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- Copyright © 2013 Laura Desch and Rainer Kunstfeld. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.
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- 10.1155/2013/327150
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Abstract
Hindawi Publishing Corporation Journal of Skin Cancer Volume 2013, Article ID 327150, 9 pages http://dx.doi.org/10.1155/2013/327150 Review Article Merkel Cell Carcinoma: Chemotherapy and Emerging New Therapeutic Options Laura Desch and Rainer Kunstfeld ¨ ¨ ¨ ¨ ¨ Universitatsklinik fur Dermatologie,AKH,MedizinischeUniversitat Wien, Wahringer Gurtel 18-20, 1090 Wien, Austria Correspondence should be addressed to Rainer Kunstfeld; rainer.kunstfeld@meduniwien.ac.at Received 25 July 2012; Accepted 10 December 2012 Academic Editor: Boban M. Erovic Copyright © 2013 L. Desch and R. Kunstfeld. This is an open access article distributed under the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. Merkel cell carcinoma (MCC) is a rare neuroendocrine skin tumor that typically occurs in elderly, immunosuppressed patients. Infection with Merkel cell virus (MCV) and immunosuppression play an important role in the development of MCC. Different staging systems make it difficult to compare the existing clinical data. Furthermore, there predominantly exist single case reports and case series, but no randomized controlled trials. However, it is necessary to develop further therapy options because MCC tends to grow rapidly and metastasizes early. In the metastatic disease, therapeutic attempts were made with various chemotherapeutic combination regimens. Because of the high toxicity of these combinations, especially those established in SCLC, and regarding the unsatisfying results, the challenge is to balance the pros and cons of chemotherapy individually and carefully. Up to now, emerging new therapy options as molecular-targeted agents, for example, pazopanib, imatinib, or somatostatin analogues as well as immunologicals, for example, imiquimod and interferons, also showed less success concerning the disease-free response rates. According to the literature, neither chemotherapy nor molecular-targeted agents or immunotherapeutic strategies have shown promising eeff cts in the therapy of the metastatic disease of MCC so far. There is a great demand for randomized controlled studies and a need for an MCC registry and multicenter clinical trials due to the tumors curiosity. 1. Clinical Features and about 5-fold higher in solid organ transplantation recip- ients [7] than in the general population. On the one hand, Merkel cell carcinoma (MCC) of the skin, formerly called these features might also explain the increasing incidence of trabecular carcinoma, is a rare, highly malignant neuroen- MCC. On the other hand, they might be key factors for the docrinetumor.Clinicallyonlyapresumptivediagnosis can successful treatment of MCC. be achieved. Clinical features that may serve as clues in The stage of patients with MCC has prognostic impact the diagnosis of MCC are summarized in the acronym and influences the therapy oer ff ed. Over the years, different AEIOU: asymptomatic/lack of tenderness, expanding rapidly, staging systems of MCC have been applied making it dif- immune suppression, older than age 50, and UV-exposed cfi ulttocompare clinical data.In2010, theAmericanJoint site on apersonwithfairskin[1]. The definitive diagnosis Committee on Cancer (AJCC) Staging system rfi st included is made by histology and immunohistopathology depicting the staging for MCC [8]. Duprat et al. [9]summarizedAJCC intermediate filaments and neuroendocrine markers [ 2]. The Staging system and vfi e-year su rvival data from Lemos et al. incidence of MCC has been rising in recent years [3, 4]. 