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Sunitinib in metastatic thymic carcinomas: Laboratory findings and initial clinical experience

Sunitinib in metastatic thymic carcinomas: Laboratory findings and initial clinical experience Translational Therapeutics British Journal of Cancer (2010) 103, 196 – 200 & 2010 Cancer Research UK All rights reserved 0007 – 0920/10 www.bjcancer.com Sunitinib in metastatic thymic carcinomas: Laboratory findings and initial clinical experience ,1 2 2 3 4 5 5 P Stro¨bel , R Bargou , A Wolff , D Spitzer , C Manegold , A Dimitrakopoulou-Strauss , L Strauss , 1 6 7 1 C Sauer , F Mayer , P Hohenberger and A Marx Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany; Division of Hematology and Medical Oncology, Department of Internal Medicine II, University of Wu¨rzburg, Klinikstraße 6, 97070 Wu¨rzburg, Germany; 3 4 Institute of General Medicine, Bodmanstr. 22, 87439 Kempten, Germany; Division of Thoracic Oncology, Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany; Clinical Cooperation Unit Nuclear Medicine, 6 7 German Cancer Research Center, Heidelberg, Germany; Department of Medical Oncology, University of Tu¨bingen, Tu¨bingen, Germany; Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany BACKGROUND: Thymic carcinoma (TC) is a rare aggressive tumour. Median survival with current treatments is only 2 years. Sunitinib is a multi-targeted tyrosine kinase inhibitor that has shown benefit in various other cancers. METHODS: Laboratory analyses of snap-frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases (RTKs) in TC samples. On the basis of molecular analyses showing activation of multiple RTKs in their tumour, four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols. RESULTS: RTK analysis in three of the patients showed activation of multiple RTKs, including platelet-derived growth factor-b and vascular endothelial growth factor 3. Mutations of EGFR, c-KIT, KRAS, and BRAF genes were not found. Administration of sunitinib yielded a partial remission (lasting 2 to 18þ months) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in 18F-FDG-PET in another one. The overall survival with sunitinib treatment ranges from 4 to 40þ months. Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re-administration of sunitinib. CONCLUSIONS: Sunitinib is an active treatment for metastatic TC. A panel of molecular analyses may be warranted for optimal patient selection. British Journal of Cancer (2010) 103, 196–200. doi:10.1038/sj.bjc.6605740 www.bjcancer.com Published online 22 June 2010 & 2010 Cancer Research UK Keywords: thymic carcinoma; thymoma; therapy; receptor tyrosine kinase; sunitinib; metastasis Thymic carcinoma (TC) is a rare aggressive tumour of the thymus 2005). Adjuvant radiation with 40–70 Gy often follows surgical (Eng et al, 2004). It affects men nearly twice as often as women, resection, but a survival advantage for radiotherapy has not been across a wide age range (Travis et al, 2004). Patients often initially clearly demonstrated (Korst et al,2009).Chemotherapywith present with cough and chest pain. Further work-up usually regimens containing cisplatin have often yielded partial remissions reveals a mediastinal mass. Histologically, TCs are rather (Evans and Lynch, 2005), but some patients do not respond at all and heterogeneous and resemble tumours found in other organs most patients do not achieve long-lasting remission. Thus, many (Travis et al, 2004). The prognosis is generally poor, and the patients eventually cannot be helped by any currently available majority of patients develop recurrences. Lymph nodes, lungs, treatments, and they succumb to the tumour’s rapid progression. liver, and bones are common sites for metastases. Patients with TC Targeted molecular therapy is a new paradigm in cancer have a median survival of 2 years (Eng et al, 2004). treatment, in which drugs selectively interfere with molecules The optimal management of TCs remains an unresolved considered important in oncogenesis. Whereas conventional question, because of their rarity and aggressiveness (Kurup and chemotherapy aims to kill all proliferating cells including tumours, Loehrer, 2004). Complete surgical resection substantially improves targeted molecular therapy aims to disrupt cancer-specific survival rates, but this is not always possible, because of invasion signalling pathways involved in tumour growth and proliferation of surrounding structures or metastasis (Wright and Kessler, (Faivre et al, 2006). Compared with the toxicity of chemotherapy, targeted molecular therapies seem to be relatively tolerable (Rutkowski and Ruka, 2009). There are multiple types of targeted *Correspondence: Professor P Stro¨bel; E-mail: philipp.stroebel@umm.de molecular therapies, but among them, multi-target tyrosine Received 22 March 2010; revised 19 May 2010; accepted 20 May 2010; kinase inhibitors have received particular attention. Tyrosine published online 22 June 2010 kinases regulate important cell functions, including survival, Sunitinib in metastatic TCs P Stro¨bel et al differentiation, and proliferation (Faivre et al, 2006). When sections were stained by a standard avidin–biotin peroxidase mutated or overexpressed, they have key roles in many cancers: technique. Primary antibodies included CD5, c-KIT, and ki67. increasing tumour cell growth and proliferation, inducing The Human Phosopho-Receptor Tyrosine Kinase Array Kit resistance to apoptosis, and promoting angiogenesis and (R&D Systems, Wiesbaden, Germany) was used according to the metastasis. manufacturer’s instructions to simultaneously detect the relative Sunitinib (Pfizer, New York, NY, USA) is a potent multi-target tyrosine phosphorylation levels of 42 different receptor tyrosine tyrosine kinase inhibitor, designed to selectively block the kinases (RTKs), as described previously in more detail (Ball et al, intracellular receptor-binding sites of several tyrosine kinases: 