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Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and review of the literature

Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and... Background: Desmoplastic small round cell tumour (DSRCT) is a rare but frequently fatal sarcoma, and many of its characteristics still require further clarification. Methods: We retrospectively analysed 41 patients treated at or referred to two regional referral centres in the UK between 1991 and 2012. A review of the current literature was also performed. Results: The median age of presentation was 27 years (range 16 to 45 years), with a male-to-female ratio of 3:1. Ninety percent of patients had disease in the abdomen. The median size of the presenting tumour was 13 cm (range 3.5 to 23 cm), and 80% had metastatic disease at diagnosis, mainly in the liver (33%) and lungs (21%). Time-to-progression (TTP) was 3.9, 2.3 and 1.1 months after first-, second- and third-line chemotherapy, respectively. First-line treatment with VIDE chemotherapy appeared to confer the longest TTP (median 14.6 months). Ifosfamide and doxorubicin resulted in TTP of >3.8 months when used in any-line setting. Eleven patients received targeted agents as part of a clinical trial. After a median follow-up of 14 months, the overall median survival (MS) was 16 months. There was no difference in MS with regards to age, gender, or size of the presenting tumour. Patients with extra-abdominal disease survived longer compared to those with tumours in the abdomen (all still alive vs MS of 15 months; P = 0.0246). Patients with non-metastatic intra-abdominal disease who underwent surgery had an MS of 47 months (16 months for those who did not have surgery; P = 0.0235). Radiotherapy for locoregional control in patients with metastatic intra-abdominal DSRCT was associated with longer survival (MS of 47 vs 14 months; P = 0.0147). Conclusions: DSRCT is a rare but often fatal disease that mainly affects younger male patients. Those with intra-abdominal DSRCT have a poorer prognosis, although surgical resection for localised disease and radiotherapy in the metastatic setting are associated with improved survival. A patient’s age, gender and size of presenting tumour do not have prognostic significance. Keywords: Desmoplastic small round cell tumour, Sarcoma, Prognosis, Survival, Treatment Background differentiated small round blue cells lying within an Desmoplastic small round cell tumour (DSRCT) is a rare abundant fibrosclerotic stroma [2]. These cells co-express but highly aggressive neoplasm that typically occurs in epithelial, mesenchymal, myogenic and neural markers [3], adolescent and young males. An earlier study has found but are distinguished by the chromosomal translocation a male-to-female ratio of approximately 5 to 1 and a t(11;22)(p13;q12) resulting in the fusion of the Ewing’s mean age at diagnosis of 22 years [1]. First described sarcoma (EWSR1) and the Wilms’ tumour (WT1)genes in 1989, it is characterised by clusters of poorly [4]. DSRCT generally develops in the abdomen and have a tendency towards peritoneal spread, with subsequent metastasis to distant lymph nodes, liver and lungs [5]. * Correspondence: han.wong@addenbrookes.nhs.uk In this study, we retrospectively reviewed 41 patients Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK with DSRCT who were treated at or referred to two Full list of author information is available at the end of the article © 2013 Wong et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 2 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Table 1 Patient characteristics (n = 41) regional sarcoma centres in the UK. Analysis of survival and prognostic factors, as well as review of the current Variables No. of patients (%) literature on the management of DSCRT, was performed. Gender This series is comparable in size with other large series Male 31 (76%) previously reported. Female 10 (24%) Median age (years) 27 (range 16 – 45) Methods Presenting site Patient groups Abdomen and pelvis 37 (90%) The Royal Marsden Hospital in London and in Sutton, Prostate 1 (2.4%) UK, and Addenbrooke’s Hospital in Cambridge, UK, are regional sarcoma referral centres for London and Testis 1 (2.4%) South East England, and for East of England, respectively. Shoulder 1 (2.4%) Patients with DSRCT treated at or referred to these Thigh 1 (2.4%) two centres between the years of 1991 and 2012 were Median tumour size at diagnosis (cm) 13 (range 3.5 – 23) identified retrospectively. Diagnosis was confirmed by Metastasis at presentation 33 (80%) immunohistochemistry and reviewed by central specialist Sites of metastasis at presentation (n = 33) histopathologists. Cytogenetic analysis for EWSR1-WT1 rearrangement was performed when available. Patients’ Liver 11 (33%) medical and treatment records were analysed. All 41 Lung 7 (21%) patients identified were included in the study. Approval Peritoneal cavity 6 (18%) from the local research ethics committee was obtained Lymph node 5 (15%) prior to data collection. Bone 3 (9%) Adrenal 1 (3%) Statistical analysis Chest wall 1 (3%) Time-to-progression (TTP) is the time interval from Prostate 1 (3%) completion of chemotherapy to radiological disease pro- gression as defined by Response Evaluation Criteria in Solid Tumours (RECIST). Survival analysis was performed Treatments using the Kaplan-Meier method and log rank test. Surviving The treatments received by this cohort of patients are patients were censored at last contact. summarised in Table 2. Thirty eight patients (93%) have had chemotherapy, with the majority of them receiving Results it with palliative intent. Four and two patients received Patient characteristics neoadjuvant and adjuvant chemotherapy, respectively. Of A total of 41 patients were referred to or treated at these, three subsequently developed metastatic disease. the centres between 1991 and 2012. Thirteen of these The commonest chemotherapeutic regimes were those were referred for opinion only and were managed sub- frequently used in other small round cell tumours, i.e. a sequently at their local hospitals. Diagnosis of DSRCT combination of an anthracycline, alkylating agent and was confirmed by central specialist histopathological vinca alkaloid. Topoisomerase inhibitors, taxanes and review. Cytogenetic testing for EWSR1-WT1 rearrange- platinums have also been used. As the effectiveness of ment was only routinely available in some centres after second- or subsequent-line chemotherapy is also unproven, 2008, therefore only 14 patients were tested and found a number of newer agents had been given as part of a to be positive. Patient characteristics are summarised in clinical trial, including inhibitor of the mammalian target Table 1. The age of presentation ranges from 16 to of rapamycin (mTOR) pathway, tyrosine kinase inhibitors 45 years, with a median of 27 years. About three quarter (TKIs), and antibody against the insulin-like growth of the patients were males. The majority of patients factor-1 receptor (IGF-1R). presented with abdominal or pelvic tumours (i.e. arising In our series, only six patients received radiotherapy. from the retroperitoneum or within the peritoneal cavity One patient each had radical radiotherapy after resection with no clear indication of organ of origin), with sizes of an abdominal (54 Gy in 30 fractions) and thigh (60 Gy ranging from 3.5 to 23 cm. Four patients with extra- in 30 fractions) tumour, respectively. The remaining four abdominal disease had disease in the prostate, testis, patients received palliative conformal radiotherapy (20 Gy shoulder and thigh, respectively. Eighty percent of the in five fractions) to the abdomen for locoregional control patients had evidence of metastasis at presentation, in metastatic disease. Resection or optimal debulking of with lungs and liver being the commonest sites. the primary tumour was done in eight patients, whereas Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 3 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Table 2 Treatment and chemotherapeutic regimens Table 2 Treatment and chemotherapeutic regimens (n = 41) (n = 41) (Continued) Variables No. of - IVADo 1 patients (%) - Liposomal doxorubicin 1 Treatment modality - VIDE 1 Chemotherapy 38 (93%) Subsequent-line (with non-standard therapies) - Neoadjuvant 4 (10%) - Figitumumab 2 - Adjuvant 2 (5%) - Sirolimus + cyclophosphamide or 2 - Palliative (including relapse after neoadjuvant/ 35 (85%) liposomal doxorubicin adjuvant treatment) - Pazopanib +/− etoposide 2 Radiotherapy - Sunitinib 2 - Radical 2 (5%) - Axitinib 1 - Palliative 4 (10%) - Goserelin 1 Surgery and its indications - Interferon 1 - Diagnosis 14 (34%) - Semaxanib 1 - Resection/optimal debulking of 8 (20%) - Sorafenib 1 primary tumour Chemotherapy in 14 patients surgery was performed for diagnostic First-line purposes. - Vincristine + ifosfamide + 13 doxorubicin + etoposide (VIDE) - Ifosfamide + vincristine + actinomycin 7 Time-to-progression and survival D + doxorubicin (IVADo) TTP after first- to third- line systemic therapies are - Cyclophosphamide or ifosfamide + etoposide 4 summarised in Table 3. Unsurprisingly, the median TTP - Vincristine + doxorubicin + 4 decreases with increasing lines of treatment. First-line cyclophosphamide (VAC) or vincristine + treatment with VIDE chemotherapy appeared to confer ifosfamide + doxorubicin the longest TTP (median of 14.6 months; range 1.9 to - Bleomycin + etoposide + cisplatin 2 33.7 months). In second-line treatment, etoposide alone - Ifosfamide + doxorubicin 2 (n = 1), or in