Recurrent Ewing Sarcoma Research Articles

Palliation of Recurrent Ewing Sarcoma of the Pelvis With Cryoablation and Somatosensory-evoked Potentials

Palliation of recurrent Ewing sarcoma can be difficult to treat due to tumor resistance to chemotherapy and previously received maximum dose radiotherapy. We report the successful use of cryoablation for pain palliation in a patient with recurrent pelvic Ewing sarcoma. Tumor location necessitated use of somatosensory-evoked potentials to prevent nerve damage to the S1 nerve root. Clinical and imaging aspects of the case are discussed.

Very late local recurrence of Ewing's sarcoma – can you ever say 'cured'? A report of two cases and literature review

We report two rare cases of very late local recurrence of Ewing's sarcoma, occurring 16 years and 19 years after treatment of the primary tumour. In both cases, disease remission had been achieved. Both patients originally underwent non-surgical combined modality therapy following initial diagnosis and both were rendered disease-free. After a long latent phase, both started experiencing unexplained local symptoms. These were investigated at their local hospital but tumour recurrence was not initially considered as a cause of these symptoms. The two patients were eventually referred back to our institution after the diagnosis of recurrent Ewing's sarcoma was established. Both have successfully undergone complete excision of the recurrences and are receiving postoperative adjuvant therapy. These cases highlight the need to remain vigilant for local recurrence, however long after the initial diagnosis.

Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence following multi‐modality therapy: A report from the Children's Oncology Group

The prognosis for patients with recurrent Ewing sarcoma (EWS) is very poor with 5-year survival of 13%. To evaluate prognostic factors for these patients we studied patients initially treated on the multi-institutional study INT0091. Two hundred sixty-two patients experienced disease recurrence. The median time to first recurrence was 1.3 years (0-7.4 years), 1.4 years (0-7.4 years) for patients with initially localized disease and 1 year (0-6 years) for patients with initially metastatic disease. Time to first recurrence from date of initial diagnosis was a predictor of post-recurrence survival (P < 0.0001). Twenty-one percent of patients, with recurrent or progressive disease >or=2 years from initial diagnosis, had an estimated 5-year survival of 30% (vs. 7% estimated 5-year survival with an earlier recurrence). No statistical difference was detected between patients whose disease recurred <1 year and between 1 and 2 years from initial diagnosis. A stepwise relative risk model and backwards stepwise regression was used to explore factors significantly associated with risk for post-recurrence death. Significant risk factors for death after recurrence included recurrence at combined local and distant sites, elevated LDH at initial diagnosis and initial recurrence less than 2 years after diagnosis. Isolated pulmonary recurrence was not predictive of survival after recurrence. Patients with a longer disease control interval represent the subset of patients most likely to survive following recurrence of EWS. All patients with recurrence would benefit from collaborative trials to investigate new therapeutic options.

Prognostic factors for patients with Ewing sarcoma (EWS) at first recurrence

10011 Background: The prognosis for patients with recurrent Ewing sarcoma (EWS) is very poor with 5-year survival of 13%. Since 30–40% of patients with newly diagnosed, non-metastatic EWS develop recurrence, the Children's Oncology Group (COG) sought to evaluate prognostic factors for these patients. Data was derived from the phase III, multi-institutional study INT 0091. Methods: Between 1988 and 1994, five hundred and seventy-eight eligible patients with previously untreated EWS or PNET of bone were enrolled on INT 0091. Patients who experienced recurrence or disease progression as their first analytic event were considered. Survival was calculated from date of disease progression to death or last patient contact. Comparisons of the risk for death across groups were accomplished using the log-rank test. Survivor functions were estimated by the method of Kaplan and Meier. Results: Two hundred and sixty-two patients experienced disease progression or recurrence. The median time to first recurrence was 1.3 years (range 0–7.4 years) for all patients, 1.4 years (range 0 to 7.4 years) for patients with initially localized disease and 1 year (range 0 to 6 years) for patients with initially metastatic disease. Time to first recurrence from date of initial diagnosis was a predictor of post-recurrence survival (p&lt;0.0001). Twenty-one percent of patients whose disease recurred or progressed experienced first recurrence 2 or more years from initial diagnosis and had an estimated 5 year post-recurrence survival of 30%. This compares with 7% for those whose first recurrence or progression was earlier. No statistical difference was detected when patients whose disease recurred &lt; 12 months were compared with those whose recurrence was 12–24 months from initial diagnosis. Significant risk factors for death after recurrence included metastatic disease at initial diagnosis, elevated LDH at initial diagnosis and female gender. In patients non-metastatic at initial diagnosis pelvic primary site was also a risk factor for death after recurrence. Conclusions: Patients with longer time to first recurrence represent the subset of patients most likely to survive following recurrence. All patients with recurrent Ewing sarcoma would benefit from collaborative trials to investigate new therapeutic options. No significant financial relationships to disclose.