5 [5] in a table. Clinicians and researchers should be cautious years aeft r diagnosis, overall survival was 40% and the age- when comparing clinical studies which applied older systems adjusted and sex-adjusted survival was 54% [5]. and with those which applied the recent AJCC Staging Infectionwiththe Merkel cell virus(MCV) andimmuno- system. suppression are the key factors in the development of MCC. MCC mostly appears as a hemispherical, rfi m-elastic, and eTh relative risk for MCC is about 13-fold higher in HIV [ 6] reddish-livid tumor with a smooth surface. It is typically 2 Journal of Skin Cancer located on sun exposed areas like head, neck, extremities, adverse reactions of these therapeutic attempts. Some of these and upper body [10]. Because of its harmless appearance, rather old patients died from sepsis caused by chemotherapy- this rare neuroendocrine tumor, first described by Toker induced leukopenia [40], progressive renal failure [17], or in 1972 [11], is oen ft misdiagnosed, for example, as a cyst impaired hepatic function [37]. [1]. Interestingly, the clinically suspected diagnosis has only In a retrospective analysis of a series of 251 patients been made correctly for one percent of the cases [1, 12]. The from a single centre treated between 1970 and 2002 (Table 1) MCC grows rapidly, is highly aggressive, and metastasizes [24], the use of adjuvant chemotherapy was associated early locoregionally as well as distantly [1, 13]illustratingthe with decreased survival. 28 of 237 patients presenting with importance of comprehensive strategies to control dissemi- locally advanced disease or locoregional metastases received nated diseases. adjuvant chemotherapy and showed a 5-year disease-specific survival rate of 28% compared to 73% of 209 patients with- out receiving chemotherapy. Furthermore, 67 node-positive 2. Therapeutic Options patients receiving chemotherapy were associated with a lower survival rate compared to not-receiving chemotherapy. eTh rareness of the disease and, possibly also the comorbidi- Beside polychemotherapy with burdensome toxicity, ties have contributed to the lack of prospective clinical studies there are better tolerated monotherapeutic options like evaluating the efficacy of therapeutic options. Up to now, only etoposide and anthracyclines [10, 25, 37]. Liposomal dox- one randomized clinical study was published [34]. All other orubicin together with radiotherapy (𝑛=5 ) yielded rapid publications refer uncontrolled data from case series or even response, but showed less adverse reactions, for exam- retrospective case descriptions. ple, gastrointestinal disorders. Tumor proceeded within 1 The only randomized controlled clinical study published to 3 months (Table 1)[25]. Orally administered etoposide in the eld fi of MCC compared regional adjuvant radio- achieved complete responses in 3 out of 4 patients (75%) therapy with observation [34]. While adjuvant radiotherapy and two of them were comparatively long lasting (16 and 36 significantly reduced the probability of regional recurrence, months) (Table 1)[26]. it hadnoeeff ct on theoverall survival.Theauthors wrote There are no randomized studies that compare different that the introduction of sentinel node dissection decreased chemotherapy regimens. In 204 patients, the most com- the recruitment rate for this study. Surgery is considered mon regimens used were cyclophosphamide, doxorubicin the mainstay of treatment for MCC [10]. However, there is (or epirubicin), vincristine plus/or minus prednisone, and no evidence basis for this treatment option. A prospective etoposide combined with cisplatin (or carboplatin). A rele- evaluation of sentinel node dissection in MCC was described vant difference in the response rate could not be described only in 9 patients [35]. (Table 1)[27]. Although high remission rates were reported after 3. Chemotherapeutic Options: chemotherapy (up to 70–75% [25, 37]), but no such prolon- gation of survival [10]. Intensity of chemotherapeutic therapy Polychemotherapy and and response rates did not correlate [37]. Main therapy still is Monotherapeutic Options wide excision of the tumor with or without node dissection, Basically MCC is assumed to be a chemosensitive tumor [12, oen ft in combination with radiotherapy. In comparison, 36, 37] but to date no broadly accepted treatment algorithm chemotherapy has been used rarely [45]. Up to now, theliteraturedoesnot provideadequate, exists. Supportively to primary excision, chemotherapy is used on MCC stages III (lymph node metastasis) and IV sucffi ient data to support the use of chemotherapy. (distant metastases) aeft r the AJCC Staging system. It may be applied either alone or in combination with radiother- apy. Furthermore, chemotherapeutics are used in locally 4. Molecular-Targeted Agents advanced disease, as palliative measure or in case of recur- rences [37]. Davids et al. (Table 2)[28] treated a patient who sueff red The following data refers to retrospective case series from metastatic pulmonary lesions with