Desmoplastic small round cell tumor: from state of the art to future clinical prospects

ABSTRACT

Introduction

Desmoplastic small round cell tumor (DSRCT) is an extremely rare and highly aggressive soft tissue sarcoma, presenting mainly in male adolescents and young adults with multiple nodules disseminated within the abdominopelvic cavity. Despite a multimodal approach including aggressive cytoreductive surgery, intensive multi-agent chemotherapy, and postoperative whole abdominopelvic radiotherapy, the prognosis for DSRCT remains dismal. Median progression-free survival ranges between 4 and 21 months, and overall survival between 17 and 60 months, with the 5-year overall survival rate in the range of 10–20%.

Area covered

This review discusses the treatment strategies used for DSRCT over the years, the state of the art of current treatments, and future clinical prospects.

Expert opinion

The unsatisfactory outcomes for patients with DSRCT warrant investigations into innovative treatment combinations. An international multidisciplinary and multi-stakeholder collaboration, involving both pediatric and adult sarcoma communities, is needed to propel preclinical model generation and drug development, and innovative clinical trial designs to enable the timely testing of treatments involving novel agents guided by biology to boost the chances of survival for patients with this devastating disease.

KEYWORDS:

• Desmoplastic small round cell tumor
• chemotherapy
• hyperthermic intraperitoneal chemotherapy
• novel agents
• prognosis
• radiotherapy
• surgery
• biomarker

1. Introduction

Desmoplastic small round cell tumor (DSRCT) is an extremely rare and highly aggressive soft tissue sarcoma that generally affects male adolescents and young adults. Its incidence is approximately 0.2 cases per million people [1,2]. When first described by Gerald and Rosai in 1989 [3], DSRCT mainly presents with multiple nodules disseminated within the abdominopelvic cavity and arising from peritoneal surfaces. Its clinical presentation is typically related to an abdominal mass, and patients are usually diagnosed already in advanced stages of the disease: at diagnosis, patients with DSRCT have synchronous peritoneal metastases in more than 90% of cases, and synchronous extraperitoneal metastases in around 50% of cases, mostly to the liver, lung, and bones [4–6]. DSRCT is associated with a chromosomal translocation t(11;22) (p13; q12) that leads to the EWSR1:WT1 fusion gene [7,8].

To date, there is no consensus on standard treatment approaches. The management of intra-abdominal DSRCT is currently based on a combination of aggressive cytoreductive surgery, intensive multi-agent chemotherapy, and postoperative whole abdominopelvic radiotherapy (WAP-RT). Other strategies that have been explored include high-dose chemotherapy with autologous stem cell transplantation, hyperthermic intraperitoneal chemotherapy (HIPEC) with cisplatin, targeted therapy and maintenance therapy. Even with an aggressive multimodal approach, the prognosis for DSRCT remains dismal. Median progression-free survival (PFS) ranges between 4 and 21 months, and overall survival (OS) between 17 and 60 months with 3- and 5-year OS rates of 44% and 15%, respectively (Table 1) [4,6,10,11,14,18,22,25,30–32]. Various clinical variables reportedly correlate with the outcome: the presence of hepatic or portal metastases, resistance to neo-adjuvant chemotherapy, and CD99 expression have been described as adverse prognostic factors [8,24,25], while the absence of extraperitoneal metastases, the feasibility of complete surgical resection, and the use of radiotherapy seem to be favorable prognostic factors [4,8]. Other factors investigated – such as age, gender, postoperative complications, disease extent at diagnosis, and tumor size – revealed no significant impact on the survival of patients with intra-abdominal DSRCT [17,18].

Table 1. Selected studies on desmoplastic small round cell tumor.

