the Hpital Sainte-Justine, Montréal Québec, Canada
    Children's Oncology Group Data Center, Gainesville, FL
    State University of New York Upstate Medical University, Syracuse
    Memorial Sloan-Kettering Cancer Center, New York, NY
    Dana-Farber Cancer Institute and Children's Hospital, Boston, MA
    University of Arkansas, Little Rock, AR
    Children's Memorial Medical Center at Chicago, Chicago, IL
    National Institute on Aging, National Institutes of Health, Gerontology Research Center, Baltimore, MD
    Phoenix Children's Hospital, Phoenix, AZ
    Stanford University Medical Center, Palo Alto, CA.

    ABSTRACT

    PURPOSE: Prognosis is poor for Ewing sarcoma patients with metastasis at diagnosis. We intensified a five-drug therapy (ifosfamide, etoposide alternated with vincristine, doxorubicin, and cyclophosphamide) using filgrastim but not stem-cell support. We studied topotecan alone and combined with cyclophosphamide in therapeutic windows before the five-drug therapy. A randomly assigned proportion of patients received amifostine as a cytoprotective agent.

    PATIENTS AND METHODS: Eligible patients were  30 years old and had histologically proven Ewing sarcoma or primitive neuroectodermal tumor (PNET) and metastasis at diagnosis. Chemotherapeutic cycles began every 21 days, after recovery from toxicities.

    RESULTS: One hundred ten of the 117 patients enrolled were eligible. Thirty-six patients received initial topotecan. Three had partial responses (PRs), and 17 had progressive disease (PD). Thirty-seven patients were administered topotecan and cyclophosphamide; 21 of these patients achieved PR, and one patient had PD. In a randomly assigned group of 69 patients, amifostine did not provide myeloprotection, which was measured by absolute neutrophil count, platelet count, or cycle intervals. The best responses to the overall therapy included 45 complete responses, 41 PRs, stable disease in 14 patients, and PD in five patients. For all patients, the 2-year event-free survival (EFS) rate was 24% (± 4%), and the overall survival rate was 46% (± 5%). For the 39 patients with isolated pulmonary metastases, the 2-year EFS rate was 31% (± 7%) compared with 20% (± 5%) for patients with more widespread disease.

    CONCLUSION: Topotecan had limited activity in patients with Ewing sarcoma or PNET metastatic at diagnosis. The topotecan-cyclophosphamide combination was active. Amifostine was not myeloprotective. Overall results showed no improvement compared with previous studies.

    INTRODUCTION

    Ewing sarcoma is the second most frequent primary neoplasm of bone in children, adolescents, and young adults.1 Outlook is unfavorable for patients with disease metastatic at diagnosis. Approximately 30% of patients in the first or second Intergroup Ewing's Sarcoma Study survived disease free for 5 years.2 In the European experience, patients with isolated pulmonary metastases had a 42% event-free survival (EFS) rate at 5 years, whereas no patients with bone metastases at diagnosis survived disease free.3

    Adding standard-dose ifosfamide and etoposide benefited patients with localized Ewing sarcoma but not patients with initial metastasis.4 However, higher doses of alkylating agents might prove more successful. For example, in a phase I study in the Pediatric Oncology Group (POG), patients with recurrent sarcoma administered ifosfamide (> 11 g/m2 in five daily doses) with etoposide (100 mg/m2/d for 5 days) had a higher response rate than patients administered lower doses. The maximum doses in that study were ifosfamide 3.5 g/m2/d for 5 days (17.5 g/m2/course) and etoposide 100 mg/m2/d for 5 days.5 The present study initially included a similar ifosfamide dose (3.6 g/m2/d for 5 days; 18 g/m2/course) for the first two courses, with etoposide 100 mg/m2/d for 5 days for the first three cycles and reduction of ifosfamide to 2.8 g/m2/d for 5 days for the final two cycles (total ifosfamide dose = 82 g/m2). Similarly, cyclophosphamide had been previously used in higher doses. Examples include doses of 70 mg/kg (approximately 2.1 g/m2) daily for 2 days with vincristine and doxorubicin (75 mg/m2 continuous infusion over 72 hours),6,7 an escalating cyclophosphamide dose to a maximum of 55 mg/kg (approximately 1.65 g/m2) daily for 3 days (4.95 g/m2/course) with vincristine and etoposide (2.5 mg/kg daily for 3 days),8 and a single-agent single course of cyclophosphamide 7 g/m2.9 We initially included cyclophosphamide 2.l g/m2 for 2 days with vincristine 2 mg/m2/d on day 1 and doxorubicin 75 mg/m2 as a continuous infusion over 48 hours. This doxorubicin dose was less than 90 mg/m2 in arm C of POG 8850 and was administered over a shorter interval (48 rather than 72 hours) to lessen regimen-related mucositis and sepsis (Miser et al, manuscript submitted for publication).

