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Journal of Clinical Oncology, Vol 22, No 14 (July 15), 2004: pp. 2873-2876 © 2004 American Society of Clinical Oncology. DOI: 10.1200/JCO.2004.01.041 Treatment of Metastatic Ewing's Sarcoma or Primitive Neuroectodermal Tumor of Bone: Evaluation of Combination Ifosfamide and Etoposide—A Children's Cancer Group and Pediatric Oncology Group StudyFrom the Division of Pediatrics, Department of Pediatric Hematology/Oncology, City of Hope National Medical Center, Duarte; Department of Preventive Medicine, Keck School of Medicine, University of Southern California, Los Angeles; Department of Pediatrics and Department of Radiation Oncology, Stanford University School of Medicine, Stanford, CA; Dana-Farber Cancer Institute and Children's Hospital; the Department of Orthopedic Surgery, Children's Hospital; the Department of Radiation Oncology, Massachusetts General Hospital; the Departments of Pediatrics, Radiation Oncology, and Orthopedic Surgery, Harvard Medical School, Boston, MA; Mayo Clinic, Rochester, MN; Department of Pathology, Children's Hospital of Pittsburgh, Pittsburgh, PA; Department of Pathology, Johns Hopkins Hospital, Baltimore, MD; Memorial Sloan-Kettering Cancer Center; Department of Pediatrics, New York University Medical Center, New York, NY; Division of Pediatric Hematology/Oncology, Washington University Medical Center; the Department of Pediatrics, Washington University School of Medicine, St Louis, MO; and Department of Paediatrics, King Khalid National General Hospital, Jeddah, Kingdom of Saudi Arabia Address reprint requests to James Miser, MD, City of Hope National Medical Center, 1500 E Duarte Rd, Duarte, CA 91010; e-mail: jmiser{at}coh.org
PURPOSE: One hundred twenty patients with metastatic Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone were entered onto a randomized trial evaluating whether the addition of ifosfamide and etoposide to vincristine, doxorubicin, cyclophosphamide, and dactinomycin improved outcomes. METHODS: Thirty-two patients had metastases to lungs only, 12 patients had metastases to bone marrow or bones only, 64 patients had metastases in multiple sites, and five patients had metastases in other sites; seven patients could not be assessed precisely. Treatment comprised 9 weeks of chemotherapy before local control and 42 weeks of chemotherapy; thereafter, regimen A consisted of vincristine 2 mg/m2, cyclophosphamide 1,200 mg/m2, and either doxorubicin 75 mg/m2 or dactinomycin 1.25 mg/m2. Regimen B consisted of regimen A alternating every 3 weeks with ifosfamide 1,800 mg/m2/d for 5 days and etoposide 100 mg/m2/d for 5 days. RESULTS: Patients treated on regimen B did not have significantly better survival than those treated on regimen A. The event-free survival (EFS) and survival (S) at 8 years were 20% (SE, 5%) and 32% (SE, 6%), respectively, for those treated on regimen A and 20% (SE, 6%) and 29% (SE, 6%), respectively, for those treated on regimen B. Patients who had only lung metastases had EFS and S of 32% (SE, 8%) and 41% (SE, 9%), respectively, at 8 years. There were six toxic deaths (5%), four from cardiac toxicity and two from sepsis (four treated on regimen B and two treated on regimen A). Two had second malignant neoplasms. CONCLUSION: Adding ifosfamide and etoposide to standard therapy does not improve outcomes of patients with Ewing's sarcoma or PNET of bone with metastases at diagnosis.
Outcomes for patients with metastatic Ewing's sarcoma have improved little during the last 20 years. The initial Intergroup Ewing’s Sarcoma Studies suggested that 30% survival could be achieved with standard therapy.1 Subsequent studies have not shown further improvement in outcomes.2 Adding total-body irradiation followed by autologous bone marrow transplantation to chemotherapy had similar results.3 Patients with metastatic disease to lungs only might fare better than those with metastatic disease in other sites.4 The addition of combined ifosfamide and etoposide to standard therapy improved outcomes of patients who did not have metastatic disease at diagnosis.5 This report details evaluation of the same strategy in 120 patients who had metastatic disease at diagnosis.