Author	Series	Treatment	Outcome
Kushner et al, 1996, MSKCC, New York, USA [9]	Prospective, single-institution study; Study period: not reported; Number of cases: 12; Median age 14 years (range 7–22)	multiagent intensive chemotherapy (P6 protocol), 11/12 had surgery, 4/12 had local radiotherapy, 4/12 had ASCT	5 pts alive with NED (10, 13, 14, 34, 39 months after diagnosis)
Goodman et al, 2002, MSKCC, New York, USA [10]	Retrospective, single-institution study; Study period: 1992–2001; Number of cases: 21; Median age, years: 16.5 (range 8–34)	multiagent chemotherapy (alkylator-based), surgery, WAP-RT ±ASCT	median PFS 19 mos, 3-year PFS 19%; median OS 32 months, 3-year OS 48%
Lal et al, 2005, MSKCC, New York, USA [11]	Retrospective, single-institution study; Study period: 1972–2003; Number of cases: 66; Median age, years: 19 (range 7–58)	44% had trimodal treatment including chemotherapy (P6 protocol), surgery and WAP-RT	3-year OS 44%, 5-year OS 15%; 3-year OS 55% for pts given trimodal therapy vs 27% for pts with one modality missing; multimodal therapy correlated with survival, while distant metastases did not
Hayes-Jordan et al, 2010, MDACC, Houston, USA [12]	Retrospective, single-institution study; Study period: 1995–2008; Number of cases: 24; Median age, years: 12	8/24 (33%) had surgery + HIPEC	3-year OS 71% for pts who were treated with HIPEC vs 26% for patients who were not
Bisogno et al, 2010, Italian Pediatric Oncology Association study (AIEOP-RMS4.99) [13]	Prospective, multi-institution study; Study period: 1999–2008; Number of cases: 14; Median age, years: 9 (range 2–18)	all pts had multiagent chemotherapy (10 IVADo, 4 CEVAIE), followed by ASCT in 10/14, 12/14 had surgery, 6/14 had WAP-RT	3-year EFS 15.5%; 3-year OS 38.9%
Cook et al, 2012, (CIBMTR) [14]	Retrospective study on registry data; Study period: 1999–2007; Number of cases: 36; Median age, years: 19 (8–46)	35/36 had ASCT (i.e. thiotepa or etoposide or melphalan or cyclophosphamide)	median OS 31 mos, 1-year OS 83%, 3-year OS 40%; 3-year OS was 57% for pts in CR before ASCT (36% of the cases) vs 28% for others
Philippe-Chomette P et al. 2012, French national series [7]	Retrospective national multicenter study; Study period: 1995–2006; Number of cases: 38; Median age, year: 13.2 (4–29.7)	all pts had multiagent chemotherapy, 9 had limited surgical resection, 22 had extensive resection, 14 had ASCT	3-year EFS 14.4%; 3-year OS 50.5%; no prognostic factors (radiotherapy, ASCT, extend of surgery)
Pinnix et al, 2012, MDACC, Houston, USA [15]	Retrospective, single-institution study; Study period: 2006–2010; Number of cases: 8; Median age, years: 11.5 (range 5–20)	multiagent chemotherapy (VAC/IE), surgery, WAP-RT (IMRT)	median PFS 8.7 months; 1/8 alive with NED after 20 months
Desai et al, 2013, MSKCC, New York, USA [16]	Retrospective, single-institution study; Study period: 1992–2011; Number of cases: 31; Median age, years: 19 (range 7–32)	all pts had multiagent chemotherapy, surgery and WAP-RT (22 2D-RT, 9 IMRT)	3-year PFS 24%; 3-year OS 50%; OS correlated with distant metastases
Wong et al, 2013, Royal Marsden Hospital, London, and Addenbrooke’s Hospital, Cambridge, UK [17]	Retrospective, multi- institution study; Study period: 1991–2012; Number of cases: 41; Median age, years: 27 (range 16–45)	multiagent chemotherapy (i.e. VIDE, IVADo, VAC/IE), 20% had surgery, 15% had WAP-RT	median PFS 4 months; median OS 16 mos, 3-year OS 27%, 5-year OS 16%; VIDE chemotherapy conferred longest TTP; surgery for localized disease and radiotherapy for metastatic disease correlated with improved OS
Hayes-Jordan et al, 2013, MDACC, Houston, USA [18]	Retrospective, single-institution study; Study period: 2006–2011; Number of cases: 26; Median age, years: 19 (range 6–53)	all pts had multiagent chemotherapy, surgery, HIPEC, ± local radiotherapy	median OS 31 months for pts who had complete surgery, 12.8 months for pts who had partial resection; 1-year DFS 42% in cases of abdominal disease vs 0% in cases of extra-abdominal disease; no benefit of HIPEC in pts with extra-abdominal disease; HIPEC morbidity lower in children
Zhang et al, 2015, Shandong Cancer Hospital, Jinan, China [19]	Retrospective, single-institution study; Study period: 2004–2014; Number of cases: 11; Median age, years: 31.4 (range 14–64)	multiagent chemotherapy (IAP, CAP), 5/11 had local radiotherapy	median PFS 8.8 months, 3-year PFS 27%; median OS 29 months, 3-year OS 36.4%, 5-year OS 10%; median OS 40.8 months for pts given radiotherapy vs 19.2 months for the others
Honoré et al, 2015, IGR, Villejuif, France [4]	Retrospective, single-institution study; Study period: 1991–2013; Number of cases: 38; Median age, years: 27 (range 13–57)	multiagent chemotherapy (alkylating/anthracyclines-based, i.e. AI, VAC), 61% had surgery, 21% had WAP-RT	median DFS 15.5 months, median OS 37.7 months; 2/38 (5%) alive with NED after 32 and 37 months; absence of extra-peritoneal disease, complete surgery, and radiotherapy were prognostic factors; no benefit of surgery for extra-peritoneal metastatic disease
Desai et al, 2015, MSKCC, New York, USA [20]	Prospective single-institution study; Study period: 1993–2004; Number of cases: 19; Median age, years: 18.5 (range 10–42)	multiagent chemotherapy followed by myeloablative chemotherapy (carboplatin-thiotepa ± topotecan), with autologous stem cell transplant (in patients with chemoresponsive DSRCT); 17/19 had radiotherapy	5-year EFS 11% 5-year OS 16%
Atallah et al, 2016, French sarcoma group [21]	Retrospective, multi-institution study; Study period: 1991–2014; Number of cases: 107; Median age, years: 25 (range 4–58)	36% of pts had chemotherapy, surgery and WAP-RT, 34% had chemotherapy and surgery	median OS 40.3 months and 3-year OS 63.1% for pts who had surgery and radiotherapy, and 28.3 months and 48.5%, respectively, for pts who had surgery without radiotherapy
Osborne et al, 2016, MDACC, Houston, USA [22]	Retrospective, single institution study; Study period: 2006–2014; Number of cases: 32; Median age, years: 18 (range 5–50)	multiagent chemotherapy, surgery HIPEC, WAP-RT (23/32 IMRT)	median DFS 10 months, 3-year DFS 9.9%; median OS 60 months, 3-years OS 64%
Honoré et al, 2017, French Network databases [18]	Retrospective, multi-institution, nation-wide study; Study period: 1991–2015; Number of cases: 107 (pts with extra-abdominal metastases were excluded); Median age, years: 22 (range 3–57)	48% had multimodal therapy with chemotherapy, surgery and WAP-RT, 23% had HIPEC	median DFS 21 months, 2-year DFS 30%, 5-year DFS 12%; median OS 42 months, 2-year OS 72%, 5-year OS 19%; whole-abdomen radiotherapy correlated with DFS
Stiles et al, 2018, Tennessee National Cancer Data Base, USA [23]	Retrospective study on registry data; Study period: 2004–2014; Number of cases: 125; Median age, years: 21	82% had multiagent chemotherapy, 60% had surgery, 17% had radiotherapy, 6% had ASCT	median OS 28 months, 3-year OS 29%, 5-year OS 10%; multimodal treatment correlated with survival; residual postoperative macroscopic disease increased risk of mortality
Subbiah et al, 2018, MDACC, Houston, USA [24]	Retrospective, single-institution study; Study period: 1990–2016; Number of cases: 187; Median age, years: 23 (range 0–53)	98% had multiagent chemotherapy (i.e. VAC/IE, VIDE, P6 protocol), 57% had surgery, 44% had HIPEC, 6% had ASCT, 49% had trimodal therapy with chemotherapy, surgery and WAP-RT	median OS 35 months, 3-year OS 48%; whole-abdomen radiotherapy did not improve OS
Hayes-Jordan et al, 2018, MDACC, Houston, USA [25]	Prospective, single-institution, phase 2 trial; Study period: 2012–2013; Number of cases: 14 (pts with extra-abdominal metastases were excluded); Median age, years: 21	14/14 had multiagent chemotherapy + complete surgery + HIPEC + WAP-RT	median RFS 15 months; median OS 58.4 months, 3-year OS 79%
Scheer et al, 2019, German Pediatric Group CWS [6]	Retrospective cooperative study; Study period: 1997–2015; Number of cases: 60; Median age, years: 15 (6–38)	all pts had multiagent chemotherapy (i.e. P6 protocol, VAIA, CEVAIE), 35% had surgery, 10% had HIPEC, 33% had radiotherapy, 15% had ASCT	3-year EFS 11%, 3-year OS 30%; VAIA chemotherapy correlated with longer EFS
Honoré et al, 2019, French Sarcoma Group [26]	Retrospective, multi-institution, nation-wide study; Study period: 1991–2018; Number of cases: 100; Median age, years: 25 (range 3–59)	80% had up-front multiagent chemotherapy (i.e. P6 protocol, VAC/IE, VIDE), 71% had surgery, followed by HIPEC in 28% of them, and by WAP-RT in 50%	median PFS 11 months, 3-year PFS 7%, 5-year PFS 6%; median OS 25 months, 3-year OS 35%, 5-year OS 4%; 5/100 alive with NED; prognostic factors: complete surgery, female sex, whole-abdomen radiotherapy
Campos et al, 2020, AC Camargo Cancer Center, São Paulo, Brazil [27]	Retrospective, single-institution study; Study period: 2007–2020; Number of cases: 19; Median age, years: 26 (15–41)	all pts had multiagent chemotherapy (i.e. VAC/IE, VAC, AI), 58% had surgery, 26% had HIPEC, 21% had WAP-RT	median PFS 8.7 months; median OS 27 months, 3-year OS 38%, 5-year 12%
Xiang et al, 2020, Chinese databases [8]	Retrospective study on registry data; Study period: 2000–2015; Number of cases: 104; Median age, years: 24 (range 15–54)	88% had chemotherapy, 66% had surgery, 23% had radiotherapy	median OS 26 months, 3-year OS 33%; prognostic factors: surgical patterns, metastatic status, and adjuvant chemotherapy
Liu et al, 2021, Dana-Farber Cancer Institute and Boston Children’s Hospital [28]	Retrospective, single-institution study; Study period: 2014–2019; Number of cases: 6; Median age, years: 15 (range 3–16)	multiagent dose-density chemotherapy (VIT/VDC/IE), followed by surgery and WAP-RT	3/6 pts alive with NED 21, 46 and 60 months after diagnosis; 2-year OS 75%
Ferrari et al, 2021, INT, Milano, Italy [29]	Retrospective, single-institution study; Study period: 2017–2018; Number of cases: 3; Median age, years: 16 (range 10–20)	multiagent dose-density chemotherapy (IrIVA/IVAd/IVE), surgery, WAP-RT, maintenance chemotherapy (vinorelbine and low-dose oral cyclophosphamide)	dose-density treatment with irinotecan was feasible; 1/3 alive with NED 37 months after diagnosis, 2 alive with disease after abdominal relapse
Giani, et al. 2023, INT, Milan [30]	Retrospective, single-institution study; Study period: 2000–2021; Number of cases: 38; Median age, years: 25 (range 7–64)	multiagent chemotherapy ± surgery (71%) ± HIPEC (26%) ± WAP-RT (24%) ± high-dose chemotherapy (13%) ± maintenance chemotherapy (32%)	median-EFS 15 months; median-OS 37 months; long-term survivors had no liver/extra-abdominal disease, and were treated with complete surgery, and possibly WAP-RT and maintenance therapy