pazopanib, which or single case reports, except [14, 15]and (Table 1)[19], is a small-molecule tyrosine kinase inhibitor acting against which are prospective case series. Several groups tried to vascular-endothelial-growth-factor-receptors- (VEGFR-) 1, treat MCC with chemotherapeutic regimens commonly used 2, and 3 and against platelet-derived-growth-factor-receptor- for small cell lung cancer (SCLC) because of histopatho- (PDGFR-)𝛼 and𝛽 .Therationale wasthatMCCshavebeen logical and cytochemical similarities—besides both of them shown having upregulated VEGFR [46, 47]and PDGFR are considered as neuroendocrine tumors [16, 38–42]. [48, 49]. Pazopanib can be administered orally. It was well These regimens combined carboplatin, cisplatin, and etopo- tolerated and provided partial response of the pulmonary side, cyclophosphamide with vincristine, doxorubicin, pred- lesions as well as complete response of the primary lesion, but nisone, bleomycin, or 5-fluorouracil ( Table 1). They were diseaserecurredorratherprogressed4months later. In this reported to provide a good initial regression of the lesion, case, every other therapy that had been tried before (surgery, but recurrences occurred mainly within 4 to 15 months. All radiotherapy, etoposide and carboplatin, paclitaxel, tegafur, these patients had locoregional or distant metastases. These and 5-chloro-2,4-dihydroxypyridine and oxonic acid) also potential benefits should be weighed against the possible ledtopartial or complete response andlesions recurred 4–8 Journal of Skin Cancer 3 ft ft Table 1: Chemotherapeutic options: polychemotherapy and monotherapeutic options. Intent of Number of patients Agents used Response Time to progression Survival chemotherapy 5-year local control of all 𝑛=34 5-year survival of all cases: McAfee et al. [14] Carboplatin, cisplatin, cases: 94%; 9 patients received CTx Adjuvant NDA 37%; prospective VP-16, etoposide 5-year locoregional control local to metastatic disease 5-year DSS of all cases: 52% of all cases: 80% 𝑛=41 Poulsen et al. [15] Adjuvant (72%); CTx combined with RTx; 3-year OS 76%; local or locoregional NDA NDA prospective therapeutic (28%) etoposide, carboplatin 3-year DFS 65% disease George et al. [16] 𝑛=1 Cyclophosphamide, Adjuvant CR:4-5 months 4months NDA retrospective metastatic disease doxorubicin, vincristin Cisplatin + etoposide or Cisplatin + etoposide + Redmond III et al. [17] 𝑛=6 CR for a median of 3,5 Adjuvant cyclophosphamide CR in 5 patients median OS of 6,5 months retrospective metastatic disease months or Cyclophosphamide + doxorubicin + vincristin First line: VP-16 + cisplatin + doxorubicin + bleomycin CR aer 6 cycles 15 months until relapse Azagury et al. [18] 𝑛=1 — Adjuvant — — NDA retrospective metastatic disease Second line: RTx CR aer 4 months NDA combined with methotrexate + cyclophosphamide + VP-16 𝑛=30 CR of MCC for 21+ NET(1MCC amongall CR in 2 patients (in 1 months; Bajetta et al. [19] 5-Fluorouracil + cases) Adjuvant patient with MCC); median duration of NDA prospective dacarbazine + epirubicin locally advanced or PR in 7 patients response of all cases was 10 metastatic disease months (range, 5+ to 24+) NDA; 𝑛=88 ; 19% received CTx without of all cases 12% had Eng et al. [20] 43 patients received RT RTx Of all cases median time to Adjuvant persistent disease, NDA retrospective and/or combined CTx most common regimen: recurrence was 8 months 40% had recurrent local to metastatic disease VP-16 + cisplatinum disease +/− RTx 𝑛=46 Eng et al. [21] most common regimen: Overall median time to 9 patients received CTx Adjuvant NDA OS rate of all cases: 37% retrospective carboplatin + etoposide + recurrence was 9 months metastatic disease vinblastin 4 Journal of Skin Cancer fi 𝑛 𝑛 𝑛 Table 1: Continued. Intent of Number of patients Agents used Response Time to progression Survival chemotherapy 𝑛=86 NDA; Veness et al. [22] most common: median time to relapse was 5-year OS 47%; 7 patients received CTx Adjuvant 55% of all cases retrospective based on platinum 3–7 months DFS rate 25% locoregional disease experienced a relapse =107 3-year OS was 17% Voog et al. [23] ORR to rst line CTx: advanced or metastatic Adjuvant different regimens; NDA NDA (metastasis) and 35% retrospective 64% disease (locally advanced) 5-year DFS of all cases: =251 NDA; of all cases median time to Allen et al. [24] most common regimen: 48%; 28 patients received CTx Adjuvant disease