    High-dose therapy followed by autologous stem-cell reinfusion also has been investigated. Some reported improved outcomes compared with historical experience, whereas others did not (see review in Kushner and Meyers10). The present study used intensified cyclic chemotherapy without end-intensification to improve survival over historical experience.

    To identify active new agents for this poor-prognosis group, our study included initial therapy with a medication or combination being evaluated for activity and toxicity before more standard treatment (an upfront window period). Topotecan was studied initially. This camptothecin agent inhibits topoisomerase I. Xenograft studies showed that topotecan had excellent activity against sarcomas. A POG phase I study of a 30-minute daily infusion for 5 days every 3 weeks terminated with a maximum-tolerated dose of topotecan 2.0 mg/m2/d for 5 days, with granulocyte colony-stimulating factor (G-CSF) 5 μg/kg subcutaneously beginning on day 6.11 In the Intergroup Rhabdomyosarcoma Study V, patients with metastatic disease were administered topotecan initially at 2 mg/m2/d for 5 days. Two of the first five patients had neutropenia longer than 7 days when G-CSF was not used. When it was used, none of the patients had prolonged neutropenia. There were no other dose-limiting toxicities.12 Therefore, the current study opened with a topotecan dose of 2 mg/m2/d for 5 days, followed by G-CSF. After completion of the single-agent topotecan window, topotecan and cyclophosphamide combined were evaluated because they have been synergistic in model systems. A dose-escalation POG phase I trial reached final doses of cyclophosphamide 250 mg/m2 and topotecan 0.75 mg/m2, both administered daily for 5 days, followed by G-CSF.13

    Amifostine [WR-2721; S-2-(3-aminopropylamino)ethyl phosphorothioic acid] has been shown to ameliorate some adverse effects of the alkylating agents.14 This prodrug is hydrolyzed by alkaline phosphatase to the active metabolite WR-1065 [S-2-(3-aminopropylamino)ethanethiol], which rapidly equilibrates across cell membranes and reacts with electrophiles.15,16 In a pediatric trial, a single, high dose of amifostine did not allow melphalan dose escalation. However, some protection may have been seen for neutrophils and platelets.17 Preliminary data from the current study suggested increasing delay of chemotherapy in later courses as a result of prolonged myelosuppression. Therefore, a randomized component was added to determine whether amifostine provides myeloprotection, particularly against the cumulative toxicities of intensive alkylator-based therapy.

