Novel patient-derived models of desmoplastic small round cell tumor confirm a targetable dependency on ERBB signaling.

Desmoplastic small round cell tumor (DSRCT) is characterized by the t(11;22)(p13;q12) translocation, which fuses the transcriptional regulatory domain of EWSR1 with the DNA-binding domain of WT1, resulting in the oncogenic EWSR1-WT1 fusion protein. The paucity of DSRCT disease models has hampered preclinical therapeutic studies on this aggressive cancer. Here, we developed preclinical disease models and mined DSRCT expression profiles to identify genetic vulnerabilities that could be leveraged for new therapies. We describe four DSRCT cell lines and one patient-derived xenograft model. Transcriptomic, proteomic and biochemical profiling showed evidence of activation of the ERBB pathway. Ectopic expression of EWSR1-WT1 resulted in upregulation of ERRB family ligands. Treatment of DSRCT cell lines with ERBB ligands resulted in activation of EGFR, ERBB2, ERK1/2 and AKT, and stimulation of cell growth. Antagonizing EGFR function with shRNAs, small-molecule inhibitors (afatinib, neratinib) or an anti-EGFR antibody (cetuximab) inhibited proliferation of DSRCT cells. Finally, treatment of mice bearing DSRCT xenografts with a combination of cetuximab and afatinib significantly reduced tumor growth. These data provide a rationale for evaluating EGFR antagonists in patients with DSRCT. This article has an associated First Person interview with the joint first authors of the paper.

Immuno-transcriptomic profiling of extracranial pediatric solid malignancies.

We perform an immunogenomics analysis utilizing whole-transcriptome sequencing of 657 pediatric extracranial solid cancer samples representing 14 diagnoses, and additionally utilize transcriptomes of 131 pediatric cancer cell lines and 147 normal tissue samples for comparison. We describe patterns of infiltrating immune cells, T cell receptor (TCR) clonal expansion, and translationally relevant immune checkpoints. We find that tumor-infiltrating lymphocytes and TCR counts vary widely across cancer types and within each diagnosis, and notably are significantly predictive of survival in osteosarcoma patients. We identify potential cancer-specific immunotherapeutic targets for adoptive cell therapies including cell-surface proteins, tumor germline antigens, and lineage-specific transcription factors. Using an orthogonal immunopeptidomics approach, we find several potential immunotherapeutic targets in osteosarcoma and Ewing sarcoma and validated PRAME as a bona fide multi-pediatric cancer target. Importantly, this work provides a critical framework for immune targeting of extracranial solid tumors using parallel immuno-transcriptomic and -peptidomic approaches.

Therapeutic Potential of NTRK3 Inhibition in Desmoplastic Small Round Cell Tumor.

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a highly lethal intra-abdominal sarcoma of adolescents and young adults. DSRCT harbors a t(11;22)(p13:q12) that generates the EWSR1-WT1 chimeric transcription factor, the key oncogenic driver of DSRCT. EWSR1-WT1 rewires global gene expression networks and activates aberrant expression of targets that together mediate oncogenesis. EWSR1-WT1 also activates a neural gene expression program. EXPERIMENTAL DESIGN: Among these neural markers, we found prominent expression of neurotrophic tyrosine kinase receptor 3 (NTRK3), a druggable receptor tyrosine kinase. We investigated the regulation of NTRK3 by EWSR1-WT1 and its potential as a therapeutic target in vitro and in vivo, the latter using novel patient-derived models of DSRCT. RESULTS: We found that EWSR1-WT1 binds upstream of NTRK3 and activates its transcription. NTRK3 mRNA is highly expressed in DSRCT compared with other major chimeric transcription factor-driven sarcomas and most DSRCTs are strongly immunoreactive for NTRK3 protein. Remarkably, expression of NTRK3 kinase domain mRNA in DSRCT is also higher than in cancers with NTRK3 fusions. Abrogation of NTRK3 expression by RNAi silencing reduces growth of DSRCT cells and pharmacologic targeting of NTRK3 with entrectinib is effective in both in vitro and in vivo models of DSRCT. CONCLUSIONS: Our results indicate that EWSR1-WT1 directly activates NTRK3 expression in DSRCT cells, which are dependent on its expression and activity for growth. Pharmacologic inhibition of NTRK3 by entrectinib significantly reduces growth of DSRCT cells both in vitro and in vivo, providing a rationale for clinical evaluation of NTRK3 as a therapeutic target in DSRCT.

