Desmoplastic Small Round Blue Cell Tumor: A Review of Treatment and Potential Therapeutic Genomic Alterations

Desmoplastic small round blue cell tumors (DSRCTs) originate from a cell with multilineage potential. A molecular hallmark of DSRCT is the EWS-WT1 reciprocal translocation. Ewing sarcoma and DSRCT are treated similarly due to similar oncogene activation pathways, and DSRCT has been represented in very limited numbers in sarcoma studies. Despite aggressive therapy, median survival ranges from 17 to 25 months, and 5-year survival rates remain around 15%, with higher survival reported among those undergoing removal of at least 90% of tumor in the absence of extraperitoneal metastasis. Almost 100% of these tumors contain t(11;22) (p13;q12) translocation, and it is likely that EWS-WT1 functions as a transcription factor possibly through WT1 targets. While there is no standard protocol for this aggressive disease, treatment usually includes the neoadjuvant HD P6 regimen (high-dose cyclophosphamide, doxorubicin, and vincristine (HD-CAV) alternating with ifosfamide and etoposide (IE) chemotherapy combined with aggressively attempted R0 resection). We aimed to review the molecular characteristics of DSRCTs to explore therapeutic opportunities for this extremely rare and aggressive cancer type.


Background
Desmoplastic small round blue cell tumors (DSRCTs) are a highly aggressive and rare mesenchymal tumor, of which approximately 200-450 cases have been described so far [1,2]. DSRCT was rst reported as a separate identity in 1989 by Gerald and Rosai [3] who proposed that DSRCT arose during development from a progenitor cell with potential for multiphenotypic di erentiation [4].

Clinical Presentation
Young men comprise the vast majority of cases with a mean age at diagnosis of 22 years [2,5,6]. Clinically, DSRCT has been shown to have a predilection for developing in the abdominal and pelvic cavity with extra-abdominal involvement being much less common [5].
In the majority of cases, patients with DSRCT present with advanced disease. Most patients remain asymptomatic for extended periods of time, and diagnosis is made when tumor burden is signi cant [2]. e most common symptoms are abdominal pain and weight loss [5]. Constipation due to mass e ect caused by the tumor and bowel obstruction have also been reported [2]. Due to a signi cant burden of peritoneal disease, some patients will present with an abdominal mass alone, but the most common presentation is abdominal distension from ascites. Liver metastases are seen both at the time of diagnosis and with relapse. Other distant sites include lymph nodes, lungs, and bones [2,7,8]. Omental and hepatic metastases can also be seen.