2007). vascular endothelial growth factors 1–3 (VEGF1–3), FMS-like Both DNA and RNA were extracted and amplified by PCR using tyrosine kinase 3 (FLT3), stem cell growth factor (c-KIT), platelet- commercial kits (QiAamp DNA FFPE and RNeasy FFPE; Qiagen, derived growth factors-a and -b (PDGFa–b), colony-stimulating Hilden, Germany) according to the manufacturer’s instructions. factor 1 (CSF1), and the ‘RET’ receptor for glial-derived c-KIT (exons 9, 11, 13, 17), EGFR (exons 18–21), KRAS (exon 2), neurotrophic factors (Faivre et al, 2007). Inhibition of these and BRAF (V600E) were sequenced according to standard tyrosine kinase receptors is believed to ultimately result in tumour procedures (details available upon request). regression primarily through anti-angiogenic effects and also through direct tumour cell apoptosis. In clinical trials, sunitinib has been reported to be beneficial against metastatic clear-cell RESULTS renal carcinoma (Motzer et al, 2007), gastrointestinal stromal Laboratory findings tumour (Demetri et al, 2006), and advanced pancreatic neuroen- docrine tumours (Kulke et al, 2008). The most commonly reported In addition to histomorphological criteria, CD5 and c-KIT were adverse events (such as fatigue, diarrhoea, nausea, anorexia, skin strongly expressed in all cases, providing very strong evidence that discolouration, and hand–foot syndrome) have been reported as these were indeed primary TCs (Travis et al, 2004). relatively tolerable (Faivre et al, 2007; Porta et al, 2007). Case A mainly showed activation of the EGFR, with a very weak For TC, there have only been a few peer-reviewed journal papers signal for the insulin receptor (IR), KIT, and Ephrin B2 (Figure 1). on any of the new targeted molecular therapies. We previously Case B showed strong activation of several RTKs, including IR and reported a single case in which imatinib led to temporary insulin-like growth factor receptor 1, fibroblast growth factor regression of liver metastases and stabilisation of the primary TC receptor 2, KIT, Erb4, and RET (Figure 1) Case C showed (Strobel et al, 2004). Another case report briefly mentioned the activation of ErB4, Tyro3/Dtk, and RON (Figure 1). unsuccessful last-resort use of imatinib in a paediatric patient Using PCR and direct sequencing of the resulting amplification (Kertesz et al, 2007). One paper reported a partial response of a products, no mutations were found for c-KIT, KRAS, BRAF,or malignant thymoma to the abl/src kinase inhibitor dasatinib EGFR (not shown). (Chuah et al, 2006). In addition, there have been two case reports on the successful usage of sorafenib in heavily pre-treated, chemotherapy-resistant Patients metastatic patients (Bisagni et al, 2009; Li et al, 2009). The patients’ basic sociodemographic and clinical characteristics are To our awareness, there have been no reports of using sunitinib presented in Table 1. Three patients in Table 1 were metastatic at the against any tumours of the thymus. The aim of this paper is to initial diagnosis. The patients’ earlier history of cancer and treatment report the clinical outcomes and laboratory findings from our is summarised in Table 2. In brief, all patients had already reached a initial usage of sunitinib in metastatic TCs. point of having metastases not responding to established treatment options, before they were started on sunitinib. METHODS Clinical outcomes Patients For patient A, sunitinib was administered for 2 years, 9 months at Tumours were classified according to criteria of the WHO a dose of 50 mg per day, taken continuously (never cycled with classification (Travis et al, 2004). Patients with metastatic TCs refractory to conventional treatment were considered eligible for treatment with sunitinib and inclusion in this report. All patients provided informed consent for treatment and reporting of their data. Tumor A Treatment Patients were treated by interdisciplinary teams experienced in the 7 9 10 application of tyrosine kinase inhibitors. Dose selection of sunitinib 5 11 Tumor B was dependent on tumour load, tumour progression slope, and expected toxicity profile related to the patients’ co-medication and medical history, not always following the 50 mg per day, 4/2 regimen (Faivre et al, 2007) (4 weeks on, 2 weeks off treatment, see details Tumor C below). Toxicity and response were closely monitored, to adjust the dosage or cycle length if required. Other concurrent therapies were used whenever indicated. Tumour response was assessed according Figure 1 Phospho-protein arrays of tumour samples from patients A–C to the revised RECIST criteria (Eisenhauer et al, 2009). Further with 42 spotted receptor tyrosine kinases (signal indicates activated medical history and adverse events were charted. protein). Tumour sample of patient A shows strong activation of EGFR (1) and weaker signals for EphB2 (2), KIT (3), and the insulin receptor (4). Tumour sample of patient B shows moderate signals for RON (5), Erb4 (6), Laboratory analyses FGFR2 (7), KIT (8), and strong signals for insulin receptor (9), IGF1R (10), Native tumour samples were available from patients A–C and kept and RET (11). Tumour sample of patient C shows moderate signals for snap frozen and stored at 801C for molecular analyses. Paraffin RON (12), Erb4 (13), and Tyro3/Dtk (14). & 2010 Cancer Research UK British Journal of Cancer (2010) 103(2), 196 – 200 Translational Therapeutics Translational Therapeutics Sunitinib in metastatic TCs P Stro¨bel et al Table 1 Patient sociodemographic and clinical characteristics Age at diagnosis Stage Stage Case Sex (years) (initial diagnosis) Histopathology (start of sunitinib) Tumour grade A M 35 IVb Squamous cell IVb 2 B M 69 IVa Squamous cell IVb 2 C M 77 II Squamous cell IVb 2 D F 28 IVb Undifferentiated IVb 3 Table 2 Previous treatment and result of sunitinib therapy Extent of tumour at start of Survival Patient Previous treatment sunitinib Treatment result (sunitinib) A Systemic