Can postoperative radiotherapy be omitted in localised standard-risk Ewing sarcoma? An observational study of the Euro-E.W.I.N.G group.

BACKGROUND: The role of postoperative radiotherapy (PORT) in Ewing sarcoma (ES) is unclear. We assessed the impact of PORT on local control in patients with localised ES and good histological response to chemotherapy (<10% cells). PATIENTS AND METHODS: All randomised patients in the EE99-R1 trial (comparing two consolidation chemotherapy regimens) undergoing surgery after induction chemotherapy were included. Local relapse (LR) cumulative incidence was estimated using a competing risk approach. Impact of PORT was assessed in multivariable models, adjusted for country, age, tumour site and volume, quality of resection and histological response. We also evaluated the heterogeneity of PORT effect by patient and tumour characteristics. RESULTS: One hundred forty-two (24%) of the 599 patients included from 1999 to 2009 received PORT (median dose: 45 Grays). With median follow-up of 6.2 years, 67 patients had an LR (with concomitant metastases in 28), leading to an 8-year LR-incidence = 11.9% (standard error [se] = 1.4%). Overall survival (OS) = 21% (se = 5%) 3 years after LR (31% in isolated LR). Controlling for possible confounders, we observed a statistically significant reduction of LR in patients treated by surgery + PORT compared to surgery alone (subdistribution-hazard ratio = 0.43, 95% confidence interval, 0.21-0.88, p = 0.02). The benefit of PORT was particularly marked for tumours larger than 200 ml at diagnosis and 100% necrosis. We observed a non-significant trend for benefit associated with PORT for disease-free, event-free and OS. CONCLUSION: Radiotherapy appears to improve local control. We now recommend PORT in case of incomplete removal of the tissues involved by the pre-chemotherapy tumour volume. Further studies are required to assess the balance between benefit and risks.

The role of radiotherapy in oseosarcoma.

A survey of the literature shows that the experience with radiotherapy (RT) in the local treatment of osteosarcoma (OS) is limited. This is due to various reasons: OS is a rare tumor and surgery is the treatment of choice with high local control rate, and uncertainty exists in regard to the efficacy and tolerance of radiotherapy. Publications on this topic were analyzed and will be reviewed. Furthermore, experience from the Cooperative Osteosarkomstudiengruppe (COSS)-Registry, including 100 patients (pts) treated using radiotherapy for OS, was analyzed. The COSS-registry includes a total of 175 pts (5% of all pts) with histologically proven OS irradiated over the period of 1980-2007. 100 pts were eligible for analysis. The median age was 18 (3-66) years. Indication for RT was a primary tumor in 66, a local recurrence in 11, and metastases in 23 pts. 94 pts got external photontherapy; 2 pts, proton therapy; 2 pts, neutron therapy; and 2 pts, intraoperative RT. In addition, a group of 17 pts received bone-targeted radionuclide therapy by samarium-153-EDTMP-therapy alone or in combination with external RT. The median dose for external RT was 55.8 Gy (30-120). All the pts received chemotherapy in accordance with different COSS-protocols. The median follow-up was 1.5 (0.2-23) years. Survival and local control rates at 5 years were calculated, and univariate and multivariate analyses performed. 41 pts are alive, 59 pts died. The overall survival rate after biopsy was 41% at 5 years, while the overall survival rates after RT for the whole group, for treatment of primary tumors, local recurrence, and metastases were 36%, 55%, 15%, and 0% respectively.In 41 cases, local control was achieved, whereas local progression or local recurrence occurred in 59 cases, with a median time to local recurrence of 0.5 (0.1-4) years after RT. 15 pts were nonresponders to radiotherapy. Local control for the whole group was 30%. Local control rates for combined surgery and RT were significantly better than those for RT alone (48% vs. 22%, p=0.002). Local control for treatment of primary tumors, local recurrence, and metastases were 40%, 17%, and 0% respectively. Local control for pts given an addition of samarium-153-EDTMP was poor, though not statistically significant. A dose of over 60 Gy had no significant effect on local control. Prognostic factors for survival were indication for RT, RT plus surgery vs. RT alone and tumor location. Prognostic factors for local control were indication for RT, and RT plus surgery vs. RT alone. For the majority of pts, surgery remains the local treatment of choice. Radiotherapy is an important option as local treatment of unresectable tumors, following intralesional resection, or as palliation of symptomatic metastases. Survival prognosis of such pts, however, is poor. Despite the fact that many of these pts will eventually die, they may benefit in terms of prolonged survival and prolonged local control. The combination of surgery, radiotherapy, and chemotherapy can be curative. The consistent use of full-dose chemotherapy is of importance for the response to radiotherapy. Prognostic factors for survival are indication for RT, RT plus surgery vs. RT alone and tumor location. Prognostic factors for local control are indication for RT, and RT plus surgery vs. RT alone.