A novel image-based system for risk stratification in patients with desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumor (DSRCT) is an aggressive soft tissue sarcoma affecting children and young adults with 5-year overall survival (OS) of approximately 20%. Despite generally poor prognosis, long-term survival does occur. However, no evidence-based system exists to risk-stratify patients at diagnosis. METHODS: We retrospectively reviewed all DSRCT cases diagnosed at our institution between January 2000 and September 2016. Demographics, diagnostic imaging, and clinical data were reviewed. Univariate and multivariate Cox proportional hazard modeling was used to evaluate associations between imaging characteristics and OS. RESULTS: There were 130 patients (85% male; median age at presentation: 21.2 years) with confirmed DSRCT and sufficient imaging and clinical information for analysis. Median 5-year OS was 28% (95% CI: 19%-37%). In univariate analysis, shorter OS was associated with presence of liver lesions (hazard ratio [HR] 2.1, 95% CI: 1.28-3.45), chest lesions (HR 1.86, 95% CI: 1.11-3.1), and ascites (HR 1.69, 95% CI: 1.06-2.7). In multivariate analysis, liver involvement and ascites were predictive and were used to stratify risk (intermediate=no liver involvement or ascites; high=either liver involvement or ascites; very high=both liver involvement and ascites). Intermediate-risk patients had a 5-year survival of 61% (95% CI: 40%-76%) versus 16% (95% CI: 6%-29%) among high-risk patients and 8% (95% CI: 1%-29%) among very high risk patients. CONCLUSION: Patients with DSRCT can be risk-stratified at diagnosis based on specific imaging characteristics. TYPE OF STUDY: Retrospective study with no comparison group. LEVEL OF EVIDENCE: Level IV.

Treatment of gastrointestinal stromal tumours in paediatric and young adult patients with sunitinib: a multicentre case series.

BACKGROUND: Gastrointestinal stromal tumours (GIST) are rarely encountered mesenchymal tumours of the gastrointestinal tract (1.5 people per 100,000/year) that are even more rarely seen in paediatric patients (1-2% of all cases). The standard treatment for advanced adult GIST is imatinib with sunitinib as a second-line option. Although the efficacy and tolerability of sunitinib in adults with GIST has been established, little is known of the profile of sunitinib in paediatric/young adult patients with GIST given the rarity of this disease. METHODS: Paediatric/young adult patients aged up to 21 years with diagnosis of GIST who were treated with sunitinib were identified from retrospective records from three centres in Europe and the US. Most patients commenced sunitinib in a 6-week cycle, however, dosing could be reduced, delayed, changed to (or initiated with) a continuous schedule. Objective response (Response Evaluation Criteria In Solid Tumours [RECIST]) and adverse events were recorded. RESULTS: We identified 9 paediatric/young adult patients (aged 11-21 years) with GIST who were treated with sunitinib de novo (n = 1) or following failure of imatinib (n = 8). Progressive disease was previously documented for all patients including 7 patients during imatinib therapy. Baseline patient and tumour profile characteristics showed a distinct profile (notably all were wild-type KIT/PDGFR) compared to that established for adults. Sunitinib treatment was associated with a best response of stable disease for 7 patients, with disease stabilisation lasting from 1 month to >73 months and a median progression free survival time of 15 months. There was some evidence of better disease control for sunitinib when compared to prior imatinib. Most adverse events with sunitinib were manageable and all were consistent with the known profile of the agent. CONCLUSION: The ability to draw firm conclusions from this case series is limited by the small number of patients and the use of retrospective data which is largely reflective of the rarity of this condition. However, our findings provide initial evidence of clinical benefit and a generally manageable toxicity profile for sunitinib when administered to paediatric/young adult patients with GIST, most of whom had documented progressive disease during prior imatinib treatment.