Diagnostic Studies
CT scan with oral and intravenous contrast is the imaging modality of choice when evaluating patients with known or suspected DSRCT. Characteristic ndings in DSRCT include soft tissue masses which are often bulky (mean, 6 cm; range, 1-28 cm), lobulated, and heterogeneous with hypodense areas; these ndings are present in up to three-quarters of patients [15], and a signi cant desmoplastic reaction differentiates DSRCTs from other small round cell tumors [16]. Adenopathies are present in approximately half of patients at the time of diagnosis (intraperitoneal, retroperitoneal, and pelvic) [15,17]. In a radiological review of 13 cases of abdominal DSRCT, the most common nding was the presence of several lobulated peritoneal soft tissue masses (mean number of masses/patient � 4). e main sites of peritoneal involvement were the pelvis, omentum, retroperitoneum, and small bowel mesentery. In six cases, moderate ascites was seen. Five of 13 patients had liver metastases, with an average of four lesions per case. Associated thoracic metastases were found in three patients [18].
MRI ndings include heterogeneous T1 low signal and heterogeneous T2 high signal. After gadolinium administration, there is heterogeneous contrast enhancement. Subtle hypointense foci are sometimes seen on T2-weighted images representing desmoplastic reaction. Hyperintense T1 signal and uid/ uid levels may suggest recent hemorrhage in a tumor [19].
FDG-PET scanning has been shown to impart important additional information and has a relevant impact on treatment planning when used in concert with CT scan [20,21]. FDG-PET is sometimes obtained at diagnosis and during surveillance. FDG-PET/CT has been found to be superior to CT in detection of lymph node involvement (sensitivity, 95% versus 25%, resp.), bone lesions (sensitivity, 90% versus 57%, resp.), and renal lesions [20]. In a study of 65 patients, FDG uptake was seen in all primary intraabdominal and pelvic tumors [22] and accurately detected 97% of all DSRCT lesions with sensitivity, speci city, positive, and negative predictive values of 96%, 99%, 98%, and 97%, respectively. However, CT is more reliable than FDG-PET in depicting lung metastases [20].
Core biopsy specimens are preferred to acquire su cient sample. Fine-needle aspiration specimens, although commonly employed, are not adequate during the workup of DSRCT due to issues with low cellularity of the sample, necrosis, and predominantly a desmoplastic reaction. Fineneedle aspiration is challenging and requires pathological expertise in the utilization of ancillary techniques such as immunocytochemistry and ow cytometric immunophenotyping.
e absence of the characteristic desmoplastic stroma in DSRCT and its cytologic features make cytologic interpretation di cult [23]. Characteristic cytologic features are seen in the right clinical context of small round blue cells with cytoplasmic densities and purple-stained connective stroma [24] and should raise suspicion of DSRCT that should be con rmed by its unique cytogenetic abnormality. e cells include granular chromatin and smooth to irregular nuclear membranes and show nuclear molding, cytoplasmic vacuoles, pseudorosettes, and metachromatic stroma [25] compared to other potential diagnoses like Ewing sarcoma. RT-PCR for EWS-WT1 transcript detection is a way of increasing diagnostic accuracy [26]. However, using a combination of both techniques, 86.4% of DSRCT can be typed accurately [26,27].

Staging
e UICC staging of sarcoma is inadequate for DSRCT as it classi es nearly all patients as metastatic [2]. Several staging methods have been proposed for DSRCT, and there is currently no validated staging system. Due to the extensive nature of the peritoneal disease frequently present, the Peritoneal Cancer Index is often used. In this system, the abdominal cavity is divided into 13 regions, and each region is assigned a lesion size score ranging from 0 (no tumor seen) to 3 (tumor >5 cm or con uence) [28]. e MD Anderson group has suggested the inclusion of liver and extraabdominal metastases into this staging system to adjust for the use of hyperthermic intraperitoneal chemotherapy (HIPEC) and the nding that extra-abdominal metastasis correlated with poor survival [29]. It is unclear if this strategy applies to the adult population since the median age in that study was 12 years in few who underwent HIPEC. e estimated median overall 3-year survival for patients not undergoing surgery or HIPEC was 26% compared with 71% in patients who underwent HIPEC and surgery compared with 62% who only received debulking surgery [7].

Imaging
CT scan with contrast is the imaging of choice for staging and surveillance. CT is more reliable than FDG-PET in depicting lung metastases [20]. Soft tissue masses seen are often bulky 2 Sarcoma (mean, 6 cm; range, 1-28 cm), lobulated, and heterogeneous with hypodense areas up to three-quarters of patients.
Adenopathy is present in about half the time of the diagnosis (intraperitoneal, retroperitoneal, and pelvic). Occasionally, moderate ascites is seen [18]. FDG-PET scanning has been shown to impart important additional information and has a relevant impact on changing treatment planning when used in concert with CT scan [20,30]. FDG-PET can be used at diagnosis and during surveillance and has been found to be superior to CT in detection of lymph node involvement (sensitivity, 95% versus 25%, resp.) and bone metastases (sensitivity, 90% versus 57%, resp.) [20].