Patients with diagnoses of Ewing's sarcoma or primitive neuroectodermal tumor (PNET) of bone with metastases at diagnosis were enrolled onto this trial. A light microscopic appearance consistent with Ewing's sarcoma, PNET of bone, or any other primitive sarcoma of bone was required for enrollment. Representative slides were reviewed centrally by one of us (P.S.D.) but this review was not required for study enrollment. This trial accrued patients from 1988 to 1992. The patients were assigned randomly to regimen A (standard therapy) or regimen B (standard therapy plus combined ifosfamide and etoposide). To participate, patients or their guardians gave written informed consent according to institutional and US National Cancer Institute guidelines, and the protocol was reviewed and approved by institutional human subjects review boards. The protocol review and implementation were in compliance with the Declaration of Helsinki. Before enrollment, every patient was assessed for the presence of metastatic disease. This evaluation included a chest x-ray and computed tomography of the lung, a bone scan, a bone marrow biopsy, and a bone marrow aspiration. Patients were randomly assigned to receive either regimen A or B, as described subsequently. The randomization was stratified according to the presence of metastatic disease. The protocol schema is shown in Figure 1. Regimen A consisted of vincristine 2 mg/m2, doxorubicin 75 mg/m2, cyclophosphamide 1,200 mg/m2, and dactinomycin 1.25 mg/m2, with each course containing doxorubicin (the first five courses) or dactinomycin (subsequent courses). Regimen B consisted of those four agents alternating every 3 weeks with combined ifosfamide 1,800 mg/m2/d for 5 days and etoposide 100 mg/m2/d for 5 days. Therapy for both arms was planned to last 51 weeks.5 Of the four agents in common to the two regimens, only the planned dose of doxorubicin was the same. Seventeen courses of therapy were to be administered. If the patient did not have treatment delays, this would be accomplished in 51 weeks.
Local control of the primary and metastatic disease was recommended at week 9. Surgery of the primary site was recommended if feasible. Patients were to receive radiation therapy to all sites of metastatic disease. This was to be administered concurrently with radiation therapy to the primary tumor site, if it was to be given. For patients who received radiotherapy only to the primary tumor site, the initial tumor volume (soft tissue and osseous extent of tumor) with a 3-cm margin was treated to 45 Gy. That was followed by reduction in treatment volume to the postchemotherapy, preradiotherapy tumor extent for 10.80 Gy more, for a total dose of 55.80 Gy. Residual tumor after surgery, including lung metastases, was irradiated using the dose-volume guidelines for gross residual disease. Radiation was given concomitantly with chemotherapy, although 2-mercaptoethane sulfonate was not to be delivered on the day radiation therapy was given. The study was designed to accrue patients with newly diagnosed Ewing's sarcoma until approximately 400 patients with nonmetastatic Ewing's sarcoma or PNET of bone were enrolled. Randomization was stratified according to metastases at diagnosis. Analysis of patients with metastatic disease was concurrent with that of patients without metastatic disease. Primary end points for estimating relative efficacy were event-free survival (EFS) and survival (S). Risk of adverse event and risk of death were compared between regimens using a two-sided log-rank test.6 EFS was defined as the time from study entry until disease progression, diagnosis of second malignant neoplasm, death, or last patient contact, whichever came first. Each disease progression was further classified according to sites of involvement as at sites of disease identified at study enrollment (original sites), at sites of disease not identified involved at study enrollment (new sites), at sites of disease identified at study enrollment as well as sites not identified at study enrollment (original and new sites), and progression at a unknown site (insufficient data submitted to determine the site if relapse). Disease progression, diagnosis of second malignant neoplasm, or death was considered an adverse event; otherwise, patients were censored at the dates of last contact. S was defined as the time from study entry until death or last patient contact, whichever came first. Death was considered an event, regardless of cause. Otherwise, patients were censored at the dates of last contact. EFS and S were estimated using the method of Kaplan and Meier.6 Risk of adverse event was compared across groups, defined by treatment or prognostic factors, using the log-rank statistic.6 Patients' randomized treatment assignments were used in all comparisons. The cumulative incidence of each event type was calculated for each regimen and compared by the method proposed by Gray.7 Deaths were classified into one of two types: disease related (Ewing's sarcoma or PNET reported as a cause of death) and not disease related (death without disease progression). The cumulative incidence of each event type was calculated for each regimen and compared by the method proposed by Gray.7
Patient Population One hundred twenty patients with metastatic disease were entered onto the trial; 62 were assigned to standard therapy and 58 were assigned to experimental therapy. The median follow-up of patients who were alive at last contact was 99 months. Details of the patient characteristics are listed in Table 1.
Toxicity There were six toxicity-related deaths: four on regimen B and two on regimen A. Four of the six deaths were a result of cardiac toxicity: two on regimen A and two on regimen B. One of the four deaths from cardiac toxicity occurred while the patient received therapy and was associated with severe infection. The other three deaths associated with cardiac toxicity occurred off protocol therapy at 14, 18, and 59 months after diagnosis, respectively. These deaths were attributed to cardiomyopathy. There were two episodes of fatal sepsis (Escherichia coli, Candida) in regimen B.