Results of the EICESS-92 Study: two randomized trials of Ewing's sarcoma treatment--cyclophosphamide compared with ifosfamide in standard-risk patients and assessment of benefit of etoposide added to standard treatment in high-risk patients.

PURPOSE: The European Intergroup Cooperative Ewing's Sarcoma Study investigated whether cyclophosphamide has a similar efficacy as ifosfamide in standard-risk (SR) patients and whether the addition of etoposide improves survival in high-risk (HR) patients. PATIENTS AND METHODS: SR patients (localized tumors, volume <100 mL) were randomly assigned to receive four courses of vincristine, dactinomycin, ifosfamide, and doxorubicin (VAIA) induction therapy followed by 10 courses of either VAIA or vincristine, dactinomycin, cyclophosphamide, and doxorubicin (VACA; cyclophosphamide replacing ifosfamide). HR patients (volume >or=100 mL or metastases) were randomly assigned to receive 14 courses of either VAIA or VAIA plus etoposide (EVAIA). Outcome measures were event-free survival (EFS; defined as the time to first recurrence, progression, second malignancy, or death) and overall survival (OS). RESULTS: A total of 647 patients were randomly assigned: 79 SR patients were assigned to VAIA, 76 SR patients were assigned to VACA, 240 HR were assigned to VAIA, and 252 HR patients were assigned to EVAIA. The median follow-up was 8.5 years. In the SR group, the hazard ratios (VACA v VAIA) for EFS and OS were 0.91 (95% CI, 0.55 to 1.53) and 1.08 (95% CI, 0.58 to 2.03), respectively. There was a higher incidence of hematologic toxicities in the VACA arm. In the HR group, the EFS and OS hazard ratios (EVAIA v VAIA) indicated a 17% reduction in the risk of an event (95% CI, -35% to 5%; P = .12) and 15% reduction in dying (95% CI, -34% to 10%), respectively. The effect seemed greater among patients without metastases (hazard ratio = 0.79; P = .16) than among those with metastases (hazard ratio = 0.96; P = .84). CONCLUSION: Cyclophosphamide seemed to have a similar effect on EFS and OS as ifosfamide in SR patients but was associated with increased toxicity. In HR patients, the addition of etoposide seemed to be beneficial.

186Re-HEDP in the treatment of patients with inoperable osteosarcoma.

UNLABELLED: The aim of this study was to examine the safety and efficacy of (186)Re-hydroxyethylidene diphosphonate (HEDP) as an adjuvant to external-beam radiotherapy (EBRT) in the treatment of patients with osteosarcoma. METHODS: Thirteen patients (9 male, 4 female; age range, 12-42 y) were treated with combination chemotherapy (standard U.K. protocol) and (186)Re-HEDP therapy (18.5 MBq/kg, intravenously), followed by EBRT. A full blood count; liver function test; and measurements of urea and electrolytes, glomerular filtration rate, and left ventricular function were performed on all patients before and after therapy. Tumor volume and composition were obtained from CT or MRI data. Dosimetric calculations were performed using the MIRD formalism. RESULTS: Of the 13 patients, 1 is still under follow-up. The median survival time was 36 mo (range, 12-216 mo) from diagnosis and 5 mo (range, 1-60 mo) from the last (186)Re-HEDP treatment. The mean tumor dose delivered with (186)Re-HEDP was calculated to be 5.8 Gy (range, 0.5-16 Gy). CT and MRI revealed the tumors to have a complex structure, comprising "ossified," "partially calcified," and "soft-tissue" components. Posttherapy scans showed a heterogeneous distribution of (186)Re-HEDP in the tumor mass: Although the "soft-tissue" component showed minimal uptake of the therapeutic dose, the "ossified component" showed intense uptake. The 3 long-term survivors in whom tumor sterilization was achieved received calculated mean tumor doses in the range of 2.0-3.1 Gy, which was believed to be an underestimate of the actual tumor doses delivered. CONCLUSION: This study indicates that a simple approach to tumor dosimetry based on mean tumor dose is inappropriate because it may underestimate the dose delivered to these heterogeneous tumors. The data also indicate that EBRT combined with a standard dose of 18.5 MBq/kg of (186)Re-HEDP does not provide a sufficient dose to achieve tumor sterilization. A dose estimation technique is required that is based on the determination of tumor dose at the individual voxel level and that is able to represent the heterogeneous uptake observed in these complex tumor structures with highly nonuniform composition. This, coupled with individualized dose escalation, may then achieve the goal of tumor sterilization.