chemotherapy, PR for 3 months, Primary tumour liver metastases (60% HR) SD of primary tumour and hepatic OS 40+ months imatinib 400/800 mg PD axillary, supraclavicular, and coeliac lymph metastases, excellent metabolic node metastases response (FDG-PET), PR of coeliac lymph node metastases B Primary tumour resection, radiation to Liver metastases PR PFS 18+ months mediastinum DFS 4 years, Systemic chemotherapy for liver metastases, PD C Primary tumour resection, DFS 14 months Bilateral lung metastases PR PFS 14+ months D Systemic chemotherapy, radiation of retinal Primary tumour, multiple bone and lung PR for 2 months OS 4 months metastases, PR for 6 months metastases (all PD) Abbreviations: PR¼ partial remission; PD¼ progressive disease; HR¼ hepatic replacement; SD¼ stable disease; OS¼ overall survival; DFS¼ disease-free survival; PFS¼ progression-free survival. Acc to RECIST (Response Evaluation Criteria In Solid Tumors) criteria. ‘off ’ periods). After just 2 weeks, the patient’s abdominal pain disappeared. The 18F-FDG-PET scans showed reduced glucose metabolism of all liver metastases after 6 weeks in comparison with pre-treatment values. After 6 months, the vessel density calculated by FDG-PET of the liver metastases was reduced to o20% of their pre-sunitinib levels (Figure 2A–B). As the primary tumour seemed to respond less to the treatment than the liver metastases, concurrent radionuclide treatment with DOTATOC was adminis- tered during the 4th–11th months of sunitinib. Thereafter, the vessel density of the metastases was still very low, and the metastases were classified as stable disease according to RECIST (Eisenhauer et al, 2009). After 22 months of sunitinib treatment, the liver metastases started to progress again with new lesions; hence, selective infusional radiotherapy was started, resulting in a PR. Another 8 months later (4 2009), the primary tumour was completely resected, followed by 54 Gy irradiation of the mediastinum. As all known tumour lesions seemed to be under Figure 2 PET scans of the primary tumour and liver metastases from control, sunitinib was discontinued in 7 2009. Three months later, patient A. (A) Baseline just before initiating sunitinib. (B) After 6 months PET-CT showed massive progression of the hepatic metastases (in 4 2007) sunitinib. (C) Three months after withdrawal of sunitinib (Figure 2C) and lymph node metastases at the coeliac axis. (10 2009) showing a highly enriched index metastasis. (D) The same lesion Sunitinib was re-administered at 50 mg per day in 10 2009. Two was undetectable 2 months after re-administration of sunitinib (12 2009). months later, a control PET-CT showed marked regression of all lesions, corresponding to PR (Figure 2D). Patient B presented with asymptomatic liver metastases. Sunitinib was started at the registered 50 mg per day, 4/2 regimen. dose was escalated to 37.5 mg per day after 4 weeks and The metastases were still progressing after one cycle but developed antihypertensive medication was intensified. The CT controls at a PR after another three cycles (Figure 3A and B). After four cycles 7 months showed partial remission of his lung metastases (Figure of 4/2, the cycling schedule was slowed to 4/4 because of side 4A–C). As the patient later on developed leukopenia with a WBC effects during the ‘on’ phase, which resolved during the ‘off phase’. of o1800 cells per ml and anaemia, sunitinib was again decreased After 10 months of therapy, the cycling was slowed to 4/6 to 25 mg per day after 9 months. After 14 months under sunitinib for another two cycles, and further 4/8 dosage thereafter. At all (2 2010), the patient is still in PR. follow-up visits since the fifth cycle of sunitinib until the present In patient D, who suffered from a particularly aggressive, widely time (i.e., for 18 months), the liver metastases were still in good disseminated tumour at initial presentation, symptoms (such as partial remission, and there has been no evidence of relapse of the shortness of breath) improved after 2 weeks of sunitinib with primary tumour (Figure 3C). 50 mg per day, 4/2 dosing. Restaging after 6 weeks showed a PR of Patient C presented with several metachronous asymptomatic the primary tumour and lung metastases. However, this was soon lung metastases. Owing to his significant co-medication for severe followed by rapid tumour progression, to which the patient NYHA III problems and hypertension, sunitinib was started at a succumbed 4 months after the start of sunitinib and 16 months dose of 25 mg per day. As the medication was well tolerated, the after initial diagnosis. British Journal of Cancer (2010) 103(2), 196 – 200 & 2010 Cancer Research UK Sunitinib in metastatic TCs P Stro¨bel et al Figure 3 CT scans of a representative liver metastasis from patient B. (A) Liver metastasis at baseline just before initiating sunitinib. (B) Liver metastases after 6 months sunitinib. (C) Liver metastases after 18 months sunitinib. Figure 4 CT scans of an index lung metastasis from patient C. (A) Lung metastasis (square) at baseline just before initiating sunitinib. (B) Lung metastasis after 3 months sunitinib. (C) Lung metastasis after 7 months sunitinib. Side effects initiation of sunitinib, consistent with an anti-angiogenic mechan- ism of action. Many other RTKs also promote angiogenesis Commonly reported side effects of sunitinib were also observed in indirectly (Al-Nedawi et al, 2009) and thus could account for this our patients. Nausea was present in three patients. Hypertension finding. Taken together, the clinical observations, laboratory and fatigue were present in patients A and C. Weakness and analyses, and previous molecular knowledge on sunitinib are oedema were present in patients C and D. Patient D had some consistent in supporting the view that sunitinib’s effectiveness in minor, non-relevant electrophysiological cardiac alterations, but these cases was due primarily to anti-angiogenesis. no