Note: Legend: pts = patients; OS = overall survival; PFS = progression-free survival; PPFS = peritoneal progression-free survival; DFS = disease-free survival; RFS = relapse-free survival; EFS = event-free survival; TTP = time to progression; NED = no evidence of disease; mos = months; WAP-RT = whole abdominopelvic radiotherapy; HIPEC = hyperthermic intraperitoneal chemotherapy; 2D = two-dimensional; IMRT = intensity-modulated radiation therapy; ASCT = autologous stem cell transplantation; P6 Protocol = HD-CAV (cyclophosphamide, doxorubicin, vincristine) alternating with ifosfamide, etoposide; VIDE = vincristine, ifosfamide, doxorubicin, etoposide; IVADo = ifosfamide, vincristine, actinomycin D, doxorubicin; VAC/IE = vincristine, adriamycin, cyclophosphamide/ifosfamide, etoposide; IAP = ifosfamide, doxorubicin, cisplatin; CAP = cyclophosphamide, doxorubicin, cisplatin; AI = doxorubicin, ifosfamide; VIT/VDC/IE = vincristine, irinotecan, temozolomide/vincristine, doxorubicin, cyclophosphamide/ifosfamide, etoposide; IrIVA = irinotecan, ifosfamide, vincristine, actinomycin-D; IVAd = ifosfamide, vincristine, adriamycin; IVE = ifosfamide, vincristine, etoposide; CEVAIE = ifosfamide, vincristine, actinomycin D, carboplatin, epirubicin, etoposide; EAM = extra-abdominal metastases, CR = complete response; MSKCC = Memorial Sloan Kettering Cancer Center; MDACC = Anderson Cancer Center; IGR = Institut Gustave Roussy; CWS = Cooperative Weichteilsarkom Studiengruppe (German Cooperative Group); INT = Istituto Nazionale dei Tumori.

2. Pathology and molecular features

DSRCT is histologically characterized by nests of undifferentiated round tumor cells surrounded by dense desmoplastic stroma. The tumor cells co-express several epithelial (cytokeratin, epithelial membrane antigen), mesenchymal (desmin, vimentin), and neural (CD56, neuron-specific enolase) markers that enable its differential diagnosis vis-à-vis other small round cell tumors and in over 90% of cases, DSRCT can show immunoreactivity to antibodies that specifically target the carboxy terminus of the WT1 protein [33,34]. The pathognomonic chimeric protein EWSR1-WT1, encoded by the EWSR1:WT1 fusion gene, acts as an aberrant transcriptional activator. It is thought to be the key driver behind the oncogenic process in DSRCT, as it influences the expression of several growth factors, receptor genes, and transcriptional regulators [35]. This process leads to collagenous stromal production (a hallmark of DSRCT), inflammatory cell infiltration, neo-angiogenesis, and proliferation. A recently conducted next-generation sequencing analysis of 68 matched DSRCT tumor vs normal samples confirmed that DSRCT is generally a genomically quiet cancer, but several recurrent molecular alterations were identified in TERT (3%), ARID1A (6%), HRAS (4%), TP53 (3%) and FGFR4 (7%), which may affect the disease’s presentation and course [36]. Other studies (not conducted on matched tumor vs normal samples) identified other genomic alterations associated with DNA damage response (DDR) in various genes, including ATM, RAD50, BARD1, BRCA1/2, PALB2 and CHEK2. Preclinical analyses also demonstrated a transcriptional modulation of several downstream targets of the fusion protein associated with essential biological pathways involved in drug resistance, including the DDR pathway and mesenchymal epithelial reverse transition [35].

For now, the DSRCT cell of origin remains unknown. Studies on the gene expression patterns of DSRCT showed that this tumor clustered separately from adjacent normal tissues and other types of sarcoma [37,38]. DNA methylation analysis confirmed that DSRCT samples have a distinct pattern [39,40]. Since the disease often presents with multiple masses, phylogenetic analyses were performed on mutations and somatic copy-number alterations (SCNAs) in samples from multiple sites to investigate whether they had a shared or independent origin. Identical EWSR1:WT1 fusion breakpoints and most mutations and SCNAs occurred within the trunks of the phylogenetic trees, confirming that DSRCT develops from a single lesion [36]. Most SCNAs in this tumor involve whole chromosome arms, or whole chromosomes, with very few significant focal events. In around one in two patients, gains have been found in chromosomes 1q, 3, 5, and 21q, and losses in chromosomes 11p, 11q, and 16q [41]. That said, the large number of genes encoded by whole chromosome arms and whole chromosomes makes it hard to establish which SCNA genes contribute to tumor formation.