Morbidity and mortality after treatment of Ewing sarcoma: A single-institution experience.

BACKGROUND: Children, adolescents, and young adults treated for Ewing sarcoma (ES) are at risk for disease-related and treatment-related complications. We aimed to describe early and late overall mortality, cause-specific mortality, and key adverse health outcomes in a large, single-institutional cohort of patients with ES. METHODS: Patients with ES diagnosed at age less than 40 years and treated at Memorial Sloan Kettering between 1974 and 2012 were included. Overall survival was estimated using Kaplan-Meier methods. Cox proportional hazards were used to examine the association of clinical and pathologic variables with overall survival. Cause-specific mortality was evaluated with the cumulative incidence function accounting for competing risks. RESULTS: Three hundred patients with ES (60.3% male; median age at diagnosis: 16.8 years [range: 0.3-39]; 30.0% with metastatic disease at diagnosis) were followed for a median of 7.8 years (range: 0.2-37). Five-year overall survival was 65.2% (95% confidence interval [95% CI], 59.8-71.1%) for the entire cohort; 78.6% for those with localized disease; 40.1% for those with isolated pulmonary metastases; and 28.1% for those with extrapulmonary metastases. In multivariable analysis, older age at diagnosis, minority race/ethnicity, and metastatic disease at diagnosis were associated with inferior survival. Ten-year cumulative incidence of relapse/progression was 40.1%, with eight late relapses occurring at a median of 6.3 years after diagnosis (range: 5-14). Seventeen patients developed subsequent neoplasms (treatment-related myelodysplastic syndrome/acute myelogenous leukemia = 9; solid tumors = 6; nonmelanoma skin cancer [NMSC] = 4). Excluding NMSC and melanoma in situ, the cumulative incidence of subsequent malignant neoplasms at 25 years was 15% (95% CI, 4.8-25.1%). CONCLUSION: Patients with ES are at high risk for relapse/progression and second cancers.

Multifocal Osteosarcoma: Unusual Presentation and Imaging Findings.

Multifocal osteosarcoma is usually defined as the occurrence of a tumor at 2 or more sites in a patient without pulmonary metastases and may be synchronous with more than one lesion seen at presentation or metachronous with new tumors developing after the initial treatment. It is difficult to determine whether these represent synchronous multiple primary lesions or metastases. We present a rare case of widespread synchronous multifocal osteosarcoma and a brief review of the literature.

Intracardiac Low-grade Sarcoma Following Treatment for Ewing Sarcoma.

A 16-year-old male was diagnosed with Ewing sarcoma of the ribcage with pulmonary metastases. Six months after completion of scheduled therapy, he was found to have a new intracardiac mass, presumed recurrent Ewing sarcoma. EWSR1 fusion was not detected by droplet digital polymerase chain reaction from blood plasma. After no improvement with salvage chemotherapy, he underwent surgical resection that identified a low-grade spindle cell sarcoma. Despite the near-synchronous presentation of 2 unrelated sarcomas, extensive genomic analyses did not reveal any unifying somatic or germline mutations nor any apparent cancer predisposition. This case also highlights the potential role of utilizing plasma cell-free DNA for diagnosing tumors in locations where biopsy confers high morbidity.

Plasma DNA-based molecular diagnosis, prognostication, and monitoring of patients with EWSR1 fusion-positive sarcomas.

