Megatherapy in children with high-risk Ewing s sarcoma in first complete remission

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1 Bone Marrow Transplantation, (1998) 21, Stockton Press All rights reserved /98 $12.00 Megatherapy in children with high-risk Ewing s sarcoma in first complete remission L Madero 1, A Muñoz 2,JSánchez de Toledo 3,MADíaz 1, MS Maldonado 2, JJ Ortega 3, M Ramírez 1, E Otheo 2, A Benito 1 and S Salas 3 Departments of Pediatric Hematology and Oncology, 1 Hospital Infantil Niño Jesús, Autonomous University of Madrid; 2 Hospital Ramón y Cajal, Madrid; and 3 Hospital Valle Hebron, Barcelona, Spain Summary: To improve the prognosis of patients with metastatic or high-risk localized sarcoma in first CR, we explored the role of consolidation therapy with megatherapy and hematopoietic rescue. From 1986 to 1995, of 72 patients with Ewing s sarcoma from three pediatric departments, 30 were diagnosed as high-risk patients. Of these 30 patients, six did not achieve complete remission and four refused megatherapy and received multimodal treatment (chemotherapy + surgery and/or radiotherapy). The remaining 20 patients received megatherapy. There were 15 males and five females with a median age of 10.8 years (range 2 18 years). Five patients had metastatic disease at initial diagnosis, nine patients had primary tumor in the pelvis and 13 had a tumor volume greater than 100 ml. Overall disease-free survival was %; % for those with metastatic disease, % for those with tumor volume greater than 100 ml and % for those with tumor in pelvic bones. In conclusion, megatherapy has improved the outcome of this group of patients relative to that expected following conventional therapy. Keywords: high-risk; Ewing s sarcoma; megatherapy; prognostic factors Ewing s sarcoma (ES) is the second most frequent bone neoplasm in children and adolescents, accounting for 10% of the total bone cancers in this age group. 1 Adjuvant chemotherapy, radiotherapy and surgery have significantly improved the prognosis for ES patients. More than 65% of patients with non-metastatic disease are long-term survivors under current protocols. 2 5 On the other hand, patients with metastatic disease at the time of diagnosis and those with non-metastatic disease but with tumor localized in the pelvis or tumor volume greater than 100 ml, constitute a group of patients with very poor prognosis, 6 9 although some authors consider pelvic localization as well as tumor volume greater than 100 ml to be Correspondence: Dr L Madero, Department of Pediatrics, Bone Marow Transplantation Unit, Hospital Infantil Niño Jesús, Avda. Menéndez Pelayo, 65, Madrid, Spain Received 23 June 1997; accepted 16 November 1997 weak prognostic factors due to modern conventional chemotherapy regimens. 10 Myeloablative radiochemotherapy followed by hematopoietic cell rescue has become a regular consolidation regimen for different pediatric high-risk solid tumors Adolescents and children with ES at high-risk of relapse should benefit from this new therapeutic approach. We have evaluated the efficacy and feasibility of megatherapy plus hematopoietic cell rescue given as consolidation treatment for patients with high-risk ES in first complete remission. Patients and methods Patients From 1986 to 1995, of 72 patients with Ewing s sarcoma from three pediatric departments, 30 were diagnosed as high-risk patients. Of these 30 patients, six did not achieve complete remission and four refused megatherapy and received multimodal treatment (chemotherapy + surgery and/or radiotherapy). The remaining 20 patients received megatherapy. There were 15 males and five females, with a median age of 10.8 years (range 2 18 years). These 20 patients with immunohistopathologically established ES comprised the study group. All these patients presented at least one of the following high-risk factors: (1) metastatic disease at the time of diagnosis; (2) primary tumor localized in the pelvis; and (3) tumor volume greater than 100 ml. This group of patients received myeloablative radiochemotherapy and hematopoietic stem cell autologous transplantation between 1986 and All patients underwent transplant in first complete remission. There were 15 males and five females, with a median age of 11.4 years (range 2 18 years) at the time of megatherapy. Five patients (25%) had metastatic disease at initial diagnosis; three lung and two bone metastasis. Patient characteristics are detailed in Table 1. Primary treatments All patients received multimodal therapy, including surgery, radiotherapy and chemotherapy. The median interval between diagnosis and ABMT was 35 weeks (range weeks). Treatment for primary tumor included surgery and/or radiotherapy. Eighteen patients received radio-