combination with platinum (n = 9) or ifosfa- - Carboplatin + etoposide 1 mide (n =2), were most commonly used, with a median - Carboplatin + paclitaxel 1 TTP of 3.4 months (range 0.3 to 13.9 months). Ifosfamide - Cisplatin + doxorubicin/paclitaxel + 1 and doxorubicin treatment resulted in a median TTP cisplatin + ifosfamide of >3.8 months when used in any line-setting. - Doxorubicin 1 The median follow-up period for all patients was - Epirubicin + cisplatin + capecitabine 1 14 months (range 1 to 127 months). Sixteen (39%) patients were still alive at a median follow-up of 12.5 months. All - Ifosfamide + carboplatin + etoposide 1 deaths were due to the disease. The overall median survival - Ifosfamide + vincristine + actinomycin D 1 (MS) was 16 months (range 2 to >127 months) (Figure 1). Subsequent-line (with chemotherapeutic agents) Three-year and 5-year survival rates were 27% and - Platinum + etoposide 10 16%, respectively. The longest surviving patient had - Etoposide 5 disease in his prostate, and he presented early with - Ifosfamide + etoposide 5 symptoms of urinary outflow obstruction. He still has no evidence of disease for more than 10 years after his - Doxorubicin 2 initial diagnosis. Three other patients who presented - Ifosfamide + doxorubicin 2 early with lumps in the testis, shoulder and thigh, - Cyclophosphamide + topotecan 2 - VAC 2 Table 3 Time-to-progression after systemic therapy - Gemcitabine or irinotecan + temozolomide 2 Line of treatment Median time-to-progression (months) - Albumin-bound paclitaxel 1 First (n = 38) 3.9 (range 0.6 to 33.7) - Cisplatin + mitomycin C + irinotecan 1 Second (n = 23) 2.3 (range 0.3 to 13.9) - Doxorubicin + etoposide 1 Third (n = 13) 1.1 (range 0.6 to 11.8) Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 4 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Multimodality treatment of DSRCT and prognostic factors The reported MS of DSRCT is in the region of 17 to 25 months [6]. Given the poor outcome of the disease and the significant morbidities and mortality associ- ated with its treatment, prognostic indicators are very important. Two retrospective studies performed at the Memorial Sloan-Kettering Cancer Center (MSKCC) have both found that aggressive surgical debulking of DSRCT is of prognostic significance [7,8]. An analysis of 32 patients by Schwarz et al. demonstrated that improved survival was found to be associated with the following: more than 90% surgical debulking either before or after chemotherapy, complete or very good partial response (PR) to multimodality treatment, and use of the P6 Figure 1 Kaplan-Meier plot of overall survival for the entire protocol (see below) [7]. In a report of 66 patients by cohort (n = 41). Lal et al., treatment with chemotherapy, surgery and radiotherapy conferred a 3-year survival of 55% com- respective, are still alive at the time of last follow-up, paredto27% forthose whodid notreceive allthree albeit with evidence of metastatic disease. treatments [8]. In addition, gross tumour resection was There was no difference in MS with regards to age also associated with prolonged survival (3-year survival (15vs 16monthsfor those ≤25 years and >25 years, of 58% compared to 0% in the non-resected patients). respectively; P = 0.7899), gender (16 vs 15 months for Naturally such an analysis performed retrospectively males and females, respectively; P = 0.5369), or whether cannot adequately control for the fact that patients the presenting tumour was ≤ or >10 cm (32 vs 13 months; with radically resectable disease are likely to have less P = 0.4195) (Figure 2). bulky and more localised tumours. Patients with extra-abdominal disease (n = 4) survived There is no general consensus on the best therapeutic longer compared to those with tumours in the abdomen approach, as strong evidence is lacking given the rarity or pelvis (n = 37) (all still alive vs MS of 15 months, of the disease, although multimodality treatment with respectively; P = 0.0246). Patients with non-metastatic, chemotherapy, surgery and radiotherapy appears to intra-abdominal and -pelvic disease at presentation who represent optimal management. The MS of patients had undergone surgical resection of the primary tumour diagnosedwith DSRCT was16monthsin thisstudy, (n = 6) survived much longer than those who did not which is slightly lower than those reported previously have surgery (n = 11) (MS of 47 vs 16 months, respectively; [6]. Comparatively, it is clear that the management in P = 0.0235). The decision on surgery depended largely our centres took a more conservative approach than on the site of disease and resectability. Four patients others, as evident by the less frequent use of radiotherapy, who underwent resection had received either neoadjuvant surgery and myeloablative chemotherapy with stem cell (n = 2) and adjuvant (n = 2) chemotherapy, one of transplantation. In a review by Hassan et al. of 12 patients whom remains disease-free 10 years after his curative with intra-abdominal DSRCT (all of whom had received surgery. multi-agent chemotherapy), those who underwent surgical Four patients with metastatic, intra-abdominal DSRCT resection had a longer MS of 34 months compared to had radiotherapy for locoregional control – when com- 14 months for those who had biopsy alone [9]. In our pared to a similar group of patients who did not receive study, the MS observed for patients who had resection radiotherapy (n = 29), a significant difference in MS fortheir abdominal orpelvic tumours was47months, wasnoted (47vs14months, respectively; P = 0.0147) compared to 16 months for those who did not. Moreover, (Figure 3). for patients with metastatic intra-abdominal DSRCT, palliative radiotherapy for locoregional disease control appeared to confer a survival advantage (MS of 47 vs Discussion and review of the literature 14 months in those who did not have radiotherapy). In this report, we present one of the largest series of Although patients with localised abdominal or pelvic patients with DSRCT. Consistent with previously pub- disease who underwent surgery appear to have similar lished data, DSRCT tends to occur in younger males. MS (i.e. 47 months) compared to those with metastatic Most patients presented with abdominal or pelvic tumours disease who received palliative radiotherapy, they are and many have evidence of metastases, the majority being by no means comparable and surgery is still indicated in the lungs and liver. in resectable DSRCT. In our series, the only patient Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 5 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Figure 2 Factors not associated with prognostic significance. Kaplan-Meier plots of overall survival stratified according to patient’s (a) age, (b) gender and (c) size of the primary tumour. Figure 3 Factors associated with prognostic significance. Kaplan-Meier plots of overall survival stratified according to (a) site of disease (abdomen/pelvis (n = 37) or other sites (n = 4)), (b) whether patients had undergone surgical resection (n = 6) or not (n = 11) for localised intra-abdominal disease and (c) whether patients with intra-abdominal metastatic disease had radiotherapy (n = 4) or not (n = 29) for locoregional control. Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 6 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 with abdominal disease who has been cured (disease-free P6 protocol, which has seven courses of chemotherapy 10 years from diagnosis) has had chemotherapy and consisting of cyclophosphamide, doxorubicin, vincristine surgical resection. Hence, a more aggressive multimod- (HD-CAV), etoposide and ifosfamide [12]. This was ality treatment approach would seem to be indicated in followed by surgery, radiotherapy, and myeloablative order to prolong survival, although larger prospective trials chemotherapy using thiotepa and carboplatin with stem with quality-of-life measures would be necessary to confirm cell rescue in some cases. All tumours showed a PR with this. This is difficult to perform in such a rare disease. this regimen although there was no CR, and survival of Subbiah et al. presented the largest series of patients around 20 months was reported. This protocol is used diagnosed with DSRCT at the 2012 American Society of in many centres, mainly in resectable cases, although Clinical Oncology meeting [10]. This was a retrospective treatment-related toxicities could be severe. Whether review of 197 patients treated at the MD Anderson Cancer the intensive P6 regimen is better than standard first-line Center (MDACC) and MSKCC. In that series, 87% were chemotherapy regimens used in other small round blue males with a mean age of presentation of 25 years. In cell tumours, such as Ewing’s sarcoma, is unknown. In total, 139 (71%) patients underwent surgery, 38 (19%) two prospective studies by Bertuzzi et al., a total of 17 had debulking surgery, 30 (15%) received radiotherapy, 27 patients were treated with induction chemotherapy (14%) had intraperitoneal chemotherapy after debulking, consisting of ifosfamide, epirubicin and vincristine – and 11 (5%) had stem cell transplant. They found that those who responded were then treated with high-dose radiotherapy, surgery, intraperitoneal chemotherapy, re- chemotherapy and stem cell rescue in conjunction with moval of primary mass and metastases, age <30 years and local therapy (surgery and/or radiotherapy) [13,14]. patients treated after 2003 were associated with improved Approximately half of them achieved an initial PR to survival. In contrast, our study did not show a