    PATIENTS AND METHODS

    Eligibility

    Eligible patients were younger than 31 years old and had newly diagnosed metastatic Ewing sarcoma or primitive neuroectodermal tumor (PNET). The tumor must have had the light microscopic appearance (hematoxylin and eosin) of a small round-cell neoplasm consistent with Ewing sarcoma or PNET of bone or soft tissue. There must have been no immunohistochemical or ultrastructural evidence to exclude the diagnosis of Ewing sarcoma or PNET. In particular, there must have been no evidence of rhabdomyosarcoma. Immunohistochemistry for desmin or muscle-specific actin, leukocyte common antigen, and CD99 (MIC-2) was recommended, as was cytogenetic analysis looking for pathognomonic t(11;22) or t(21;22). All pathology diagnostic materials were centrally reviewed by one of the authors (P.S.D. or E.J.P.). Evaluation for metastases included bone marrow aspiration and biopsy, computed tomography of the lungs using 1-cm intervals, and radionuclide bone scan. Confirmatory radiographs and magnetic resonance images for possible bone or soft tissue metastases were recommended. Patients with chest wall tumors and separate pleural masses were considered to have metastatic disease and were eligible. Patients with positive pleural fluid cytology were considered to have nonmetastatic disease and were ineligible. Biopsy was encouraged for patients with questionable lesions, especially small pulmonary nodules.

    The patients must have received no chemotherapy or irradiation. Normal organ function was required, including normal creatinine for age, bilirubin less than 1.5x normal, ALT and AST less than 3x normal, cardiac function normal by echocardiogram or radionuclide scan, and absolute neutrophil count (ANC) more than 1,200/μL with platelets more than 120,000/μL. If abnormal blood counts were a result of extensive bone marrow infiltration, the patient was allowed onto the study. Written informed consent according to institutional and US National Cancer Institute guidelines and the Declaration of Helsinki was obtained before entry.

    Treatment Regimen

    Patients who agreed to window therapy and were sufficiently stable, with no evidence of immediately life-threatening disease (eg, extensive pulmonary metastatic disease requiring artificial ventilation) or severe impairment of function (eg, vertebral lesion with spinal cord compression), were started on topotecan 2.0 mg/m2/d intravenous (IV) for 5 days, followed by G-CSF 5 μg/kg subcutaneously beginning on day 6 until the ANC was greater than 5,000/μL after nadir. After the first eight patients were enrolled onto the topotecan window, data from the Intergroup Rhabdomyosarcoma Study V indicated that the topotecan dose could be escalated safely to 2.4 mg/m2/d for 5 days, followed by G-CSF as above. Therefore, 28 patients received topotecan at the increased dose of 2.4 mg/m2 during the window period. After completing the topotecan window, the next therapeutic window consisted of cyclophosphamide 250 mg/m2 IV over 30 minutes, followed by topotecan 0.75 mg/m2 IV over 30 minutes; both drugs were administered daily for 5 days. Prehydration with 0.5 L/m2 of 5% dextrose in 0.25% NaCl and continued hydration with at least 1.5 L/m2 oral or IV was continued for each 24-hour period after chemotherapy. Antiemetics were administered at the investigator's discretion. Beginning on day 6, G-CSF was administered. Patients with clear clinical or radiologic evidence of disease progression after the first window cycle proceeded directly to induction therapy (see the next paragraph). Patients with no evidence of progressive disease (PD) received a second cycle of window therapy at week 3. Patients were evaluated for response at week 6, which was the end of the window period.

    High-dose induction therapy followed the window period (Fig 1). In weeks 6, 12, and 18, etoposide was administered IV over 45 minutes at 100 mg/m2 in 250 mL/m2 of 5% dextrose in 0.45% NaCl, followed by ifosfamide 3.6 g/m2 in 200 mL/m2 of 5% dextrose in 0.45% NaCl over 2 hours, daily for 5 days. Vigorous hydration, mesna (total dose, 4 g/m2/d), antiemetics, and G-CSF were administered. In weeks 9 and 15, vincristine (2.0 mg/m2; maximum dose, 2 mg) IV bolus was followed by cyclophosphamide (2.1 g/m2 in 200 mL/m2 of 5% dextrose in 0.45% NaCl over 30 minutes) daily for 2 days. After the first cyclophosphamide infusion, doxorubicin (75 mg/m2 in 4,800 mL/m2 of 5% dextrose in 0.45% NaCl) was administered as a 48-hour continuous IV infusion through a functioning central venous catheter. Mesna was administered (total dose, 2.4 g/m2). G-CSF was begun 24 hours after chemotherapy.