Reports on single cases or small samples of DSRCT patients only occasionally describe genomic sequencing performed to identify crucial genetic alterations other than EWSR1:WT1. These studies found that DSRCT has a low mutation burden with a few recurrently mutated cancer genes [36,37,41,42]. This confirms the role of EWSR1:WT1 fusion as the main driver of tumor initiation, and is consistent with the idea that fusion-positive sarcomas are driven mainly by the fusion oncoprotein, with few other genomic alterations. The low mutation burden found in DSRCT may be one of the reasons for the low overall immune infiltrate levels primarily associated with this tumor. In fact, PD-L1 expression reportedly varies considerably in DSRCT, and PD-1 is expressed on tumor cells instead of on tumor-infiltrating lymphocytes [43,44]. Interestingly, this tumor is associated with the loss of the whole of chromosome 6, where immunoregulatory genes are located [37].

The lack of specific prognostic biomarkers for DSRCT poses a challenge. Liquid biopsy offers the chance to assess tumor burden by analyzing circulating tumor material (tumor cells, DNA, RNA, exosomes, etc.) in several biofluids, such as blood, ascites, and pleural fluid [45]. Circulating tumor DNA (ctDNA) can be used to perform molecular studies on tumor-derived fragmented DNA in the bloodstream. Two published studies used ctDNA in one and six patients with DSRCT to monitor disease burden based on the detection of EWSR1:WT1 [46,47]. Such studies may, in the future, enable the early detection of a patient’s failure to respond to treatment, and prompt the use of alternative therapies.

MicroRNAs (miRNAs) are short RNA molecules that regulate the post-transcriptional silencing of target genes. They have been investigated as biomarkers in liquid biopsy because miRNA profiles may distinguish between normal and cancerous tissue, reflect tumor expression in the serum of cancer patients, and predict outcomes or responses to therapy [48,49]. EWS reportedly regulates DROSHA expression, and modulates miRNA biogenesis, pointing to an alteration of miRNA regulatory mechanisms mediated by this protein [50].

Epithelial–mesenchymal transition (EMT) and mesenchymal–epithelial reverse transition (MErT) are fundamental to DSRCT plasticity and have an important role in tumor progression, metastasis, and chemoresistance. EMT and MErT undergo a dual epigenetic regulation via miRNA-200 or miRNA-34, which govern the switch: high miRNA-200 and/or miRNA-34, and low ZEB1 levels correspond to an epithelial phenotype, whereas high ZEB1 and low miRNA-200 and/or miRNA-34 levels correspond to a mesenchymal phenotype [51].

Circulating miRNAs were also investigated in circulating exosomes, small membrane vesicles 30–100 nm in diameter, isolated in the plasma of three patients with different stages of DSRCT [52]. Among the five miRNAs modulated in all three patients, three (miR-34a-5p, miR-22-3p, and miR-324-5p) were upregulated compared with four healthy pediatric controls, while two (miR-150-5p and miR-342-3p) were downregulated. These miRNAs were found dysregulated in several cancers, and involved in cell growth, proliferation, migration, and invasion. Among them, miR-34 was strongly upregulated. All these studies shed light on the potential role of miRNAs in DSRCT pathogenesis.

3. Loco-regional treatment: surgery

Aggressive cytoreductive surgery is generally part of the standard approach to intra-abdominal DSRCT, which usually involves resecting all peritoneal metastases, but preserving macroscopically unaffected peritoneum [4]. As reported in various studies, complete macroscopic cytoreductive surgery has been associated with a longer survival [4,8,11,19,23,32,53,54]. In a series described by the French cooperative group, for example, the median OS was 38 months for patients who underwent complete surgery versus 21 months for those with incomplete or no surgery [4]. Similarly, in the series from the Mayo Clinic, the median OS was 34 months for patients treated with complete cytoreductive surgery and chemotherapy, and 14 months for those who had biopsy alone [53]. In another series from the MD Anderson Cancer Center, the median OS was 31 months for patients who had undergone complete surgery, and 13 months for those whose surgery was incomplete [32]. These findings reflect a selection bias, however, as patients who were candidates for surgery had generally responded better to chemotherapy. Macroscopically complete resection is also generally achievable in only a limited proportion (25% to 44%) of cases [11,55].

Despite surgery, the most common site of recurrence for intra-abdominal DSRCT is the peritoneum, reflecting the difficulty of eradicating all microscopic residual tumors even with an aggressive frontline approach. The extent of disease can be measured preoperatively in terms of the peritoneal cancer index (PCI), but in two MD Anderson series there was no correlation with survival [25,32]. The French group suggested using a PCI of 12 as the cutoff for selecting potential candidates for extensive surgery. Patients with no liver metastases are candidates for surgery whenever it is feasible, and complete cytoreduction can be achieved. Patients with synchronous liver metastases are generally not considered for surgery because their survival afterward is comparable with the results achieved with systemic chemotherapy alone [26].

The indication for aggressive surgery should be balanced against the postoperative morbidity and decline in quality of life due, for instance, to multiple visceral resections. It is extremely important for the surgeon to remove all macroscopic disease because incomplete resections do not bring any survival benefit compared with chemotherapy alone. Accurate patient selection remains the key to identifying patients who can benefit from aggressive surgery [35,56].

4. Loco-regional treatment: hyperthermic intraperitoneal chemotherapy

HIPEC is a procedure involving the application of a concentrated chemotherapeutic solution at a high temperature inside the peritoneal cavity. It is performed after cytoreductive surgery in cases of gastric cancer, for instance, peritoneal mesothelioma, or ovarian cancer with disseminated peritoneal carcinomatosis [57–59]. After the surgical removal of all cancerous lesions, the heated chemotherapeutic agents are applied directly inside the abdomen to eliminate any remaining cancer cells.

HIPEC has been used in patients with intra-abdominal DSRCT as well, adopting various chemotherapy regimens [12,18,25,32,60–63]. It is worth mentioning the phase 1 study that identified the maximum tolerated dose of intraperitoneal cisplatin as 100 mg/m² (90 min, 41°C). Chemotherapeutic agents administered at high temperatures can cause significant morbidity, which reportedly ranges from 12% to 52% in adults, but the treatment is better tolerated in children [12,57–59].

HIPEC was shown to increase patient survival in selected series (generally from single centers) [12,18,25,32,60–62]. In the sizable MD Anderson experience, there were survival benefits for patients with no liver or portal metastases [25,62]. A 3-year OS of 79% was reported in a selected series of patients given HIPEC in addition to the multimodal treatment regimens described by the group at the Memorial Sloan-Kettering Cancer Center [11]. On the other hand, a French randomized study on patients with all types of peritoneal sarcomatosis failed to demonstrate any improvement in OS for patients who received intraperitoneal chemotherapy (IPEC) after the surgical resection of their tumors [60]. A retrospective nationwide French survey involving 107 patients treated for DSRCT with no extraperitoneal metastases (EPM) between 1991 and 2015 also found no benefit deriving from HIPEC after complete cytoreductive surgery [18].