difference induction chemotherapy, but no CR was achieved with in survival with regards to age of presentation. We also high-dose chemotherapy. The MS reported was 14 months, found that the patient’s gender and size of the presenting leading the authors to question the role of high-dose tumours do not have an impact on survival. Although chemotherapy in the treatment of DSRCT. More recently uncommon, patients who did not have disease in the in a retrospective study using data obtained from the abdomen appeared to have a better outcome. This is likely Center for International Blood and Marrow Transplant to be related to earlier presentation, less advanced disease Research, Cook et al. reported the outcome of 36 DSRCT and in some cases the feasibility of radical resection. patients who had undergone autologous stem cell transplantation [15]. The benefit was much greater for Chemotherapy those who achieved a CR pre-transplantation compared DSRCT is sensitive to chemotherapy although a transient to those who did not, with MS of 36 and 21 months, response followed by disease progression is the norm. respectively. Chemotherapeutic regimes used are normally similar to The use of other chemotherapy drugs has been reported, those for treating Ewing’s sarcoma. Farhat et al.treated including irinotecan, temozolomide and vinorelbine, five patients with a chemotherapeutic regime consisted but none of them showed superiority [16,17]. Evidence of cisplatin, etoposide, cyclophosphamide and an anthra- and experience is emerging on the role of trabectedin cycline – disease stabilisation lasting 4 to 9 months were in the management of metastatic DSRCT [18-20]. In a noted in four patients with intra-abdominal DSRCT case report, an 18-year-old boy with abdominal DSRCT after initial surgery, whereas one patient with relapsed was initially treated by complete surgical excision, followed metastatic disease from an initial paratesticular primary by adjuvant chemotherapy with cyclophosphamide, do- attained a complete response (CR) [11]. The authors also xorubicin/actinomycin D, vincristine, alternating with reviewed the literature of 60 patients who were treated by ifosfamide and etoposide [20]. Disease recurrence was treated with surgery and cisplatin and irinotecan, but this chemotherapy with or without abdominal radiotherapy, and objective responses were found in 17 patients, was followed by further progression for which trabectedin eight of whom achieved a CR. The chemotherapy was given, resulting in PR. This resulted in a survival of 4 years from diagnosis. agents associated with CR were those of doxorubicin, cyclophosphamide, vincristine and cisplatin. These are Similar to ovarian cancer, the use of hyperthermic in line with our results, with these drugs providing the intraperitoneal chemotherapy has also been reported given the tendency of the disease to spread within the longest TTP. Chemotherapy is often given in the metastatic setting; and although often used, the role of neoadjuvant peritoneum. Heated cisplatin is given at a dose 100 to and adjuvant chemotherapy in localised disease remains 150 mg/m intraperitoneally after optimal cytoreductive unknown. surgery. The series reported by the MDACC showed Kushner et al. reported 12 patients (10 treatment-naïve that this method is safe and might have activity in and two had previous chemotherapy) who received the paediatric patients, and a survival benefit has also been Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 7 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 reported [10,21-23]. Further studies are required before Chromosomal translocation resulting in the fusion of this could be widely adopted. the EWSR1 and WT1 genes is the molecular characteristic of DSRCT. The resulting fusion protein has been found to activate the IGF-1R gene promoter, causing the expression Radiotherapy of this anti-apoptotic receptor tyrosine kinase [30-32]. The Whole-abdominopelvic radiotherapy (WAP-RT) after max- understanding of this mechanism has provided a novel imal surgery was first reported by Kushner et al.atthe target for the treatment of this disease. In a recent phase MSKCC as part of a multimodality treatment using the II study, 16 patients with DSRCT who had had previous P6 protocol, with the aim of improving local control treatments were given 12 mg/kg of the anti-IGF-1R anti- [12]. A total dose of 30 Gy was delivered post-operatively, body ganitumab intravenously [33]. Common side effects with simultaneous boost given to sites of gross residual include fatigue, nausea, dyspnoea and peripheral oedema. disease. Conventional two-dimensional radiotherapy was PR was noted in one (6%) patient, whereas 10 (63%) associated with significant gastrointestinal and haemato- had stable disease (SD) as their best response, with 3 logic toxicities, with long term side effects including (18%) achieving SD lasting ≥24 weeks. Median PFS was small bowel obstruction and ureteral stenosis [24]. For 19 months, indicating a potential role of ganitumab this reason, the use of WAP intensity-modulated radiation used either alone or in combination with chemotherapy therapy (WAP-IMRT) was studied by Pinnix et al.at for patients with DSRCT. In a phase I study of another the MDACC [25]. All of the eight patients had received anti-IGF-1R antibody cixutumumab in combination prior chemotherapy and surgical debulking (seven of with temsirolimus, two out of three patients with them also had intraperitoneal cisplatin). One patient was previously-treated DSRCT had SD lasting longer than still disease-free 20 months after treatment, although 5months[34]. the rest experienced either local or distant failure after Tumour-specific antigens have also been studied as amedianof8.73monthsfromWAP-IMRT. Aretrospective targets for immunotherapy, including the disialoganglio- analysis at the MSKCC looked at 31 patients who under- side GD2 and the antigen recognised by the antibody went WAP-RT, either with conventional two-dimensional 8H9 (expressed in 70% and 96% of DSRCT, respectively) radiotherapy (n = 22) or IMRT (n = 9) after chemotherapy [35]. In particular, studies of anti-GD2 antibodies have and maximal debulking surgery [26]. IMRT was associated shown some promising results in the treatment of with lower incidence of acute gastrointestinal and neuroblastoma [36]. Another potential therapeutic target haematologic toxicities. The 3-year overall survival and is the lysine-specific demethylase 1, a key histone modifi- progression-free survival (PFS) rates were 50% and 24%, cation enzyme involved in controlling gene expression respectively. Anecdotally, a patient in this series who which if dysregulated, could result in tumourigenesis received WAP-RT developed a serious malabsorption [37]. It is found to be highly expressed in several highly syndrome subsequent to gastrointestinal damage. Given malignant sarcomas including DSRCT [38]. It could the limited data of efficacy, WAP-RT is currently not be inhibited by small molecule inhibitors and further routinely used in the management of DSRCT. investigation is warranted. Targeted therapies Conclusions In recent years, targeted therapies have been studied in Advanced DSRCT is a rare, aggressive disease with DSRCT. Drugs that have shown activity against this invariably poor outcome that generally occurs in young disease include the TKI sunitinib and the mTOR in- men. It has a propensity to metastasise and at present, hibitor temsirolimus [27,28]. In our cohort of patients, surgery, combination cytotoxic chemotherapy and radio- other non-standard agents used include the anti-IGF-1R therapy remain the only standard therapeutic options. In antibody figitumumab, the TKIs axitinib, pazopanib, our study, we found that patients with intra-abdominal sorafenib and sunitinib, as well as the mTOR inhibitor DSRCT have a poorer prognosis, although surgical sirolimus. The number of patients is too small to draw resection for localised disease and radiotherapy, even any conclusion about their efficacy. Due to the fact in the metastatic setting for locoregional control, are that DSRCT has a predilection to occur in young associated with improved survival. males, Fine et al. discovered that androgen receptor is Clearly more efforts are needed to improve the progno- expressed in 37% of DSRCT [29]. Six of their patients sis of patients with DSRCT, and the development of novel were treated with combined androgen blockade and targeted agents is likely to have a major role in altering the three attained a clinical benefit. In our study, one patient course of the disease. It is also hope that the International had received the gonadotropin-releasing hormone agonist Rare Cancers Initiative, a multinational collaboration with goserelin. However, no significant anti-tumoural efficacy the aim of developing clinical trials for uncommon malig- was noted. nancies, will help to address this issue in the future. Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 8 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Competing interests stem cell transplantation in adult patients with advanced desmoplastic The authors declare that they have no competing interests. small round-cell tumour. Br J Cancer 2003, 89:1159–1161. 