2 796 Table 1 Ewing s tumors in first CR Patient Sex Age at Primary Metastatic Metastatic Tumor First line Surgery Radio- Mega- Follow-up No. diagnois tumor disease site volume chemo- therapy therapy months (years) site ( 100 ml) therapy 1 M 2 Iliac crest No Yes T-9 No Yes Bu L-PAM 130, ADF 2 F 9 Iliac crest Yes Lung No T-9 No Yes Bu L-PAM 7, DOD 3 M 13 Iliac crest No No VAC+AD No Yes Bu L-PAM 5, DOD 4 F 14 Sacro-iliac No No VAC+AD No Yes TBI L-PAM 30, ADF 5 M 15 Iliac crest No No VAC+AD No Yes TBI L-PAM 54, ADF 6 M 9 Rib Yes Bone No VAIVA No Yes Bu L-PAM 9, DOD 7 F 14 Tibia Yes Lung No VAC+AD Yes Yes TBI L-PAM 6, DOD 8 M 11 Iliac crest No Yes T-9 No Yes L-PAM 1, TD 9 M 13 Femur Yes Bone No VAIA Yes Yes L-PAM 31, ADF 10 M 13 Sacro-iliac Yes Lung Yes VAIA No Yes L-PAM 16, ADF 11 M 7 Femur No Yes VAIA No Yes TBI L-PAM 50, ADF 12 M 3 Femur No Yes VAIA No Yes TBI L-PAM 48, ADF 13 M 9 Tibia No Yes VAIA No Yes Bu L-PAM 16, ADF 14 F 15 Scapula No Yes VAIA Yes Yes Bu L-PAM 20, ADF 15 M 18 Rib No Yes VAIA No Yes Bu L-PAM 11, ADF 16 M 10 Tibia No Yes EVAIA Yes No Bu L-PAM 1, TD 17 F 14 Femur No Yes VAIA Yes Yes Bu L-PAM 10, ADF 18 M 15 Iliac crest No Yes VAIA No Yes Bu L-PAM 30, ADF 19 M 14 Femur No Yes VAIA Yes Yes Bu L-PAM 36, ADF 20 M 10 Iliac crest No Yes VAIA No Yes Bu L-PAM 14, DOD DOD = died of disease; TD = toxic death; ADF = alive dsease-free. First line chemotherapy and megatherapy as described in Methods. therapy and four of these patients also underwent surgery. Two patients underwent surgery alone as treatment for the primary tumor. The radiation dose varied between 30 and 60 Gy, depending upon the tumor localization and type of surgery (compartmental or noncompartmental). All patients received conventional chemotherapy. The different regimens were: VAC (vincristine, D-actinomycin, cyclophosphamide) plus adriamycin 14 in four patients; VAIA (vincristine, D-actinomycin, ifosfamide, adriamycin) 14 in 12 patients; T-9 protocol (methotrexate, bleomycin, vincristine, D-actinomycin, cyclophosphamide, adriamycin) 15 in three patients; and EVAIA (etoposide, vincristine, D-actinomycin, ifosfamide, adriamycin) 16 in one patient. The patients received a median of 10 courses of chemotherapy before ABMT (range 1 13 courses). Marrow and peripheral blood stem cell (PBSC) collection and processing Bone marrow (BM) was harvested from the iliac crests by standard techniques 17 in seven patients who had been treated between 1986 and No purging was performed. PBSC collections were performed on days +5 and +6 after granulocyte colony-stimulating factor (G-CSF; Amgen, Thousand Oaks, CA, USA) (12 g/kg/day) mobilization by continuous flow cell separator (Cobe Spectra, COBE, Denver, CO, USA) 18 in 13 patients who had been treated after BM and PBSC cryopreservation and infusion Mononuclear BM cells and PBSCs were cryopreserved with dimethylsulfoxide (l0% final concentration), frozen according to standard methods in a controlled-rate freezer (Cryoson MYC 15, Schölkrippen, Germany), and stored in liquid nitrogen until their infusion. Thawing was rapidly performed in a 37 C waterbath, and immediately infused through a central venous catheter. Preparative regimens for transplants Busulphan 4 mg/kg for 4 days (days 5, 4, 3 and 2) and L-PAM (melphalan) 140 mg/m 2 were administered in 12 patients, L-PAM 40 mg/m 2 for 4 days ( 7, 6, 5 and 4), carboplatin 500 mg/m 2 i.v. for 3 days (days 4, 3 and 2), and VP mg/kg for one day (day 3). Five patients received total body irradiation (12 Gy) on days 5, 4 and 3 and L-PAM 160 mg/m 2 for 1 day (day 2). Supportive care Marrow and PBSC transplantation were carried out in the BMT unit. A central venous catheter was placed in each patient. Patients were isolated in filtered air rooms. Prophylaxis for Pneumocystis carinii (cotrimoxazole, 8 mg/kg/day from day 7 to day 0, and then from day +50 to +150 post-transplant) and for herpes simplex virus (acyclovir 500 mg/m 2 /day from days 7 to +24) was employed. Nonabsorbable antibiotics given for gut decontamination were vancomycin, nystatin and colimycin. All hemoderived transfusion products were irradiated. G-CSF (l0 g/kg/day) was administered intravenously from day +1 until the ANC was more than l 10 9 /l for 3 consecutive days in three patients undergoing ABMT and in 13 patients undergoing PBSCT.