hypertension or haematological complications. Grade 2/3 Nonetheless, sunitinib may have had other mechanisms of hand–foot syndrome in patient B lead to prolonged ‘off’ phases action, in addition to anti-angiogenesis or instead of it. Sunitinib in the treatment cycles to allow for recovery. blocks many more RTKs than the literature or the manufacturer currently discusses. Furthermore, our array only tested for 42 of B300 RTKs; hence, many other RTKs may have been activated in DISCUSSION our patients. Further clinical studies will be required to analyse the underlying mechanisms more thoroughly. Thymic carcinoma is a rare tumour that is difficult to treat in Although our findings are limited by the small sample advanced stages. Cisplatin-based multi-agent chemotherapy can be size, sunitinib seems to be a particularly good choice of second- beneficial, but often the responses do not last long. There is line therapy for patients with metastatic TC. The tumours currently no other established second-line treatment for TC. reported in this study were histologically and immunohisto- Targeted molecular therapy could open new therapeutic options in these patients. chemically comparable and representative for a majority of Our initial experience shows that sunitinib seems promising for TCs in the broader population. Moreover, in line with previous patients with metastatic TC. The rationale for choosing this drug reports (Tsuchida et al, 2008; Yoh et al, 2008), there were no came from our observation that three of the available tumour mutations of c-KIT, KRAS, BRAF,or EGFR; therefore, samples showed simultaneous activation of multiple RTKs. Hence, apparently the effectiveness of sunitinib does not depend on such it seemed reasonable to interfere with several of these processes abnormalities. Our initial observations suggest that sunitinib (and possibly also concurrently to prevent tumour escape mechanisms through other multi-kinase inhibitors such as sorafenib (Bisagni et al, alternative signalling pathways (Faivre et al, 2006; Potapova 2009)) may be more effective against TC than the disappointing et al, 2006). results reported in the grey literature for single-target molecular The new targeted molecular therapies are clinically effective therapies, such as gefinitinib (Kurup et al, 2005), erlotinib (Bedano because they have been designed to disrupt the cellular signalling et al, 2008), and imatinib (Salter et al, 2008). These earlier pathways involved in various aspects of oncogenesis, such as results seem plausible in the light of the broad and rather growth signal transduction, cell invasion, evasion of apoptosis, and heterogeneous spectrum of activated RTKs in the few samples metastatic dissemination. Sunitinib was originally designed and described in this study. developed for its high potency against VEGFR2 and PDGFR-b Our ‘index’ patient A provides very strong circumstantial (Burstein et al, 2008), and it is known to block the intracellular evidence that sunitinib was able to control his disease over more ATP-binding sites of several other RTKs: VEGF1, VEGF3, FLT3, than 3 years and even at relapse of sunitinib pre-treated c-KIT, PDGFa, CSF1, and RET (Faivre et al, 2007). Thus, on the metastases. Similar favourable findings in two other patients basis of past scientific knowledge (Chow and Eckhardt, 2007) as (Bþ C) indicate that sunitinib may be able to block tumour escape well as our clinical observations and laboratory results, it seems mechanisms and may be a promising option for long-term plausible that the predominant mechanism of action of sunitinib in treatment. Patient D (with an unusually aggressive tumour) our patients was anti-angiogenesis, even though its main known obtained a temporary partial remission, which we estimate targets were not prominently activated in the tumour samples prolonged her life by about 1–3 months. It is noteworthy that studied herein. However in case A, the patient’s PET scans showed although tumours from patients A–C were ‘classical’ squamous a rapid and substantial reduction in tumour vessel density after the & 2010 Cancer Research UK British Journal of Cancer (2010) 103(2), 196 – 200 Translational Therapeutics Translational Therapeutics Sunitinib in metastatic TCs P Stro¨bel et al cell TCs, the tumour from patient D was undifferentiated and had seems to be one of the types of cancer that is responsive to unusually high mitotic counts, prompting us to rule out EBV sunitinib. It will be important to investigate whether patients with association or a so-called ‘carcinoma with t(15;19) translocation’ malignant thymomas may also benefit from this drug. (French et al, 2003) at initial presentation by respective molecular techniques. In conclusion, sunitinib could be a promising new treatment ACKNOWLEDGEMENTS option for TCs. Compared with many other tumours such as advanced prostate cancer (Dror Michaelson et al, 2009), metastatic We thank Michael Hanna, PhD, (Mercury Medical Research and colorectal cancer (Saltz et al, 2007), metastatic breast cancer Writing) for providing publication consulting and medical writing (Burstein et al, 2008), or advanced non-small-cell lung cancer services. This work was supported by grant no. 10-1740 from the (Socinski et al, 2008), in which sunitinib was either inefficient Deutsche Krebshilfe and by Project grant 781025 of the or had only weak benefits were overridden by serious risks, TC Tumorzentrum Heidelberg/Mannheim. 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Lung Cancer 62: 316–320 British Journal of Cancer (2010) 103(2), 196 – 200 & 2010 Cancer Research UK http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png British Journal of Cancer Springer Journals

Sunitinib in metastatic thymic carcinomas: Laboratory findings and initial clinical experience

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Springer Journals
Copyright
Copyright © 2010 by The Author(s)
Subject