    Vincristine 2.0 mg/m2 (maximum dose, 2 mg) IV bolus was administered on weeks 10, 11, 16, and 17. Week 21 chemotherapy consisted of vincristine 2.0 mg/m2 (maximum dose, 2 mg), doxorubicin (75 mg/m2 as a 48-hour infusion), and cyclophosphamide (1.5 g/m2) with mesna. Local primary site control followed. Continuation therapy after the local control period consisted of vincristine (2.0 mg/m2 on day 1 only; maximum dose, 2 mg), etoposide (150 mg/m2/d for 3 days), and cyclophosphamide (1.5 g/m2 on day 1 only) on weeks 24, 27, 42, and 45. Additionally, vincristine (2.0 mg/m2) was administered during weeks 22, 25, 28, 43, and 46. During weeks 30 and 36, ifosfamide (2.1 g/m2/d for 5 days with mesna) and etoposide (100 mg/m2/d for 5 days) were administered. Week 33 chemotherapy initially consisted of vincristine (2.0 mg/m2; maximum dose, 2 mg), doxorubicin (75 mg/m2 over 48 hours), and cyclophosphamide (2.1 g/m2/d for 2 days with mesna). Vincristine (2.0 mg/m2; maximum dose, 2 mg) was administered during weeks 34 and 35. Week 39 chemotherapy also consisted of vincristine, doxorubicin, and cyclophosphamide, with the same vincristine and doxorubicin doses but with a lower cyclophosphamide dose (1.5 g/m2 on day 1 only). Local control of metastatic disease sites was begun just after week 39 of chemotherapy.

    Local control was at the discretion of the treating institutional investigators and consisted of complete surgical resection, full-dose irradiation, or lower dose irradiation to areas of microscopic residual disease after gross total resection with microscopically positive margins. Up to three metastatic sites, excluding bone marrow, were treated at week 39. If more than one third of the myeloproliferative tissue was to be irradiated or if more than three sites were to be irradiated, the radiotherapy coordinator was to be contacted.

    Patients treated with irradiation alone for local control were administered a dose of 45 Gy in 1.8-Gy daily fractions to the initial tumor volume. The original bony tumor and postinduction chemotherapy soft tissue volumes were treated to 55.8 Gy with a 2-cm margin. Standard precautions were taken to avoid irradiation of joints or the circumference of an extremity. If a 2-cm margin necessitated irradiation of an adjacent epiphysis, then a smaller margin was allowed to exclude it. Patients with microscopic residual disease had initial bone and soft tissue volume treated to 45 Gy in 1.8-Gy daily fractions. Initial bony and postinduction chemotherapy soft tissue volumes were treated to 50.4 Gy with a 2-cm margin. Patients with chest wall tumors and ipsilateral cytology–positive pleural fluid were treated with ipsilateral lung irradiation (15 Gy in 1.5-Gy daily fractions). Patients with pulmonary or pleural metastases received bilateral whole-lung irradiation including the entire pleural surface. A dose of 18.4 Gy was administered in twice-daily fractions of 1.15 Gy, separated by at least 6 hours, with cone-down boosts to areas of residual tumor, if the total volume of lung to be irradiated was less than 25% of total lung volume. The boost dose was 27 Gy in 15 daily fractions of 1.8 Gy, for a total dose of 45.4 Gy in 31 fractions. Bone metastases were treated to 45 Gy in 25 fractions of 1.8 Gy. Whole-brain irradiation to 45 Gy in 25 daily fractions of 1.8 Gy was administered to patients with brain metastases, with 30 Gy to the spine in patients with positive CNS cytology. Patients who were to receive pulmonary irradiation did not receive doxorubicin at week 33.