The importance of age, fludarabine, and total body irradiation in the incidence and severity of chronic renal failure after allogeneic hematopoietic cell transplantation.

Nonmalignant late effects, including chronic renal failure (CRF), impair the quality of life of long-term survivors after allogeneic hematopoietic cell transplantation. One of the major risk factors is the use of total body irradiation (TBI) in the preparative regimen; TBI is currently fractionated in an attempt to reduce toxicity. We analyzed 241 patients who had TBI-based preparative regimens for allogeneic hematopoietic cell transplantation. TBI was delivered as a single fraction of 7.5 Gy (7.5S group), 12 Gy in 6 fractions (12F group), or 14.4 Gy in 8 fractions (14.4F group). The cumulative incidence of CRF at 2 years was 12%. Statistical analysis revealed that older age (P < .001) and fludarabine administration (P = .016) had a significant effect on the incidence of CRF. Furthermore, single-fraction TBI was also significantly associated with CRF severity, because 7 (6.3%) of 111 patients in the 7.5S group developed severe CRF, as opposed to 1 (0.8%) of 130 patients in the 12F and 14.4F groups combined (P = .044). However, these conclusions should be regarded as preliminary in view of the retrospective and nonrandomized nature of this study.

Improving Outcomes After Relapse in Ewing's Sarcoma: Analysis of 114 Patients From a Single Institution.

The outcome for patients with relapsed Ewing's sarcoma is poor. A retrospective analysis was carried out to identify factors associated with improved survival. Between 1992 and 2002, 114 patients presented with relapsed or progressive disease. Median time to progression/relapse was 13 months (range, 2-128). Treatment at relapse included high dose treatment (HDT) in 29 patients, and surgery or definitive radiotherapy in 29. 2 and 5-year post relapse survival (PRS) was 23.5% and 15.2%, respectively. In multivariate analysis, the most significant factors associated with improved survival were disease confined locally or to the lungs (2-year PRS, 40% versus 6%; P < .001), relapse > 18 months from diagnosis (2-year PRS, 53% versus 8%; P < .001), HDT at relapse (2-year PRS, 62% versus 11%; P < .001), and surgery and/or radiotherapy at relapse (2-year PRS, 51% versus 14%; P < .001). First treatment failure in Ewing's sarcoma is mostly fatal. Improved survival can be achieved in selective patients with aggressive treatment. These improvements are confined to those without bone or bone marrow metastases.

A new technique of laparoscopic ovariopexy before irradiation.

OBJECTIVE: To report a new technique of laparoscopic ovarian transposition to preserve ovarian function in women who require pelvic irradiation for musculoaponeurotic fibromatosis (extra abdominal desmoid). DESIGN: Case report. SETTING: University teaching hospital. PATIENT(S): Two nulliparous women who required adjunctive radiotherapy for musculoaponeurotic fibromatosis where radiotherapy planning indicated that the right ovary could be removed from the field of radiation by anterior transposition. INTERVENTION(S): Laparoscopic suturing of the right ovary to the right round ligament with intracorporeal polypropylene sutures. MAIN OUTCOME MEASURE(S): Technical feasibility, recovery, postoperative adhesions, ease of ovarian repositioning, and evidence of ovulation after completion of radiotherapy. RESULT(S): The technique was easily performed without needing to divide the ligament of the ovary. Recovery was rapid, and there were no postoperative adhesions. The ovary showed evidence of continued function and was easily repositioned by dividing the sutures. CONCLUSION(S): In selected cases, this method of ovarian transposition has the advantages not only of being technically easy but also of allowing for repositioning of the ovary with minimal disruption of its anatomical relationship to the fallopian tube, thereby favoring fertility.