Biomedicine; Biomedicine, general; Cancer Research; Epidemiology; Molecular Medicine; Oncology; Drug Resistance
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0007-0920
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1532-1827
DOI
10.1038/sj.bjc.6605740
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Abstract

Translational Therapeutics British Journal of Cancer (2010) 103, 196 – 200 & 2010 Cancer Research UK All rights reserved 0007 – 0920/10 www.bjcancer.com Sunitinib in metastatic thymic carcinomas: Laboratory findings and initial clinical experience ,1 2 2 3 4 5 5 P Stro¨bel , R Bargou , A Wolff , D Spitzer , C Manegold , A Dimitrakopoulou-Strauss , L Strauss , 1 6 7 1 C Sauer , F Mayer , P Hohenberger and A Marx Institute of Pathology, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany; Division of Hematology and Medical Oncology, Department of Internal Medicine II, University of Wu¨rzburg, Klinikstraße 6, 97070 Wu¨rzburg, Germany; 3 4 Institute of General Medicine, Bodmanstr. 22, 87439 Kempten, Germany; Division of Thoracic Oncology, Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany; Clinical Cooperation Unit Nuclear Medicine, 6 7 German Cancer Research Center, Heidelberg, Germany; Department of Medical Oncology, University of Tu¨bingen, Tu¨bingen, Germany; Division of Surgical Oncology and Thoracic Surgery, Department of Surgery, University Medical Center Mannheim, University of Heidelberg, Theodor-Kutzer-Ufer 1-3, 68135 Mannheim, Germany BACKGROUND: Thymic carcinoma (TC) is a rare aggressive tumour. Median survival with current treatments is only 2 years. Sunitinib is a multi-targeted tyrosine kinase inhibitor that has shown benefit in various other cancers. METHODS: Laboratory analyses of snap-frozen tumour tissues were performed to detect activation and genetic mutations of receptor tyrosine kinases (RTKs) in TC samples. On the basis of molecular analyses showing activation of multiple RTKs in their tumour, four patients with metastatic TCs refractory to conventional therapies were treated with sunitinib according to standard protocols. RESULTS: RTK analysis in three of the patients showed activation of multiple RTKs, including platelet-derived growth factor-b and vascular endothelial growth factor 3. Mutations of EGFR, c-KIT, KRAS, and BRAF genes were not found. Administration of sunitinib yielded a partial remission (lasting 2 to 18þ months) according to the RECIST criteria in three patients and stable disease with excellent metabolic response in 18F-FDG-PET in another one. The overall survival with sunitinib treatment ranges from 4 to 40þ months. Withdrawal of the drug in one patient prompted rapid tumour progression that could be controlled by re-administration of sunitinib. CONCLUSIONS: Sunitinib is an active treatment for metastatic TC. A panel of molecular analyses may be warranted for optimal patient selection. British Journal of Cancer (2010) 103, 196–200. doi:10.1038/sj.bjc.6605740 www.bjcancer.com Published online 22 June 2010 & 2010 Cancer Research UK Keywords: thymic carcinoma; thymoma; therapy; receptor tyrosine kinase; sunitinib; metastasis Thymic carcinoma (TC) is a rare aggressive tumour of the thymus 2005). Adjuvant radiation with 40–70 Gy often follows surgical (Eng et al, 2004). It affects men nearly twice as often as women, resection, but a survival advantage for radiotherapy has not been across a wide age range (Travis et al, 2004). Patients often initially clearly demonstrated (Korst et al,2009).Chemotherapywith present with cough and chest pain. Further work-up usually regimens containing cisplatin have often yielded partial remissions reveals a mediastinal mass. Histologically, TCs are rather (Evans and Lynch, 2005), but some patients do not respond at all and heterogeneous and resemble tumours found in other organs most patients do not achieve long-lasting remission. Thus, many (Travis et al, 2004). The prognosis is generally poor, and the patients eventually cannot be helped by any currently available majority of patients develop recurrences. Lymph nodes, lungs, treatments, and they succumb to the tumour’s rapid progression. liver, and bones are common sites for metastases. Patients with TC Targeted molecular therapy is a new paradigm in cancer have a median survival of 2 years (Eng et al, 2004). treatment, in which drugs selectively interfere with molecules The optimal management of TCs remains an unresolved considered important in oncogenesis. Whereas conventional question, because of their rarity and aggressiveness (Kurup and chemotherapy aims to kill all proliferating cells including tumours, Loehrer, 2004). Complete surgical resection substantially improves targeted molecular therapy aims to disrupt cancer-specific survival rates, but this is not always possible, because of invasion signalling pathways involved in tumour growth and proliferation of surrounding structures or metastasis (Wright and Kessler, (Faivre et al, 2006). Compared with the toxicity of chemotherapy, targeted molecular therapies seem to be relatively tolerable (Rutkowski and Ruka, 2009). There are multiple types of targeted *Correspondence: Professor P Stro¨bel; E-mail: philipp.stroebel@umm.de molecular therapies, but among them, multi-target tyrosine Received 22 March 2010; revised 19 May 2010; accepted 20 May 2010; kinase inhibitors have received particular attention. Tyrosine published online 22 June 2010 kinases regulate important cell functions, including survival, Sunitinib in metastatic TCs P Stro¨bel et al differentiation, and proliferation (Faivre et al, 2006). When sections were stained by a standard avidin–biotin peroxidase mutated or overexpressed, they have key roles in many cancers: technique. Primary antibodies included CD5, c-KIT, and ki67. increasing tumour cell growth and proliferation, inducing The Human Phosopho-Receptor Tyrosine Kinase Array Kit resistance to apoptosis, and promoting angiogenesis and (R&D Systems, Wiesbaden, Germany) was