Metastatic Ewing Sarcoma Research Articles

Resection of pulmonary metastases in pediatric patients with Ewing sarcoma improves survival

Background Ewing sarcoma (ES) is the second most common bone tumor in children, and survival of those with metastatic ES has not improved. Previous studies have shown a survival benefit to whole lung irradiation in patients with pulmonary metastases and may be given either before, after, or instead of surgical pulmonary metastasectomy (PM). The contribution of surgery compared with irradiation in ES has not previously been studied. Methods A retrospective review of patients younger than 21 years (median age, 16 years) treated at a single institution (1990-2006) was performed. Kaplan-Meier survival curves were compared using log-rank test and a multivariate Cox proportional hazards model. P ≤ .05 was regarded as significant. Results Eighty patients with ES were identified. Of these, 31 (39%) had pulmonary metastases. Nine patients had incomplete details of their full treatment regimen, but the following groups could be defined from the remainder: resection alone (n = 5), radiation alone (n = 3), radiation and resection (n = 3), or chemotherapy alone (n = 11). There were 24 deaths overall, with a median overall survival (OS) of 2.7 (95% confidence interval [CI], 1.7-5.2) years. Patients who had PM had the best OS (80%), whereas those who underwent radiation to the lung without PM compared with chemotherapy only for pulmonary metastasis both had similar OS of 0% at 5 years ( P = .002). Patients who had radiation followed by PM for lung metastasis had a 5-year OS of 65%. Patients with PM had a longer OS compared with those without lung resection ( P < .0001). Conclusion These data suggest a possible benefit for ES patients who undergo surgical resection of lung metastases.

Ewing sarcoma of the clavicle: A case series

Clavicle is a rare primary site for Ewing sarcoma (ES). We analyzed 4 patients with clavicular ES under our follow up and reviewed the literature on management of this rare tumor. All our patients were females with a median age of 16 years and were non metastatic at presentation. After a median follow-up of 21.5 months, 3 out of 4 patients are in complete remission. Clavicular ES in contrast to ES of other sites seems to have a female preponderance and outcomes are similar to non metastatic ES of other common sites.

Current Therapeutic Approaches in Metastatic and Recurrent Ewing Sarcoma

Ewing sarcoma (ES) is the second most common type of primary bone malignancy in children and young adults. Survival rates for localized ES have improved to upwards of 70% with aggressive chemotherapy and local control. On the other hand, there has been little improvement in survival rates for patients with metastatic or recurrent ES. Herein we review the different current therapeutic approaches available, including the different upfront and salvage chemotherapy regimens, the role for stem cell transplantation, and potential use of immunotherapy.

Intercohort Gene Expression Co-Analysis Reveals Chemokine Receptors as Prognostic Indicators in Ewing's Sarcoma

We report a novel analytic method, named intercohort co-analysis or Ican, which aids in the discovery of genes with predictive value for the progression or outcome of diseases from small-size cohorts. We tested this premise in Ewing's sarcoma (ES), a highly metastatic cancer of bone and soft tissues that lacks validated molecular metastasis and prognostic indicators. To uncover genes significantly expressed in ES patient subsets, we first determined a nonarbitrary gene expression significance cutoff based on expression levels in validated expressing and nonexpressing tissues. We next searched for genes that were consistently significantly expressed in several ES cohort and cell line datasets. Significantly expressed genes were independently validated by quantitative reverse transcription-PCR in an additional ES cohort. Analysis of ES cohorts revealed marked intercohort gene expression variability. After filtering out the intercohort variability, CXCR4 and CXCR7 were found to be consistently associated with specific ES subsets. Pairwise analyses showed CXCR4 to correlate with ES metastases, and CXCR4 and CXCR7 to patient survival, but not with several other clinicopathological variables. Ican is a powerful novel method to identifying genes consistently associated with particular disease states in cancers for which large cohorts are not available, currently the case of most cancers. We report for the first time that high CXCR4 expression preferentially associates with metastatic ES, and that of CXCR7 with poor patient survival.