Molecular Findings
As in certain other tumors, the function of the Wilms tumor protein (WT1) in repressing gene transcription is lost in DSRCT [31]. ere is reported loss of the zinc nger region of WT1 in EWS-WT1 which serves to convert WT1 from a repressor of transcription to a dominant transcriptional activator oncogene including some 35 target genes [14,32]. Some of these are growth factor genes such as PDGFα; growth factor receptor genes such as IGF-1 receptor, EGFR, and IL-2/15Rβ [13,33]; transcriptional regulators including c-MYC, n-MYC, PAX2-2, ENT4, and WT-1; and extracellular protein-encoding genes such as e-Syndecan, E-cadherin, and TALLA-1 which is a tetraspanin-family genes that encodes transmembrane proteins responsible for regulating cell adhesion, migration, and metastasis [34]. CCN2 (connective tissue growth factor) is highly expressed in DSRCT and may have autocrine or paracrine roles in disease progression [31]; however, the precise contribution of these molecular events and their potential as a therapeutic target remain poorly understood and applied. Embryologically, WT1 is involved in urogenital development [35]. Normal WT1 protein is expressed in tissues which undergo mesenchymal-epithelial conversion from mesoderm [36] and may have a role in mesothelial formation in embryonic development [37]. is may explain the mesenchymal propensity of the tumor and some usage of the name "mesothelioblastoma." Variant fusion isoforms generated due to alternative mRNA splicing have led to discovery of two protein isoforms. Some of these cases express full-length WT1 or have variant transcripts (KTS+), resulting in atypical staining patterns. e KTS+ variant has di erent transcriptional targets than the KTS− isoform [38].
Neither isoform of EWS-WT1 is su cient to transform wild-type murine embryonic broblasts (MEFs). e oncogenic potential of both can be unmasked by p53 loss as seen by nuclear localization of p53, and copy-number ampli cation and gene-set enrichment analysis demonstrated augmentation of the WNT pathway [39]. In the absence of intact p53 protein, WT1 acts as a transcriptional activator [40].
Genomic analysis on LMS, UPS, and MPNST has shown novel genetic alterations; however, DSRCT has been represented in very limited numbers [41]. Limited sequencing studies have been performed on DSRCT because of the small number of cases shown. Protein biomarkers show c-kit in 19% of cases, and HER2/neu overexpression (3+) is also seen but uncommon in desmoplastic small round cell tumors [42]. EGFR gene ampli cation occurs at a rate of 16.9% by FISH. is was also true for LMS, MPNST, osteosarcoma, and UPS [41].
Molecular pro ling on 35 DSRCTs sampled from patients having surgery for DSRCT (Caris Life Sciences, Phoenix, AZ) that were compared with Ewing sarcoma revealed low immunogenicity (<10 mutations/Mb) and low frequency of actionable mutations including PD-L1 in both tumor types. High AR expression could present as a potential therapeutic target for DSRCT while taxanes may be more e ective in Ewing sarcoma compared to DSRCT based on TUBB3 expression [43]. Given the male predominance of this subset of disease, it is not surprising that, when compared to Ewing sarcoma, no signi cant di erence was seen in protein expressions with the exception of a signi cantly higher overexpression of AR in DSRCT (59% versus 3%, p � 1.7E-10) and TUBB3 (56% versus 29%, p � 0.03) [43].
