Ovarian function in female survivors after multimodal Ewing sarcoma therapy.

BACKGROUND: With advances in cancer care, more young women with Ewing sarcoma (ES) survive after treatment. Thus, we sought to analyze the ovarian function in prepubertal, pubertal and postpubertal females and young women receiving multimodal therapy for ES, and to identify patients at risk of infertility on whom fertility preservation would be indicated. PROCEDURES: Twenty-seven female survivors of ES were included in this retrospective multiinstitutional study. Patients were classified into four groups according to the treatment received: chemotherapy (CHT) without pelvic radiation (pRT), chemotherapy and pRT, CHT and autologous hematopoietic cell stem rescue (aHSCT) without pRT, and CHT + pRT + aHSCT. The ovarian function and fertility outcomes were analyzed. RESULTS: At a median follow-up of 5.7 years from diagnosis, and at median age at follow-up of 16.3 years, 67% of the survivors had premature ovarian insufficiency, including all patients receiving pelvic RT and 87.5% of patients who underwent aHSCT, independent of chemoprotection. Thirty-seven percent of patients had a clinical syndrome of premature menopause. The relative risk (RR) of premature ovarian insufficiency of a survivor was 3.9 (p 0.03) for pRT, and 2.4 (p 0.07) for aHSCT. On multivariate analysis, radiation therapy was a significant predictor of higher risk of premature ovarian insufficiency over chemotherapy alone. CONCLUSIONS: A large proportion of women receiving multimodal therapy for ES develop premature ovarian insufficiency. Patients and guardians should be informed about the reproductive potential and strategies for preservation of ovarian function should be considered individually. Pediatr Blood Cancer 2015;62:341-345. © 2014 Wiley Periodicals, Inc.

Validation of a multi-modal treatment protocol for Ewing sarcoma--a report from the polish pediatric oncology group.

BACKGROUND: Ewing sarcoma (ES) is the second most common paediatric malignant bone tumor. Advances in multi-disciplinary care have resulted in significant improvement in cure rates over the last decades. However, the generalization of those results in countries traditionally excluded from large cooperative trials has yet to be demonstrated. We report the results of modern multi-disciplinary care for patients with ES in Poland. PROCEDURES: One hundred and thirty-two patients with ES were treated using modern multi-modal therapy during the period 2000-2009. Overall survival was estimated by Kaplan-Meier methods and compared using long-rank test and Cox models. Factors predictive of outcome in our setting were analyzed to identify distinct risk groups that could help identify areas for improvement. RESULTS: The median age at the time of diagnosis was 12.3 years. With a median follow-up of 5.0 years, the 5-year event-free survival (EFS) and OS estimates for localized disease were 54.88% and 68.29%, respectively. For patients with metastatic disease, 5-year EFS and OS estimates were 36% and 42%, respectively. There was no correlation between age and stage or site. Patients with localized, non-pelvic disease had better outcome than patients with axial tumors (71% vs. 44%, respectively, P = 0.00073). Treatment failure was associated with stage, pelvic primary, poor histological response, and type of local control. CONCLUSIONS: Successful treatment of ES requires optimal systemic and local therapy. We were able to replicate the results of modern multi-modal protocols. Validation of current treatment protocols in countries with more limited cancer treatment resources is required.

[Assessment of anthropometric parameters and serum leptin and fetuin-A levels in children and adolescents with osteosarcoma after anticancer treatment]. / Ocena parametrów antropometrycznych oraz stezen leptyny i fetuiny-A u dzieci i mlodziezy po zakonczeniu leczenia miesaka kosciopochodnego.