The lack of any standardization of the chemotherapeutic agents used and the procedures for their administration, and – more importantly – the absence of any standard patient selection criteria make it very difficult to assess the value of HIPEC in patients with DSRCT.

5. Loco-regional treatment: radioimmunotherapy

Intra-compartmental delivery of radioimmunotherapy (RIT) could be a promising approach for intraperitoneal DSRCT. A recent phase I study investigated the murine monoclonal antibody ¹³¹I-omburtamab targeting antigen B7H3, which is expressed on cancer cells. The study included 48 patients with DSRCT and showed that the intraperitoneal administration of RIT was well tolerated, with minimal toxicities and low radiation exposure to normal organs, suggesting that this locoregional approach could be combined with other therapies [64].

6. Loco-regional treatment: radiotherapy

Radiotherapy generally has two main indications in DSRCT: i) postoperative WAP-RT for consolidation or adjuvant purposes; or ii) local irradiation in the palliative setting.

Consolidation WAP-RT as part of a multimodal approach, after cytoreductive surgery and intensive multidrug chemotherapy, was first described in a series from the Memorial Sloan-Kettering Cancer Center, the aim being to improve loco-regional disease control [9]. A multimodal treatment that included systemic chemotherapy, complete cytoreductive surgery, and postoperative whole abdominal irradiation prolonged survival in a series of DSRCT patients with no extraperitoneal metastases treated at the MD Anderson Cancer Center [4]. These results were confirmed in a retrospective analysis by the French GSF-GETO team: postoperative WAP-RT was the only variable associated with a longer peritoneal recurrence-free survival and disease-free survival after complete cytoreductive surgery [18]. Another study from the Memorial Sloan-Kettering Cancer Center remarked on the role of trimodal treatment, reporting a 3-year OS of 55% in patients receiving chemotherapy, surgery, and radiotherapy, as opposed to 27% in patients when one of these three treatment modalities was missing [11]. A retrospective French study on 103 patients identified a survival benefit deriving from the use of WAP-RT [21]. Two subsequent reports (from the French cooperative group and the Dana-Faber Cancer Institute) reiterated the call to include WAP-RT as part of the first-line multi-modal treatment strategy for DSRCT [26,28].

Concerning the technique involved, WAP-RT is administered postoperatively for a maximum allowable total dose of 30 Gy, with or without a focal boost on residual disease. Gastrointestinal and hematological toxicities are quite common, especially after neoadjuvant chemotherapy, but might be contained by using an intensity-modulated radiation therapy (IMRT) technique [15,16].

7. Systemic treatments: conventional multi-agent chemotherapy

DSRCT responds to chemotherapy, which can induce significant, though only transient disease regressions [65]. Neoadjuvant chemotherapy is always indicated in patients with unresectable, advanced intra-abdominal DSRCT due to evidence of a clinical benefit in chemo-sensitive tumors correlating with a longer OS, compared with unresponsive tumors [24].

Generally speaking, the chemotherapy regimens conventionally administered to DSRCT patients resemble the protocols used for Ewing sarcoma. They include a combination of anthracyclines, alkylating agents, and vinca alkaloids, in both neoadjuvant and adjuvant settings [65]. The so-called P6 protocol originally developed by the Memorial Sloan-Kettering Cancer Center is used at many centers: it combines cyclophosphamide, doxorubicin and vincristine, alternating with ifosfamide and etoposide [9]. Other regimens that have been described involve vincristine, ifosfamide, doxorubicin and etoposide (VIDE) [17]; vincristine, actinomycin-D ifosfamide and adriamycin (VAIA) [6]; and cyclophosphamide, pirarubicin, etoposide and cisplatin (the modified PAVEP regimen) [66]. No remarkable differences in response rates and in outcome according to the different chemotherapy regimens adopted have been clearly reported. In addition, no prospective studies have been conducted on DSRCT, because of the disease’s rarity. Therefore, it remains extremely difficult to consider any chemotherapy regimen as the best choice or as the standard of care.

In various studies, high-dose chemotherapy was followed by autologous stem cell transplantation, with unclear results [13,14,67–71]. A study by the Italian pediatric cooperative group showed limited improvements in terms of prognosis [13]. A retrospective analysis conducted by the University of Wisconsin on 36 cases included in an international registry showed a benefit for the subset of patients with no residual disease before myeloablative chemotherapy: the median OS was 36 months, as opposed to 21 months for patients with a residual tumor before consolidation [14]. A prospective study conducted at Memorial Sloan-Kettering Cancer Center enrolled 19 patients who received myeloablative chemotherapy with autologous stem cell transplantation and reported 5-year EFS and OS of 11% and 16%, respectively [20]. High-dose chemotherapy is consequently no longer used to manage DSRCT, as confirmed by the French experience in which only one patient received this treatment [26].

Maintenance therapy with low-dose oral cyclophosphamide and weekly intravenous vinorelbine may be used, as it has proved effective in rhabdomyosarcoma, but its use in DSRCT has yet to be validated. Other strategies have been tested in cases of disease recurrence, with disappointing results. In patients with progressive disease resistant to first-line treatment according to the P6 protocol or similar chemotherapy schedules, a transient efficacy has been reported with second- or third-line treatments involving temozolomide/irinotecan, cyclophosphamide/topotecan, gemcitabine/docetaxel or high-dose ifosfamide (as used in Ewing-like strategies) [17,24,72]. Irinotecan (in combination with vincristine) and vinorelbine (in combination with low-dose cyclophosphamide) have been proposed as potentially effective options (Table 2) [66,80]. Irinotecan seems a promising drug for DSRCT. It is a camptothecin derivative with a multifaceted mechanism of action that stops replication and induces double-strand breaks in the DNA by inhibiting the topoisomerase I. In various solid tumors, irinotecan also prevents the effect of several transcription factors, such as the epidermal growth factor receptor (EGFR) [92]. It may be useful in DSRCT, considering the transcriptional activation induced by the EWS:WT1 fusion protein. Recent studies in the sphere of pediatric oncology examined the feasibility of a dose-dense approach that integrated irinotecan in standard chemotherapy for high-risk pediatric sarcomas [29]. A recent study by the Istituto Nazionale Tumori in Milan envisaged adding irinotecan to standard ifosfamide-based regimens (including doxorubicin and etoposide) in cases of DSRCT, followed by maintenance chemotherapy with vinorelbine and low-dose oral cyclophosphamide [29]. A study at the Dana-Faber Cancer Institute considered adding vincristine and temozolomide, as well as irinotecan, to interval-compressed chemotherapy for pediatric DSRCT, suggesting another tolerable and potentially active strategy worth further investigating [28].

Table 2. Potential therapeutic agents for desmoplastic small round cell tumor.