    Patients treated with amifostine were premedicated with dexamethasone 12 mg/m2 (maximum dose, 20 mg) 12 and 6 hours before amifostine administration. They also received ondansetron 16 mg/m2 (maximum dose, 24 mg) 30 minutes before amifostine, diphenhydramine 1 mg/kg, and cimetidine or ranitidine just before amifostine infusion.14 Amifostine (825 mg/m2) was administered over 15 minutes beginning 30 minutes before ifosfamide or cyclophosphamide and again 3 hours later. Infusion was interrupted if systolic blood pressure decreased by more than 20 mmHg. The patient was placed in the Trendelenburg position, and 20 mL/kg of 0.9% NaCl was infused over 20 minutes. If the blood pressure returned to normal, amifostine resumed. Patients randomly assigned to amifostine also received amifostine 200 mg/m2 as a bolus injection 15 minutes before each radiation treatment. Amifostine and mesna levels were measured in the plasma, RBCs, and peripheral-blood mononuclear cells as previously described.15,16

    Dosage Modification

    Five of the first 72 patients enrolled died from infections during periods of myelosuppression. These deaths occurred after chemotherapy weeks 12, 21, 30, 30, and 33, likely reflecting cumulative toxicity of this intensive therapy. Therefore, all ifosfamide doses after the first treatment (week 6) were decreased by approximately 25%. Also, the week 33 cyclophosphamide dose was decreased from 2.1 g/m2 daily for 2 days to 1.5 g/m2 on day 1 only. Mesna doses were decreased to approximately equal the ifosfamide or cyclophosphamide doses in total grams. One of five infection deaths was from Pneumocystis carinii pneumonia. The use of trimethoprim-sulfamethoxazole prophylaxis was re-emphasized.

    Response Criteria

    Response was assessed after the therapeutic window (week 5), after the end of induction therapy (week 20), after local therapy to the primary site of disease (week 29), after continuation therapy (week 38), and after the end of treatment (week 48). Complete response (CR) was defined as no evidence of disease. Patients rendered disease free by surgery were considered as having a CR, provided that the margins were negative, even if viable tumor was in the surgical specimen. Partial response (PR) was defined as at least a 50% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions. There must have been no evidence of progression in any lesion and no new lesions. Stable disease (SD), or no response, was defined as a less than 50% decrease in the sum of the products of the maximum perpendicular diameters of all measurable lesions, and PD was defined as at least a 25% increase in the sum of the products of the maximum perpendicular diameters of all measurable lesions or the appearance of new lesions.

    Study Design

    Time to adverse event was defined as days from registration date until recurrence of tumor at any site, PD, second malignancy, or death from any cause. Patients without events were censored as of the date of last contact. Overall survival (OS) and EFS estimates were computed using the Kaplan-Meier method,18 and SEs of estimates were determined according to Peto and Peto.19

    The number of days the platelets were less than 50,000/μL, the number of days the ANC was less than 500/μL, and the number of days until the next chemotherapy cycle were collected starting from completion of the ifosfamide-etoposide courses with amifostine at weeks 6, 12, and 18. The arithmetic means of each variable over the 3 weeks for each patient from the three courses of amifostine in the induction phase were the primary analysis variables. A Wilcoxon rank sum test was used to compare the amifostine and no amifostine arms. A repeated-measures analysis of variance also was conducted to determine any difference between the two arms in data over time (weeks 6, 12, and 18).

    RESULTS

    Patient Characteristics

    Of the 117 patients enrolled, 110 were eligible. The reasons for ineligibility were incorrect histology (n = 3), localized (rather than metastatic) disease (n = 1), and other (n = 3; registration violation and institutional review board/consent issues). Table 1 lists the patient characteristics.

    Window Therapy

    Toxicity of High-Dose Therapy

    As noted in Patients and Methods, the protocol was modified after a fifth patient died of sepsis. The deaths occurred after weeks 12, 21, 30, 30, and 33 of chemotherapy. One patient who did not receive prophylaxis died from Pneumocystis carinii pneumonia. Ifosfamide doses after the first course of ifosfamide-etoposide were decreased by approximately 25%, and the week 33 dose of cyclophosphamide was decreased from 2.1 g/m2/d for 2 days to 1.5 g/m2 on 1 day only. After the protocol amendment, only one of the last 38 patients died of infection. That patient was poorly compliant and came to the hospital only 24 hours after the onset of fever during a period of neutropenia.