UNLABELLED: Cancer and the use of a comprehensive anti-cancer treatment are unfavorable factors, which have a significant impact on bone mass accumulation, bone mineralization and consequently the occurrence of osteoporosis. Bone turnover is regulated by complex mechanisms, among which an important role play OPG/RANK/RANKL signaling pathway, adipokines, and fetuin-A. The aim of the study was to evaluate bone mineral density and concentrations of leptin and fetuin-A in patients with osteosarcoma after anti-cancer treatment. MATERIALS AND METHODS: The study included 50 children and adolescents aged 10-21 years. The study group consisted of 25 patients with osteosarcoma and 25 healthy counterparts as a control group. The examination was conducted 2 months after the last course of postoperative chemotherapy and included densitometric measurements: bone mineral content (BMC), bone mineral density (BMD), fat mass, lean mass and biochemical measurements: serum concentrations of calcium, magnesium, phosphate, 25-hydroksyvitamin D, alkaline phosphatase, leptin and fetuin-A. Concentrations of leptin and fetuin-A were determined by immunoenzymatic methods. RESULTS: In patients with osteosarcoma after anti-cancer treatment, we observed significantly reduced bone mineral content, bone mineral density and lean body mass compared with the healthy children (p < 0.05, p < 0.01, p < 0.05, respectively). Mean values of z-score of the whole body BMD and z-score of the lumbar BMD L1-L4 were significantly lower in patients than in the controls (p < 0.001). The serum concentrations of phosphate, magnesium, and alkaline phosphatase in both studied groups were similar, while calcium was significantly lower (p < 0.05) in patients than in the healthy children. The concentration of 25-hydroxyvitamin D was about two-fold lower, while leptin approximately 2.5-fold higher in patients than in the controls. The mean value of fetuin-A was similar in both studied groups. Statistically significant positive correlations between body composition parameters and the values of BMD, as well as between anthropometric parameters and leptin and fetuin-A were observed. CONCLUSION: The deficit in bone mass observed in patients with malignant bone tumors after anti-cancer treatment might be the result of decreased serum calcium and vitamin D concentrations. The observed correlation between anthropometric and biochemical parameters may indicate the link between bone and adipose tissue metabolism.

Vincristine, irinotecan, and temozolomide in patients with relapsed and refractory Ewing sarcoma.

BACKGROUND: Patients with metastatic, progressive or recurrent Ewing sarcoma (ES) have a dismal outcome. The combination of irinotecan and temozolomide has been proposed as an effective salvage regimen for some pediatric malignancies. Thus, we sought to evaluate this combination with vincristine for patients with relapsed and refractory ES. MATERIALS AND METHODS: Twenty-two patients with relapsed or refractory ES were treated with the combination of vincristine (1.5 mg/m(2) i.v. day 1), irinotecan (50 mg/m(2) /day i.v. days 1-5) and temozolomide (125 mg/m(2) /day p.o. days 1-5) (VIT) during the period 2008-2012. All toxicities were documented. RESULTS: A total of 91 cycles (median 4.1 cycles/patient) were administered. A complete response (CR) was achieved in five patients, partial response (PR) in seven patients, stable disease (SD) in three patients, and progression disease (PD) in seven patients, with an overall response rate of 68.1%. Median time to progression was 3.0 months (range 1.1-37.1 months). Five patients (22.7%) are alive with no evidence of disease with a median follow-up of 10.3 months (range 2.1-46.5); four of them received consolidation with high-dose chemotherapy and autologous hematopoietic stem cell transplant after responding to VIT. Outcome was better for patients with relapsed ES compared with patients who progressed to initial therapy (estimated 2 year overall survival 36.4% vs. 0%, respectively). There were no significant toxicities. CONCLUSIONS: The shorter, 5-day VIT regimen is an active and well-tolerated regimen in refractory ES. This combination deserves further investigation in the upfront management of patients with metastatic disease.

[Chemotherapy in patients with refractory Ewing sarcoma]. / Chemioterapia u dzieci i mlodziezy z opornymna leczenie miesakiem Ewinga

BACKGROUND: Patients with metastatic, progressive or recurrent Ewing sarcoma have a poor prognosis. In addition to increasing the intensity of conventional chemotherapy, the combination of irinotecan and temozolomide has been proposed as an effective salvage regimen for some pediatric malignancies. AIM: To evaluate the effect of two different salvage regimens on the final outcome of patients with refractory Ewing sarcoma. MATERIAL AND METHODS: During the period 2008-2012, twenty-two patients (age between 2.9 -19.3 years) with recurrent or refractory Ewing sarcoma were treated with the combination of vincristine, irinotecan and temozolomide (VIT regimen), and twenty patients were treated with the combination of cisplatin, doxorubicin, cyclophosphamide and teniposide (PACE regimen). All patients had standard tumour imaging and laboratory evaluation. All toxicities were documented. The WHO criteria were used to evaluate response. Statistical analysis was performed using STATA 10.0 for Windows. Results distributions were estimated using the method of Kaplan-Meier. The log-rang test was used to compare the groups. RESULTS: A total of 91 cycles of VIT and 65 cycles of PACE were administered. For VIT therapy the overall response rate was 68.1%. Median time to progression was 3.0 months. Five patients are alive with no evidence of disease with a median follow-up of 10.3 months. For PACE therapy the overall response rate was 75%. Median time to progression was 3.5 months. Four patients are alive with no symptoms of disease with a median follow-up of 17.6 months. The 2 years overall survival probability after recurrence was 29.94%; no differences were detected between therapy groups. Toxicity for PACE was significantly higher. CONCLUSIONS: The effectiveness of VIT regimen in refractory Ewing Sarcoma is comparable to conventional chemotherapy. The VIT regimen has less associated toxicities than the PACE regimen.

