Background
Desmoplastic small round cell tumor (DSRCT) was first described in 1989 by Gerald and Rosai [
1], as a tumor made of small round blue cells separated by abundant desmoplastic stroma. Fewer than 800 cases have been reported in the literature. DSRCT is therefore rare. DSRCT is an aggressive tumor, which mainly affects teenagers and young adults, predominantly males (sex ratio 4:1 to 9:1) with a peak incidence in the third decade of life.
On histological examination, tumor cells may display epithelial, mesenchymal and neuronal markers [
2]. DSRCT is associated with a unique translocation t(11:22) (p13, q12) resulting in a fusion of the EWSR1 and the Wilm’s tumor WT1 genes. The chimeric product acts as an aberrant transcriptional factor and several transcriptional oncogenic targets have been identified including platelet derived growth factor A (PDGFA), insulin like growth factor 1 (IGF1) and WT-1 [
3]. However, this has not yet been translated in efficient targeted therapy in this disease.
DRSCT typically involves the abdominal and peritoneal cavity, but extra-peritoneal organs may be affected [
4‐
6]. Retroperitoneal lymph nodes, liver or lung metastases occur up to 50% cases at diagnosis [
7]. There is no validated disease staging system, although the peritoneal cancer index (PCI) may be used for peritoneal disease [
8] and Hayes-Jordan et al. have proposed a staging system specific to DSRCT [
9].
With only one large case series described, the best therapeutic strategy remains unclear. DSRCT has a poor prognosis with a median OS of 25 months [
7] and a 29 and 18% 3 and 5-years survival rate [
10,
11]. A few small series suggest that intensive chemotherapy followed by extensive debulking surgery and abdominal radiation may improve the outcome of patients with operable disease [
7,
12,
13]. Polychemotherapy schedule using alkylating agents and anthracyclins such as P6 protocol (cyclophosphamide, doxorubicin, vincristine, ifosfamide, etoposide, irinotecan and platinum alternating schedule) is associated with better outcome. A few centers have advocated the use of hyperthermic intraperitoneal chemotherapy (HIPEC) but, in the absence of randomized study, it is difficult to decipher the actual treatment effect from a selection bias in these series [
14,
15]. Whole abdominal pelvic radiation therapy (WAP RT) and increasing development of intensity modulated radiation therapy were also described as a part of the adjuvant treatment [
16,
17].
Overall, despite multimodal strategy, long term survivor rate remains low, with fewer than 20% of patients achieving 5-year survival [
12]. Tumor recurrence and progression is the rule. After first line treatment, several cytotoxic agents have been studied, alone or in combination, including vinorelbine and cyclophosphamide [
18], irinotecan [
19], trabectedin [
20,
21]. However, response rates are low and only partial responses are described and response duration remains short, range from 3 to 9 months.
Recently, there has been interest in the potential role of antiangiogenic tyrosine kinase inhibitors. Indeed, expression of EWS-WT1 induces PDGFA, a potent mitogen for fibroblast and endothelial cells. Particularly, PDGFA blockade may be interesting in DSRCT because of a profuse stromal reaction and neoangiogenesis surrounding tumor cells [
3]. Thus, tyrosine kinase PDGFA receptor (PDGFRA) inhibitors such as imatinib and multikinase inhibitors, sunitinib and pazopanib, have been tested in DSRCT [
22‐
24]. Our study reports nine cases of progressive DSRCT treated with antiangiogenic targeted agents, and registered in the national registry “OUTC’s” dedicated to the use of off-labeled targeted therapy in sarcoma.
Discussion
Relapsed and refractory DSRCT remains associated with very poor prognosis. As noted above, multimodal therapy that combines polychemotherapy, debulking surgery and radiotherapy is associated with better outcome than less comprehensive treatment [
7,
12].
In our case series, clinical patients characteristics are comparable to those of previous series. Seven of our nine patients had debulking surgery even in presence of metastatic disease at diagnosis. First-line chemotherapy was based on anthracyclines, ifosfamide and etoposide using regimens adapted from the P6 protocol. These approaches are similar than those used in the most studies reported to date and are considered as standard care. The median PFS following first-line treatment was 19.5 months, which is comparable with PFS reported in the literature [
11,
27].
There is no standard approach beyond first line, and patients received in most cases chemotherapy and salvage surgery when feasible. Gemcitabine, temozolamide, irinotecan and trabectedine were the main cytotoxic agents used. Overall, second line treatment was associated with a median PFS of 10.5 months (range 2–17 months). The only one patient who was treated with sunitinib monotherapy had a PFS of only 2 months. These data suggest that, if performance status allows, treatment for relapsed disease should again be based on combination chemotherapy.