recurred in recurrence was 9 months retrospective carboplatin + etoposide 5-year DSS of patients localorregionaldisease 102 patients (range, 2 to 70 months) receiving CTx: 28% Wobser et al. [25] 𝑛=5 +RTx an average of 2 months Survival time:range 3to20 Adjuvant PR in 4 patients retrospective metastatic disease liposomal doxorubicin until progression months Schlaak et al. [26] 𝑛=4 2ofCRlastedfor 16 and36 Adjuvant Etoposide CR in 3 patients NDA retrospective metastatic disease months most common regimens: ORR 75,7% Cyclophosphamide + (35,1% CR, 35,1% PR, Median OS of all cases: 21,5 doxorubicin (or =204 5,4% minor Median response duration months (range, 1 to 118 Tai et al. [27] epirubicin) + vincristin locoregional and Adjuvant responses) of patients receiving CTx: months); retrospective +/− prednisone metastatic disease — 1–12 months 2-year OS of all cases: 36%; ORR 60% 5-year OS of all cases: 17% Etoposide + cisplatin (or (36% CR, 24% PR) carboplatin) NDA: no data available; NET: neuroendocrine tumor(s); MCC: merkel cell carcinoma; PR: partial response; CR: complete response; CTx: chemotherapy; RTx: radiation therapy; Sx: surgery; DFS: disease free survival; OS: overall survival; ORR: overall response rate; DSS: disease-specific survival. Journal of Skin Cancer 5 ft ft ft ff Table 2: Molecular-targeted agents. Number of patients Agent used Dosage Tolerability Response Median time to progression Minimal adverse eects; After 2 months: CR of 𝑛=1 dose reduction aer Davids et al. [28] Pazopanib 800 mg daily primary lesion, PR of 4months metastatic disease gallstone pancreatitis to metastatic lesions 400mg daily Mainly Grade 1-2 toxicities; 𝑛=23 3 episodes of Grade 4 no CR; Samlowski et al. [29] metastatic or Imatinib 400 mg daily toxicities; 1-2 months PR: 4% unresectable disease Grade 3 toxicities in 3 patients Carcinoid syndrome and 𝑛=58 Median survival time of 22 500 or abnormal urinary Disease stabilized for at Di Bartolomeo et al. metastatic disease months (range, 1–32+ Octreotide 1000 micrograms 3 5-hydroxy-indoloacetic least 6 months (range, [30] (neuroendocrine months); times a day acid excretion were 1–32+ months) tumors) PR: 3% reported 𝑛=1 90Y-DOTATOC; PR after 1 week; 10 weeks until locoregional Meier et al. [31] 85 mCi Fatigue was main side effect locoregional disease targeted radiotherapy CR aer 4 weeks relapse 𝑛=1 15 mg i.m. injection Clinically CR aer 2 Fakiha et al. [32] clinically locoregional Lanreotide No side effects reported 7 months until relapse every two weeks months disease Including Grade 3 and 𝑛=12 Grade 4 events, for metastatic or 7 mg per kilogram No responses; stable disease Shah et al. [33] Oblimersen sodium example, lymphopenia, PD in 9 patients regionally recurrent daily in 3 patients renal failure, cytopenia, and disease hyperkalemia CR: complete response; PR: partial response; PD: progressive disease. 6 Journal of Skin Cancer and once 24 months later. In this paper, the authors conclude Oblimersen sodium (Genasense), which inhibits the pro- that pazopanib appears to have a promising antitumor and duction of Bcl-2 (which is a protein acting against apoptosis antiangiogenic function and a good oral bioavailability; as per in cancer cells), was applied intravenously to 12 patients and them, this has been demonstrated in preclinical studies. showed no responses (Table 2)[33]. In this patient, single nucleotide polymorphism (SNP) in PDGFR-𝛼 gene was found, namely, 1432T>Cmutation 5. Immunotherapeutic Strategies in codon478.Thesamemutationwas shownintwo other samples of MCCs that were examined by this group and in MCC is associated with immunosuppression [1, 4]. Cases of three other patients with MCC from another study [49]. It spontaneous regressions of MCCs were reported that were is not clear whether this mutation leads to an activation of deemed to be caused by the regained activity of the immune PDGFR-𝛼 and consequently to a better response to tyrosine system [56, 57]. MCCs that showed a high infiltration with kinase inhibitors, for example, pazopanib or not. CD8+ lymphocytes were attributed to a better prognosis Similarly well tolerated is another tyrosine kinase (100% MCC-specific survival, 𝑛=26 )comparedtoMCCs inhibitor called imatinib mesylate (Gleevec) (Table 2)[29]. with lower infiltration (60% survival, 𝑛=120 )[58]. KIT (CD117), a tyrosine kinase receptor which belongs to the Some patients developed MCC during treatment