Surgical treatment of patients with disseminated Ewing sarcoma in our clinical experience.

BACKGROUND: Survival in advanced Ewing's sarcoma is unsatisfactory even with combination treatment. This paper tries to evaluate the impact of surgical treatment on treatment results. MATERIAL AND METHODS: We discuss a series of 24 patients aged 6.1-18.9 years with disseminated Ewing's sarcoma treated in the years 2000-2008. The patients had metastases to the lungs (13 patients), bone (6 patients), or multiple sites (5 patients). The follow-up period ranged from 8 months to 8.5 years. The patients were treated in accordance with the EE99 protocol. 19 out of the 24 patients underwent surgery. Patients with lung metastases underwent resection of both the primary focus (12 children) as well as the lung metastases (6 children) or radiotherapy. Patients with metastases located elsewhere underwent resection of the primary focus and lung metastases, while the remaining metastatic sites were irradiated (7 children). The 6 remaining children received chemotherapy and radiotherapy. RESULTS: Ten of the 19 patients who were operated on are alive. All those patients that were not operated on have died. The length of survival in the whole group has ranged from 8 months to 8.5 years (mean 2.8 years). Mean overall survival among these patients that were operated on is 3.1 years, and among those who had lung metastases at baseline and underwent metastatectomy, the survival rate is 4.3 years. The average survival rate among the non-operated on patients is 1.6 years. CONCLUSIONS: Surgery appears to prolong survival among patients with disseminated Ewing's sarcoma.

[Nephrotoxicity of ifosfamide with special reference to Fanconi Syndrome]. / Niefrotoksycznosc ifosfamidu ze szczególnym uwzglednieniem zespolu Fanconiego.

UNLABELLED: The article is a case presentation of Fanconi syndrome in a patient treated with high doses of ifosfamide. ifosfamide nephrotoxicity relates to glomerular and tubular disfunction. Tubular disfunction type 2 (Fanconi Syndrome) is observed most often. In this syndrome hypophosphatemia, hyperphosphaturia, glucosuria, polyuria, aminoaciduria, hypokalemia and tubular acidosis are present. The treatment consists of electrolyte supplementation and acidosis reduction. Nephrotoxicity risk factors are: total ifosfamide doses and age under 3 years. Early diagnosis is possible by estimating b2 microglobulin and retinal binding protein. Normally used parameters of renal function are insufficient. MATERIAL AND METHODS: case report - N. W - 13-year-old patient with a skin's tumour was treated in our clinic. Euro Ewing-99 protocol with 100.8 g/m2 of ifosfamide was applied for 18 months. During treatment serum electrolytes, urea, creatinine and creatinine clearance were normal. 6 months after treatment a metastasis in the lung was detected. RESULTS: Fanconi Syndrome symptoms were noticed before introduction of chemotherapy. After treatment with small doses of ifosfamide (4.5 g/m2) the disorders became severe. For this reason, nephrotoxic cytostatics were excluded from further treatment, decreasing its efficiency. CONCLUSIONS: 1. Renal complications of ifosfamide may appear after treatment completion. Monitoring of renal function parameters is necessary during and after treatment. 2. When protocols with cyclophosphamide (less nephrotoxic than ifosfamide) prove to be of similar efficiency, this treatment could be an alternative for patients' with renal disfunction. 3. Patients with completed ifosfamide treatment shall be qualified for repeated chemotherapy carefully due to high-risk of renal disfunction.