p \ 0.0001) [9]. Following this finding, sorafenib has became the first TKI approved by the US Food and Drug Administration (FDA) for the treatment of RAIrefractory DTC. Given that the study cohort of the DECISION trial included only TKIs-naive patients, sorafenib V. Marotta (&) M. Rubino C. Sciammarella R. Modica M. Del Prete F. Marciello V. Ramundo P. Buonomano A. Colao A. Faggiano Department of Clinical Medicine and Surgery, Section of Endocrinology, Federico II University of Naples, Via S. Pansini 5, 80131 Naples, Italy e-mail: [email protected]
can be fully considered the first-line systemic therapy for this clinical setting. Nevertheless, sorafenib has some crucial limits. As reported for all TKIs, it is never curative and has a temporally limited effect. Furthermore, sorafenib induced the development of adverse events leading to drug withdrawal in about 20 % of patients [9]. To date, clear indications about management of RAI-refractory DTC patients after the failure of first-line sorafenib are lacking. Sunitinib is a TKI with a pharmacodynamic profile similar to sorafenib, but broader, targeting RET, c-Kit, VEGFR1, -2, PDGFR-a and -b [10]. Despite few studies have been performed so far, sunitinib seems to be effective for the treatment of RAI-refractory DTC [11–14]. Furthermore, several trials of renal cancer have showed that sunitinib was effective in achieving clinical benefit in the majority of patients who experienced the failure of first-line sorafenib [15], even inducing a longer median PFS. Hence, sunitinib may represent a feasible option as salvage treatment after sorafenib failure also in iodine-refractory DTC. Here we report clinical histories of 3 patients (followed at Federico II University, Department of Clinical Medicine and Surgery, Section of Endocrinology, Naples) with iodinerefractory DTC who were treated with sunitinib after the failure of first-line sorafenib.
Patients and methods C. Di Somma IRCCS SDN, Naples, Italy L. Camera Department of Advanced Biomedical Sciences, Federico II University of Naples, Naples, Italy L. Circelli A. Faggiano National Cancer Institute, ‘‘Fondazione G. Pascale’’, Naples, Italy
Second-line sunitinib was offered to patients with iodinerefractory DTC who had been subjected to first-line sorafenib at our center. Inclusion criteria were as follows: (a) histological diagnosis of DTC (b) RAI-refractoriness, as indicated by the presence of at least one tumor focus without any uptake of radio-iodine or by persistence/ progression of the disease during the year after a
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Endocrine Table 1 Baseline features and clinical outcome of patients subjected to sequential treatment sorafenib-sunitinib Parameter
Patient 1
Patient 2
Patient 3
Gender
F
F
M
Age at diagnosis (years)
56
63
55
Histology
Follicular
Papillary, classic variant
Papillary, classic variant
Stage
III
IV
III
ECOG status at the beginning of treatment
2 (2)
1 (2)
1 (1)
Site of metastases before starting TKIs’ treatment
Lymph nodes (cervical and mediastinal), lung, liver, bone
Relapse in thyroid bed, cervical lymph nodes, lung
Mediastinal lymph nodes, lung
Follow-up since TKIs treatment (months)
41
38
35
Reasons for sorafenib failure
Disease progression
Disease progression
Untreatable toxicity (handfoot syndrome)
Radiological response (according to RECIST)
SD (SD)
PR (PR)
SD (SD)
9 (16)
11 (18)
14 (17)
Sorafenib (Sunitinib)
Sorafenib (Sunitinib) PFS (months) Sorafenib (Sunitinib) F female, M male, SD stable disease, ECOG eastern cooperative oncology group, PR partial response PFS progression-free survival
RAI-treatment course [16] (c) Eastern Cooperative Oncology Group performance status 0 to 2 (d) documented disease progression and/or development of untreatable toxicity under sorafenib. Treatment was performed by offlabel protocol, with approval of the institutional review board. The starting dose was 37.5 mg q.d. Dose reductions were performed if patients developed toxicities, being 25 mg q.d. the minimum allowed dosage. Sunitinib was administered with a 7-day interval after sorafenib withdrawal. Radiological response was defined by performing computed tomography (CT) scans at baseline and at 12-week intervals, in accordance to RECIST criteria version 1.1 [17]. Data were retrospectively retrieved after obtaining patients’ consent and with approval from the institutional review board.