3 Definitions Complete remission (CR) was defined as the complete resolution of all clinical and pathologic evidence of malignancy as well as any radiographic evidence of associated soft tissue masses. Disappearance of metastatic lesions in the lungs on CT scan, no evidence of tumor on BM aspirates and only residual metastatic healing lesions on 99Tc scan were necessary criteria. Non-hematological toxicity was graded by the method described by Bearman et al. 19 DFS Statistical methods The software program Stata (Stata Corporation, College Station, TX, USA) was used for statistical analysis. The results are expressed in mean standard deviation. Results were considered significant if the P value was We estimated disease-free survival (DFS) by the Kaplan Meier model. Finally, we compared survival among the different groups using the log-rank test. Results Response and survival Disease-free survival was % (range %), with a mean follow-up of months (7 130) (Figure 1). Thirteen out of 20 patients were alive at the end of the study (December 1996), with a mean follow-up of months (13 130). Survival for patients with non-metastatic disease was % vs % for those with metastatic disease (P = 0.08). Survival for non-metastatic patients with tumor in pelvic bones was % and survival for non-metastatic patients with a tumor volume greater than 100 ml was % (Figure 2). Seven patients died, with a mean follow-up of months. Three of these patients had metastatic disease at diagnosis; three had tumor in pelvic bones and one had a tumor volume greater than 100 ml. Five of these seven patients died of disease progression, and two deaths were related to toxicity; one from fulminant sepsis caused by Streptococcus viridans and one from veno-occlusive hep- DFS Months Figure 1 Disease-free survival curve for the 20 patients Months Figure 2 Disease-free survival curves based on the risk factors. Patients were grouped by the following high-risk factors: (1) metastatic disease at the moment of diagnosis; (2) non-metastatic disease with the primary tumor localized at the pelvis; and (3) non-metastatic disease with a tumor volume above 100 ml. atic disease. Gut toxicity was mucositis grade I (12 patients), mucositis grade II (four patients). All patients had nausea and vomiting, but only one experienced grade I gastrointestinal toxicity. No other non-hematological toxicities were observed. Survival for patients conditioned with chemotherapy was % vs % for those conditioned with chemoradiotherapy (P = 0.39). Hematopoietic recovery The median time from transplant to a neutrophil count /l was 21 days (range 13 40) for ABMT patients and 11 days (range 8 13) for PBSCT patients. The median time from transplant to an unsupported platelet count /l was 25 days (range 15 72) for ABMT patients and 13 days (range 9 16) for PBSCT patients. Discussion Multimodal therapy has significantly improved survival for a group of ES patients. Those patients with neither gross metastatic disease at diagnosis nor bulky primary tumors of distal localization constitute a good prognosis group. However, there is another group of ES patients with a very poor clinical outcome. Adverse prognostic factors for this second group have been identified and include: tumor volume greater than 100 ml, 2,7 metastatic disease at diagnosis, 8 tumors in pelvic bones, 9 high serum LDH levels, 20 older age, 21 poor response to induction therapy 22 and soft tissue extension at diagnosis. 23 All our patients were high-risk ES patients according to the widely accepted prognostic factors: 24,25 metastatic disease at diagnosis, non-metastatic tumor with a volume greater than 100 ml, or non-metastatic tumors in pelvic bones. Conventional therapy for such patients is followed by poor clinical outcome, 26 although the Memphis team reported a favorable event-free survival following conventional therapy in metastatic ES. 27 Megatherapy with hematopoietic rescue for ES patients in first CR has not been

4 798 as systematically studied as it has been for patients with neuroblastoma. 28 Studies regarding ES patients have dealt with recurrent disease, 29,30 or multifocal primary or early relapsing ES patients. 31 There are few reported experiences with ES patients who received a transplant in first CR. 24,25 Disease-free survival was 62.7%. However, these results must be interpreted with caution considering the number of patients with metastatic disease is smaller than that published by others, ie Ladenstein et al, 32 and the fact that all our patients were in first CR. Megatherapy for patients in second CR 33 or with refractory disease 30,34 is followed by very poor results, except in the report by Ladenstein and co-workers. 32 Based on our results, we consider the best timing for megatherapy for high-risk ES patients is at the end of conventional therapy, when the patients are in first CR. To date, the best conditioning regimen for these patients has not yet been established. Like others, 26,32,35 we did not find any improvement in survival using total body irradiation, although we achieved better but not statistically significant results. A preparative regimen containing busulphan and melphalan has been reported to be effective for ES patients who underwent transplantation in first CR. 32 In summary, our results suggest that children with highrisk ES may benefit from megatherapy and hematopoietic rescue as consolidation therapy at the end of conventional treatment. References 1 Crist WM, Kun LE. Common solid tumors of childhood. New Engl J Med 1991; 324: Jurgens H, Exner U, Gadner H et al. Multidisciplinary treatment of primary Ewing s sarcoma of bone. A 6-year experience of a European Cooperative Trial. Cancer 1988; 61: Nesbit ME Jr, Gehan EA, Burgert EO Jr et al. Multimodal therapy for the management of primary, nonmetastatic Ewing s sarcoma of bone: a long-term follow-up of the First Intergroup study. 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