15. Cook RJ, Wang Z, Arora M, Lazarus HM, Kasow KA, Champagne MA, Saber W, van Besien KM, Hale GA, Copelan EA, Elmongy M, Ueno NT, Horn BN, Slavin S, Authors’ contributions Bishop MR, Stadtmauer EA: Clinical outcomes of patients with desmoplastic All authors were involved in data collection. HHW, HMH and OA analysed small round cell tumor of the peritoneum undergoing autologous HCT: a the data. HHW and HMH drafted the manuscript. HHW, HMH, CB, GH, CF, CIBMTR retrospective analysis. Bone Marrow Transpl 2012, 47:1455–1458. HME and IJ all contributed to the manuscript preparation. All authors read 16. Rosoff PM, Bayliff S: Successful clinical response to irinotecan in and approved the final manuscript. desmoplastic round blue cell tumor. Med Pediatr Oncol 1999, 33:500–503. 17. Ferrari A, Grosso F, Stacchiotti S, Meazza C, Zaffignani E, Marchianò A, Casanova M: Response to vinorelbine and low-dose cyclophosphamide Acknowledgements chemotherapy in two patients with desmoplastic small round cell tumor. We acknowledge support from the NIHR RM/ICR Biomedical Research Centre. Pediatr Blood Cancer 2007, 49:864–866. Author details 18. Hendifar AE, Chawla SP, Leahy MG, Italiano A, Patel S, Santoro A, Staddon AP, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Penel N, Piperno-Neumann S, Demetri GD, Hayward L, White J, Gouw LG, De Trust, Hills Road, Cambridge CB2 0QQ, UK. Sarcoma Unit, The Royal Miguel B, Lardelli P, Soto A, Nieto A, Blay J-Y: Results of the randomized phase Marsden, Fulham Road, London SW3 6JJ, UK. Department of III trial of trabectedin (T) versus doxorubicin-based chemotherapy (DXCT) as Histopathology, The Royal Marsden, Fulham Road, London SW3 6JJ, UK. first-line therapy in patients (pts) with translocation-related sarcoma (TRS). University of Cambridge Department of Oncology and NIHR Cambridge JClin Oncol 2013, 31:10517. Biomedical Research Centre, Hills Road, Cambridge CB2 0QQ, UK. 19. Chuk MK, Aikin A, Whitcomb T, Widemann BC, Zannikos P, Bayever E, Balis FM, Fox E: A phase I trial and pharmacokinetic study of a 24-hour infusion of Received: 3 October 2013 Accepted: 22 November 2013 trabectedin (Yondelis , ET-743) in children and adolescents with relapsed or Published: 26 November 2013 refractory solid tumors. Pediatr Blood Cancer 2012, 59:865–869. 20. López-González A, Cantos B, Tejerina E, Provencio M: Activity of trabectidin in desmoplastic small round cell tumor. Med Oncol 2011, References 28(Suppl 1):S644–S646. 1. Gerald WL, Ladanyi M, de Alava E, Cuatrecasas M, Kushner BH, LaQuaglia MP, 21. Hayes-Jordan A, Anderson P, Curley S, Herzog C, Lally KP, Green HL, Hunt K, Rosai J: Clinical, pathologic, and molecular spectrum of tumors associated Mansfield P: Continuous hyperthermic peritoneal perfusion for with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. desmoplastic small round cell tumor. J Pediatr Surg 2007, 42:E29–E32. JClin Oncol 1998, 16:3028–3036. 22. Aguilera D, Hayes-Jordan A, Anderson P, Woo S, Pearson M, Green H: 2. Gerald WL, Rosai J: Case 2. Desmoplastic small cell tumor with divergent Outpatient and home chemotherapy with novel local control strategies differentiation. Pediatr Pathol 1989, 9:177–183. in desmoplastic small round cell tumor. Sarcoma 2008, 2008:261589. 3. Chang F: Desmoplastic small round cell tumors: cytologic, histologic, and 23. Hayes-Jordan A, Green H, Fitzgerald N, Xiao L, Anderson P: Novel treatment immunohistochemical features. Arch Pathol Lab Med 2006, 130:728–732. for desmoplastic small round cell tumor: hyperthermic intraperitoneal 4. Ladanyi M, Gerald W: Fusion of the EWS and WT1 genes in the perfusion. J Pediatr Surg 2010, 45:1000–1006. desmoplastic small round cell tumor. Cancer Res 1994, 54:2837–2840. 24. Goodman KA, Wolden SL, La Quaglia MP, Kushner BH: Whole 5. Kretschmar CS, Colbach C, Bhan I, Crombleholme TM: Desmoplastic small abdominopelvic radiotherapy for desmoplastic small round-cell tumor. cell tumor: a report of three cases and a review of the literature. J Pediatr Int J Radiat Oncol Biol Phys 2002, 54:170–176. Hematol Oncol 1996, 18:293–298. 25. Pinnix CC, Fontanilla HP, Hayes-Jordan A, Subbiah V, Bilton SD, Chang EL, 6. Dufresne A, Cassier P, Couraud L, Marec-Bérard P, Meeus P, Alberti L, Blay J-Y: Grosshans DR, McAleer MF, Sulman EP, Woo SY, Anderson P, Green HL, Desmoplastic small round cell tumor: current management and recent Mahajan A: Whole abdominopelvic intensity-modulated radiation therapy findings. Sarcoma 2012, 2012:714986. for desmoplastic small round cell tumor after surgery. Int J Radiat Oncol 7. Schwarz RE, Gerald WL, Kushner BH, Coit DG, Brennan MF, La Quaglia MP: Biol Phys 2012, 83:317–326. Desmoplastic small round cell tumors: prognostic indicators and results 26. Desai NB, Stein NF, LaQuaglia MP, Alektiar KM, Kushner BH, Modak S, of surgical management. Ann Surg Oncol 1998, 5:416–422. Magnan HM, Goodman K, Wolden SL: Reduced toxicity with intensity 8. Lal DR, Su WT, Wolden SL, Loh KC, Modak S, La Quaglia MP: Results of modulated radiation therapy (IMRT) for desmoplastic small round cell multimodal treatment for desmoplastic small round cell tumors. J Pediatr tumor (DSRCT): an update on the whole abdominopelvic radiation therapy Surg 2005, 40:251–255. (WAP-RT) experience. Int J Radiat Oncol Biol Phys 2013, 85:e67–e72. 9. Hassan I, Shyyan R, Donohue JH, Edmonson JH, Gunderson LL, Moir CR, 27. Italiano A, Kind M, Cioffi A, Maki RG, Bui B: Clinical activity of sunitinib in Arndt CAS, Nascimento AG, Que FG: Intraabdominal desmoplastic small patients with advanced desmoplastic round cell tumor: a case series. round cell tumors: a diagnostic and therapeutic challenge. Cancer 2005, Target Oncol 2013, 8:211–213. 104:1264–1270. 28. Thijs AMJ, van der Graaf WTA, van Herpen CML: Temsirolimus for metastatic 10. Subbiah V, Viny AD, Anderson PM, Hayes-Jordan AA, Qiao W, Benjamin RS, desmoplastic small round cell tumor. Pediatr Blood Cancer 2010, 55:1431–1432. Maki RG, Ludwig JA: Optimizing the therapy of desmoplastic small round 29. Fine RL, Shah SS, Moulton TA, Yu I-R, Fogelman DR, Richardson M, Burris HA, cell tumor: combined experience from the two major cancer centers. Samuels BL, Assanasen C, Gorroochurn P, Hibshoosh H, Orjuela M, J Clin Oncol 2012, 30:10021. Garvin J, Goldman FD, Dubovsky D, Walterhouse D, Halligan G: Androgen 11. Farhat F, Culine S, Lhommé C, Duvillard P, Soulié P, Michel G, Terrier-Lacombe MJ, and c-Kit receptors in desmoplastic small round cell tumors resistant to Théodore C, Schreinerova M, Droz JP: Desmoplastic small round cell chemotherapy: novel targets for therapy. Cancer Chemother Pharmacol 2007, tumors: results of a four-drug chemotherapy regimen in five adult patients. 59:429–437. Cancer 1996, 77:1363–1366. 30. Karnieli E, Werner H, Rauscher FJ, Benjamin LE, LeRoith D: The IGF-I receptor 12. Kushner BH, LaQuaglia MP, Wollner N, Meyers PA, Lindsley KL, Ghavimi F, gene promoter is a molecular target for the Ewing’s sarcoma-Wilms’ tumor Merchant TE, Boulad F, Cheung NK, Bonilla MA, Crouch G, Kelleher JF, 1 fusion protein. JBiol Chem 1996, 271:19304–19309. Steinherz PG, Gerald WL: Desmoplastic small round-cell tumor: prolonged 31. Finkeltov I, Kuhn S, Glaser T, Idelman G, Wright JJ, Roberts CT, Werner H: progression-free survival with aggressive multimodality therapy. J Clin Transcriptional regulation of IGF-I receptor gene expression by novel Oncol 1996, 14:1526–1531. isoforms of the EWS-WT1 fusion protein. Oncogene 2002, 21:1890–1898. 13. Bertuzzi A, Castagna L, Nozza A, Quagliuolo V, Siracusano L, Balzarotti M, 32. Werner H, Idelman G, Rubinstein M, Pattee P, Nagalla SR, Roberts CT: A Compasso S, Alloisio M, Soto Parra H, Santoro A: High-dose chemotherapy novel EWS-WT1 gene fusion product in desmoplastic small round cell in poor-prognosis adult small round-cell tumors: clinical and molecular tumor is a potent transactivator of the insulin-like growth factor-I receptor results from a prospective study. J Clin Oncol 2002, 20:2181–2188. (IGF-IR) gene. Cancer Lett 2007, 247:84–90. 14. Bertuzzi A, Castagna L, Quagliuolo V, Ginanni V, Compasso S, Magagnoli M, 33. Tap WD, Demetri G, Barnette P, Desai J, Kavan P, Tozer R, Benedetto PW, Balzarotti M, Nozza A, Siracusano L, Timofeeva I, Sarina B, Parra HS, Santoro A: Friberg G, Deng H, McCaffery I, Leitch I, Badola S, Chang S, Zhu M, Tolcher A: Prospective study of high-dose chemotherapy and autologous peripheral Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 9 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic ewing family tumors or desmoplastic small round cell tumors. JClin Oncol 2012, 30:1849–1856. 34. Naing A, LoRusso P, Fu S, Hong DS, Anderson P, Benjamin RS, Ludwig J, Chen HX, Doyle LA, Kurzrock R: Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res 2012, 18:2625–2631. 35. Modak S, Gerald W, Cheung N-K V: Disialoganglioside GD2 and a novel tumor antigen: potential targets for immunotherapy of desmoplastic small round cell tumor. Med Pediatr Oncol 2002, 39:547–551. 36. Yang RK, Sondel PM: Anti-GD2 strategy in the treatment of neuroblastoma. Drugs Futur 2010, 35:665. 37. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004, 119:941–953. 38. Schildhaus H-U, Riegel R, Hartmann W, Steiner S, Wardelmann E, Merkelbach-Bruse S, Tanaka S, Sonobe H, Schüle R, Buettner R, Kirfel J: Lysine-specific demethylase 1 is highly expressed in solitary fibrous tumors, synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors, and malignant peripheral nerve sheath tumors. Hum Pathol 2011, 42:1667–1675. doi:10.1186/2045-3329-3-14 Cite this article as: Wong et al.: Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and review of the literature. Clinical Sarcoma Research 2013 3:14. 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Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and review of the literature

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Copyright © 2013 by Wong et al.; licensee BioMed Central Ltd.