Purpose: Ewing Sarcoma (ES) and Desmoplastic Small Round Cell Tumors (DSRCT) are aggressive sarcomas molecularly characterized by EWSR1 gene fusions. As pathognomonic genomic events in these respective tumor types, EWSR1 fusions represent robust potential biomarkers for disease monitoring. Patients and Methods: To investigate the feasibility of identifying EWSR1 fusions in plasma derived cell-free DNA (cfDNA) from ES and DSRCT patients, we evaluated two complementary approaches in samples from 17 patients with radiographic evidence of disease. The first approach involved identification of patient-specific genomic EWSR1 fusion breakpoints in formalin-fixed, paraffin-embedded tumor DNA using a broad, hybridization capture-based next generation sequencing (NGS) panel, followed by design of patient-specific droplet digital PCR (ddPCR) assays for plasma cfDNA interrogation . The second approach employed a disease-tailored targeted hybridization capture-based NGS panel applied directly to cfDNA which included EWSR1 as well as several other genes with potential prognostic utility. Results: EWSR1 fusions were identified in 11/11 (100%) ES and 5/6 (83%) DSRCT samples by ddPCR, while 10/11 (91%) and 4/6 (67%) were identified by NGS. The ddPCR approach had higher sensitivity, ranging between 0.009-0.018% sensitivity. However, the hybrid capture-based NGS assay identified the precise fusion breakpoints in the majority of cfDNA samples, as well as mutations in TP53 and STAG2, two other recurrent, clinically significant alterations in ES, all without prior knowledge of the tumor sequencing results. Conclusion: These results provide a compelling rationale for an integrated approach utilizing both NGS and ddPCR for plasma cfDNA-based biomarker evaluations in prospective cooperative group studies.

A single-center experience with undifferentiated embryonal sarcoma of the liver.

Undifferentiated embryonal sarcoma of the liver (UESL) is a rare aggressive mesenchymal pediatric tumor. Previously, reported outcomes have been very poor. Here, we report a single-center experience of five patients with UESL treated with upfront gross total resection and adjuvant chemotherapy. We have a median follow-up of 8 years with a range from 5 to 19 years with 100% event-free survival.

Myeloablative chemotherapy with autologous stem cell transplant for desmoplastic small round cell tumor.

Desmoplastic small round cell tumor (DSRCT), a rare, aggressive neoplasm, has a poor prognosis. In this prospective study, we evaluated the role of myeloablative chemotherapy, followed by autologous stem cell transplant in improving survival in DSRCT. After high-dose induction chemotherapy and surgery, 19 patients with chemoresponsive DSRCT underwent autologous stem cell transplant. Myeloablative chemotherapy consisted of carboplatin (400-700 mg/m(2)/day for 3 days) + thiotepa (300 mg/m(2)/day for 3 days) ± topotecan (2 mg/m(2)/day for 5 days). All patients were engrafted and there was no treatment-related mortality. Seventeen patients received radiotherapy to sites of prior or residual disease at a median of 12 weeks after transplant. Five-year event-free and overall survival were 11 ± 7% and 16 ± 8%, respectively. Two patients survive disease-free 16 and 19 years after transplant (both in complete remission before transplant). 14 patients had progression and died of disease at a median of 18 months following autologous transplant. These data do not justify the use of myeloablative chemotherapy with carboplatin plus thiotepa in patients with DSRCT. Alternative therapies should be considered for this aggressive neoplasm.

Desmoplastic small round cell tumor 20 years after its discovery.

Desmoplastic small round cell tumor (DSRCT) was proposed as a distinct disease entity by William L Gerald and Juan Rosai in 1991. Over 850 patients have been reported in the medical literature. A specific translocation, t(11;22)(p13;q12), is seen in almost all cases, juxtaposing the EWS gene to the WT1 tumor suppressor gene. DSRCT is composed of nests of small round cells with polyphenotypic differentiation, typically a mixture of epithelial, mesenchymal and neural features, surrounded by a prominent desmoplastic stroma. DSRCT has a predilection for adolescent and young adult males, and primarily involves the abdominal cavity and pelvis. Survival is low despite their initial response to multimodal treatment. Most patients relapse with disseminated disease that is unresponsive to further therapy.

Ifosfamide dose-intensification for patients with metastatic Ewing sarcoma.