Combination of pegylated-liposomal doxorubicin (PLD) and bevacizumab (B) (PLD-B) in sarcoma (SAR)

20506 Background: Vascular endothelial growth factor (VEGF) plays an important role in many tumors including SAR. Because of the known efficacy of PLD in SAR and the presumed importance of VEGF in SAR, we have treated SAR patients with PLD-B. It is possible that the addition of B to PLD might alter the toxicity profile. The toxicities of this combination are not well described. Methods: To better define the toxicity of the combination of PLD-B in SAR, we reviewed our experience with PLD-B in patients treated between 2004 and 2006. Results: We identified 20 patients with SAR treated with PLD-B at our institution. There were 9 men and 11 women, with a median age of 47.5 years (range 23–77). Ten patients initiated therapy with PLD q28 days at a median dose of 45 mg/m2 (range 45–50), and 10 q14 days at a median dose of 21.2 mg/m2 (range 20–25), in combination with B at 5 mg/kg q14 days. A median of 5 cycles was given (range 1–15). Dose delay was required in 3 patients for the second cycle, and dose reduction was required in 9 patients by cycle 3. Of the 10 patients starting with monthly PLD, 7 were changed to q14 day PLD by cycle 4. Mucositis and skin toxicity were the dose limiting toxicities (DLT) in 14/20 patients, and myelosuppression was the DLT in 1/20 patients. Nine patients were felt to have clinical benefit; 3 had a PR and 6 had SD. Notably, 2/4 recurrent Ewing sarcoma patients had symptomatic improvement and at least SD for 10 and 11 months, respectively, with minor toxicity allowing a good quality of life. Conclusions: This report describes the toxicity profile of PLD-B in 20 patients with SAR. The toxicities observed were similar to those seen with PLD alone, however, these toxicities appeared more pronounced with the addition of B. Since VEGF is important for wound healing, the known effects of B on this process may contribute to more skin and mucosal toxicity of PLD at a given dose. Future studies of PLD-B should consider the potential of increased mucosal and skin toxicity. The use of q14 day PLD to allow more control over toxicity is suggested; a maximal starting dose of 20 mg/m2 is reasonable, although dose reduction will be common due to skin or mucosal toxicity. This combination can be given with limited toxicity, and meaningful responses were observed in recurrent sarcomas, including 2/4 Ewing sarcomas. No significant financial relationships to disclose.

A phase II study of imatinib mesylate in children with refractory or relapsed solid tumors: A Children's Oncology Group study

Imatinib mesylate is a small molecule inhibitor of certain tyrosine kinases, most notably the chimeric bcr-abl fusion protein found in CML. It also inhibits KIT and PDGF receptor tyrosine kinases in vitro. Ewing sarcoma, osteosarcoma, neuroblastoma, desmoplastic small round cell, and synovial sarcomas often overexpress KIT or the PDGF receptor. A phase II study of imatinib in children and young adults with select solid tumors was performed. Patients less than 30 years of age with refractory or recurrent Ewing sarcoma, osteosarcoma, neuroblastoma, desmoplastic small round cell, synovial sarcomas or GIST were eligible. Imatinib was administered daily for 28 day courses at a dose of 440 mg/m(2)/day. Responses were assessed according to Response Evaluation Criteria in Solid Tumor (RECIST). Seventy eligible patients, 48 male and 22 female, were enrolled and 59 were evaluable for response. Only one partial response was seen among 24 patients with Ewing sarcoma. There were no other objective responses. Hemorrhagic pleural effusions occurred in seven patients with pulmonary lesions, four of whom had progressive disease at the time of the hemorrhage. Intratumoral bleeding was reported in three additional patients. Imatinib as a single agent at a dose of 440 mg/m(2)/day demonstrated little or no activity as a single agent in children with relapsed or refractory Ewing sarcoma, osteosarcoma, neuroblastoma, or desmoplastic small round cell tumors.