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Biomedicine; Cancer Research; Oncology; Surgical Oncology
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Abstract

Background: Desmoplastic small round cell tumour (DSRCT) is a rare but frequently fatal sarcoma, and many of its characteristics still require further clarification. Methods: We retrospectively analysed 41 patients treated at or referred to two regional referral centres in the UK between 1991 and 2012. A review of the current literature was also performed. Results: The median age of presentation was 27 years (range 16 to 45 years), with a male-to-female ratio of 3:1. Ninety percent of patients had disease in the abdomen. The median size of the presenting tumour was 13 cm (range 3.5 to 23 cm), and 80% had metastatic disease at diagnosis, mainly in the liver (33%) and lungs (21%). Time-to-progression (TTP) was 3.9, 2.3 and 1.1 months after first-, second- and third-line chemotherapy, respectively. First-line treatment with VIDE chemotherapy appeared to confer the longest TTP (median 14.6 months). Ifosfamide and doxorubicin resulted in TTP of >3.8 months when used in any-line setting. Eleven patients received targeted agents as part of a clinical trial. After a median follow-up of 14 months, the overall median survival (MS) was 16 months. There was no difference in MS with regards to age, gender, or size of the presenting tumour. Patients with extra-abdominal disease survived longer compared to those with tumours in the abdomen (all still alive vs MS of 15 months; P = 0.0246). Patients with non-metastatic intra-abdominal disease who underwent surgery had an MS of 47 months (16 months for those who did not have surgery; P = 0.0235). Radiotherapy for locoregional control in patients with metastatic intra-abdominal DSRCT was associated with longer survival (MS of 47 vs 14 months; P = 0.0147). Conclusions: DSRCT is a rare but often fatal disease that mainly affects younger male patients. Those with intra-abdominal DSRCT have a poorer prognosis, although surgical resection for localised disease and radiotherapy in the metastatic setting are associated with improved survival. A patient’s age, gender and size of presenting tumour do not have prognostic significance. Keywords: Desmoplastic small round cell tumour, Sarcoma, Prognosis, Survival, Treatment Background differentiated small round blue cells lying within an Desmoplastic small round cell tumour (DSRCT) is a rare abundant fibrosclerotic stroma [2]. These cells co-express but highly aggressive neoplasm that typically occurs in epithelial, mesenchymal, myogenic and neural markers [3], adolescent and young males. An earlier study has found but are distinguished by the chromosomal translocation a male-to-female ratio of approximately 5 to 1 and a t(11;22)(p13;q12) resulting in the fusion of the Ewing’s mean age at diagnosis of 22 years [1]. First described sarcoma (EWSR1) and the Wilms’ tumour (WT1)genes in 1989, it is characterised by clusters of poorly [4]. DSRCT generally develops in the abdomen and have a tendency towards peritoneal spread, with subsequent metastasis to distant lymph nodes, liver and lungs [5]. * Correspondence: han.wong@addenbrookes.nhs.uk In this study, we retrospectively reviewed 41 patients Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Trust, Hills Road, Cambridge CB2 0QQ, UK with DSRCT who were treated at or referred to two Full list of author information is available at the end of the article © 2013 Wong et al.; licensee BioMed Central Ltd. This is an Open Access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/2.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 2 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Table 1 Patient characteristics (n = 41) regional sarcoma centres in the UK. Analysis of survival and prognostic factors, as well as review of the current Variables No. of patients (%) literature on the management of DSCRT, was performed. Gender This series is comparable in size with other large series Male 31 (76%) previously reported. Female 10 (24%) Median age (years) 27 (range 16 – 45) Methods Presenting site Patient groups Abdomen and pelvis 37 (90%) The Royal Marsden Hospital in London and in Sutton, Prostate 1 (2.4%) UK, and Addenbrooke’s Hospital in Cambridge, UK, are regional sarcoma referral centres for London and Testis 1 (2.4%) South East England, and for East of England, respectively. Shoulder 1 (2.4%) Patients with DSRCT treated at or referred to these Thigh 1 (2.4%) two centres between the years of 1991 and 2012 were Median tumour size at diagnosis (cm) 13 (range 3.5 – 23) identified retrospectively. Diagnosis was confirmed by Metastasis at presentation 33 (80%) immunohistochemistry and reviewed by central specialist Sites of metastasis at presentation (n = 33) histopathologists. Cytogenetic analysis for EWSR1-WT1 rearrangement was performed when available. Patients’ Liver 11 (33%) medical and treatment records were analysed. All 41 Lung 7 (21%) patients identified were included in the study. Approval Peritoneal cavity 6 (18%) from the local research ethics committee was obtained Lymph node 5 (15%) prior to data collection. Bone 3 (9%) Adrenal 1 (3%) Statistical analysis Chest wall 1 (3%) Time-to-progression (TTP) is the time interval from Prostate 1 (3%) completion of chemotherapy to radiological disease pro- gression as defined by Response Evaluation Criteria in Solid Tumours (RECIST). Survival analysis was performed Treatments using the Kaplan-Meier method and log rank test. Surviving The treatments received by this cohort of patients are patients were censored at last contact. summarised in Table 2. Thirty eight patients (93%) have had chemotherapy, with the majority of them receiving Results it with palliative intent. Four and two patients received Patient characteristics neoadjuvant and adjuvant chemotherapy, respectively. Of A total of 41 patients were referred to or treated at these, three subsequently developed metastatic disease. the centres between 1991 and 2012. Thirteen of these The commonest chemotherapeutic regimes were those were referred for opinion only and were managed sub- frequently used in other small round cell tumours, i.e. a sequently at their local hospitals. Diagnosis of DSRCT combination of an anthracycline, alkylating agent and was confirmed by central specialist histopathological vinca alkaloid. Topoisomerase inhibitors, taxanes and review. Cytogenetic testing for EWSR1-WT1 rearrange- platinums have also been used. As the effectiveness of ment was only routinely available in some centres after second- or subsequent-line chemotherapy is also unproven, 2008, therefore only 14 patients were tested and found a number of newer agents had been given as part of a to be positive. Patient characteristics are summarised in clinical trial, including inhibitor of the mammalian target Table 1. The age of presentation ranges from 16 to of rapamycin (mTOR) pathway, tyrosine kinase inhibitors 45 years, with a median of 27 years. About three quarter (TKIs), and antibody against the insulin-like growth of the patients were males. The majority of patients factor-1 receptor (IGF-1R). presented with abdominal or pelvic tumours (i.e. arising In our series, only six patients received radiotherapy. from the retroperitoneum or within the peritoneal cavity One patient each had radical radiotherapy after resection with no clear indication of organ of origin), with sizes of an abdominal (54 Gy in 30 fractions) and thigh (60 Gy ranging from 3.5 to 23 cm. Four patients with extra- in 30 fractions) tumour, respectively. The remaining four abdominal disease had disease in the prostate, testis, patients received palliative conformal radiotherapy (20 Gy shoulder and thigh, respectively. Eighty percent of the in five fractions) to the abdomen for locoregional control patients had evidence of metastasis at presentation, in metastatic disease. Resection or optimal debulking of with lungs and liver being the commonest sites. the primary tumour was done in eight patients, whereas Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 3 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Table 2 Treatment and chemotherapeutic regimens Table 2 Treatment and chemotherapeutic regimens (n = 41) (n = 41) (Continued) Variables No. of - IVADo 1 patients (%) - Liposomal doxorubicin 1 Treatment modality - VIDE 1 Chemotherapy 38 (93%) Subsequent-line (with non-standard therapies) - Neoadjuvant 4 (10%) - Figitumumab 2 - Adjuvant 2 (5%) - Sirolimus + cyclophosphamide or 2 - Palliative (including relapse after neoadjuvant/ 35 (85%) liposomal doxorubicin adjuvant treatment) - Pazopanib +/− etoposide 2 Radiotherapy - Sunitinib 2 - Radical 2 (5%) - Axitinib 1 - Palliative 4 (10%) - Goserelin 1 Surgery and its indications - Interferon 1 - Diagnosis 14 (34%) - Semaxanib 1 - Resection/optimal debulking of 8 (20%) - Sorafenib 1 primary tumour Chemotherapy in 14 patients surgery was performed for diagnostic First-line purposes. - Vincristine + ifosfamide + 13 doxorubicin + etoposide (VIDE) - Ifosfamide + vincristine + actinomycin 7 Time-to-progression and survival D + doxorubicin (IVADo) TTP after first- to third- line systemic therapies are - Cyclophosphamide or ifosfamide + etoposide 4 summarised in Table 3. Unsurprisingly, the median TTP - Vincristine + doxorubicin + 4 decreases with increasing lines of treatment. First-line cyclophosphamide (VAC) or vincristine + treatment with VIDE chemotherapy appeared to confer ifosfamide + doxorubicin the longest TTP (median of 14.6 months; range 1.9 to - Bleomycin + etoposide + cisplatin 2 33.7 months). In second-line treatment, etoposide alone - Ifosfamide + doxorubicin 2 (n = 1), or in combination with platinum (n = 9) or ifosfa- - Carboplatin + etoposide 1 mide (n =2), were most commonly used, with a median - Carboplatin + paclitaxel 1 TTP of 3.4 months (range 0.3 to 13.9 months). Ifosfamide - Cisplatin + doxorubicin/paclitaxel + 1 and doxorubicin treatment resulted in a median TTP cisplatin + ifosfamide of >3.8 months when used in any line-setting. - Doxorubicin 1 The median follow-up period for all patients was - Epirubicin + cisplatin + capecitabine 1 14 months (range 1 to 127 months). Sixteen (39%) patients were still alive at a median follow-up of 12.5 months. All - Ifosfamide + carboplatin + etoposide 1 deaths were due to the disease. The overall median survival - Ifosfamide + vincristine + actinomycin D 1 (MS) was 16 months (range 2 to >127 months) (Figure 1). Subsequent-line (with chemotherapeutic agents) Three-year and 5-year survival rates were 27% and - Platinum + etoposide 10 16%, respectively. The longest surviving patient had - Etoposide 5 disease in his prostate, and he presented early with - Ifosfamide + etoposide 5 symptoms of urinary outflow obstruction. He still has no evidence of disease for more than 10 years after his - Doxorubicin 2 initial diagnosis. Three other patients who presented - Ifosfamide + doxorubicin 2 early with lumps in the testis, shoulder and thigh, - Cyclophosphamide + topotecan 2 - VAC 2 Table 3 Time-to-progression after systemic therapy - Gemcitabine or irinotecan + temozolomide 2 Line of treatment Median time-to-progression (months) - Albumin-bound paclitaxel 1 First (n = 38) 3.9 (range 0.6 to 33.7) - Cisplatin + mitomycin C + irinotecan 1 Second (n = 23) 2.3 (range 0.3 to 13.9) - Doxorubicin + etoposide 1 Third (n = 13) 1.1 (range 0.6 to 11.8) Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 4 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Multimodality treatment of DSRCT and prognostic factors The reported MS of DSRCT is in the region of 17 to 25 months [6]. Given the poor outcome of the disease and the significant morbidities and mortality associ- ated with its treatment, prognostic indicators are very important. Two retrospective studies performed at the Memorial Sloan-Kettering Cancer Center (MSKCC) have both found that aggressive surgical debulking of DSRCT is of prognostic significance [7,8]. An analysis of 32 patients by Schwarz et al. demonstrated that improved survival was found to be associated with the following: more than 90% surgical debulking either before or after chemotherapy, complete or very good partial response (PR) to multimodality treatment, and use of the P6 Figure 1 Kaplan-Meier plot of overall survival for the entire protocol (see below) [7]. In a report of 66 patients by cohort (n = 41). Lal et al., treatment with chemotherapy, surgery and radiotherapy conferred a 3-year survival of 55% com- respective, are still alive at the time of last follow-up, paredto27% forthose whodid notreceive allthree albeit with evidence of metastatic disease. treatments [8]. In addition, gross tumour resection was There was no difference in MS with regards to age also associated with prolonged survival (3-year survival (15vs 16monthsfor those ≤25 years and >25 years, of 58% compared to 0% in the non-resected patients). respectively; P = 0.7899), gender (16 vs 15 months for Naturally such an analysis performed retrospectively males and females, respectively; P = 0.5369), or whether cannot adequately control for the fact that patients the presenting tumour was ≤ or >10 cm (32 vs 13 months; with radically resectable disease are likely to have less P = 0.4195) (Figure 2). bulky and more localised tumours. Patients with extra-abdominal disease (n = 4) survived There is no general consensus on the best therapeutic longer compared to those with tumours in the abdomen approach, as strong evidence is lacking given the rarity or pelvis (n = 37) (all still alive vs MS of 15 months, of the disease, although multimodality treatment with respectively; P = 0.0246). Patients with non-metastatic, chemotherapy, surgery and radiotherapy appears to intra-abdominal and -pelvic disease at presentation who represent optimal management. The MS of patients had undergone surgical resection of the primary tumour diagnosedwith DSRCT was16monthsin thisstudy, (n = 6) survived much longer than those who did not which is slightly lower than those reported previously have surgery (n = 11) (MS of 47 vs 16 months, respectively; [6]. Comparatively, it is clear that the management in P = 0.0235). The decision on surgery depended largely our centres took a more conservative approach than on the site of disease and resectability. Four patients others, as evident by the less frequent use of radiotherapy, who underwent resection had received either neoadjuvant surgery and myeloablative chemotherapy with stem cell (n = 2) and adjuvant (n = 2) chemotherapy, one of transplantation. In a review by Hassan et al. of 12 patients whom remains disease-free 10 years after his curative with intra-abdominal DSRCT (all of whom had received surgery. multi-agent chemotherapy), those who underwent surgical Four patients with metastatic, intra-abdominal DSRCT resection had a longer MS of 34 months compared to had radiotherapy for locoregional control – when com- 14 months for those who had biopsy alone [9]. In our pared to a similar group of patients who did not receive study, the MS observed for patients who had resection radiotherapy (n = 29), a significant difference in MS fortheir abdominal orpelvic tumours was47months, wasnoted (47vs14months, respectively; P = 0.0147) compared to 16 months for those who did not. Moreover, (Figure 3). for patients with metastatic intra-abdominal DSRCT, palliative radiotherapy for locoregional disease control appeared to confer a survival advantage (MS of 47 vs Discussion and review of the literature 14 months in those who did not have radiotherapy). In this report, we present one of the largest series of Although patients with localised abdominal or pelvic patients with DSRCT. Consistent with previously pub- disease who underwent surgery appear to have similar lished data, DSRCT tends to occur in younger males. MS (i.e. 47 months) compared to those with metastatic Most patients presented with abdominal or pelvic tumours disease who received palliative radiotherapy, they are and many have evidence of metastases, the majority being by no means comparable and surgery is still indicated in the lungs and liver. in resectable DSRCT. In our series, the only patient Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 5 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Figure 2 Factors not associated with prognostic significance. Kaplan-Meier plots of overall survival stratified according to patient’s (a) age, (b) gender and (c) size of the primary tumour. Figure 3 Factors associated with prognostic significance. Kaplan-Meier plots of overall survival stratified according to (a) site of disease (abdomen/pelvis (n = 37) or other sites (n = 4)), (b) whether patients had undergone surgical resection (n = 6) or not (n = 11) for localised intra-abdominal disease and (c) whether patients with intra-abdominal metastatic disease had radiotherapy (n = 4) or not (n = 29) for locoregional control. Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 6 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 with abdominal disease who has been cured (disease-free P6 protocol, which has seven courses of chemotherapy 10 years from diagnosis) has had chemotherapy and consisting of cyclophosphamide, doxorubicin, vincristine surgical resection. Hence, a more aggressive multimod- (HD-CAV), etoposide and ifosfamide [12]. This was ality treatment approach would seem to be indicated in followed by surgery, radiotherapy, and myeloablative order to prolong survival, although larger prospective trials chemotherapy using thiotepa and carboplatin with stem with quality-of-life measures would be necessary to confirm cell rescue in some cases. All tumours showed a PR with this. This is difficult to perform in such a rare disease. this regimen although there was no CR, and survival of Subbiah et al. presented the largest series of patients around 20 months was reported. This protocol is used diagnosed with DSRCT at the 2012 American Society of in many centres, mainly in resectable cases, although Clinical Oncology meeting [10]. This was a retrospective treatment-related toxicities could be severe. Whether review of 197 patients treated at the MD Anderson Cancer the intensive P6 regimen is better than standard first-line Center (MDACC) and MSKCC. In that series, 87% were chemotherapy regimens used in other small round blue males with a mean age of presentation of 25 years. In cell tumours, such as Ewing’s sarcoma, is unknown. In total, 139 (71%) patients underwent surgery, 38 (19%) two prospective studies by Bertuzzi et al., a total of 17 had debulking surgery, 30 (15%) received radiotherapy, 27 patients were treated with induction chemotherapy (14%) had intraperitoneal chemotherapy after debulking, consisting of ifosfamide, epirubicin and vincristine – and 11 (5%) had stem cell transplant. They found that those who responded were then treated with high-dose radiotherapy, surgery, intraperitoneal chemotherapy, re- chemotherapy and stem cell rescue in conjunction with moval of primary mass and metastases, age <30 years and local therapy (surgery and/or radiotherapy) [13,14]. patients treated after 2003 were associated with improved Approximately half of them achieved an initial PR to survival. In contrast, our study did not show a difference induction chemotherapy, but no CR was achieved with in survival with regards to age of presentation. We