used according to the metastasis. manufacturer’s instructions to simultaneously detect the relative Sunitinib (Pfizer, New York, NY, USA) is a potent multi-target tyrosine phosphorylation levels of 42 different receptor tyrosine tyrosine kinase inhibitor, designed to selectively block the kinases (RTKs), as described previously in more detail (Ball et al, intracellular receptor-binding sites of several tyrosine kinases: 2007). vascular endothelial growth factors 1–3 (VEGF1–3), FMS-like Both DNA and RNA were extracted and amplified by PCR using tyrosine kinase 3 (FLT3), stem cell growth factor (c-KIT), platelet- commercial kits (QiAamp DNA FFPE and RNeasy FFPE; Qiagen, derived growth factors-a and -b (PDGFa–b), colony-stimulating Hilden, Germany) according to the manufacturer’s instructions. factor 1 (CSF1), and the ‘RET’ receptor for glial-derived c-KIT (exons 9, 11, 13, 17), EGFR (exons 18–21), KRAS (exon 2), neurotrophic factors (Faivre et al, 2007). Inhibition of these and BRAF (V600E) were sequenced according to standard tyrosine kinase receptors is believed to ultimately result in tumour procedures (details available upon request). regression primarily through anti-angiogenic effects and also through direct tumour cell apoptosis. In clinical trials, sunitinib has been reported to be beneficial against metastatic clear-cell RESULTS renal carcinoma (Motzer et al, 2007), gastrointestinal stromal Laboratory findings tumour (Demetri et al, 2006), and advanced pancreatic neuroen- docrine tumours (Kulke et al, 2008). The most commonly reported In addition to histomorphological criteria, CD5 and c-KIT were adverse events (such as fatigue, diarrhoea, nausea, anorexia, skin strongly expressed in all cases, providing very strong evidence that discolouration, and hand–foot syndrome) have been reported as these were indeed primary TCs (Travis et al, 2004). relatively tolerable (Faivre et al, 2007; Porta et al, 2007). Case A mainly showed activation of the EGFR, with a very weak For TC, there have only been a few peer-reviewed journal papers signal for the insulin receptor (IR), KIT, and Ephrin B2 (Figure 1). on any of the new targeted molecular therapies. We previously Case B showed strong activation of several RTKs, including IR and reported a single case in which imatinib led to temporary insulin-like growth factor receptor 1, fibroblast growth factor regression of liver metastases and stabilisation of the primary TC receptor 2, KIT, Erb4, and RET (Figure 1) Case C showed (Strobel et al, 2004). Another case report briefly mentioned the activation of ErB4, Tyro3/Dtk, and RON (Figure 1). unsuccessful last-resort use of imatinib in a paediatric patient Using PCR and direct sequencing of the resulting amplification (Kertesz et al, 2007). One paper reported a partial response of a products, no mutations were found for c-KIT, KRAS, BRAF,or malignant thymoma to the abl/src kinase inhibitor dasatinib EGFR (not shown). (Chuah et al, 2006). In addition, there have been two case reports on the successful usage of sorafenib in heavily pre-treated, chemotherapy-resistant Patients metastatic patients (Bisagni et al, 2009; Li et al, 2009). The patients’ basic sociodemographic and clinical characteristics are To our awareness, there have been no reports of using sunitinib presented in Table 1. Three patients in Table 1 were metastatic at the against any tumours of the thymus. The aim of this paper is to initial diagnosis. The patients’ earlier history of cancer and treatment report the clinical outcomes and laboratory findings from our is summarised in Table 2. In brief, all patients had already reached a initial usage of sunitinib in metastatic TCs. point of having metastases not responding to established treatment options, before they were started on sunitinib. METHODS Clinical outcomes Patients For patient A, sunitinib was administered for 2 years, 9 months at Tumours were classified according to criteria of the WHO a dose of 50 mg per day, taken continuously (never cycled with classification (Travis et al, 2004). Patients with metastatic TCs refractory to conventional treatment were considered eligible for treatment with sunitinib and inclusion in this report. All patients provided informed consent for treatment and reporting of their data. Tumor A Treatment Patients were treated by interdisciplinary teams experienced in the 7 9 10 application of tyrosine kinase inhibitors. Dose selection of sunitinib 5 11 Tumor B was dependent on tumour load, tumour progression slope, and expected toxicity profile related to the patients’ co-medication and medical history, not always following the 50 mg per day, 4/2 regimen (Faivre et al, 2007) (4 weeks on, 2 weeks off treatment, see details Tumor C below). Toxicity and response were closely monitored, to adjust the dosage or cycle length if required. Other concurrent therapies were used whenever indicated. Tumour response was assessed according Figure 1 Phospho-protein arrays of tumour samples from patients A–C to the revised RECIST criteria (Eisenhauer et al, 2009). Further with 42 spotted receptor tyrosine kinases (signal indicates activated medical history and adverse events were charted. protein). Tumour sample of patient A shows strong activation of EGFR (1) and weaker signals for EphB2 (2), KIT (3), and the insulin receptor (4). Tumour sample of patient B shows moderate signals for RON (5), Erb4 (6), Laboratory analyses FGFR2 (7), KIT (8), and strong signals for insulin receptor (9), IGF1R (10), Native tumour samples were available from patients A–C and kept and RET (11). Tumour sample of patient C shows moderate signals for snap frozen and stored at 801C for molecular analyses. Paraffin RON (12), Erb4 (13), and Tyro3/Dtk (14). & 2010 Cancer Research UK British Journal of Cancer (2010) 103(2), 196 – 200 Translational Therapeutics Translational Therapeutics Sunitinib in metastatic TCs P Stro¨bel et al Table 1 Patient sociodemographic