Temozolomide and intravenous irinotecan for treatment of advanced Ewing sarcoma

BACKGROUND: Preclinical models show sequence-dependent synergy with the combination of temozolomide and irinotecan, and a Phase I trial has demonstrated the combination to be tolerable and active in children with relapsed solid tumors. Because responses were seen in patients with Ewing sarcoma (ES) on that trial, additional patients were treated with this combination following study completion. PROCEDURE: We reviewed data from all ES patients treated with temozolomide and irinotecan at four institutions, including seven patients treated on the above Phase I trial. RESULTS: Sixteen patients received a total of 95 courses, with a median of five courses per patient. All patients had either progressive disease (PD) during initial therapy (n = 5) or relapse within 2 years of diagnosis (n = 11). Twelve patients had metastatic disease at diagnosis, including 5 with bone and/or marrow metastases. Patients received oral temozolomide 100 mg/m(2)/day on days 1-5 plus intravenous irinotecan 10-20 mg/m(2)/day on days 1-5 and 8-12, with courses repeated every 21-28 days. We observed 1 complete, 3 partial, and 3 minor responses in 14 evaluable patients, with a median duration of response of 30 weeks. Planned 21-day courses were tolerable and no more toxic than 28-day courses. Myelosuppression was minimal despite heavy pretreatment. Grade 3-4 diarrhea occurred in 11% of courses and was related to higher irinotecan doses. Over 600 irinotecan doses were administered uneventfully at home. CONCLUSIONS: Temozolomide and protracted intravenous irinotecan given in 21-day courses was tolerable and active in patients with advanced ES. Home administration of irinotecan with temozolomide was safe and is reasonable palliative therapy. A formal Phase II study using a uniform dose and schedule is warranted to better define activity.     

Ewing sarcoma/primitive neuroectodermal tumor of the kidney treated with chemotherapy including ifosfamide

Ewing sarcoma/primitive neuroectodermal tumor (ES/PNET) of the kidney is extremely rare, and is usually diagnosed after nephrectomy without neoadjuvant chemotherapy. Although ifosfamide and etoposide improve survival to a great extent in ES/PNET, the use of nephrotoxic agent, particularly ifosfamide, is a concern after nephrectomy. We describe the case of a 14‐year‐old female patient with abdominal mass who was diagnosed with ES/PNET of the right kidney after nephrectomy. Adjuvant chemotherapy including ifosfamide and etoposide were given. The estimated glomerular filtration rate decreased to 75% after the end of therapy. There was no evidence of recurrence 70 months after initial diagnosis.     

Challenges in the management of localized Ewing sarcoma in a developing country

Abstract

Survival in pediatric Ewing sarcoma (ES) lags in low- and middle-income countries (LMICs). This study analyzed factors contributing to a lower outcome in an LMIC center. A retrospective case review of children with localized ES treated from January 2011 till December 2017 was performed. Neoadjuvant chemotherapy with alternating cycles of vincristine, doxorubicin, cyclophosphamide; and ifosfamide, etoposide was administered 3-weekly for 48 weeks. Reassessment was planned for week 12, followed by local therapy (surgery/radiotherapy or both) tailed by adjuvant chemotherapy. Forty-eight patients with mean age 8 years (range: 0.7–14) were evaluated. Extremity and central axis tumors were seen in 25 (52%) and 23 (48%) patients. Three patients died of neutropenic sepsis and five abandoned therapy. Local therapy included primary surgery, radiotherapy and a combination of surgery and radiotherapy in 7 (16%), 20 (45%) and 17 (39%) patients. The 3-year event-free survival (EFS) and disease-free survival (DFS) for the cohort were 47.7?±?11% and 57.6?±?11.2%. Time to local therapy >16 weeks was associated with inferior DFS vs. local therapy administered within 16 weeks [46.6?±?12.4 vs. 63.9?±?19.4, p=.046]. Older age, axial site, large size and incomplete surgical resection did not predict relapse/progression. Patients who received wide local excision, as local therapy, had 100% DFS. Coordinated efforts to ensure timely therapy can improve outcome in pediatric ES. Abandonment and treatment-related mortality (TRM) are additional challenges that need to be tackled in LMICs.     

Treatment results and prognostic factors in Ewing sarcoma

Files of 133 children with Ewing sarcoma (median age 10 years) were reviewed. Frequent primary sites were extremities, trunk, pelvis, and cranium. Half of 43 patients with metastases had disease in the lungs. Ten-year overall and event-free survival rates were 31% and 19%, respectively. Five-year overall survival rates were 42% in localized and 15% in metastatic disease (p < .0001); 66% in cases with primary tumors < 8 cm and 29% in larger tumors (p = .013). VAC (vincristine, actinomycin D, and cyclophosphamide) regimens with anthracyclines resulted in better survival. Presence of distant metastases, large primary tumors, and pelvic localization were related to poor prognosis. Novel therapeutic approaches are needed to produce better results, especially in high-risk patients.     