Agent	Author	Findings
Trabectidin	Lopez-Gonzalez et al, 2011 [73]	1 patient with PR, 8 months of PFS
	Brunetti et al, 2014 [74]	1 patient with SD, 4 months of PFS
	Frezza et al, 2014 [75]	2 patients with SD, 4 months of PFS
	Verret et al, 2017 [76]	6 patients, 2 with SD and 4 with PD, 1–4 months of PFS
Irinotecan	Ambar et al. [66]	irinotecan + vincristine (plus radiotherapy) 1 patient with PR, 26 months of PFS
Irinotecan and trabectidin	Ferrari et al, 2022 [77]	trabectidin + irinotecan: 2 patients, 1 with CR, 1 with SD
Temsirolimus	Thijs et al, 2010 [78]	1 patient with SD, 9 months of PFS
	Naing et al, 2012 [79]	temsirolimus + cixutumumab: 3 patients, 2 with PR, 5 months of PFS
	Tarek et al, 2018 [80]	temsirolimus + vinorelbine + cyclophosphamide: 5 patients with PR, 8.6 months of PFS
Vinorelbine	Ferrari et al, 2007 [81]	vinorelbine + cyclophosphamide: 2 patients with PR, 4 months of PFS
	Tarek et al, 2018 [71]	vinorelbine + cyclophosphamide + temsirolimus: 5 patients with PR, 8.6 months of PFS
Antiangiogenic agents	Bétrian et al, 2017 [82]	sunitinib, bevacizumab, sorafenib: 9 patients, 2 with PD, 7 with SD, 3 months of PFS
Pazopanib	Frezza et al, 2014 [75]	9 patients, 5 with SD, 2 with PD, 2 with PR, <16 months of PFS
	Menegaz et al, 2018 [83]	29 patients, 16 with SD, 1 with PD, 11 with PR, 5 months of PFS
Imatinib	De Sanctis et al, 2017 [84]	8 patients, 1 with SD, 7 with PD, 3 months of PFS
Ganitumab	Tap et al, 2012 [85]	16 patients, 6 with PR, 10 with SD, 19 months of PFS
Sunitinib	Italiano et al. 2013 [86]	8 patients, 3 with SD, 3 with PD, 2 with PR, 1–20 months of PFS
Eribulin	Emambux et al. 2017 [87]	3 patients, 2 with SD, 1 with PD, 2–9 months of PFS
Anlotinib	Chen et al, 2019 [88]	1 patient with PR
	Cheng et al, 2022 [89]	1 patient with PR
Apatinib	Tian et al, 2020 [82]	1 patient with PR
Androgen receptor pathway	Fine, 2007 [90]	bicalutamide + leuprorelin: 6 patients, 3 with SD, 3–4 months of PFS bicalutamide: 1 patient with PD, 2.5 months of PFS
Prexasertib	Slotkin, et al 2022 [91]	Prexasertib+irinotecan 19 patients, 9 with SD, 6 with PR, 3 with SD, 1 with PD

Note: Legend: PFS = progression-free survival; PD = progressive disease; SD = stable disease; PR = partial response; CR = complete remission.

8. Systemic treatments: new therapeutic options

Given the unsatisfactory outcomes for patients with DSRCT, further investigations are needed on new agents and innovative treatment combinations. Clinical trials recruiting patients with DSRCT (as in October 2022) are reported in Table 3.

Table 3. Trials recruiting patients with desmoplastic small round cell tumor as of October 2022.

Phase	Title/design/age criteria	Primary outcome	ClinicalTrials.gov Identifier
Phase I/II	Ramucirumab IV + Cyclophosphamide p.o. + Vinorelbine IV (experimental arm), versus Cyclophosphamide p.o. + Vinorelbine IV. Age inclusion criteria: 12 months −29 years	PFS	NCT04145349
Phase II	131 I-Omburtamab in Combination with External Beam Radiotherapy. Age inclusion criteria: >1 year	PFS	NCT04022213
Phase I/II	PBI-200 in Subjects with NTRK-Fusion-Positive Advanced or Metastatic Solid Tumors. Age inclusion criteria: >18 years	Safety and tolerability ORR	NCT04901806
Phase II	Trabectedin and Low-dose Radiation Therapy in Advanced/Metastatic Sarcomas. Age inclusion criteria: 16–75 years	ORR in irradiated nodules	NCT05131386
Phase I	LSD1 Inhibitor Seclidemstat (SP 2577) With and Without Topotecan and Cyclophosphamide in Patients with Relapsed or Refractory Ewing Sarcoma and Selected Sarcomas. Age inclusion criteria: 12 years	Safety and tolerability	NCT03600649
Phase I	B7-H3-Specific Chimeric Antigen Receptor Autologous T-Cell Therapy for Pediatric Patients with Solid Tumors (3CAR), Age inclusion criteria: < 21 years	Safety of B7-H3-CAR T cells	NCT04897321
Phase I	EGFR806 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults, Age inclusion criteria: 1–30 years	Safety and tolerability	NCT03618381
Phase I	B7H3 CAR T Cell Immunotherapy for Recurrent/Refractory Solid Tumors in Children and Young Adults Age inclusion criteria: 0–26 years	Safety and tolerability	NCT04483778
Phase II	Multimodal Immune Characterization of RAre Soft Tissue Sarcoma – MIRAS Project from SARRA (SARcome RAre) Project of the French Sarcoma Group.Age inclusion criteria: >18 years	MFS for localized disease, PFS for metastatic disease	NCT03967834
Phase I	A Prospective Study of Heated Intra-Peritoneal Chemotherapy (HIPEC) with Doxorubicin and Cisplatin in Pediatric Patients with Pelvic and Abdominal Tumors. Age inclusion criteria: 1–25 years	Adverse events of surgery with HIPEC	NCT04213794
Phase II	A Study of the Drug I131-Omburtamab in People With Desmoplastic Small Round Cell Tumors and Other Solid Tumors in the Peritoneum	PFS	NCT04022213
Phase I/II	A Study of Repotrectinib in Combination With Chemotherapy in Children and Young Adults With Solid Tumor Cancer	Safety and tolerability	NCT05004116

Note: Legend:.

IV, intravenous; p.o., per os; PFS, progression-free survival; ORR, overall response rate; MFS, metastasis-free survival; HIPEC, Hyperthermic intraperitoneal chemotherapy; CAR T cell, chimeric antigen receptor T-cell.

The identification of new therapeutic targets, and the rational design of clinical trials for DSRCT have been hindered over time, however, by the lack of preclinical models and the rarity of the disease. For over twenty years, most of the preclinical research exploited the single published cell-line JN-DSRCT-1, first described in 2002 [93,94]. Four fully characterized cell lines, and two patient-derived xenograft (PDX) models recently provided an opportunity for more representative preclinical research into new therapeutic targets, which were identified in studies that extensively profiled DSRCT [95].