also high-dose chemotherapy. The MS reported was 14 months, found that the patient’s gender and size of the presenting leading the authors to question the role of high-dose tumours do not have an impact on survival. Although chemotherapy in the treatment of DSRCT. More recently uncommon, patients who did not have disease in the in a retrospective study using data obtained from the abdomen appeared to have a better outcome. This is likely Center for International Blood and Marrow Transplant to be related to earlier presentation, less advanced disease Research, Cook et al. reported the outcome of 36 DSRCT and in some cases the feasibility of radical resection. patients who had undergone autologous stem cell transplantation [15]. The benefit was much greater for Chemotherapy those who achieved a CR pre-transplantation compared DSRCT is sensitive to chemotherapy although a transient to those who did not, with MS of 36 and 21 months, response followed by disease progression is the norm. respectively. Chemotherapeutic regimes used are normally similar to The use of other chemotherapy drugs has been reported, those for treating Ewing’s sarcoma. Farhat et al.treated including irinotecan, temozolomide and vinorelbine, five patients with a chemotherapeutic regime consisted but none of them showed superiority [16,17]. Evidence of cisplatin, etoposide, cyclophosphamide and an anthra- and experience is emerging on the role of trabectedin cycline – disease stabilisation lasting 4 to 9 months were in the management of metastatic DSRCT [18-20]. In a noted in four patients with intra-abdominal DSRCT case report, an 18-year-old boy with abdominal DSRCT after initial surgery, whereas one patient with relapsed was initially treated by complete surgical excision, followed metastatic disease from an initial paratesticular primary by adjuvant chemotherapy with cyclophosphamide, do- attained a complete response (CR) [11]. The authors also xorubicin/actinomycin D, vincristine, alternating with reviewed the literature of 60 patients who were treated by ifosfamide and etoposide [20]. Disease recurrence was treated with surgery and cisplatin and irinotecan, but this chemotherapy with or without abdominal radiotherapy, and objective responses were found in 17 patients, was followed by further progression for which trabectedin eight of whom achieved a CR. The chemotherapy was given, resulting in PR. This resulted in a survival of 4 years from diagnosis. agents associated with CR were those of doxorubicin, cyclophosphamide, vincristine and cisplatin. These are Similar to ovarian cancer, the use of hyperthermic in line with our results, with these drugs providing the intraperitoneal chemotherapy has also been reported given the tendency of the disease to spread within the longest TTP. Chemotherapy is often given in the metastatic setting; and although often used, the role of neoadjuvant peritoneum. Heated cisplatin is given at a dose 100 to and adjuvant chemotherapy in localised disease remains 150 mg/m intraperitoneally after optimal cytoreductive unknown. surgery. The series reported by the MDACC showed Kushner et al. reported 12 patients (10 treatment-naïve that this method is safe and might have activity in and two had previous chemotherapy) who received the paediatric patients, and a survival benefit has also been Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 7 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 reported [10,21-23]. Further studies are required before Chromosomal translocation resulting in the fusion of this could be widely adopted. the EWSR1 and WT1 genes is the molecular characteristic of DSRCT. The resulting fusion protein has been found to activate the IGF-1R gene promoter, causing the expression Radiotherapy of this anti-apoptotic receptor tyrosine kinase [30-32]. The Whole-abdominopelvic radiotherapy (WAP-RT) after max- understanding of this mechanism has provided a novel imal surgery was first reported by Kushner et al.atthe target for the treatment of this disease. In a recent phase MSKCC as part of a multimodality treatment using the II study, 16 patients with DSRCT who had had previous P6 protocol, with the aim of improving local control treatments were given 12 mg/kg of the anti-IGF-1R anti- [12]. A total dose of 30 Gy was delivered post-operatively, body ganitumab intravenously [33]. Common side effects with simultaneous boost given to sites of gross residual include fatigue, nausea, dyspnoea and peripheral oedema. disease. Conventional two-dimensional radiotherapy was PR was noted in one (6%) patient, whereas 10 (63%) associated with significant gastrointestinal and haemato- had stable disease (SD) as their best response, with 3 logic toxicities, with long term side effects including (18%) achieving SD lasting ≥24 weeks. Median PFS was small bowel obstruction and ureteral stenosis [24]. For 19 months, indicating a potential role of ganitumab this reason, the use of WAP intensity-modulated radiation used either alone or in combination with chemotherapy therapy (WAP-IMRT) was studied by Pinnix et al.at for patients with DSRCT. In a phase I study of another the MDACC [25]. All of the eight patients had received anti-IGF-1R antibody cixutumumab in combination prior chemotherapy and surgical debulking (seven of with temsirolimus, two out of three patients with them also had intraperitoneal cisplatin). One patient was previously-treated DSRCT had SD lasting longer than still disease-free 20 months after treatment, although 5months[34]. the rest experienced either local or distant failure after Tumour-specific antigens have also been studied as amedianof8.73monthsfromWAP-IMRT. Aretrospective targets for immunotherapy, including the disialoganglio- analysis at the MSKCC looked at 31 patients who under- side GD2 and the antigen recognised by the antibody went WAP-RT, either with conventional two-dimensional 8H9 (expressed in 70% and 96% of DSRCT, respectively) radiotherapy (n = 22) or IMRT (n = 9) after chemotherapy [35]. In particular, studies of anti-GD2 antibodies have and maximal debulking surgery [26]. IMRT was associated shown some promising results in the treatment of with lower incidence of acute gastrointestinal and neuroblastoma [36]. Another potential therapeutic target haematologic toxicities. The 3-year overall survival and is the lysine-specific demethylase 1, a key histone modifi- progression-free survival (PFS) rates were 50% and 24%, cation enzyme involved in controlling gene expression respectively. Anecdotally, a patient in this series who which if dysregulated, could result in tumourigenesis received WAP-RT developed a serious malabsorption [37]. It is found to be highly expressed in several highly syndrome subsequent to gastrointestinal damage. Given malignant sarcomas including DSRCT [38]. It could the limited data of efficacy, WAP-RT is currently not be inhibited by small molecule inhibitors and further routinely used in the management of DSRCT. investigation is warranted. Targeted therapies Conclusions In recent years, targeted therapies have been studied in Advanced DSRCT is a rare, aggressive disease with DSRCT. Drugs that have shown activity against this invariably poor outcome that generally occurs in young disease include the TKI sunitinib and the mTOR in- men. It has a propensity to metastasise and at present, hibitor temsirolimus [27,28]. In our cohort of patients, surgery, combination cytotoxic chemotherapy and radio- other non-standard agents used include the anti-IGF-1R therapy remain the only standard therapeutic options. In antibody figitumumab, the TKIs axitinib, pazopanib, our study, we found that patients with intra-abdominal sorafenib and sunitinib, as well as the mTOR inhibitor DSRCT have a poorer prognosis, although surgical sirolimus. The number of patients is too small to draw resection for localised disease and radiotherapy, even any conclusion about their efficacy. Due to the fact in the metastatic setting for locoregional control, are that DSRCT has a predilection to occur in young associated with improved survival. males, Fine et al. discovered that androgen receptor is Clearly more efforts are needed to improve the progno- expressed in 37% of DSRCT [29]. Six of their patients sis of patients with DSRCT, and the development of novel were treated with combined androgen blockade and targeted agents is likely to have a major role in altering the three attained a clinical benefit. In our study, one patient course of the disease. It is also hope that the International had received the gonadotropin-releasing hormone agonist Rare Cancers Initiative, a multinational collaboration with goserelin. However, no significant anti-tumoural efficacy the aim of developing clinical trials for uncommon malig- was noted. nancies, will help to address this issue in the future. Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 8 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Competing interests stem cell transplantation in adult patients with advanced desmoplastic The authors declare that they have no competing interests. small round-cell tumour. Br J Cancer 2003, 89:1159–1161. 15. Cook RJ, Wang Z, Arora M, Lazarus HM, Kasow KA, Champagne MA, Saber W, van Besien KM, Hale GA, Copelan EA, Elmongy M, Ueno NT, Horn BN, Slavin S, Authors’ contributions Bishop MR, Stadtmauer EA: Clinical outcomes of patients with desmoplastic All authors were involved in data collection. HHW, HMH and OA analysed small round cell tumor of the peritoneum undergoing autologous HCT: a the data. HHW and HMH drafted the manuscript. HHW, HMH, CB, GH, CF, CIBMTR retrospective analysis. Bone Marrow Transpl 2012, 47:1455–1458. HME and IJ all contributed to the manuscript preparation. All authors read 16. Rosoff PM, Bayliff S: Successful clinical response to irinotecan in and approved the final manuscript. desmoplastic round blue cell tumor. Med Pediatr Oncol 1999, 33:500–503. 