with same family of tyrosine kinase receptors like PDGFR-𝛼 ,is tumor necrosis factor (TNF) alpha inhibitors, which usu- reported to be highly expressed (84–95%) in MCCs [50–52]. ally promotes inflammatory response. Therefore, TNF-alpha Activating mutations of KIT were found in 88,2% (𝑛=127 ) inhibitors are assumed to increase the risk of occurring of of gastrointestinal stromal tumors (GISTs) and showed a MCC [59, 60]. significantly higher partial response rate to imatinib for exon The detection of the Merkel cell polyomavirus (MCV) 11 KIT mutation (83.5%) compared to exon 9 KIT mutation andits geneticmaterial, foundinMCC tumorcells of about (47.8%) or no found mutation (0.0%) [53]. Because of the 80% of the concerned patients, provided new opportunities successful treatment of KIT expressing GISTs [53, 54]and and possibilities regarding therapy strategies [61, 62]. For because of the recent insight that KIT receptor activation instance, interferons (𝛼 and𝛽 ) have been suggested to be through its ligand stem cell factor (SCF) stimulates growing a possible therapeutic option [63]. However, there are only of MCC cells in vitro [55], imatinib was assumed to be a few reports on the use of immunomodulating substances promising therapeutic option for MCC. In fact, there were in MCC. In two case reports, interferon-𝛼 -2b caused severe only few adverse events but imatinib appeared to provide asthenia and depression, leading to discontinuation of the insufficient effects on progression-free and overall survival. therapy, considering that no tumor regression was observed. Just one out of 23 patients with KIT expressing MCCs The tumors were positive for MCV [ 63]. Recently, it has been responded partially and the progression happened rapidly shown that viral T-antigens represent an important signal for aer ft 1 or 2 months in most of the patients. u Th s, the study MCV-infected MCC cells concerning survival and growth was prematurely discontinued [29]. [64]. Consequently, the inhibition of T-antigens might be a Kartha and Sundram [48] examined primary and therapeutic option. metastatic MCCs (𝑛=32 )toevaluatethe expressionand Imiquimod, which induces immune response by binding mutations of KIT and PDGFR in MCCs. KIT expression was to TLR7 (toll like receptor-7, located on the surface of found in 53% of the cases. Coexpression of KIT and SCF immune cells, e.g., macrophages), was topically applied to was shown in 16% only, whereas coexpression of PDGFR- MCC (𝑛=1 ) and combined with radiotherapy. Complete 𝛼 and its ligand PDGF-A was found in 81% of the cases. response of the lesion lasted 7 months [65]. In this study, no activating mutations could be found (KIT Another new therapeutic approach is based on cytokine exons 9, 11, 13, and 17 and PDGFR-𝛼 exons 10, 12, and 18 were inducted inflammatory response. To avoid systemic reac- analyzed). eTh refore, ecffi acy of imatinib is questionable, also tions, fusion proteins were developed consisting of antibodies considering results of Samlowski et al. [29]. and cytokines, which bind to their corresponding antigens Somatostatin receptors were also reported to be expressed located on the tumor cell surface [66]. In general, combined in MCCs. Somatostatin analogue octreotide showed unfruit- therapy of cytokine-based antibodies and regular chemother- ful results concerning tumor regression with a partial apy seems to be well tolerated. response rate of 3% (𝑛=58 )(Table 2)[30]. Radiopeptide therapy is used to treat neuroendocrine tumors by binding of edotreotide (DOTATOC, which contains the active peptide 6. Conclusions of somatostatin, namely, octreotid) to somatostatin receptors. In onecase, theradiolabeledsomatostatinanalog90Y- There is a considerable lack of prospective clinical studies and DOTATOC led to complete remissions after a few days, but in particular randomized controlled studies that evaluated relapse and progression occurred within weeks. It has to the therapeutic options for MCC. For the time being, nearly be pointed out that the tolerability was very good (Table 2) all conclusions are based on case series or even isolated [31]. Lanreotide, a nonradiolabeled somatostatin analog, was cases and theoretic considerations, rather than evidence- intramuscularly administered in one patient every two weeks based medicine. and showed a complete response of the lesion. 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