BACKGROUND: Outcomes for patients with metastatic Ewing sarcoma (ES) remain poor. We investigated whether the intensification of ifosfamide improved survival for patients with metastatic ES. PROCEDURE: We conducted a retrospective chart review of 30 patients with metastatic ES treated with the MSKCC "EFT regimen." The regimen included an intensification of ifosfamide dosing from 1,800 mg/m(2) /day × 5 days per cycle to 2,800 mg/m(2) /day × 5 days per cycle. RESULTS: Twenty six of the 30 patients completed planned chemotherapy. Two patients experienced disease progression during therapy. There were no toxic deaths. One patient developed secondary leukemia. The 4-year event free survival (EFS) was 27% and the overall survival (OS) was 39%. CONCLUSIONS: Intensification of ifosfamide was tolerated and did not increase toxicity in patients with metastatic ES. The intensification did not improve outcomes for these patients with metastatic disease.

Radiation for bone metastases in Ewing sarcoma and rhabdomyosarcoma.

BACKGROUND: The role, optimal dose, and efficacy of radiotherapy (RT) for the treatment of bone metastases in rhabdomyosarcoma (RMS) and Ewing sarcoma (ES) are unclear. PROCEDURE: All patients with ES or RMS who received RT for bone metastases with curative intent during frontline therapy at Memorial Sloan Kettering Cancer Center (MSKCC) between 1995 and 2013 were reviewed. Among the 30 patients (8 RMS and 22 ES), 49 bone metastases were irradiated. RESULTS: Median biologically effective dose (BED) was 42.4 Gy (range, 34.9-59.7) for RMS and 50.7 Gy (range, 31.3-65.8) for ES. Tumor recurrence occurred in six of 49 irradiated bone metastases. Cumulative incidence of local failure at a treated metastatic site was 6.6% at 1 year and 9.0% at 3 years. Dose, fractionation, and RT technique did not impact local control at an irradiated site. The presence of >5 bone metastases was associated with worse local control at an irradiated site (P = 0.07). The 3-year EFS was 33% in RMS and 16% in ES. CONCLUSIONS: RT appears to be an effective modality of local control for bone metastases in ES and RMS. Local control at sites of metastatic bone irradiation is similar to local control at the primary site after definitive RT. Doses in the biologic range prescribed for the definitive treatment of primary disease should be used for metastatic sites of disease.

20-year experience with intraoperative high-dose-rate brachytherapy for pediatric sarcoma: outcomes, toxicity, and practice recommendations.

PURPOSE: To assess outcomes and toxicity of high-dose-rate intraoperative radiation therapy (HDR-IORT) in the management of pediatric sarcoma. METHODS AND MATERIALS: Seventy-five pediatric patients underwent HDR-IORT for sarcoma from May 1993 to November 2013. The median age was 9 years old (36 patients were ≤ 6 years old). HDR-IORT was part of initial therapy in 37 patients (49%) and for recurrent disease in 38 patients (51%). Forty-one patients (55%) received HDR-IORT and postoperative external beam RT (PORT), and 22 patients (29%) were previously treated with external beam radiation therapy to the IORT site. Local control (LC), overall survival (OS) and event-free survival (EFS) were estimated using Kaplan-Meier methods. RESULTS: At a median follow-up of 7.8 years for surviving patients, 5-year projected rates of LC, EFS, and OS were 63% (95% confidence interval [CI] 50%-76%), 33% (95% CI 21%-45%), and 43% (95% CI 30%-55%), with a median survival of 3.1 years. The 5-year LC, EFS, and OS rates for patients with recurrent disease were 46% (95% CI, 28%-64%), 30% (95% CI, 13%-46%), and 36% (95% CI, 18%-54%). Acute toxicity ≥ grade 3 occurred in 2 (2.5%) treatments; late toxicity ≥ grade 3 occurred in 4 (5.3%) patients 0.3-9.9 years after HDR-IORT. The incidence of toxicity ≥ grade 3 was not associated with HDR-IORT applicator size, HDR-IORT dose, prior RT or PORT, or prior or postoperative chemotherapy, but all toxicity ≥ grade 3 occurred in patients ≤ 6 years treated with HDR-IORT doses ≥ 12 Gy. CONCLUSIONS: HDR-IORT is a well-tolerated component of multimodality therapy for pediatric sarcoma, allowing additional local treatment while reducing external beam exposure. Taking clinical considerations into account, doses between 8-12 Gy are appropriate for HDR-IORT in patients ≤ 6 years of age.