Bevacizumab in pediatric cancer patients (pts): Safety concerns.

e20002 Background: Bevacizumab (BV) is a monoclonal antibody against vascular endothelial growth factor (VEGF) with a reportedly acceptable safety profile and some antitumor activity also in pediatric cancers. Feasibility and toxicity of BV were evaluated in a case-series of children with recurrent or resistant solid tumors. Methods: Pts received intravenous BV at 5-10 mg/kg every 14-28 days. 12 pts had a relapsed/refractory solid tumor while 5 pts had a poor prognosis tumor. The diagnoses were: relapsed metastatic neuroblastoma (7), relapsed rhabdomyosarcoma (4), hepatocellular carcinoma (3), metastatic renal cell carcinoma (1), Ewing sarcoma (1) and abdominal mesothelioma (1). Toxicity was reported according to CTC version 3. Results: 17 pts, M/F 9/8, median age 112 months (range 30-222) received a total of 156 courses, with a median of 5 courses per patient (range 2-25). BV was used in combination with chemotherapy in 15 pts, with sunitinib in one pt and was administered alone in one pt. Median treatment duration was 2 months (range 1-26). 9/17 patients progressed during treatment after a median progression-free survival of 2 months (range 1-13). Two patients (both hepatocellular carcinoma) are still receiving BV 21 and 26 months since diagnosis, while one pt (relapsed rhabdomyosarcoma) stopped treatment after 6 months in CR. One patient refused to continue treatment after one month while four patients discontinued treatment after a median of 5 months (range 3-21) for occurrence of severe adverse events (SAE). Grade II-III lymphopenia was reported in 11 patients while a grade III proteinuria and grade I epistaxis were recorded in one patient each. SAE were: 1) a reversible posterior leukoencephalopathy syndrome with grade IV seizures and grade IV severe hypertension, 2) postoperative grade IV entero-cutaneous fistula, 3) grade IV wound dehiscence and 4) grade IV hypertension. Conclusions: In this case series, the incidence of SAE (24%) was higher than previously reported. Further studies with BV alone or in homogeneous drug combinations are needed to better characterize the safety profile of BV in the pediatric patient population. No significant financial relationships to disclose.

Abstract 1440: Pediatric pulmonary microenvironment differs from adults: Implications for pulmonary metastasis

Abstract Background: Ewing's sarcoma (ES) is the second most common bone tumor in children. Still, despite multimodal therapy, lung metastasis are the most common cause of demise. Older age has been found to portend a poorer survival in ES. Here we identify differences in the pulmonary micro-environment comparing pediatric to adult lung tissue. Purpose: To identify molecular differences in the pediatric and adult lung micro-environment. Methods: To evaluate whether adult lungs provide a more permissive metastatic environment compared to pediatric lungs, we measured the migration and invasion of ES cells in a modified Boyden chamber assay. ES TC-71 cells, know to have moderate metastatic potential and ES LM-7 cells which are highly metastatic, were compared normal lung epithelial cells (CRL2300). Lungs from 4 week old adolescent and 9 week old adult nude mice, were morselated and placed in a modified Boyden chamber. To compare expression of metastatic genes in pediatric compared to adult lung, RNA was extracted from 4 week and 9 week nude mouse lung and a focused microarray of 128 genes were evaluated for differential expression. Results: The TC-71 cell line and the CRL2300 cells had equal area of migration to adolescent and adult lung. Whereas, LM-7 had a significantly larger area of cell migration to the adult lung compared to the adolescent lung.(p=0.033) The focused gene expression profile demonstrated significant differential expression of 2 genes, Interleukin 1-beta (IL1-B), and Integrin beta-3 (ItgB3). IL1-B was significantly under-expressed and ItgB3 was significantly over-expressed in adolescent lung tissue compared to adult lung tissue. Conclusions: Highly metastatic ES LM-7 cells have a significantly decreased migration to the adolescent/pediatric lung compared to adult lung tissue. This implies a different microenvironment in adolescent lung which does not have the same affinity for metastatic Ewing's sarcoma cells as the adult lung. Furthermore, differential gene expression of IL1-B and ItgB3 and may contribute to the cause of this difference since ItgB3 regulates cell adhesion, invasion and low doses of IL1-B can cause tumor cell eradication. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1440.

Therapy-Related Acute Myeloid Leukemia with 11q23 Abnormality Coexisting with Refractory Metastatic Ewing Sarcoma: Report of a Case and Review of the Literature

Intensified chemotherapy is one of the strategies currently used in the treatment of children with metastatic Ewing sarcoma. However, the increasing dose intensity has not significantly improved the event-free survival. We report a patient who initially presented with localized Ewing sarcoma and later developed metastatic disease that required dose-intensified chemotherapy. The patient's Ewing sarcoma remained refractory to treatment despite continuous intensified chemotherapy and was complicated by a therapy-related acute myeloid leukemia with 11q23 abnormality. Examination of bone marrow at the last clinical follow up demonstrated both acute myeloid leukemia and residual metastatic Ewing sarcoma.