Results Between March 2010 and November 2013, 3 patients with metastatic iodine-refractory DTC were subjected to sequential treatment sorafenib-sunitinib (baseline features and clinical outcomes have been reported in Table 1). Patient 1 was a 56-year-old woman affected with metastatic, progressive FTC. When admitted to our center, the CT-scan demonstrated wide disease burden and neoplastic progression, as compared with the previous morphological examination (performed 5 months before): (a) multiple cervical lymph node metastases increased in number and size; (b) multiple mediastinal lymph node metastases with
123
pericardial effusion; (c) multiple pulmonary metastases increased in number and size; (d) de novo occurrence of 1 liver metastasis; (e) de novo occurrence of 1 lytic bone metastasis at the sternum. Treatment with sorafenib was started in April 2011. Best radiological response per RECIST was SD with a 18.2 % tumor shrinkage. Furthermore, the occurrence of tumor necrosis, as determined by measurement of density expressed in Hounsfield units (HU), was detected in all target lesions (shrinkage and necrosis of a mediastinal lymph node at the level of the aorto-pulmonary window is reported in Fig. 1a). Before initiation of sorafenib, Tg was 7,700 ng/ml. During such treatment, a biochemical PR was obtained, being a 77.7 % decrease of Tg levels after 4.5 months of treatment the maximum response. In January 2012, a CT scan revealed disease progression with tumor increase at lymph nodes, liver, and bone. Tg at the time of progression had almost recovered baseline levels (7,303 ng/ml). Second-line sunitinib obtained SD as best radiological response, with a 19.5 % tumor shrinkage, and tumor necrosis was detected in all target lesions (shrinkage and necrosis of a mediastinal lymph node at the level of the aorto-pulmonary window is reported in Fig. 1b). During sunitinib treatment, a biochemical PR was achieved, with a 71 % Tg reduction after 10 months of treatment. In June 2013, tumor progression was detected at lymph node, liver, and bone metastases. Combined PFS of sequential treatment sorafenib-sunitinib was 25 months (9 and 16 months, respectively). Patient 2 was a 63-year-old woman affected with metastatic, progressive classic variant PTC. When admitted to our center,
Endocrine
Fig. 1 contrast-enhanced multi-detector-CT in a 56-year-old female with DTC refractory to RAI (patient 1). A First-line sorafenib. Baseline examination (A1) shows a huge (diam. max 6.9 cm) mediastinal lymph node at the level of the aorto-pulmonary window. After 3 months of treatment (A2), considerable tumor shrinkage could be appreciated (diam. max 5.1 cm) along with associated tumor
necrosis as best tumor response. B Second-line sunitinib. Baseline examination (B1) shows a progression of the mediastinal lymph node at the level of the aorto-pulmonary window (diam. max 7.6 cm). After 3 months of treatment (B2), considerable tumor shrinkage could be appreciated (diam. max 5.9 cm) along with associated tumor necrosis as best tumor response
the CT scan demonstrated wide disease burden and neoplastic progression, as compared with the previous morphological assessment (performed 4 months before): (a) an enlarged tumor mass in the thyroid bed (b) multiple cervical lymph node metastases increased in number and size; (c) multiple pulmonary metastases increased in number and size. Treatment with sorafenib was started in July 2011. Best radiological response per RECIST was PR with a 39.6 % tumor shrinkage. Furthermore, all target lesions showed tumor necrosis. Before initiation of sorafenib, Tg was 246 ng/ml. During such treatment, a biochemical PR was obtained, being a 80.7 % decrease of Tg levels after 8 months of treatment the maximum response. In June 2012, a CT scan revealed disease progression of the locoregional relapse in the thyroid bed and of the pulmonary lesions. Tg at the time of progression had almost recovered baseline levels (218 ng/ml). After switching to sunitinib, best radiological response per RECIST was PR, with a 31.5 % tumor shrinkage. Again, tumor necrosis was detected in all target lesions. During sunitinib treatment, a biochemical PR was obtained, being a 73.3 % decrease of Tg levels after 8 months of treatment the maximum response. In December 2013, tumor progression was detected with de novo occurrence of 1 liver and 2 brain metastases. Combined PFS of sequential treatment sorafenib-sunitinib was 29 months (11 and 18 months,