Is methylene diphosphonate bone scan necessary for initial staging of Ewing sarcoma if 18F-FDG PET/CT is performed?

OBJECTIVE: The purpose of this study was to determine whether methylene diphosphonate (MDP) bone scans are necessary during initial staging in patients with Ewing sarcoma (ES) in whom (18)F-FDG PET/CT is performed. MATERIALS AND METHODS: A retrospective review was performed of patients who underwent FDG PET/CT and MDP bone scan before treatment of newly diagnosed ES from January 2004 to November 2012. Studies were reviewed to document suspected primary and metastatic malignancy. Pathology and imaging follow-up were used to determine the presence or absence of disease at suspected sites. RESULTS: Sixty patients were identified in whom FDG PET/CT and MDP bone scans were performed before treatment of newly diagnosed ES. Forty-four primary malignancies had a lytic CT appearance, three were sclerotic, and 13 involved only soft tissue. In 11 of 12 patients with osseous metastases, these were detected on PET/CT, with the one false-negative occurring in a sclerotic primary tumor; in nine of 12 patients with osseous metastases, these were detected on MDP bone scan, with the three false-negatives occurring in patients with lytic primary tumors. Only one of 13 patients with a soft-tissue primary malignancy had bone metastases on both bone scan and PET/CT. PET/CT also showed that eight patients had lung metastases and three patients had lymph node metastases, which were not evident on MDP bone scan. CONCLUSION: When ES is lytic, MDP bone scan does not add to staging performed by FDG PET/CT; thus, MDP bone scanning may be omitted. However, when ES is sclerotic, MDP bone scan may detect osseous metastases not detected by FDG PET/CT.

Ewing sarcoma in adults treated with modern radiotherapy techniques.

BACKGROUND AND PURPOSE: To evaluate local control and survival outcomes in adults with Ewing sarcoma (ES) treated with radiotherapy (RT). MATERIAL AND METHODS: Retrospective review of all 109 patients age ⩾18 treated for ES with RT to the primary site at Memorial Sloan Kettering Cancer Center between 1990 and 2011. RT was used as the definitive local control modality in 44% of patients, preoperatively for 6%, and postoperatively for 50%. RESULTS: Median age at diagnosis was 27years (range, 18-67). The 5-year local failure (LF) was 18%. Differences in LF were not identified when evaluated by modality of local control (RT versus combined surgery and RT), RT dose, fractionation, and RT technique. However, margin status at time of resection significantly predicted LF. The 5-year event-free survival and overall survival rates were 44% and 66% for patients with localized disease, compared with 16% and 26% for metastatic disease (p=0.0005 and 0.0002). Tumor size, histopathologic response to chemotherapy, and treatment on or according to a protocol were also significantly associated with survival. CONCLUSIONS: This series of adults treated with modern chemotherapy and RT had prognostic factors and outcomes similar to adolescents with ES. All adults with ES should be treated with an aggressive, multidisciplinary approach.

Positron emission tomography for response assessment in desmoplastic small round cell tumor.

BACKGROUND: Desmoplastic small round cell tumors (DSRCT) typically have a large stromal component and often are extensively disseminated in the peritoneal cavity at diagnosis. These factors contribute to difficulty in quantifying response to chemotherapy using RECIST or WHO criteria. This study compares the overall disease response to chemotherapy by fluorodeoxyglucose-positron emission tomography (FDG-PET) and computed tomography (CT) in patients with DSRCT. METHODS: We conducted a retrospective chart review of 7 patients with DSRCT who were imaged by FDG-PET and CT at diagnosis and after 3 cycles of chemotherapy. Response to chemotherapy was graded according to EORTC metabolic response guidelines and RECIST. RESULTS: All tumors demonstrated some decrease in SUVmax (51%±21%) and longest diameter (23%±8%) with chemotherapy. The best response achieved by FDG-PET was a partial response in 6 patients and by CT was a partial response in 1 patient. Measured response was concordant between the 2 modalities in 2 patients. CONCLUSIONS: In this small series response measurement by FDG-PET did not always correlate with response measurement by CT. A greater decrease in metabolic activity as compared with size was seen in all patients. Further studies are needed to define the role of FDG-PET in assessing early response of DSRCT to chemotherapy.