Therapy-Rrelated Acute Myeloid Leukemia with 11q23 Abnormality Co-existing with Refractory Metastatic Ewing Sarcoma: Report of A Case and Review of the Literature

Therapy-Rrelated Acute Myeloid Leukemia with 11q23 Abnormality Co-existing with Refractory Metastatic Ewing Sarcoma: Report of A Case and Review of the Literature

CXCR4-CXCL12 axis: Pivotal role as a metastatic mediator in small cell sarcoma

10569 Background: The chemokine CXCL12, and its receptor CXCR4, are expressed in over 23 different types of cancers, and have been associated with the metastatic phenotype and inferior clinical outcomes. Given the poor prognosis after failure of front-line therapy for patients with metastatic Ewing's sarcoma (EWS) and rhabdomyosarcoma (RMS), we examined the functional role of CXCR4 in these small cell sarcoma in vitro. Methods: Human EWS and RMS cell lines and tissue were used to study CXCR4 expression and activation. Immunoblotting techniques were used to evaluate CXCR4 activation and inhibition. Cell viability, cell cycle, apoptosis, chemosensitivity, migration, and invasion assays were utilized to assess the effects of the small peptide CXCR4 antagonist, CTCE-9908 (Chemokine Therapeutics) on cultured cells. Results: CXCR4 was highly expressed on 46 % of human RMS tumor samples. CXCR4 underwent phosphorylation after stimulation with CXCL12 in EWS and RMS cell lines with downstream activation of Akt, p42/44 MAPK, JAK2 and PLCγ1 in select cell lines. CTCE-9908 was able to specifically inhibit downstream signaling of Akt, p42/44 MAPK and JAK2. Decrease in cell proliferation (20–30%, p &lt; .05), increase in cell apoptosis (20–40 %, p &lt; .05) and cell cycle arrest was also observed with CXCR4 blockade. CTCE-9908 significantly inhibited migration and invasion (68–93 %, p &lt; .05) in our cell lines. Conclusions: CXCR4-CXCL12 axis may be important in EWS and RMS metastasis. These results provide evidence that CTCE-9908 may be a novel therapy for these sarcomas. No significant financial relationships to disclose.

Multimodality Image Guided Total Marrow Irradiation and Verification of the Dose Delivered to the Lung, PTV, and Thoracic Bone in a Patient: A Case Study

This work reports our initial experience using multimodality image guidance to improve total marrow irradiation (TMI) using helical tomotherapy. We also monitored the details of the treatment delivery to glean information necessary for the implementation of future adaptive processes. A patient with metastatic Ewing's sarcoma underwent MRI, and bone scan imaging prior to TMI. A whole body kilovoltage CT (kVCT) scan was obtained for intensity modulated TMI treatment planning, including a boost treatment to areas of bony involvement. The delivered dose was estimated by using MVCT images from the helical tomotherapy treatment unit, compared to the expected dose distributions mapped onto the kVCT images. Clinical concerns regarding patient treatment and dosimetric uncertainties were also evaluated. A small fraction of thoracic bone volume received lower radiation dose than the prescribed dose. Reconstructed planned treatment volume (PTV) and the dose delivered to the lung were identical to planned dose. Bone scan imaging had a higher sensitivity for detecting skeletal metastasis compared to MR imaging. However the bone scan lacked sufficient specificity in three dimensions to be useful for planning conformal radiation boost treatments. Inclusion of appropriate imaging modalities improves detection of metastases, which allows the possibility of a radiation dose boost to metastases during TMI. Conformal intensity modulated radiation therapy via helical tomotherapy permitted radiation delivery to metastases in the skull with reduced dose to brain in conjunction with TMI. While TMI reduces irradiation to the lungs, onboard megavoltage computed tomography (MVCT) to verify accurate volumetric dose coverage to marrow-containing thoracic bones may be essential for successful conformal TMI treatment.

MULTIPLE CHROMOSOME ABNORMALITIES IN THE PLEURAL FLUID OF A PATIENT WITH RECURRENT EWING SARCOMA

The authors report a 5.5-year-old male patient with a right paraspinal tumor, diagnosed as metastatic Ewing sarcoma. The pleural fluid along with the bone marrow was sent to the authors’ laboratory for karyotyping. Bone marrow cultures revealed a normal karyotype, whereas 48, XY, i(1)(q11), +10, t(11;22)(q24;q12) karyotype was found in the cells obtained from the pleural fluid cultures. Trisomy 1q is quite frequently observed in Ewing sarcoma patients, mostly as part of unbalanced translocations, along with the common t(11;22) translocation. This patient's findings were significant, as the complex karyotype in the pleural effusion cells was observed.