Second Malignant Neoplasms
Outcomes
Patients experienced 94 events. Six were toxicity-related deaths, two were second malignant neoplasms, and 86 were associated with disease progression. One patient died and 15 patients had disease progression before the planned start of the local control phase. The cumulative incidence of each of the event types did not differ significantly when the two randomized regimens were compared (Table 2).
Patients with metastases to lungs only seemed to have somewhat better EFS and S than those with metastases to bones, bone marrow, or other sites (Fig 4). Thirty-four percent of patients with metastases to lung only were event free at 8 years compared with 17% of patients with metastases to other sites (P = .060). Forty-one percent of patients with metastases to lung only survived at 8 years compared with 28% of patients with metastases to other sites (P = .09). Postrecurrence survival was similar when the two groups were compared. Seventeen percent of patients with metastases to lung only survived at 8 years postrecurrence compared with 14% of patients with metastases to other sites (P = .18).
At 8 years, the cumulative incidence of death as a result of second malignant neoplasms was 0%, death as a result of toxicities was 5%, and death as a result of disease was 64%.
There has been little improvement in outcomes of patients with Ewing's sarcoma and PNET of bone with metastases at diagnosis during the last 20 years. Standard chemotherapy from the first and second Intergroup Ewing Sarcoma Studies, using primarily vincristine, dactinomycin, cyclophosphamide, and doxorubicin, had survival rates of approximately 30%.1 The addition of fluorouracil in the second Intergroup study did not improve outcomes.1,2 The addition of total-body irradiation followed by autologous bone marrow transplantation after remission with standard agents (vincristine, doxorubicin, and cyclophosphamide) produced similar poor results.3,8 A report from a single institution has documented slightly better results in a selected group of patients.4 Patients with metastatic disease limited to lungs seem to fare better than those with metastatic disease in other sites. This observation has been made by other investigators.9,10 The outcomes remain relatively poor for that group, however. The combination of ifosfamide and etoposide studied in this trial, which improved the overall outcomes of patients without metastatic disease at diagnosis, did not improve EFS or S of patients with metastatic disease at diagnosis.5 Alternative strategies are needed to improve outcomes in this difficult group of patients.
The authors indicated no potential conflicts of interest.
Authors' disclosures of potential conflicts of interest are found at the end of this article.
1. Vietti TJ, Gehan EA, Nesbit ME Jr, et al: Multimodal therapy in metastatic Ewing's sarcoma: An Intergroup Study. Natl Cancer Inst Monogr 56:279–284, 1981 2. Cangir A, Vietti TJ, Gehan EA, et al: Ewing's sarcoma metastatic at diagnosis: Results and comparisons of two intergroup Ewing's sarcoma studies. Cancer 66:887–893, 1990[CrossRef][Medline]
3. Horowitz ME, Kinsella TJ, Wexler LH, et al: Total-body irradiation and autologous bone marrow transplant in the treatment of high-risk Ewing's sarcoma and rhabdomyosarcoma. J Clin Oncol 11:1911–1918, 1993
4. Hayes FA, Thompson EI, Parvey L, et al: Metastatic Ewing's sarcoma: Remission induction and survival. J Clin Oncol 5:1199–1204, 1987 5. Grier HE, Krailo MD, Tarbell NJ, et al: Addition of ifosfamide and etoposide to standard chemotherapy in Ewing sarcoma/primitive neuroectodermal tumor of bone: A Children's Cancer Group/Pediatric Oncology Study. N Engl J Med 384:694–701, 2003 6. Kalbfleisch JD, Prentice RL. The Statistical Analysis of Failure Time Data. New York, NY, John Wiley, 1980 7. Gray RJ: A class of k-sample tests for comparing the cumulative incidence of a competing risk. Ann Stat 16:1141–1154, 1988
8. Meyers PA, Krailo MD, Ladayni M, et al: High dose melphalan, etoposide, total body irradiation, and autologous stem cell reconstitution as consolidation therapy for high risk Ewing's sarcoma does not improve prognosis. J Clin Oncol 19:2812–2820, 2001
9. Paulussen M, Ahrens S, Craft AW, et al: Ewing's tumor with primary lung metastases: Survival analysis of 114 (European Intergroup) Cooperative Ewing's sarcoma studies patients. J Clin Oncol 16:3044–3052, 1998
10. Paulussen M, Ahrens S, Burdach S, et al: Primary metastatic (stage IV) Ewing tumor: Survival analysis of 171 patients from the EICESS studies. Ann Oncol 9:275–281, 1998 Submitted January 6, 2003; accepted April 28, 2004.
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Copyright © 2004 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