    Myelosuppression was the most frequent toxicity, with infection being relatively frequent during profound neutropenia. Stomatitis was also relatively common and sometimes served as the infection portal. Other grade 3 and 4 toxicities are listed in Table 2. Only one incident of myelodysplastic syndrome was noted (20 months after diagnosis). Cytogenetics showed the following 11q23 abnormality: t(11;16)(q23;p13), inv 17. Induction therapy for acute myeloid leukemia was administered, followed by matched-sibling stem-cell transplantation. The patient remained in remission from both diseases at last follow-up date (June 27, 2003).

    Amifostine

    Sixty-nine patients were randomly assigned to receive or not receive amifostine during each cycle of chemotherapy. Thirty-five patients received amifostine, and 34 did not. Toxicities directly attributable to amifostine included increased nausea and vomiting despite premedication with dexamethasone, ondansetron, and diphenhydramine. Three adverse event reports were filed for two patients for hyperemesis. There were also two grade 2, two grade 3, and one grade 4 hypotension events despite prehydration. Amifostine-induced hypotension was rapidly reversible by interruption of drug administration and saline infusion. Thirteen patients who received amifostine developed grade 3 hypocalcemia, and three patients developed grade 4 hypocalcemia. All episodes were asymptomatic and responded to calcium supplementation. No myeloprotection was seen. The number of days with ANC less than 500/μL, the number of days with platelet count less than 50,000/μL, and the number of days until the next cycle were collected at weeks 6, 12, and 18 for patients randomly assigned to amifostine or no amifostine. No reduction in the number of days with ANC less than 500/μL or platelets less than 50,000/μL was seen. Although change was seen in each of these variables over time on each arm, there was no significant difference in pattern of change between the amifostine and no-amifostine arms. Intervals in all patients tended to become more prolonged later in therapy, but there was no difference between patients who did and did not receive amifostine (Table 3).

    The plasma levels of amifostine decayed with an average initial half-life of approximately 10 minutes. In both the plasma and blood cells, WR-1065 was recovered mostly as a free thiol (initial half-life, approximately 16 minutes). At the end of amifostine infusion, WR-1065 concentration was 74 ± 28 mmol/L in the plasma (n = 18), 80 ± 24 mmol/L in the RBCs (n = 14), and 52 ± 21 mmol/L in the peripheral-blood mononuclear cells (n = 4). Mesna distributed mostly in the plasma and was recovered as disulfides. At the end of mesna infusion, mesna concentration was 347 ± 238 mmol/L in the plasma (n = 4), 73 ± 26 mmol/L in the RBCs (n = 4), and 85 ± 33 mmol/L in the peripheral-blood mononuclear cells (n = 4).

    Outcome

    Among 105 patients assessable for response, 45 (43%) achieved CR, and 41 (39%) achieved PR (Table 4). Fourteen patients (14%) had no response, and five patients (5%) had PD. Overall response rates to protocol therapy were similar in patients who received the topotecan window (12 CRs, 14 PRs, seven SDs, and three PDs), the topotecan-cyclophosphamide window (22 CRs, 14 PRs, four SDs, and no PDs), or no window (11 CRs, 13 PRs, three SDs, and two PDs). There were no statistically significant differences in response patterns (Fisher's exact test, P = .26) between these three groups. Similarly, the overall responses for patients who received amifostine were as follows: 16 CRs, 17 PRs, two SDs, and no PDs. For patients who did not receive amifostine, the responses were as follows: 16 CRs, 12 PRs, four SDs, and one PD (P = .46).