Carboplatin and paclitaxel adjuvant chemotherapy in primitive neuroectodermal tumor of the uterine corpus

Primitive neuroectodermal tumor of the uterine corpus (PNET) is rare and appears to have an aggressive clinical course. We report on a postmenopausal woman with optimal surgically cytoreduced advanced-stage PNET in which adjuvant combination chemotherapy with platinum and taxane agents was unsuccessful in extending her disease-free survival.

Ewing sarcoma: prognostic criteria, outcomes and future treatment

Ewing sarcoma (EWS) is a bone tumor occurring primarily in adolescence and young adulthood. Multi-institutional clinical trials have improved the outcome for patients with nonmetastatic EWS, but not with metastatic EWS. Furthermore, although 30% of EWS recur, multi-institutional studies have not been completed for this high-risk group. Planning such studies has been hampered by both the lack of novel therapies and the inability to incorporate the biology of EWS. While the importance and detail of the EWS-FLI-1 translocation between chromosomes 11 and 22 are described, these have not yet led to new drug development for this orphan tumor. However, recent evidence supporting novel cytotoxic therapy, antiangiogenic therapy, and receptor-targeted therapy provides reason for optimism for patients with high-risk disease.

Allogeneic stem cell transplantation in a patient with relapsed Ewing sarcoma

Ewing sarcoma (ES) can express tumor antigens which can be recognized by T cells, making allogeneic stem cell transplant (SCT) a potential option for those patients with refractory disease. A 6-year old with multifocal ES developed a recurrence of pulmonary metastases and underwent an allogeneic bone marrow transplant from her human leukocyte antigen (HLA) 10/10 matched mother. During a taper of her immunosuppression, she developed grade 1 skin and oral graft versus host disease (GVHD). CT scans performed 9 months post-transplant revealed a marked decrease in the size of her pulmonary lesions compared to scans 2 months post-transplant. This case highlights the possibility of treating patients with refractory metastatic ES with allogeneic SCT.

High-dose chemotherapy and autologous stem cell transplantation in treating paediatric malignancies

Most paediatric malignancies can be cured with conventional chemotherapy. Autologous stem cell transplantation makes it possible to dramatically increase chemotherapy doses and cure tumours that were resistant to conventional chemotherapy, such as high-risk neuroblastoma and metastatic Ewing sarcoma. High-dose chemotherapy and autologous transplantation are major tools in treating patients who have very high-risk malignancies. In patients with brain tumours, it aims at improving prognosis and decreasing sequelae. Maintenance therapy has been developed to follow high-dose chemotherapy and treat minimal, persistent, residual disease.

Does consolidation with autologous stem cell transplantation improve the outcome of children with metastatic or relapsed Ewing sarcoma?

To evaluate the role of high-dose chemotherapy (HDC) and autologous stem cell transplantation (ASCT) as consolidation therapy for children with high-risk Ewing sarcoma (ES) treated at The Hospital for Sick Children (SickKids), Toronto. The charts of children treated for high-risk ES (defined as metastatic at diagnosis or relapsed) between 1990 and 2005 at SickKids were reviewed. Forty-five children were identified. Twenty patients received ASCT after induction with vincristine, doxorubicin, ifosfamide, cyclophosphamide, and etoposide. Patients with resectable tumor or lung metastases underwent surgery and those with non-resectable tumors were treated with irradiation. Twenty-five patients were treated with conventional chemotherapy (CC). Primary metastatic patients were treated with either a local protocol or as per POG 9354. At relapse, patients were treated with topotecan, cyclophosphamide, then ifosfamide, carboplatin, and etoposide (ICE). Local control was attained with surgery and/or irradiation. Ten of the 20 patients treated with ASCT are alive (median follow-up 6 years), with 8/10 being in remission more than 5 years from diagnosis. The 3-year overall survival (OS) for ASCT was 59%, (95% CI: 36%, 81%) compared to 34% (14%, 53%) for patients treated with CC (P-value = 0.06). The 3-year event-free survival (EFS) for the ASCT was 39% (17%, 60%) compared to 32% (13%, 50%) in the CC group (P = 0.08). ASCT appears to add some benefit to conventional multimodality therapy for children with high-risk ES. Randomized controlled trials are warranted.