and clinical characteristics Age at diagnosis Stage Stage Case Sex (years) (initial diagnosis) Histopathology (start of sunitinib) Tumour grade A M 35 IVb Squamous cell IVb 2 B M 69 IVa Squamous cell IVb 2 C M 77 II Squamous cell IVb 2 D F 28 IVb Undifferentiated IVb 3 Table 2 Previous treatment and result of sunitinib therapy Extent of tumour at start of Survival Patient Previous treatment sunitinib Treatment result (sunitinib) A Systemic chemotherapy, PR for 3 months, Primary tumour liver metastases (60% HR) SD of primary tumour and hepatic OS 40+ months imatinib 400/800 mg PD axillary, supraclavicular, and coeliac lymph metastases, excellent metabolic node metastases response (FDG-PET), PR of coeliac lymph node metastases B Primary tumour resection, radiation to Liver metastases PR PFS 18+ months mediastinum DFS 4 years, Systemic chemotherapy for liver metastases, PD C Primary tumour resection, DFS 14 months Bilateral lung metastases PR PFS 14+ months D Systemic chemotherapy, radiation of retinal Primary tumour, multiple bone and lung PR for 2 months OS 4 months metastases, PR for 6 months metastases (all PD) Abbreviations: PR¼ partial remission; PD¼ progressive disease; HR¼ hepatic replacement; SD¼ stable disease; OS¼ overall survival; DFS¼ disease-free survival; PFS¼ progression-free survival. Acc to RECIST (Response Evaluation Criteria In Solid Tumors) criteria. ‘off ’ periods). After just 2 weeks, the patient’s abdominal pain disappeared. The 18F-FDG-PET scans showed reduced glucose metabolism of all liver metastases after 6 weeks in comparison with pre-treatment values. After 6 months, the vessel density calculated by FDG-PET of the liver metastases was reduced to o20% of their pre-sunitinib levels (Figure 2A–B). As the primary tumour seemed to respond less to the treatment than the liver metastases, concurrent radionuclide treatment with DOTATOC was adminis- tered during the 4th–11th months of sunitinib. Thereafter, the vessel density of the metastases was still very low, and the metastases were classified as stable disease according to RECIST (Eisenhauer et al, 2009). After 22 months of sunitinib treatment, the liver metastases started to progress again with new lesions; hence, selective infusional radiotherapy was started, resulting in a PR. Another 8 months later (4 2009), the primary tumour was completely resected, followed by 54 Gy irradiation of the mediastinum. As all known tumour lesions seemed to be under Figure 2 PET scans of the primary tumour and liver metastases from control, sunitinib was discontinued in 7 2009. Three months later, patient A. (A) Baseline just before initiating sunitinib. (B) After 6 months PET-CT showed massive progression of the hepatic metastases (in 4 2007) sunitinib. (C) Three months after withdrawal of sunitinib (Figure 2C) and lymph node metastases at the coeliac axis. (10 2009) showing a highly enriched index metastasis. (D) The same lesion Sunitinib was re-administered at 50 mg per day in 10 2009. Two was undetectable 2 months after re-administration of sunitinib (12 2009). months later, a control PET-CT showed marked regression of all lesions, corresponding to PR (Figure 2D). Patient B presented with asymptomatic liver metastases. Sunitinib was started at the registered 50 mg per day, 4/2 regimen. dose was escalated to 37.5 mg per day after 4 weeks and The metastases were still progressing after one cycle but developed antihypertensive medication was intensified. The CT controls at a PR after another three cycles (Figure 3A and B). After four cycles 7 months showed partial remission of his lung metastases (Figure of 4/2, the cycling schedule was slowed to 4/4 because of side 4A–C). As the patient later on developed leukopenia with a WBC effects during the ‘on’ phase, which resolved during the ‘off phase’. of o1800 cells per ml and anaemia, sunitinib was again decreased After 10 months of therapy, the cycling was slowed to 4/6 to 25 mg per day after 9 months. After 14 months under sunitinib for another two cycles, and further 4/8 dosage thereafter. At all (2 2010), the patient is still in PR. follow-up visits since the fifth cycle of sunitinib until the present In patient D, who suffered from a particularly aggressive, widely time (i.e., for 18 months), the liver metastases were still in good disseminated tumour at initial presentation, symptoms (such as partial remission, and there has been no evidence of relapse of the shortness of breath) improved after 2 weeks of sunitinib with primary tumour (Figure 3C). 50 mg per day, 4/2 dosing. Restaging after 6 weeks showed a PR of Patient C presented with several metachronous asymptomatic the primary tumour and lung metastases. However, this was soon lung metastases. Owing to his significant co-medication for severe followed by rapid tumour progression, to which the patient NYHA III problems and hypertension, sunitinib was started at a succumbed 4 months after the start of sunitinib and 16 months dose of 25 mg per day. As the medication was well tolerated, the after initial diagnosis. British Journal of Cancer (2010) 103(2), 196 – 200 & 2010 Cancer Research UK Sunitinib in metastatic TCs P Stro¨bel et al Figure 3 CT scans of a representative liver metastasis from patient B. (A) Liver metastasis at baseline just before initiating sunitinib. (B) Liver metastases after 6 months sunitinib. (C) Liver metastases after 18 months sunitinib. Figure 4 CT scans of an index lung metastasis from patient C. (A) Lung metastasis (square) at baseline just before initiating sunitinib. (B) Lung metastasis after 3 months sunitinib. (C) Lung metastasis after 7 months sunitinib. Side effects initiation of sunitinib, consistent with an anti-angiogenic mechan- ism of action. Many other RTKs also promote angiogenesis Commonly reported side effects of sunitinib were also observed in indirectly (Al-Nedawi et al, 2009) and thus could account for this our patients. Nausea was present in three