Phase II investigation of docetaxel in pediatric patients with recurrent solid tumors

Docetaxel, which is an antitubulin agent, has demonstrable activity against murine and human tumors. The current study was designed to determine response rates to docetaxel in various strata of recurrent solid tumors of childhood and to assess toxicity in a group of patients who were assigned to receive it. Docetaxel was given at a dose of 125 mg/m2 once every 21 days as a 1-hour intravenous infusion for a maximum of 12 courses. From January 1997 to November 2001, 109 male patients and 68 female patients (total, 177 patients) were enrolled, and 173 patients were eligible. The median patient age at entry was 13 years (range, 1-27 yrs). One hundred sixty patients were evaluable for response. There were no deaths attributable to study drug. Hematologic toxicity was common during therapy. Dermatologic, neurologic, pulmonary, and infectious side effects as well as edema were significant. One patient each had acute myeloid leukemia, acute lymphoid leukemia, and high-grade glioma reported as secondary malignancies. One patient with osteosarcoma and 1 patient with rhabdomyosarcoma achieved a complete response. Partial responses were observed in patients with Ewing sarcoma (3 patients), osteosarcoma (1 patient), squamous cell carcinoma (1 patient), and medulloblastoma (1 patient). Seventeen patients had stable disease. The 1-year and 5-year overall survival rates for the 160 evaluable patients were 24% (standard error = 4%) and 6% (standard error = 2%), respectively. Docetaxel demonstrated activity in patients with recurrent Ewing sarcoma but was found to be ineffective for treating the other types of recurrent solid tumors that were studied.

Recurrent Ewing's sarcoma after a 18-year-interval: a case report

Recurrent Ewing's sarcoma after a 18-year-interval: a case report

Outcome of patients with recurrent Ewing's sarcoma family of tumors (ESFT)

8517 Background: The overall survival (OS) of relapsed ESFT is poor, and the relative benefit of high-dose therapy (HDT) is controversial. To determine the factors associated with outcome for relapsed ESFT, we performed the following analysis. Methods: We retrospectively identified 52 consecutive ESFT patients initially diagnosed before December 31, 2000, with disease recurrence between 1985 and 2002, who were treated at CHRMC and had adequate medical records for review. Results: All patients initially received multi-agent chemotherapy, most frequently vincristine, doxorubicin, cyclophospamide (C), etoposide (E), and ifosfamide (I) (27 patients). Twenty-five patients had metastatic disease at presentation. The median relapse-free interval (RFI) was 17 months (range 5–90 months). Most recurrences were metastatic only (36 patients) or local and metastatic (10 patients). Forty patients received second-line treatment with systemic chemotherapy, most frequently IE (23 patients), IE with carboplatin (6 patients), or topotecan and C (5 patients), with or without additional surgery and/or radiotherapy. Twenty-six (50%) patients achieved a partial or complete response to second-line treatment, with a median duration of response of 30 months (range 5–119 months). The 5-year OS for all relapsed patients was 23% (95% CI, 11–35%). By univariate analysis, improved OS was associated with response to second-line treatment (47% vs. 0%, p <0.0001), RFI > 24 months (51% vs. 12%, p = 0.0001), and no metastases at initial diagnosis (34% vs. 12%, p = 0.03). Because all 13 patients who received HDT also had responsive relapse, we performed a multivariate analysis. Reduced risk of death was associated with response to second-line therapy (odds ratio 0.16, 95% CI 0.05–0.48), RFI > 24 months (odds ratio 0.28, 95% CI 0.12–0.66) and receiving HDT (odds ratio 0.29, 95% CI 0.09–0.93), but not metastases at initial diagnosis (odds ratio 1.0, 95% CI 0.4–2.4). Nine of the 12 surviving patients received HDT. Conclusions: HDT as consolidation therapy for relapsed ESFT is associated with improved OS, even after adjusting for RFI and response to second-line treatment. No significant financial relationships to disclose.