Recent data suggest the interest of novel targeted therapy, against several biological processes involved in DSRCT pathogenesis, to treat recurrent diseases. Based on Ewing sarcoma model and EWS-Fli translocation, leading to dysregulation of insulin growth factor 1 (IGF1) receptor and dependence on IGF1 [
28,
29], humanized monoclonal antagonist IGF1 receptor (IGF1R) antibodies have been developed [
30,
31]. As part of clinical trial, one of our patients received the IGF1R antibody dalotuzumab, with a low PFS.
The modest efficacy of these signaling inhibitors and the development of resistance provide a rationale for the use of antiangiogenic multi-targeted kinase inhibitors. Only a few AATs have been tested in patients with relapsed and refractory DSRCT. Imatinib was used in a phase II study for two patients with DSRCT expressing KIT and/or PDGFRα with very limited response [
22]. This may be explained by the fact that KIT expression probably leads to tumorigenicity as a spectrum, with more reliance on other kinase pathways, and may be targeted by other tyrosine kinase small molecules inhibitors [
22]. Sunitinib is a multi-targeted agent that potently inhibits PDGFR, KIT, FLT3, CSF-1 and RET, as well as vascular endothelial growth factor (VEGF) receptor tyrosine kinases. It targets multiple signaling pathways in tumor, stromal, and endothelial compartments that are relevant to DSRCT [
32]. Six of our patients received sunitinib as AAT for progressive disease with a median PFS of 3.1 months. Thus, sunitinib activity seems to be comparable to recent eight cases reported by Italiano et al. with median PFS of 2.6 months [
23].
Overall, our results are similar to those described in the other retrospective analyses of monochemotherapy and most AAT for progressive DSRCT (Table
4). Efficacy was modest and the best response obtained was stable disease. However, a retrospective study of pazopanib in nine DSRCT cases reported promising results with a 9.2 months PFS [
24]. Such as sunitinib, pazopanib is an orally available inhibitor of the tyrosine kinases of several factors including the vascular endothelial growth factor receptors (VEGFR) 1–3, c-KIT, and the platelet-derived growth factor receptors (PDGFR) alpha and beta, and has been approved for advanced soft tissue sarcoma.
Table 4
Literature data of chemotherapy agents and TT for advanced TT
Vinorelbine-Cyclophosphamide | 2 | 2 PR | 4 and 15 months | |
Irinotecan | 8 | 4 SD, 4 PD | Unknown | |
Trabectedine | 2 | 2 SD | 4 months | |
TT agent |
Imatinib | 7 | 1 PR, 4 PD, 2 NA | 1 month | |
Sunitinib | 8 | 2 PR, 3 SD, 3 PD | 2.6 months | |
Pazopanibc
| 9 | 2 PR, 5 SD, 2 PD, CBRa 78% | 9.2 months | |
Temsirolimus | 1 | SD | 10 months | |
Ganitumab | 16 | 1 PR, 10 SD, 4 PD, CBRb 25% | 19 months | |
This cohort, although small and retrospective, confirms the safety of AATs. AEs were mostly low grade and manageable, similar to those previously reported in other series.
Moreover, recent data on olaratumab, a recombinant human IgG1 monoclonal antibody that specifically binds PDGFRA and receptor activation, and its FDA approval, may significantly improve outcome of patients with soft tissue sarcoma. In this study, only one patient had an undifferentiated round cell sarcoma negative for EWS in olaratumab treatment arm [
34].
Conclusions
OUTC’S program allows the collection of data on the off-label use of TTs in rare tumors such as DSRCT. This is especially useful since such patients are generally ineligible for clinical trials. Moreover new treatment development in DSRCT remains poor. Despite negative results, this study suggests that AAT with sunitinb, sorafenib or bevacizumab monotherapy doesn’t seem to be the best approach to treat progressive DSRCT. Identification of molecular pathways and specific mutations involved in DSRCT pathogenesis may allow the development of new targeted and combination treatments to improve response rate and survival in relapsed and progressive DSRCT. Thus, IGFR1 inhibitors and multi-targeted kinase inhibitors may be another treatment strategy, probably in combination with chemotherapy. Prospective collection of cases of these rare tumors treated with targeted therapies together with increased molecular data understanding should improve therapeutic decision and enhance outcome.
Authors’ contributions
Study conception and design: JYB, IRC. Acquisition of data: CB, JYB, EP, PC, JF, CG, ALC, PMB, IRC, CC. Data management: LC, MG. Analysis and interpretation of data: SB, CC IRC. Drafting and revision of the manuscript: SB, CC, IRC, PMB. Obtained funding: IRC. Administrative, technical and material support: IRC. Study supervision: CC, IRC. All authors read and approved the final manuscript.