Haploidentical Stem Cell Transplantation in Patients with Pediatric Solid Tumors: Preliminary Results of a Pilot Study and Analysis of Graft versus Tumor Effects

Pediatric patients with relapsed metastatic tumors have a poor prognosis and new treatment strategies are warranted. We present preliminary results of a pilot study, evaluating the feasibility and toxicity of transplantation of haploidentical T and B cell depleted grafts with high numbers of NK cells. 6 patients with relapsed metastatic neuroblastomas (n = 4), rhabdomyosarcoma (n = 1) or Ewing's sarcoma (n = 1) after previous autologous transplantation received CD3/CD19 depleted grafts from mismatched family donors with a median number of 16 x 10 (6)/kg stem cells, 167 x 10 (6)/kg Natural Killer cells and only 5.4 x 10 (4)/kg residual T cells. A melphalan-based, reduced intensity conditioning was used. Despite pretransplant chemotherapy, patients entered transplantation with significant tumor burden. Primary engraftment occurred in 6/6 patients. One patient had secondary graft failure. Hematopoietic recovery was rapid (ANC > 0.5 x 10 (9)/L: 11 days (9-12); independence from platelet substitution: 8 days (7-11)). Four patients had acute GvHD grade II, limited chronic GvHD was observed in 2 patients. No transplant-related mortality and only low toxicity occurred. Four patients died from progression, two patients are alive. Overall median survival time is 6 months (2-11) to date. Analysis of posttransplant NK cell function revealed stable cytotoxic activity against K562 targets, whereas activity against neuroblastoma targets was low. Stimulation with cytokines and use of appropriate antibodies clearly enhanced specific lysis in vitro. In summary, these preliminary results indicate the feasibility and low toxicity even in intensively pre-treated patients with neuroblastomas/sarcomas. This approach may form the basis for posttransplant immunomodulation and other therapeutic strategies. Further experience is warranted to evaluate the method.

Metastatic Ewing sarcoma masquerading as olfactory neuroblastoma

Ewing sarcoma is a malignant tumor of bone that rarely spreads to the head and neck. We describe an unusual case of metastatic Ewing sarcoma involving the calvarium mimicking olfactory neuroblastoma, an uncommon neuroectodermal tumor of the anterior skull base. Pertinent clinical, radiological, and pathologic features of these tumors are described, with particular attention to their imaging characteristics.

Palliative radiation therapy for metastatic Ewing sarcoma

Although radiotherapy is an accepted component of curative treatment for Ewing sarcoma (EWS), to the authors' knowledge, there are scant data evaluating its use for palliation. The authors reviewed the Duke University Medical Center experience to evaluate treatment response and response durability. Between 1980 and 2002, 21 patients with metastatic EWS received palliative radiotherapy. Pain was the primary indication for treatment. The majority of patients were male (n = 16 patients), and the median age at diagnosis was 11.6 years (range, 2.7-28.8 yrs). Fifty-two percent of patients had metastases at initial diagnosis. For the others, the median interval from initial diagnosis to metastases was 1.7 years. Sixty-three metastatic sites were irradiated (median dose, 30 gray [Gy]; range, 4.5-68.5 Gy), and a median of 3 sites were treated per patient (range, 1-16 sites per patient). At the time of last follow-up, 1 patient with a solitary brain metastasis has been disease free for 3.4 years after resection and cranial radiotherapy; all other patients died of their disease. Censoring this survivor, patients lived for a median of 1.0 year after metastatic diagnosis (range, from 17 days to 6.8 years), 41 days of which were spent in treatment (range, 1-93 days). Of all sites, 55% had a complete clinical response of symptoms, and 29% had a partial response. The median response duration was 4.0 months (range, 10 days to 4.8 years). Only the survivor was noted to have a treatment complication (growth hormone insufficiency). It was possible to treat metastatic EWS effectively with palliative radiotherapy. Because these patients live a median of 1 year after diagnosis of metastases, providing symptom relief without a protracted treatment course is valuable and appropriate therapy.

MDP Bone Scan: A Key Step in Assessment and Staging of a Rare Presentation of Ewing Sarcoma in a Young Adult Man

A Spanish speaking young man who presented with a painful supra-orbital head mass causing progressive diplopia and epistaxis. Initial clinical and radiological work-up suggested an esthesioneuroblastoma (i.e., olifactory neuroblastoma) with its associated good prognosis. However, further history (obtained through an interpreter) caused the primary physician to order a nuclear bone scan. The results from this scan dramatically changed the clinical approach, tumor work-up, diagnosis and treatment of this patient who was found to have an atypical metastatic Ewing sarcoma.