ere is known to be relatively low concordance across platforms and for individual genes or proteins. cKIT overexpression by IHC in one study did not associate with cKIT mutations [41]. is is in contrast to GIST, where more than 80% of cases carry an activating mutation in the KIT gene and more concordance is seen [44]. ere is in fact quite a low frequency of actionable mutations detected in series that looked at genomic alterations which overall included only 9 patients of DSRCT [41].
Given the interest in immunotherapy, currently, most of the interest lies with PD-1 and PD-L1 inhibitors. Previous work has shown that both PD-1 positivity and PD-L1 positivity were independent prognostic indicators of OS and EFS in sarcoma [45]. Intratumoral in ltration of PD-1positive lymphocytes and PD-L1 expression have been seen in 65% and 58% of STS, respectively [45]. PD-1 positivity and PD-L1 expression are associated with advanced clinicopathological parameters and presence of distant metastasis, and both PD-1 positivity and PD-L1 positivity are independent prognostic indicators of overall survival (OS) [45,46]. Over 150 sarcoma subtypes have been analyzed for PD-L1 tumor expression and the presence of PD-1+ tumorin ltrating lymphocytes (TILs): up to 65% of sarcomas expressed PD-L1 which, along with PD-1 TIL positivity, correlates with poorer overall survival and aggressive tumor features [47]. DSRCT, however, is not very well represented in these studies.
We now know that a higher mutational rate is observed in melanoma (median of 13.2 mutations per Mb) and in NSCLC, re ecting their high responses to immunotherapy. e median of somatic mutations per Mb is 10.5 for smokers and 0.6 for nonsmokers, in which mutations are known to be secondary caused by selective pressures such as UV light and tobacco smoke exposure, respectively.
Mutational loads are lower in MSS colorectal tumors (3.2 mutations per Mb), with higher mutational loads in MSIhigh tumors [48] re ecting their response to PD-1 inhibitors [49]. Low mutational loads of 1.53 mutations per Mb in RCC may re ect why PD-1 staining was not suggestive of activity to nivolumab [50]. Cytokine-based immunotherapies have also shown limited bene t in the advanced setting Sarcoma 3 of sarcomas. A large randomized trial of adjuvant interferon maintenance in resected osteosarcoma patients did not provide signi cant improvement [51]. DSRCT is not a very immunogenic tumor. Some soft tissue and bone sarcomas have been shown to express PD-1 ligand, and additional information is emerging about the role of somatic mutations in predicting response [46,51,52]. ere is recent evidence showing SLFN11 mRNA transcript and protein levels in DSRCT-1 are comparable to EWS cell lines. Schlafen-11 (SLFN11), a putative biomarker for defective DNA damage repair, and SCRT-1 demonstrated sensitivity to PARPi as single agent or in combination with either the topoisomerase I inhibitor irinotecan or ionizing radiation [53].