Imatinib mesylate therapy for recurrent Ewing's family of tumors (EFT)

9054 Background: The prognosis for patients with recurrent Ewing's sarcoma (ES) and primitive neuroectodermal tumors (PNET) remains poor. Novel therapies are urgently needed. We previously demonstrated that EFT cell lines express the c-Kit and PDGFR-α tyrosine kinase receptors (TKRs). Further, we noted that imatinib mesylate blocks the functional activation of these TKRs, and inhibits EFT clonogenicity (Proc AACR 43: 336a, 2002). Additionally, we reported that these TKRs are detectable by immunohistochemistry (IHC) in a majority of primary EFT and DSRCT (Proc ASCO 22: 826a). Based upon these findings, we treated a patient with recurrent EFT that expressed both c-Kit and PDGFR-α with imatinib mesylate. We report our experience. Methods: The index patient was enrolled in an IRB-approved clinical trial. She satisfied standard physiologic and performance criteria. The starting dose of imatinib mesylate was 400 mg BID. Standard dosage reductions were followed for hematologic and non-hematologic toxicities. Results: The index patient is a 29 y/o W/F who presented in August, 2002 with back and abdominal pain. CT scan in October, 2002 revealed a large retroperitoneal mass, extensive retroperitoneal adenopathy, and ascites; a biopsy revealed PNET. Staging evaluation revealed bone and bone marrow involvement. Chemotherapy with vincristine, doxorubicin and cyclophosphamide, altenating with ifosfamide and etoposide was initiated. Concomitant radiation was offered during the sixth and seventh cycles. Progression was documented after 11 cycles of chemotherapy. She required long-acting morphine (160 mg every 8 hours) for pain. IHC of the original tumor revealed 3+/3 IHC positivity for both c-Kit and PDGFR-α. She was enrolled on the present trial on April 28, 2003. Within 2 weeks she discontinued morphine. Partial remission (RECIST criteria) was documented on October 21, 2003. She presently continues in partial response. Conclusions: This case report demonstrates that imatinib mesylate was an effective alternative therapy for this patient with recurrent EFT whose tumor expressed the c-Kit and PDGFR-α TKRs. Imatinib mesylate should be further studied in this area (Sponsored by Novartis). Author Disclosure Employment or Leadership Consultant or Advisory Stock Ownership Honoraria Research Funding Expert Testimony Other Remuneration Novartis Novartis

Outcome of patients with recurrent Ewing's sarcoma family of tumors (ESFT)

8517 Background: The overall survival (OS) of relapsed ESFT is poor, and the relative benefit of high-dose therapy (HDT) is controversial. To determine the factors associated with outcome for relapsed ESFT, we performed the following analysis. Methods: We retrospectively identified 52 consecutive ESFT patients initially diagnosed before December 31, 2000, with disease recurrence between 1985 and 2002, who were treated at CHRMC and had adequate medical records for review. Results: All patients initially received multi-agent chemotherapy, most frequently vincristine, doxorubicin, cyclophospamide (C), etoposide (E), and ifosfamide (I) (27 patients). Twenty-five patients had metastatic disease at presentation. The median relapse-free interval (RFI) was 17 months (range 5–90 months). Most recurrences were metastatic only (36 patients) or local and metastatic (10 patients). Forty patients received second-line treatment with systemic chemotherapy, most frequently IE (23 patients), IE with carboplatin (6 patients...