Therapy and outcome of orbital primitive neuroectodermal tumor

Primary orbital primitive neuroectodermal tumor (PNET) is rare with no reported series. We report six cases of orbital PNET treated at a tertiary care oncology center in northern India from 2003 to 2008. None of them had distant metastases. All were treated with neoadjuvant chemotherapy followed by exenteration in two, radiotherapy and adjuvant chemotherapy in five cases. Three out of six achieved complete remission at end of therapy with globe salvage in three and vision in two cases. Chemoradiotherapy may help us to avoid mutilating surgery in large or locally advanced tumors, allowing preservation of vision or the globe. Pediatr Blood Cancer 2009;52:544–547. © 2008 Wiley‐Liss, Inc.     

Brainstem primitive neuroectodermal tumors (bstPNET): results of treatment with intensive induction chemotherapy followed by consolidative chemotherapy with autologous hematopoietic cell rescue

We have evaluated the response rate and survival utilizing intensified chemotherapy followed by myeloablative chemotherapy with autologous hematopoietic cell rescue (AuHCR) and adjuvant radiation therapy in six young children with newly diagnosed brainstem primitive neuroectodermal tumors (bstPNET). Following maximum surgical resection of the tumor, patients received high dose induction chemotherapy including vincristine, cisplatin, cyclophosphamide, and etoposide. Eligible patients received a single cycle of myeloablative chemotherapy followed by AuHCR. Two patients survive at least 32 months with stable disease. This approach provides an alternative for young patients with bstPNET who in prior reports have had a uniformly fatal prognosis.     

Grossly-resected synovial sarcoma treated by the German and Italian Pediatric Soft Tissue Sarcoma Cooperative Groups: discussion on the role of adjuvant therapies

Differently from adult oncologists that considered synovial sarcoma (SS) a tumor with uncertain chemosensitiveness, since two decades pediatric oncologists in Europe assumed that chemotherapy played an important role in SS treatment, so most pediatric patients were included in rhabdomyosarcoma protocols, receiving adjuvant chemotherapy regardless of risk factors. The German and Italian groups reviewed the data of grossly resected SS patients in order to define a risk-adapted treatment program for the next European protocol. A total of 150 patients < 21 years with localized SS who underwent initial gross resection between 1975 and 2002 were the object of this study. All but four cases received adjuvant chemotherapy. Post-operative radiotherapy was administered to 50% Group I and to 92% Group II patients. Five-year event-free survival (EFS) and overall survival (OS) were 77% and 89%, respectively. Survival rates were influenced by tumor size (EFS 92% and 56% for size < or = and > 5 cm, respectively) and local invasiveness, not by surgical margins. No metastatic relapses occurred in Group I < or = 5 cm patients, while the outcome was poor for T2B patients (EFS 41%) due to a high rate of metastatic relapse. Our study was unable to assess the role of adjuvant treatments in grossly-resected SS, but identified a subset of low-risk patients (IRS Group I, size < or = 5 cm), for which the omission of adjuvant chemotherapy could be suggested, and a subset of high-risk patients (T2B), who need treatment intensification.     

Therapy and outcome of primitive neuroectodermal tumor of the jaw

Data pertaining to outcomes in jaw primitive neuroectodermal tumor (PNET) are lacking. Eleven cases of jaw PNET (five maxillary and six mandibular) were treated at our cancer center with the same chemotherapeutic agents from June 2003 to January 2009. Four patients underwent surgery after neoadjuvant chemotherapy and all received local radiotherapy. At median follow-up of 56 months (range: 19-77 months), 7/11 patients are in sustained remission. There was no difference in outcome with respect to site of tumor, and whether surgery was performed or not. These results support the use of chemoradiation as initial modality of treatment rather than going for extensive and mutilating surgery.     

药物难治性颞叶癫患儿手术效果及其影响因素:附76例分析

目的总结药物难治性颞叶癫(MITLE)患儿的手术效果,探讨影响其手术预后的因素。方法以2005年6月—2009年3月进行手术,并至少随访1年的76例MITLE患儿为研究对象,应用多因素Logistic回归分析判断影响MITLE患儿手术效果的独立预测因素。结果 MITLE患儿手术后,根据Engel分级法,46例(60.5%)达到Ⅰ级,22例(28.9%)Ⅱ～Ⅲ级。多因素Logistic回归分析提示,首发年龄(P=0.034,OR=4.734,95%CI:1.121～17.067)、发作类型(P=0.033,OR=3.610,95%CI:1.111～11.732)是影响MITLE患儿手术效果的独立预测因素;既往病因、病程、MRI检查结果、发作频率、手术侧别、发作间期放电范围、IQ、服用抗癫药物对手术效果无独立预测作用。结论手术治疗儿童MITLE有效。首发年龄小、继发全面性发作的MITLE患儿手术治疗效果较差。     

Primitive Neuroectodermal Tumor of the Brain Associated with Malignant Rhabdoid Tumor of the Liver: A Histologic, Immunohistochemical, and Electron Microscopic Study

A 14-day-old white male, born with a large primitive neuroectodermal tumor of the left cerebral hemisphere, was found to have a solitary rhabdoid tumor in the liver incidentally at autopsy. Cells resembling the liver rhabdoid cells were also found by histology, immunohistochemistry, and electron microscopy in the brain tumor. The concurrence of rhabdoid cells in the tumors of the brain and liver suggests a common histogenesis and further supports the previous suggestion that the rhabdoid tumor is of neuroectodermal origin. The rhabdoid tumor in the liver in this case is likely to be a metastatic tumor from the brain rather than a second primary tumor.