Treatment
Aggressive attempts at R0 resection have been a cornerstone of any curative intent strategy for DSRCT. HIPEC has been shown to optimize outcomes in single-center retrospective studies for disease in the abdomen [54]. Complete cytoreduction is performed prior to HIPEC using cisplatin. Because of large tumor sizes on clinical presentation and unresectable metastatic disease, surgery is usually preceded by induction of neoadjuvant HD chemotherapy, which is followed by consolidation treatment with either radiation or myeloablative treatment (Table 1) [6,29,55,56]. e surgical goal is to remove >90% of the tumor [56], and resection to less than 1.0 cm tumor size [7]. is mostly requires omentectomy, peritoneal stripping, splenectomy for hilar involvement, and local resection of the diaphragmatic peritoneum [55,56]. Microscopic negative margins are di cult to achieve because of the desmoplastic nature of the tumor; therefore consolidative 30 Gy WAP-RT [57]/IMRT [58], HIPEC [29], [ 90 Y]yttrium microspheres radioembolotherapy [59], myeloablative chemotherapy (rarely used now) [55,56,60], or consolidative chemotherapy has been employed in most of these studies, and relapses occur early without consolidation. R0 resection and HIPEC to sterilize extensive peritoneal metastasis can lead to median survival of up to 63 months [54].
DSRCT is somewhat alkylator sensitive, and response seems to be dose responsive [55]. Doxorubicin is a common thread in the treatment of patients who either achieved longterm survival or had response to a standard consolidative radiotherapy dose of 30 Gy when delivered by external beam to the whole abdomen and pelvis [57,58]. Myeloablative chemotherapy with thiotepa and carboplatin, etoposide followed by autologous bone marrow, or peripheral stem cell rescue has been employed with limited success [56,61]. Case report of [ 90 Y]yttrium microspheres radioembolotherapy leading to a dramatic sustained reduction in the hepatic metastatic load has also been reported [59,62].
Most of the early case reports in the last 2 decades have used standard dose alkylating agents, Adriamycin-based treatment with less than favorable responses [3,9,63]. Irinotecan and temozolomide combination has shown up to 68% objective response in recurrent Ewing sarcoma during early retrospective studies [64]. Phase II study (TEMIRI) of temozolamide 100-125 mg/m 2 /day (days 1-5) and irinotecan 10 mg/m 2 /day (days 1-5 and 8-12) every 3 weeks show responses between 33% in a familiar tumor histology of medulloblastoma with some of the patients having a desmoplastic variant [65].
e regimen was chosen due to its prior e ectiveness and experience of use in Ewing sarcomas and metastatic neuroblastoma in children and young adults where it was called the "N6" protocol; N likely represents neuroblastoma [66,67].
A modi ed P6 regimen and a modi ed PAVEP regimen [63,68] (cyclophosphamide, pirarubicin, etoposide, and cisplatin) have been employed to decrease severe adverse events and to improve the completion rate of chemotherapy. ese modi ed regimens use Cytoxan of 4 g/m 2 and replace Adriamycin with pirarubicin. e modi ed P6 regimen use higher ifosfamide dose (12 g/m 2 divided for ve days) instead of 9 g/m 2 in the original P6 regimen. e addition of irinotecan, topotecan, carboplatin, and cisplatin leads to few months of stable disease at best in selected patients [56,57]. e insensitivity of the tumor to high-dose chemotherapy may implicate a stem cell hypothesis in DSRCT [69,70]. is may re ect on the heterogeneity of the tumor and contribute to the general di culty in eradicating the tumor. Unlike Ewing sarcoma, the putative CD133+ stem cell has not been identi ed to date [69,70]. Quantitative real-time PCR analysis of putative stem cell maintenance revealed that CD133+ ESFT cells express signi cantly higher levels [70]. is could certainly explain tumor characteristics and lead to the identi cation of new targets for more e ective therapies [70]. Radiation is more easily tolerated in pediatric patients and may improve local control [57,58]. Most relapses are intraperitoneal and/or hepatic WAP-RT. Acute toxicities are approximately 80%, and almost a third of patients experience acute hematologic toxicity, with grade 4 thrombocytopenia seen in 76% of patients. Small bowel obstruction occurred in 7 patients (33%) after surgery and WAPI [57]. In one study, postoperative WAP-RT was predictive of 3-year overall survival, as were the absence of EPM and complete surgical resection. Heated intraperitoneal chemoinfusion with cisplatin had no impact on overall survival in that analysis [1].