patients. Hypertension finding. Taken together, the clinical observations, laboratory and fatigue were present in patients A and C. Weakness and analyses, and previous molecular knowledge on sunitinib are oedema were present in patients C and D. Patient D had some consistent in supporting the view that sunitinib’s effectiveness in minor, non-relevant electrophysiological cardiac alterations, but these cases was due primarily to anti-angiogenesis. no hypertension or haematological complications. Grade 2/3 Nonetheless, sunitinib may have had other mechanisms of hand–foot syndrome in patient B lead to prolonged ‘off’ phases action, in addition to anti-angiogenesis or instead of it. Sunitinib in the treatment cycles to allow for recovery. blocks many more RTKs than the literature or the manufacturer currently discusses. Furthermore, our array only tested for 42 of B300 RTKs; hence, many other RTKs may have been activated in DISCUSSION our patients. Further clinical studies will be required to analyse the underlying mechanisms more thoroughly. Thymic carcinoma is a rare tumour that is difficult to treat in Although our findings are limited by the small sample advanced stages. Cisplatin-based multi-agent chemotherapy can be size, sunitinib seems to be a particularly good choice of second- beneficial, but often the responses do not last long. There is line therapy for patients with metastatic TC. The tumours currently no other established second-line treatment for TC. reported in this study were histologically and immunohisto- Targeted molecular therapy could open new therapeutic options in these patients. chemically comparable and representative for a majority of Our initial experience shows that sunitinib seems promising for TCs in the broader population. Moreover, in line with previous patients with metastatic TC. The rationale for choosing this drug reports (Tsuchida et al, 2008; Yoh et al, 2008), there were no came from our observation that three of the available tumour mutations of c-KIT, KRAS, BRAF,or EGFR; therefore, samples showed simultaneous activation of multiple RTKs. Hence, apparently the effectiveness of sunitinib does not depend on such it seemed reasonable to interfere with several of these processes abnormalities. Our initial observations suggest that sunitinib (and possibly also concurrently to prevent tumour escape mechanisms through other multi-kinase inhibitors such as sorafenib (Bisagni et al, alternative signalling pathways (Faivre et al, 2006; Potapova 2009)) may be more effective against TC than the disappointing et al, 2006). results reported in the grey literature for single-target molecular The new targeted molecular therapies are clinically effective therapies, such as gefinitinib (Kurup et al, 2005), erlotinib (Bedano because they have been designed to disrupt the cellular signalling et al, 2008), and imatinib (Salter et al, 2008). These earlier pathways involved in various aspects of oncogenesis, such as results seem plausible in the light of the broad and rather growth signal transduction, cell invasion, evasion of apoptosis, and heterogeneous spectrum of activated RTKs in the few samples metastatic dissemination. Sunitinib was originally designed and described in this study. developed for its high potency against VEGFR2 and PDGFR-b Our ‘index’ patient A provides very strong circumstantial (Burstein et al, 2008), and it is known to block the intracellular evidence that sunitinib was able to control his disease over more ATP-binding sites of several other RTKs: VEGF1, VEGF3, FLT3, than 3 years and even at relapse of sunitinib pre-treated c-KIT, PDGFa, CSF1, and RET (Faivre et al, 2007). Thus, on the metastases. Similar favourable findings in two other patients basis of past scientific knowledge (Chow and Eckhardt, 2007) as (Bþ C) indicate that sunitinib may be able to block tumour escape well as our clinical observations and laboratory results, it seems mechanisms and may be a promising option for long-term plausible that the predominant mechanism of action of sunitinib in treatment. Patient D (with an unusually aggressive tumour) our patients was anti-angiogenesis, even though its main known obtained a temporary partial remission, which we estimate targets were not prominently activated in the tumour samples prolonged her life by about 1–3 months. It is noteworthy that studied herein. However in case A, the patient’s PET scans showed although tumours from patients A–C were ‘classical’ squamous a rapid and substantial reduction in tumour vessel density after the & 2010 Cancer Research UK British Journal of Cancer (2010) 103(2), 196 – 200 Translational Therapeutics Translational Therapeutics Sunitinib in metastatic TCs P Stro¨bel et al cell TCs, the tumour from patient D was undifferentiated and had seems to be one of the types of cancer that is responsive to unusually high mitotic counts, prompting us to rule out EBV sunitinib. It will be important to investigate whether patients with association or a so-called ‘carcinoma with t(15;19) translocation’ malignant thymomas may also benefit from this drug. (French et al, 2003) at initial presentation by respective molecular techniques. In conclusion, sunitinib could be a promising new treatment ACKNOWLEDGEMENTS option for TCs. Compared with many other tumours such as advanced prostate cancer (Dror Michaelson et al, 2009), metastatic We thank Michael Hanna, PhD, (Mercury Medical Research and colorectal cancer (Saltz et al, 2007), metastatic breast cancer Writing) for providing publication consulting and medical writing (Burstein et al, 2008), or advanced non-small-cell lung cancer services. This work was supported by grant no. 10-1740 from the (Socinski et al, 2008), in which sunitinib was either inefficient Deutsche Krebshilfe and by Project grant 781025 of the or had only weak benefits were overridden by serious risks, TC Tumorzentrum Heidelberg/Mannheim. 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