On the clinical side, various conventional anticancer agents, such as eribulin [87] or trabectedin, have been used in clinical trials or as an off-label option for patients with relapsing and advanced DSRCT. Trabectedin’s mechanism of action in DSRCT is thought to involve a reduced expression of EWS-WT1 mRNA and impaired binding of the fusion protein to the promoter of its target genes, such as insulin-like growth factor 2 (IGF2), platelet-derived growth factor A (PDGFA), and EGFR [87]. Trabectedin would consequently affect the expression of genes involved in cell proliferation and apoptosis in cases of DSRCT. Interestingly, androgen receptor (AR) and vascular endothelial growth factor receptor (VEGFR) are also included in these genes [96]. There has recently been a report on the potential efficacy of a combination of trabectedin and irinotecan [77].

A further promising clinical candidate for DSRCT may be lurbinectedin, a synthetic alkaloid derived from the natural product trabectedin. With a similar mechanism of action, lurbinectedin inhibits EWS-WT1 transcription factor and blocks the expression of downstream targets. Preclinical data showed very interesting results with tumor regressions in multiple mice in PDX model of DSRCT [77,97] and led to upcoming trials with this drug.

The specific chromosomal rearrangement t(11; 22)(p13; q12) and the fusion protein EWS-WT1 form the primary driver of tumorigenesis, upregulating several growth factor genes, such as PDGFRα. Several pathways have been targeted in the treatment of DSRCT, including androgen receptor pathway inhibition, angiogenesis, tyrosine kinase receptor inhibition, PI3K/AKT/mTOR pathway inhibition, DNA damage repair protein inhibition, c-MET and insulin growth factor pathway inhibition [65]. The use of tyrosine kinase inhibitors directed against proteins involved in the tumor’s vascular proliferation is supported by the capacity of EWSR1:WT1 to induce PDGFA expression, and activation of the IGF1R gene [50,82,84,85,88,89,98–100]. Retrospective studies on anti-angiogenic agents in DSRCT suggest that pazopanib, sunitinib, sorafenib, and apatinib may have some effect [100,101]. The French group described a series of eight patients with advanced DSRCT treated with sunitinib, with a median PFS of 2.6 months [86]. The activity of the mTOR inhibitor temsirolimus has also been reported [78,79].

Androgen receptor (AR) emerged as a therapeutic target for DSRCT after it was suggested that the disease’s relatively high incidence in young males might be partly related to an AR dependence. In a preliminary report from Fine et al in 2007, about two in three DSRCTs exhibited some level of AR positivity on immunohistochemistry (IHC), and half of these tumors stained strongly [90,102]. Remarkably, treatment in vitro with dihydrotestosterone (DHT) of DSRCT cells derived from one patient’s peritoneal fluid confirmed AR functionality, based on tumor growth induction. A small cohort of patients with DSRCT who tested positive for AR (N = 6) was treated with combined androgen blockade (CAB) therapy, consisting of the AR blocker biculatamide (50 mg p.o. QD for 1 week), then Lupron (7.5 mg im. monthly). Three patients showed some clinical benefit, including a partial response, that persisted for 3–4 months. Following this report, AR blockade has been considered by some clinicians for relapsing DSRCT [78]. A very recent, comprehensive preclinical analysis on the molecular impact and therapeutic potential of AR expression and signaling in DSRCT examined 60 DSRCT tumor tissues, the JN-DSRCT cell-line model, and several patient-derived xenograft (PDX) models of DSRCT, comparing them with prostate cancer tissues and cells. This study confirmed nuclear overexpression of AR in 65% of DSRCT on immunohistochemistry. Intriguingly, the study went on to compare AR expression and the preclinical effects of its inhibition with older- and newer-generation AR inhibitors to prostate cancer tumor tissue and cell lines [103,104]. In preclinical, in vitro and in vivo models of DSRCT (including JN-DSRCT and PDX lines), enzalutamide and AR-directed antisense oligonucleotides (AR-ASO) were effective in counteracting tumor proliferation induced by 5α-dihydrotestosterone (DHT). Unsupervised double-hierarchical clustering analysis, conducted in this study using the 1500 most variable genes across all samples, placed DSRCT (n = 22) next to prostate cancer (n = 12), and away from 71 other sarcoma samples. This may suggest that DSRCT is a type of cancer in which AR may have a key part in the tumor’s biology, as in prostate cancer, and AR inhibition therapy could have a disease-transforming impact.

In the pediatric oncology setting, a drug development statement in 2017 that focused on the mechanism of action of AR inhibitors (relying on information available at the time) judged that they were ‘not relevant’ for pediatric cancer [105]. This view now has to be revisited, and clinical studies should be undertaken with AR inhibitors, ideally already in combination with chemotherapy, as developed for prostate cancer. When the mechanism of action of these AR inhibitory agents in DSRCT was investigated in depth, using gene expression analysis and chromatin immunoprecipitation sequencing (ChIP-seq), it emerged that AR signaling regulated cellular epigenetic programs through novel DSRCT-specific AR DNA binding sites adjacent to key oncogenic regulators – including WT1, which is the C-terminal partner of the fusion protein. AR also occupied enhancer sites that regulate other pathways, such as the Wnt pathway, and those involved in neural differentiation and embryonic organ development.

DSRCT harbors features of a multiphenotypic differentiation, expressing proteins on IHC that are associated with neural/neuroendocrine differentiation [106]. When staining for neuron-specific enolase (NSE) was examined in a small morphological study on nine tumors, eight of them showed at least a focal expression of NSE [105]. This preliminary evidence was confirmed when a thorough characterization of the tumor’s molecular profile showed that DSRCT lacking AR expression has a transcriptomic profile resembling that of neuroendocrine prostate cancer [107,108]. At tumor presentation, the presence of a neuroendocrine genotype and phenotype in prostate cancer is extremely rare; it is an event that can occur during the course of the disease, and the treatment options are very limited. In DSRCT, nobody knows whether neuroendocrine features present with different expression levels at the disease’s onset might also be acquired during the course of the disease, or following the onset of resistance to anti-cancer therapies.

Similarities between prostate cancer and DSRCT suggest that therapeutic strategies involving the AR receptor in prostate cancer might be effective for DSRCT as well. For instance, DSRCT strongly expresses polymerase 1 (PARP-1) [109]. PARP inhibitors are effective in the treatment of patients with metastatic castration-resistant prostate cancer, particularly in cases of homologous recombination deficiency (HRD), although such an event is not necessary when PARP inhibition is combined with new-generation hormone therapies [110].

A phase II study was designed to consider the neuroendocrine phenotype and genotype of DSRCT. ONC201 is an antagonist of the tumor dopamine-like DRD2, and an agonist of the antagonist/caseinolytic protease P (ClpP) that causes an increased integrated stress response, a decreased Ras signaling (lower ERK/AKT), and TRAIL induction. These mechanisms result in more cell death signals and fewer cell survival signals in cancer cells. In a preclinical study on DSRCT cell lines and orthotropic peritoneal xenotransplants, ONC201 induced the protein expression of TRAIL and DR5, a receptor that – together with DR4 – triggers TRAIL-induced apoptosis. This orally administered drug was subsequently tested in a phase II clinical trial on patients with neuroendocrine tumors or DSRCT [111]. Two of 10 patients with DSRCT enrolled in this study were treated, one for more than a year, the other for more than 4 years. A further patient, who had limited disease progression at 3 months, came off the study and was given radiotherapy for progressive lung metastases: he has remained off any therapy and without any relapse for more than 3 years.