Targeted Agents
It is unclear if, despite poor long-term outcomes, we should continue treating these patients with HD chemotherapy [2] and prolonged in-patient hospital protocols. A standard Ewing sarcoma alternating VAC/IE protocol with standard alkylator doses (Cytoxan 1200 mg/m 2 over 60 min) and 1800 mg of ifosfamide per square meter per day for ve days [71], given with mesna, could be evaluated since oncogene 4 Sarcoma 6 Sarcoma activation pathways in DSRCT may be similar to those in Ewing sarcoma [72]. Some centers are using a modi ed P6 protocol [2,68] which is similar to VDC/IE (vincristine, total dose of 2 mg; Adriamycin, 75 mg/m 2 ; and cyclophosphamide, 1200 mg/m 2 with mesna). Dactinomycin at 1.25 mg per square meter per dose is substituted for doxorubicin when a total doxorubicin dose of 375 mg per square meter is reached. Ifosfamide and etoposide are administered (1800 mg/m 2 of ifosfamide for ve days, given with mesna, and 100 mg/m 2 of etoposide over ve days) [71]. e Ewing sarcoma regimen whether used in a dose-dense or three weekly schedule also provides a maintenance phase of treatment of up to 49 weeks [71]. ere is suggestion of longer outcomes with an outpatient maintenance therapy that consisted of irinotecan and temozolomide followed by XRT and HIPEC in a 5-year-old patient [73].
Small molecule TKIs have shown dismal results so far including sorafenib and sunitinib. In a DSRCT cell line, the mTOR inhibitor induces apoptosis [74]; in practice, however, rapamycin and temsirolimus have had limited PFS [75,76]. erefore, mTOR inhibition may only have a role in a combination setting rather than as single therapy. In a retrospective review of patients who received pazopanib within EORTC trials, a clinical bene t rate (PR + SD >12 weeks) of 78% was reported among patients who had progressed on prior treatments among 9 patients [77].
Recently, olaratumab, a novel PDGFRa inhibitor, was approved with doxorubicin in soft tissue sarcomas (STS) with a histology subtype for which an anthracycline-containing regimen may be appropriate; however, in the study, DSRCT was not represented [78]. DSRCT had more limited representation with pazopanib approval in the PALETTE trial [79], with eribulin [80], and with the approval of trabectedin [81].
Eribulin has shown activity in pretreated patients with L-sarcomas and recently showed a 2-month survival bene t in the phase III study compared to dacarbazine [80]; however, outcomes in pretreated patients with synovial sarcoma and other types of soft tissue sarcoma did not meet the prespeci ed primary e cacy endpoint for activity [82]. Ewing family tumors were excluded in the study; however, three-quarters of patients were still alive at 6 months [82], suggesting that microtubule inhibition may warrant further study since vinca alkaloids have historically shown activity with Ewing family tumors [83,84]. We must perform tumor biomarker evaluations in these clinical trials comparing responding patients with nonresponders to understand who may truly bene t or not from these therapies [83].
Gemcitabine and docetaxel have been used as an outpatient regimen for STS other than leiomyosarcoma and could have bene t in patients unable to tolerate very aggressive chemotherapy [85][86][87]. A clinical trial undergoing (NCT01532687) is currently looking at gemcitabine with or without pazopanib and is currently recruiting.
IGF-1R inhibition has been seen to mitigate mTOR activation and is supported by preclinical data supporting its additive antitumor e ects by combining them [88]. Cixutumumab at 6 mg/kg IV weekly was combined with temsirolimus in heavily pretreated patients with Ewing family tumors that included DSRCT with one-third of the patients achieving relatively durable CR/PR [89]. is was well tolerated, with preliminary evidence of durable antitumor activity, and attempts to evaluate response in a phase II study for STS after stratifying for the expression of IGF-1R on tumor tissue [90]. Other DSRCT targeted agents include GD2 [91] and ganitumab, a fully human monoclonal antibody against type-1 insulin-like growth factor receptor (IGF-1R), showing 6% ORR and 17 (49%) SD rate in an open label phase II trial [92].
ese novel clinical trials with biomarker and molecular data-driven interventions re ect the direction this eld is moving with the availability of newer diagnostic tools.