respectively). Patient 3 was a 55-year-old man affected with metastatic classic variant PTC. When admitted to our center, the CT scan demonstrated a wide disease burden: (a) bilateral multiple lung metastases, the majority being more than 1 cm in size; (b) a voluminous (3 cm in size) metastatic mediastinal lymph node. Treatment with sorafenib was started in November 2011. Best radiological response per RECIST was SD with a 5.8 % tumor shrinkage. The occurrence of tumor necrosis was detected in all target lesions. During sorafenib treatment, a biochemical PR was obtained, being a 79.6 % decrease of Tg levels after 12 months of treatment the maximum response. In January 2013, the patient developed a grade 3 hand-foot syndrome which led to sorafenib withdrawal. After switching to sunitinib, a regression of the hand-foot syndrome was obtained, being grade 1 diarrhea the only reported adverse event. Best radiological response per RECIST was SD, with a 8.8 % tumor shrinkage. After initiation of sunitinib, no tumor necrosis was detected in target lesions. Sunitinib induced a biochemical SD with non-significant fluctuations of Tg levels. The CT scan performed in June 2014 demonstrated disease progression with the occurrence of a new mediastinal lymph node metastasis ([2 cm in size). Combined PFS after sequential treatment with sorafenib-sunitinib was 31 months (14 and 17 months, respectively).
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Discussion
References
To date, only few cases of second-line sunitinib after sorafenib failure are available in the literature, but clinical description was not so detailed as patients were included in larger trials having different objectives [7, 11, 12, 18]. In patient 1 and 2 who discontinued sorafenib because of disease progression, sunitinib achieved durable clinical benefit lasting more than that observed with sorafenib. This restoration of anti-neoplastic activity was further confirmed by the biochemical PR and the detection of tumor necrosis, which is a recognized marker of response to targeted therapies [19]. The regain of tumor sensibility obtained by second-line sunitinib may be explained by its more pronounced anti-angiogenic action, with lower IC50 for the angiogenic receptor kinases, as compared with sorafenib. Indeed, upregulation of plasma VEGF and other angiogenic factors seems to be the main mechanism leading to resistance to single-agent anti-angiogenic therapy [20]. This hypothesis is further empowered by several studies on renal cancer, where the sequence sorafenib-sunitinib obtained longer median PFS, as compared with the reverse regimen sunitinib-sorafenib [15]. In patient 3, failure of initial sorafenib was due to grade 3 hand-foot syndrome, which developed while the patient was still responsive to treatment, both at the morphological and the biochemical level. Switching from sorafenib to sunitinib allowed a regression of dermatological toxicity, without any other moderate/severe adverse events occurring during the whole treatment period. Furthermore, sunitinib perfectly replaced sorafenib in its anti-tumor effect by obtaining a durable morphological stability and by prolonging the biochemical response. In iodine-refractory DTC, hand-foot syndrome is the most common adverse event related to sorafenib, representing the major reason for drug interruptions, reductions, and withdrawal [9]. The VEGFblockage seems to play a minor role in the pathogenesis of this toxicity, being the inhibition of non-angiogenic tyrosinekinases, particularly c-kit and Raf, the key pathogenetic event [21]. Importantly, sunitinib has a stronger anti-angiogenic action, as compared with sorafenib, but elicits a weaker inhibiton of c-kit and Raf. Given this pharmacodynamic profile, sunitinib may allow to overcome hand-foot syndrome related to sorafenib. In conclusion, we showed that sunitinib may be a feasible tool for overcoming failure of first-line sorafenib in iodine-refractory DTC, both with the occurrence of disease progression and untreatable toxicity. Nevertheless, dedicated and larger studies are needed to better address this issue.
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Conflict of interest The authors declare that there is no conflict of interest that could be perceived as prejudicing the impartiality of the research reported. Nothing to declare about financial disclosure.
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