17. Ferrari A, Grosso F, Stacchiotti S, Meazza C, Zaffignani E, Marchianò A, Casanova M: Response to vinorelbine and low-dose cyclophosphamide Acknowledgements chemotherapy in two patients with desmoplastic small round cell tumor. We acknowledge support from the NIHR RM/ICR Biomedical Research Centre. Pediatr Blood Cancer 2007, 49:864–866. Author details 18. Hendifar AE, Chawla SP, Leahy MG, Italiano A, Patel S, Santoro A, Staddon AP, Addenbrooke’s Hospital, Cambridge University Hospitals NHS Foundation Penel N, Piperno-Neumann S, Demetri GD, Hayward L, White J, Gouw LG, De Trust, Hills Road, Cambridge CB2 0QQ, UK. Sarcoma Unit, The Royal Miguel B, Lardelli P, Soto A, Nieto A, Blay J-Y: Results of the randomized phase Marsden, Fulham Road, London SW3 6JJ, UK. Department of III trial of trabectedin (T) versus doxorubicin-based chemotherapy (DXCT) as Histopathology, The Royal Marsden, Fulham Road, London SW3 6JJ, UK. first-line therapy in patients (pts) with translocation-related sarcoma (TRS). University of Cambridge Department of Oncology and NIHR Cambridge JClin Oncol 2013, 31:10517. Biomedical Research Centre, Hills Road, Cambridge CB2 0QQ, UK. 19. Chuk MK, Aikin A, Whitcomb T, Widemann BC, Zannikos P, Bayever E, Balis FM, Fox E: A phase I trial and pharmacokinetic study of a 24-hour infusion of Received: 3 October 2013 Accepted: 22 November 2013 trabectedin (Yondelis , ET-743) in children and adolescents with relapsed or Published: 26 November 2013 refractory solid tumors. Pediatr Blood Cancer 2012, 59:865–869. 20. López-González A, Cantos B, Tejerina E, Provencio M: Activity of trabectidin in desmoplastic small round cell tumor. Med Oncol 2011, References 28(Suppl 1):S644–S646. 1. Gerald WL, Ladanyi M, de Alava E, Cuatrecasas M, Kushner BH, LaQuaglia MP, 21. Hayes-Jordan A, Anderson P, Curley S, Herzog C, Lally KP, Green HL, Hunt K, Rosai J: Clinical, pathologic, and molecular spectrum of tumors associated Mansfield P: Continuous hyperthermic peritoneal perfusion for with t(11;22)(p13;q12): desmoplastic small round-cell tumor and its variants. desmoplastic small round cell tumor. J Pediatr Surg 2007, 42:E29–E32. JClin Oncol 1998, 16:3028–3036. 22. Aguilera D, Hayes-Jordan A, Anderson P, Woo S, Pearson M, Green H: 2. Gerald WL, Rosai J: Case 2. Desmoplastic small cell tumor with divergent Outpatient and home chemotherapy with novel local control strategies differentiation. Pediatr Pathol 1989, 9:177–183. in desmoplastic small round cell tumor. Sarcoma 2008, 2008:261589. 3. Chang F: Desmoplastic small round cell tumors: cytologic, histologic, and 23. Hayes-Jordan A, Green H, Fitzgerald N, Xiao L, Anderson P: Novel treatment immunohistochemical features. Arch Pathol Lab Med 2006, 130:728–732. for desmoplastic small round cell tumor: hyperthermic intraperitoneal 4. Ladanyi M, Gerald W: Fusion of the EWS and WT1 genes in the perfusion. J Pediatr Surg 2010, 45:1000–1006. desmoplastic small round cell tumor. Cancer Res 1994, 54:2837–2840. 24. Goodman KA, Wolden SL, La Quaglia MP, Kushner BH: Whole 5. Kretschmar CS, Colbach C, Bhan I, Crombleholme TM: Desmoplastic small abdominopelvic radiotherapy for desmoplastic small round-cell tumor. cell tumor: a report of three cases and a review of the literature. J Pediatr Int J Radiat Oncol Biol Phys 2002, 54:170–176. Hematol Oncol 1996, 18:293–298. 25. Pinnix CC, Fontanilla HP, Hayes-Jordan A, Subbiah V, Bilton SD, Chang EL, 6. Dufresne A, Cassier P, Couraud L, Marec-Bérard P, Meeus P, Alberti L, Blay J-Y: Grosshans DR, McAleer MF, Sulman EP, Woo SY, Anderson P, Green HL, Desmoplastic small round cell tumor: current management and recent Mahajan A: Whole abdominopelvic intensity-modulated radiation therapy findings. Sarcoma 2012, 2012:714986. for desmoplastic small round cell tumor after surgery. Int J Radiat Oncol 7. Schwarz RE, Gerald WL, Kushner BH, Coit DG, Brennan MF, La Quaglia MP: Biol Phys 2012, 83:317–326. Desmoplastic small round cell tumors: prognostic indicators and results 26. Desai NB, Stein NF, LaQuaglia MP, Alektiar KM, Kushner BH, Modak S, of surgical management. Ann Surg Oncol 1998, 5:416–422. Magnan HM, Goodman K, Wolden SL: Reduced toxicity with intensity 8. Lal DR, Su WT, Wolden SL, Loh KC, Modak S, La Quaglia MP: Results of modulated radiation therapy (IMRT) for desmoplastic small round cell multimodal treatment for desmoplastic small round cell tumors. J Pediatr tumor (DSRCT): an update on the whole abdominopelvic radiation therapy Surg 2005, 40:251–255. (WAP-RT) experience. Int J Radiat Oncol Biol Phys 2013, 85:e67–e72. 9. Hassan I, Shyyan R, Donohue JH, Edmonson JH, Gunderson LL, Moir CR, 27. Italiano A, Kind M, Cioffi A, Maki RG, Bui B: Clinical activity of sunitinib in Arndt CAS, Nascimento AG, Que FG: Intraabdominal desmoplastic small patients with advanced desmoplastic round cell tumor: a case series. round cell tumors: a diagnostic and therapeutic challenge. Cancer 2005, Target Oncol 2013, 8:211–213. 104:1264–1270. 28. Thijs AMJ, van der Graaf WTA, van Herpen CML: Temsirolimus for metastatic 10. Subbiah V, Viny AD, Anderson PM, Hayes-Jordan AA, Qiao W, Benjamin RS, desmoplastic small round cell tumor. Pediatr Blood Cancer 2010, 55:1431–1432. Maki RG, Ludwig JA: Optimizing the therapy of desmoplastic small round 29. Fine RL, Shah SS, Moulton TA, Yu I-R, Fogelman DR, Richardson M, Burris HA, cell tumor: combined experience from the two major cancer centers. Samuels BL, Assanasen C, Gorroochurn P, Hibshoosh H, Orjuela M, J Clin Oncol 2012, 30:10021. Garvin J, Goldman FD, Dubovsky D, Walterhouse D, Halligan G: Androgen 11. Farhat F, Culine S, Lhommé C, Duvillard P, Soulié P, Michel G, Terrier-Lacombe MJ, and c-Kit receptors in desmoplastic small round cell tumors resistant to Théodore C, Schreinerova M, Droz JP: Desmoplastic small round cell chemotherapy: novel targets for therapy. Cancer Chemother Pharmacol 2007, tumors: results of a four-drug chemotherapy regimen in five adult patients. 59:429–437. Cancer 1996, 77:1363–1366. 30. Karnieli E, Werner H, Rauscher FJ, Benjamin LE, LeRoith D: The IGF-I receptor 12. Kushner BH, LaQuaglia MP, Wollner N, Meyers PA, Lindsley KL, Ghavimi F, gene promoter is a molecular target for the Ewing’s sarcoma-Wilms’ tumor Merchant TE, Boulad F, Cheung NK, Bonilla MA, Crouch G, Kelleher JF, 1 fusion protein. JBiol Chem 1996, 271:19304–19309. Steinherz PG, Gerald WL: Desmoplastic small round-cell tumor: prolonged 31. Finkeltov I, Kuhn S, Glaser T, Idelman G, Wright JJ, Roberts CT, Werner H: progression-free survival with aggressive multimodality therapy. J Clin Transcriptional regulation of IGF-I receptor gene expression by novel Oncol 1996, 14:1526–1531. isoforms of the EWS-WT1 fusion protein. Oncogene 2002, 21:1890–1898. 13. Bertuzzi A, Castagna L, Nozza A, Quagliuolo V, Siracusano L, Balzarotti M, 32. Werner H, Idelman G, Rubinstein M, Pattee P, Nagalla SR, Roberts CT: A Compasso S, Alloisio M, Soto Parra H, Santoro A: High-dose chemotherapy novel EWS-WT1 gene fusion product in desmoplastic small round cell in poor-prognosis adult small round-cell tumors: clinical and molecular tumor is a potent transactivator of the insulin-like growth factor-I receptor results from a prospective study. J Clin Oncol 2002, 20:2181–2188. (IGF-IR) gene. Cancer Lett 2007, 247:84–90. 14. Bertuzzi A, Castagna L, Quagliuolo V, Ginanni V, Compasso S, Magagnoli M, 33. Tap WD, Demetri G, Barnette P, Desai J, Kavan P, Tozer R, Benedetto PW, Balzarotti M, Nozza A, Siracusano L, Timofeeva I, Sarina B, Parra HS, Santoro A: Friberg G, Deng H, McCaffery I, Leitch I, Badola S, Chang S, Zhu M, Tolcher A: Prospective study of high-dose chemotherapy and autologous peripheral Wong et al. Clinical Sarcoma Research 2013, 3:14 Page 9 of 9 http://www.clinicalsarcomaresearch.com/content/3/1/14 Phase II study of ganitumab, a fully human anti-type-1 insulin-like growth factor receptor antibody, in patients with metastatic ewing family tumors or desmoplastic small round cell tumors. JClin Oncol 2012, 30:1849–1856. 34. Naing A, LoRusso P, Fu S, Hong DS, Anderson P, Benjamin RS, Ludwig J, Chen HX, Doyle LA, Kurzrock R: Insulin growth factor-receptor (IGF-1R) antibody cixutumumab combined with the mTOR inhibitor temsirolimus in patients with refractory Ewing’s sarcoma family tumors. Clin Cancer Res 2012, 18:2625–2631. 35. Modak S, Gerald W, Cheung N-K V: Disialoganglioside GD2 and a novel tumor antigen: potential targets for immunotherapy of desmoplastic small round cell tumor. Med Pediatr Oncol 2002, 39:547–551. 36. Yang RK, Sondel PM: Anti-GD2 strategy in the treatment of neuroblastoma. Drugs Futur 2010, 35:665. 37. Shi Y, Lan F, Matson C, Mulligan P, Whetstine JR, Cole PA, Casero RA, Shi Y: Histone demethylation mediated by the nuclear amine oxidase homolog LSD1. Cell 2004, 119:941–953. 38. Schildhaus H-U, Riegel R, Hartmann W, Steiner S, Wardelmann E, Merkelbach-Bruse S, Tanaka S, Sonobe H, Schüle R, Buettner R, Kirfel J: Lysine-specific demethylase 1 is highly expressed in solitary fibrous tumors, synovial sarcomas, rhabdomyosarcomas, desmoplastic small round cell tumors, and malignant peripheral nerve sheath tumors. Hum Pathol 2011, 42:1667–1675. doi:10.1186/2045-3329-3-14 Cite this article as: Wong et al.: Desmoplastic small round cell tumour: characteristics and prognostic factors of 41 patients and review of the literature. Clinical Sarcoma Research 2013 3:14. 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Clinical Sarcoma ResearchSpringer Journals

Published: Nov 26, 2013

References