Bone HDR brachytherapy in a patient with recurrent Ewing's sarcoma of the acetabulum: Alternative to aggressive surgery

A 17-year-old girl diagnosed with a previously irradiated, locally recurrent Ewing's sarcoma involving the puboischiatic rami and the adjacent acetabulum was referred to our institution for consideration of salvage hindquarter resection. A conservative resection with implantation of the acetabular remnant for high-dose rate brachytherapy was performed instead. The patient died 11 months after surgery without signs or symptoms of bony damage and retained the ability to walk for the remainder of her life.

All-trans retinoic acid and interferon-α in the treatment of a patient with resistant metastatic osteosarcoma

A boy age 14 years who was in complete remission from Stage IIB small cell osteosarcoma, which was misdiagnosed as Ewing sarcoma and consequently was treated, developed inoperable lung metastases when he was off therapy. He received second-line treatment for recurrent Ewing sarcoma, including chemotherapy and radiotherapy, and obtained only a temporary response. A compassionate treatment with all-trans retinoic acid (ATRA) and interferon-alpha (IFNalpha) was then undertaken.The patient initially was treated according to the national SE91 protocol for nonmetastatic Ewing sarcoma. After a bilateral pulmonary recurrence, he received second-line chemotherapy and irradiation of the largest metastasis, with a temporary partial response. The patient was then treated with a combination of oral ATRA (90 mg/m(2) for 3 days per week) and subcutaneous IFNalpha (3 x 10(6) U/m(2) 5 days per week) for 4 months. The same therapy also was administered for the control of residual disease after surgery for a total duration of 1 year of ATRA/IFN treatment. During the first 3 weeks of therapy, ATRA pharmacokinetics were studied.After progression of the patient's disease, despite the administration of first-line and second-line chemotherapy, combined treatment with ATRA/IFNalpha yielded a partial remission, which allowed surgical resection of the largest metastasis. The same therapy was effective in preventing tumor recurrence after incomplete removal of the remaining metastases. Treatment was well tolerated, and the patient is in stable complete remission 14 months after the end of therapy. The pharmacokinetics results confirmed the indication of an intermittent schedule for oral ATRA therapy.ATRA/IFNalpha treatment may be considered as an alternative approach in the treatment of patients with metastatic osteosarcoma who have disease that is resistant to conventional chemotherapy and in the treatment of patients with minimal tumor residue.

Comparison of technetium-99m sestamibi and indium-111 octreotide imaging in a patient with ewing's sarcoma before and after stem cell transplantation

We report the use of two novel nuclide agents, Technetium-99m (99Tc)sestamibi (MIBI) and indium-111 (In-111) octreotide, in comparison with conventional computed tomography (CT) imaging in a patient with metastatic Ewing's sarcoma (ES) before and after high dose chemotherapy with autologous peripheral stem cell transplantation (PSCT). MIBI is taken up actively by metabolically active tumor cells. Octreotide, a somatostatin analog, binds specifically to somatostatin receptors.The patient was a 20-year-old male with recurrent metastatic ES to the lung. Before and sequentially after high dose chemotherapy and PSCT, the patient was imaged with MIBI. Whole body planar and single photon emission computed tomography (SPECT) images were obtained after the injection of 30 mCi of 99Tc MIBI. Prior to PSCT the patient was imaged with 6 mCi In-111 pentreotide.Conventional CT scans also were performed. Initial CT revealed pulmonary metastasis in the right lower lobe along with multiple left pleural-based lesions. These lesions were visualized clearly with MIBI. Octreotide detected only the left lung involvement. Sequential MIBI scans after PSCT correlated with tumor reduction in the right lung field and tumor progression in the left lung as well as the development of new pulmonary metastasis. These findings were confirmed on CT.MIBI imaging was highly concordant with CT scanning in the detection of metastatic ES. MIBI scanning holds promise for the direct detection of a variety of human malignancies, and may prove useful as a rapid whole body imaging modality.

Reimplantation of autoclaved tumour bone in limb salvage surgery.