Role of Immunotherapy
Tumor mutational load (TML) may a ect response rates to immunotherapy as seen in NSCLC and melanoma. Higher TML tumors are more responsive to immune checkpoint inhibition [52]. Single-agent anti-PD-1 antibodies have had limited e cacy across sarcomas to date. A phase II study (SARC028) is evaluating the role of pembrolizumab across various sarcoma histologies (NCT02301039) [47]. None of the patients in a recently reported DSRCT cohort had identi able tumoral PD-L1 expression by SP142 antibody testing, and the signi cance of PD-1-positive TILs is unclear at this time [43]. e composite of tumoral PD-L1 positivity and PD-1 positivity among tumor-in ltrating lymphocytes has been suggested as an indicator of prognosis in soft tissue sarcoma patients [45]. Another small, but heterogeneous, patient cohort at MSKCC demonstrated no association between PD-L1 expression, TIL and clinicopathological features, and overall survival using the DAKO 5H-1 antibody [93]. DSRCT patients, however, were not represented in these small data sets. B7H3, an immunomodulatory cell surface molecule, is seen in >90% DSRCTs. In a phase I study, a radioimmunoconjugate showed promise in an ongoing clinical trial (NCT01099644).

Future Directions
An ongoing NCT01189643 trial is looking at addition of two cycles of irinotecan, temozolomide, and bevacizumab followed by a standard P6 protocol utilizing the data, suggesting that VEGFR-2 and VEGFA overexpress in DSRCT cell lines and xenograft models [94]. A pilot study evaluating the combination of irinotecan, temozolomide, and bevacizumab is active in patients with DSRCT, and it is feasible to combine these agents with standard chemotherapy without greater than expected toxicity with response rates around 27% [95].
A phase I/II clinical trial is studying the side e ects and the most e ective dose of the notch signaling pathway inhibitor RO4929097 when given together with vismodegib in DSRCT patients (NCT01154452). A study looking at intraperitoneal radioimmunotherapy with a novel antibody 8H9 for patients with DSRCT is also recruiting (NCT01099644).
A current study which is ongoing but not recruiting adds irinotecan, temozolomide, and bevacizumab to the chemotherapy regimen currently used in DSRCT. An ongoing phase II study (SARC028) is looking at the role of pembrolizumab in Sarcoma 7 sarcoma (NCT01189643). Similar to many general sarcoma studies, DSRCT is not represented in this study because of the limited number of patients with this disease.

Conclusion
Because of the rarity of DSRCT, limited data are available regarding the impact of various treatment modalities on survival. Aggressive surgery, radiotherapy, and chemotherapy have all been used to control DSRCT. Unfortunately, durable responses are limited, and the prognosis for patients with DSRCT remains poor [1]. e largest available singleinstitution study of 66 patients with DSRCT reported a 3-year and 5-year overall survival rate of 44% and 15%, respectively. Use of a combined surgery and a Ewing-based chemotherapy regimen of vincristine, doxorubicin, and cyclophosphamide (VAC) and ifosfamide + etoposide (IE) in various combinations achieves a maximal tumor debulking and is associated with improved overall survival relative to other chemotherapy regimens. Greater than 90% tumor   [56]. e impact of optimal debulking was also con rmed in these studies [7,29]. High-dose chemotherapy, radiotherapy to high-risk sites, and myeloablative chemotherapy with stem cell rescue have been described in selected cases [55]. Some investigators have described the use of cytoreduction and hyperthermic intraperitoneal chemotherapy using cisplatin for treatment of carcinomatosis and yttrium microspheres for treatment of liver metastasis from DSRCT [7]. Consolidative IMRT after debulking and/or HIPEC although used can lead to suboptimal outcomes secondary to GI and hematological toxicities and inferior DFS [96,97]. Based upon the available data, the treatment strategy currently associated with the best overall survival includes optimal resection of ≥90% of the tumor and high-dose chemotherapy regimens. Given the signi cant tumor response seen in many patients following systemic chemotherapy, deferring resection until a maximal response to systemic therapy is achieved is currently advocated by some clinical investigators [62].
Little progress has been made in the eld of small molecule TKIs for sarcomas since the approval of imatinib for GIST in 2002, and despite the recent FDA approval of the multi-tyrosine kinase inhibitor pazopanib, any direct ecacy for DSRCT is limited and from small retrospective studies. Rather than pursuing di erent chemotherapy combinations without a solid genomic basis, the eld has moved to patient selection based on identifying the optimal combination of targeted therapy, chemotherapy based on chemotherapy sensitivity studies and possibly for high mutational load patient checkpoint inhibitors, or immunotherapy using a tumor signature to determine an approach so as to improve outcomes in clinically applicable ways.
A collaborative e ort to include DSRCTs in clinical trials with targeted agents is crucial to determine if there truly is a clinical bene t from this novel treatment option. Recently concluded trials are eagerly awaiting to provide insight into these questions (Table 2) to show a hitherto unsurpassed survival bene t of 26.5 months in SRS with the drug olaratumab and have prompted an accelerated FDA approval in October 2016.
It is unlikely that combinational chemotherapy will signi cantly improve outcomes in DSRCT. Surgery should remain the cornerstone of treatment. Extended genome sequencing and immunotherapy are being assessed in future clinical trials (Table 3), and it remains to be determined what the role will be in the future for many of the emerging agents.

Conflicts of Interest
Joanne Xiu is employed by Caris Life Sciences, Phoenix, AZ. e other authors have no con icts of interest.