Characteristic imaging features of desmoplastic small round cell tumour.

BACKGROUND: Desmoplastic small round cell tumour (DSRCT) is a rare malignant neoplasm. Its radiological features have rarely been described. OBJECTIVE: To assess the CT parameters characteristic of DSRCT. We also report our experience with combined FDG PET/CT in staging and follow-up for DSRCT. MATERIALS AND METHODS: The pretreatment diagnostic CT's of 65 patients with DSRCT were evaluated. Pertinent imaging findings were catalogued, with histopathology or serial follow-up studies as reference standard. Combined FDG PET/CT examinations of 11 of these patients who underwent pretreatment imaging were also reviewed. RESULTS: Sixty-two patients presented with primary intra-abdominal disease; three had primary extra-abdominal tumours at presentation. The most common imaging finding of patients with intra-abdominal DSRCT was multiple peritoneal soft tissue masses, with a dominant mass in the retrovesical or rectouterine location in more than half of the cases. Forty percent had metastatic disease to the liver, lungs, spleen or bones at diagnosis. FDG PET/CT accurately detected 97.4% of all DSRCT lesions. CONCLUSION: DSRCT typically presents as a large abdominopelvic mass with widespread peritoneal involvement predominantly in young males. Familiarity with its radiological features can help guide diagnosis and treatment. Functional imaging with PET/CT offers advantage over anatomical imaging for accurate disease staging.

Reduced toxicity with intensity modulated radiation therapy (IMRT) for desmoplastic small round cell tumor (DSRCT): an update on the whole abdominopelvic radiation therapy (WAP-RT) experience.

PURPOSE: Desmoplastic small round cell tumor (DSRCT) is a rare malignancy typically involving the peritoneum in young men. Whole abdominopelvic radiation therapy (WAP-RT) using conventional 2-dimensional (2D) radiation therapy (RT) is used to address local recurrence but has been limited by toxicity. Our objectives were to assess the benefit of intensity modulated radiation therapy (IMRT) on toxicity and to update the largest series on radiation for DSRCT. METHODS AND MATERIALS: The records of 31 patients with DSRCT treated with WAP-RT (22 with 2D-RT and 9 with IMRT) between 1992 and 2011 were retrospectively reviewed. All received multi-agent chemotherapy and maximal surgical debulking followed by 30 Gy of WAP-RT. A further focal boost of 12 to 24 Gy was used in 12 cases. Boost RT and autologous stem cell transplantation were nearly exclusive to patients treated with 2D-RT. Toxicities were assessed with the Common Terminology Criteria for Adverse Events. Dosimetric analysis compared IMRT and simulated 2D-RT dose distributions. RESULTS: Of 31 patients, 30 completed WAP-RT, with a median follow-up after RT of 19 months. Acute toxicity was reduced with IMRT versus 2D-RT: P=.04 for gastrointestinal toxicity of grade 2 or higher (33% vs 77%); P=.02 for grade 4 hematologic toxicity (33% vs 86%); P=.01 for rates of granulocyte colony-stimulating factor; and P=.04 for rates of platelet transfusion. Post treatment red blood cell and platelet transfusion rates were also reduced (P=.01). IMRT improved target homogeneity ([D05-D95]/D05 of 21% vs 46%) and resulted in a 21% mean bone dose reduction. Small bowel obstruction was the most common late toxicity (23% overall). Updated 3-year overall survival and progression-free survival rates were 50% and 24%, respectively. Overall survival was associated with distant metastasis at diagnosis on multivariate analysis. Most failures remained intraperitoneal (88%). CONCLUSIONS: IMRT for consolidative WAP-RT in DSRCT improves hematologic toxicity in particular. Although the long-term efficacy of current treatment options remains disappointing, the improved therapeutic index of IMRT may aid in generalizing its use and allowing the addition of novel approaches such as intraperitoneal immunotherapy.