Another neural marker, the neurotrophic tyrosine kinase receptor 3 (NTRK3) is considered a druggable receptor tyrosine kinase in DSRCT. NTRK3 mRNA is more strongly expressed in DSRCT than in other sarcomas (particularly those driven by a specific transcription factor), or cancers harboring fusion proteins involving NTRK3 [94]. In fact, most DSRCTs are strongly immunoreactive for the NTRK3 protein. The fusion protein EWSR1-WT1 activates the NTRK promoter, and increases the expression of NTRK3, resulting in the promotion of tumor growth [95]. Preclinical evidence in DSRCT cell lines and patient-derived xenografts showed that the NTRK inhibitor entrectinib counteracts this oncogenic mechanism. These recent results point to the need for investigations on NTRK inhibitors in the clinical setting, and a clinical trial is currently testing a combination of irinotecan, repotrectinib and temozolomide [95] (Clinicaltrial.gov NCT05004116).

Other hypotheses paving the way to clinical trials were formulated following the development of new cell lines and PDX models. One example concerns the Salt-Inducible Kinase 1 (SIK1), a member of the AMPK-related kinase family involved in a broad spectrum of biological processes, which is a direct target of the EWSR1:WT1 fusion protein[112]. Interestingly, a reduction in SIK1 causes a tumor cell growth inhibition comparable with what happens when EWSR1:WT1 expression is abolished, and SIK1 silencing leads to the cessation of DNA replication and tumor growth inhibition. Targeting SIK1 with the YKL-05-099 small-molecule inhibitors resulted in significant cytotoxicity. Another relevant example concerns the activation of the ERBB pathway in DSRCT, which occurred through the fusion protein EWSR1:WT1 and resulted in the upregulation of EGFR, ERBB2, ERK1/2, and AKT, and the stimulation of cell growth. DSRCT cell line proliferation could be blocked by antagonizing EGFR function with shRNAs, the small-molecule inhibitors afatinib and neratinib, or the anti-EGFR antibody cetuximab [113]. Remarkably, a combination of cetuximab and afatinib inhibited tumor growth in PDX of DSRCT, giving rise to a preclinical hypothesis promoting the clinical testing of agents that target EGFR in DSRCT.

Further agents of interest may be DNA damage response agents. Prexasertib is an inhibitor of CHK1: it prevents DNA repair leading to mitotic catastrophe and can enhance the activity of DNA-damaging chemotherapy. Translocation driven sarcomas (including DSRCT) have demonstrated susceptibility to CHK1 inhibition in preclinical models. A very recent phase I/II study on prexasertib in combination with irinotecan (on 19 patients with DSRCT) showed preliminary interesting findings [91].

Finally, studies are analyzing the different sequences and the lengths of peptides that are found in the fusion gene of DSCRT [114]. This data may lead to the generation of mRNA-based anti-cancer vaccine that select the best neoantigens accounting for HLA type and neoantigen binding.

9. Conclusions

Despite the multimodal approach to their treatment, including aggressive cytoreductive surgery, intensive multi-agent chemotherapy, and postoperative WAP-RT, the prognosis for patients with DSRCT remains dismal, with a 5-year overall survival rate in the range of 10–20%.

Such unsatisfactory outcomes make it essential to conduct further collaborative research and clinical trials in an effort to improve these patients’ chances. Preclinical models are needed, and multidisciplinary collaborative programs should be established, involving both the pediatric and the adult sarcoma communities [27,115]. Extensive international cooperation can improve our knowledge of the pathogenesis of DSRCT, explore new molecular targets, and find potentially effective biological agents for this aggressive disease.

10. Expert opinion

The treatment of patients with DSRCT remains a huge challenge for sarcoma specialists. Attempts to improve patient outcomes over the past two decades have produced very limited results, and a standard treatment approach is still lacking. Generally speaking, patients are still treated with alkylating and anthracycline-based conventional multi-agent chemotherapy regimens, which often prompt an initial tumor response but fail to improve overall survival. Surgery should still be considered the mainstay of treatment and should be performed by an expert team at a highly qualified sarcoma reference center. The aim should be to achieve a microscopically complete resection, which correlates with better outcomes. The role of postoperative whole-abdomen radiotherapy, high-dose chemotherapy with autologous stem cell rescue or hyperthermic intraperitoneal chemotherapy remains unclear.

We believe that there are two aspects to consider in our efforts to improve our understanding of DSRCT and our patients’ outcomes.

- First, we need to rise to the challenge to establish highly predictive preclinical models of DSRCT because the lack of such models has hindered efforts to identify new therapeutic strategies for these patients. It is only recently that some PDX models and patient-derived cell lines have been generated, and used to test new targets. These targets were identified in retrospective series managed at sarcoma reference centers, where cases of DSRCT were profiled to assess the disease’s genomic vulnerabilities and over-expressed druggable genes. These new models have led to the identification of novel potentially effective therapies and are informing the design of new clinical trials. Some of these trials are already opening, while others are expected to be designed soon. The generation of further, histologically and molecularly well-characterized patient-derived models should be strongly encouraged with a view to setting the preclinical stage for next-generation clinical trials.

- Second, it is crucially important to develop international collaborative schemes involving multiple stakeholders – including clinicians (both pediatric and adult oncologists), pharma, parent/patient advocacy groups, regulatory bodies, and clinical statisticians/trialists – to tackle a rare and complex disease like DSRCT. Only such large-scale and far-reaching efforts can generate up-to-date and timely clinical investigations on innovative agents and promising drug combinations for this cancer, relying on an effective, modern trial design.

Since nothing has come to light so far to indicate that the tumor biology and/or clinical presentation of DSRCT differ between pediatric and adult patients, the ultimate goal should be to develop shared clinical trials for children, adolescents and adults with the same disease. On the other hand, the latest preclinical studies do suggest that there may be at least two different biological subtypes of DSRCT (as seen in prostate cancer), one AR-positive and the other neuroendocrine. Although such a hypothesis will require prospective validation, this biological/molecular distinction might enable patients to be pre-selected for targeted therapies. Since there are no clear prognostic markers at diagnosis (apart from likely localized disease), DSRCT is known to quickly become chemo-resistant, and patient survival rates are extremely low, it would be tempting to propose an international frontline clinical study with several biology-driven treatment arms – including novel agents, not only alone, but also in combinations with known multimodal therapies.

Article highlights

• Desmoplastic small round cell tumor carries a very poor prognosis

• To date, there is no standard first-line treatment

• A multimodal approach is the common strategy

• Novel agents seem promising, judging from studies in preclinical models.

Declaration of interest

The authors have no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

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Funding

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