    A total of 110 patients were assessable for EFS and OS analyses. Table 5 lists the outcome data. Overall EFS rate was 65% (± 5%) and 24% (± 4%) at 1 and 2 years, respectively (Fig 2). OS rate was 77% (± 4%) and 46% (± 5%) at 1 and 2 years, respectively (Fig 2). One-year EFS rate was 72% (± 7%) and 2-year EFS rate was 31% (± 7%) in patients who presented with isolated pulmonary metastases (n = 39). For patients with other or more than isolated pulmonary metastases at diagnosis (n = 71), 1-year EFS rate was 62% (± 6%), and 2-year EFS rate was 20% (± 5%). There was no statistically significant difference between groups (P = .39; Table 5 and Fig 3). OS rate (Fig 4) was 82% (± 6%) at 1 year and 49% (± 8%) at 2 years for patients with isolated pulmonary metastases, and the OS rate was 74% (± 5%) at 1 year and 44% (± 6%) at 2 years for the other patients (P = .47). The EFS and OS rates were also not significantly different for patients who received the topotecan window, the topotecan-cyclophosphamide window, or no window (P = .57 and P = .39, respectively) and for patients randomly assigned to receive amifostine or no amifostine (P = .79 and P = .91, respectively). Of 45 patients with CR, 33 experienced disease recurrence. Thirteen recurrences were at known sites of disease. Among patients whose disease recurred at new sites, four recurrences were in lung, eight were in bone, two were in lung and bone, and six were at other sites. As of the time of last contact, 14 patients were alive with no evidence of disease, with a median follow-up of 5.2 years (minimum follow-up, 3.5 years), and four patients were alive with disease, with a median follow-up of 5 years (minimum follow-up, 4.2 years).

    DISCUSSION

    Patients with Ewing sarcoma that is metastatic at initial diagnosis have an unfavorable outlook.2,20,21 Most studies have shown a slightly improved outlook for patients with initially isolated pulmonary metastatic disease.20,22 Several groups have used end-intensification followed by peripheral-blood stem-cell infusion in studies performed both before and after the current study was initiated.3,23 Unfortunately, no improvement has been seen in the dismal outlook for patients with initial bone or bone marrow metastases.11,24 The European Ewing Tumor Working Initiative of National Groups Ewing Tumor Studies 1999 study is investigating end-therapy intensification for patients with Ewing sarcoma and isolated pulmonary metastases at presentation. Patients in complete remission after induction are assigned randomly to continuation or high-dose chemotherapy with busulfan and melphalan followed by autologous stem-cell reconstitution. The Children's Oncology Group has recently joined this stratum to speed accrual and answer this question more quickly.25

    The present study used intensified cyclic chemotherapy based on initially promising results in the preceding Ewing study (POG 8850, arm C), with G-CSF but no stem-cell support (Miser et al, manuscript submitted for publication). Our study used a similar regimen in a larger group of patients. Ifosfamide was prescribed initially at a total dose of 82 g/m2 to limit renal Fanconi syndrome. After an excess number of toxic deaths, the ifosfamide dose was reduced after the first course by approximately 25% in each cycle. Thus, the total ifosfamide dose was 67 g/m2 in the last 38 patients enrolled. The cyclophosphamide dose also was reduced at week 33 from 2.1 g/m2/d daily for 2 days to 1.5 g/m2 on day 1 only. Arm C of the POG 8850/Children's Cancer Group (CCG) 7881 was complicated by a high incidence of therapy-induced leukemia.26 In contrast, only one incident of an induced myelodysplastic syndrome was reported on the current study, which is similar to the 1% to 2% incidence noted in previous studies of Ewing sarcoma or rhabdomyosarcoma. The high incidence in arm C may indicate a threshold effect for induction of leukemia.

    Compared with standard doses in POG 8850/CCG 7881 arms A and B and total doses in both arms of POG 9354, an overall increase of approximately 25% in total alkylator dose on the present POG 9457 study did not improve outcome. The 2-year EFS rate was 24% (± 4%), with an OS rate of 46% (± 5%). In this study, outcome was slightly better, although still poor, for 39 patients with isolated pulmonary metastases at initial diagnosis (2-year EFS rate of 31% v 20% for the other patients; P = .39).