This is a prospective clinical study of 7 patients with malignant bone tumours who were treated by resection of the tumour, followed with reconstruction by reimplantation of the resected autoclaved tumour bone. There were 3 male and 4 female patients between 10 and 36 years of age. All the tumours were Stage IIB. Five of the 7 were in the region of the knee joint. Histologically, 5 were osteosarcomas, 1 a recurrent chondrosarcoma and 1 a recurrent Ewing's sarcoma. All the patients were treated by en bloc resection of the tumour with wide margins. The resected length ranged from 13 cm to 28 cm. After removal of soft tissue and cartilage, the resected bone segment was autoclaved for 5 min at 132 degrees C and 29 pounds per square inch pressure (0.2 mega Pascal). This autoclaved segment of bone was then reimplanted and fixed with an appropriate implant. The average follow-up was 20 months with a range of 14 to 27 months. None of the tumours recurred and, at the most recent follow-up, all the patients were alive, 6 with no evidence of disease and one with a lung metastasis. Six of the 7 patients were available for radiological assessment. Solid bone union was seen in 4 patients, delayed union in 1 and nonunion in 1. This method of reconstruction using an autoclaved tumour bone graft is useful in countries where facilities for allograft or tumour prostheses are not available owing to financial, technical or sociocultural reasons.

High‐dose‐rate brachytherapy in childhood sarcomas: A local control strategy preserving bone growth and function

The administration of external beam radiation therapy (EBRT) has been an integral part of the successful treatment of childhood sarcomas. However, EBRT has severe late morbidity in the developing child. In an attempt to deliver adequate tumoricidal radiation while preserving bone growth and organ function, 13 children with diverse sarcomas were treated with high dose rate brachytherapy (HDR). Seven patients had rhabdomyosarcoma and six patients had other soft tissue sarcoma variants. All patients were treated with disease-appropriate chemotherapy, usually according to the intergroup Rhabdomyosarcoma Study. Eleven patients received fractionated 36 Gy HDR alone at a mean of 3.5 months from diagnosis. Two patients received 10-12.5 Gy intraoperative HDR brachytherapy and additional 27 Gy EBRT. Nine of 11 patients in first remission have had no recurrences. One died of recurrent pulmonary metastases. The other patient that did recur is disease-free 21 months post-recurrence. Two additional patients were treated with HDR after tumor recurrence. One patient with recurrent Ewing's sarcoma, relapsed and died. The second is disease free 3 months after autologous bone marrow transplant. Grade 1 morbidity occurred in 46%, Grade 2 in 15%, and Grade 3 in 8% of the children, while relatively good bone and organ growth was maintained. The combination of conservative surgery, chemotherapy, and HDR offers the potential for disease control in young children while preserving bone growth and organ function.

1202 High-dose chemotherapy (HDC) with stemcell rescue for patients with metastatic Ewing's sarcoma

Metastatic Ewing's sarcoma has generally a fatal outcome. Patients with bone metastases cannot be cured by conventional treatment and only 10% of patients with pulmonary disease have a considerable diseasefree survival (DFS). From 1990 six patients with metastatic Ewing's sarcoma have been treated in Leiden Univ. Hospital with HDC, followed by either bone marrow and/or peripheral stemcell rescue (SCR). Three of them suffered from recurrent Ewing's sarcoma, the other three had metastases at primary presentation. Pat. characteristics: 5 × male, one female. Mean age: 23 yrs. Localisation of primary tumor: rib 1 ×, vertebra 1 ×, scapula 2 ×, pelvis 2×. Metastases: bone 2×, lung 4×, lhn 2×. Induction treatment: VP16-Ifosfamide 4×, CDDP 2×. HDC: VP-16, Melphalan, Carboplatin 4×, VP-16-Melphalan 2×. TBI 1 ×. Four patients got 2 cycles of HDC; bone lesions were irradiated. Results mean PFS 9+ months (3–20+). Overall survival: 12+ months (6–26+). Conclusion HDC with bone marrow and/or peripheral SCR is still an experimental treatment. Although toxicity is substantial some patients do have a relative long DFS.

Effectiveness of ifosfamide (IFO) alone and in combination with cisplatinum (DDP) in patients with recurrent ewing's sarcoma

Effectiveness of ifosfamide (IFO) alone and in combination with cisplatinum (DDP) in patients with recurrent ewing's sarcoma