    Toxicity comprised mainly myelosuppression, mucositis, and infection. Myelosuppression seemed to be cumulative, with increased delay between cycles despite decreased dose as therapy continued, most frequently caused by a delayed platelet count recovery. Five of the first 72 patients enrolled died of sepsis often late in the course; this is a reflection of the cumulative myelosuppression. After decreases in ifosfamide dose in all cycles after the first cycle and decreases in cyclophosphamide dose at week 33, there was only one additional toxicity-related death. Significant neurologic toxicity was rare and rapidly reversible. Significant renal electrolyte loss also was relatively uncommon and easily controllable.

    Amifostine was randomly assigned to 35 of 69 patients in this study to determine whether myelotoxicity, particularly cumulative myelotoxicity, could be limited. If so, patients would have recovered from myelosuppression induced by chemotherapy more rapidly, permitting dose intensification without stem-cell support. The number of days with an ANC less than 500/μL, the number of days with platelet counts less than 50,000/μL, and the number of days between cycles were not different between patients who did and did not receive amifostine during weeks 6, 12, and 18. Amifostine also had significant reversible toxicities, especially hypotension and increased chemotherapy-associated nausea and vomiting, which led some patients to refuse further amifostine.

    Cellular uptake of WR-1065 is more efficient than the uptake of mesna. However, in vitro, both drugs prevented cellular glutathione depletion by 4-hydroperoxycyclophosphamide, and their effects are additive.30

    Intensified chemotherapy without stem-cell support did not improve outcome in patients with Ewing sarcoma metastatic at initial diagnosis, which has also been shown by the mature results of the intensive arm C of POG 8850/CCG 7881. The combination of topotecan and cyclophosphamide was well tolerated, showed good activity, and is worthy of investigation in patients with initially localized disease.

    Authors' Disclosures of Potential Conflicts of Interest

    The authors indicated no potential conflicts of interest.

    Author Contributions

    Conception and design: Mark L. Bernstein, Meenakshi Devidas, Abdul-Kader Souid, Elizabeth J. Perlman, Michael P. Link, Allen Goorin, Holcombe E. Grier, Abdul-Kadar Souid

    Administrative support: Elizabeth J. Perlman

    Provision of study materials or patients: Mark L. Bernstein, Dominique Lafreniere, Abdul-Kader Souid, Paul A. Meyers, Mark Gebhardt, Kimo Stine, Richard Nicholas, Elizabeth J. Perlman, Ronald Dubowy, Irving W. Wainer, Paul S. Dickman, Michael P. Link, Holcombe E. Grier

    Collection and assembly of data: Mark L. Bernstein, Meenakshi Devidas, Dominique Lafreniere, Abdul-Kader Souid, Paul A. Meyers, Mark Gebhardt, Kimo Stine, Richard Nicholas, Elizabeth J. Perlman, Ronald Dubowy, Irving W. Wainer, Paul S. Dickman, Michael P. Link, Holcombe E. Grier

    Data analysis and interpretation: Mark L. Bernstein, Meenakshi Devidas, Dominique Lafreniere, Abdul-Kader Souid, Paul A. Meyers, Mark Gebhardt, Kimo Stine, Richard Nicholas, Elizabeth J. Perlman, Ronald Dubowy, Irving W. Wainer, Paul S. Dickman, Michael P. Link, Holcombe E. Grier

    Manuscript writing: Mark L. Bernstein, Meenakshi Devidas, Paul A. Meyers, Mark Gebhardt, Kimo Stine, Elizabeth J. Perlman, Allen Goorin, Abdul-Kadar Souid, Holcombe E. Grier

    Final approval of manuscript: Mark L. Bernstein, Meenakshi Devidas, Dominique Lafreniere, Abdul-Kader Souid, Paul A. Meyers, Mark Gebhardt, Kimo Stine, Richard Nicholas, Elizabeth J. Perlman, Ronald Dubowy, Irving W. Wainer, Michael P. Link, Allen Goorin, Holcombe E. Grier

    NOTES

    Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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《临床肿瘤学医学期刊》2006年1月第24卷第1期