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© 1999 American Society for Clinical Oncology Chemotherapy Dose-Intensification for Pediatric Patients With Ewing's Family of Tumors and Desmoplastic Small Round-Cell Tumors: A Feasibility Study at St. Jude Children's Research HospitalFrom the Departments of Hematology-Oncology, Pathology and Laboratory Medicine, Surgery, Biostatistics and Epidemiology, and Radiation Oncology, St. Jude Children's Research Hospital; and the Departments of Pediatrics, Pathology, Radiology, and Surgery, University of Tennessee, Memphis, Tennessee. Address reprint requests to Neyssa M. Marina, MD, Stanford University School of Medicine, Stanford University Medical Center, 300 Pasteur Dr, Stanford, CA 94305-5119.
PURPOSE: To evaluate the feasibility of dose-intensification for patients with Ewing's family of tumors (EFT) and desmoplastic small round-cell tumors. PATIENTS AND METHODS: From February 1992 to June 1996, we treated 53 consecutive patients on our Ewing's protocol. Induction comprised three cycles of ifosfamide/etoposide on days 1 to 3 and cyclophosphamide (CTX)/doxorubicin on day 5, followed by granulocyte colony-stimulating factor. Local control using surgery and/or radiotherapy started at week 9 along with vincristine/dactinomycin. Maintenance included four alternating cycles of ifosfamide/ etoposide and doxorubicin/CTX, with randomization to one of two CTX dose levels to determine the feasibility of dose-intensification during maintenance. RESULTS: Patients had a median age of 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Nineteen patients presented with metastatic disease, 29 had tumors greater than 8 cm in diameter, and 26 had primary bone tumors. These patients received 155 induction cycles, 91% of which resulted in grade 4 neutropenia, 68% in febrile neutropenia, and 68% in grade 3 to 4 thrombocytopenia. During maintenance, grade 4 neutropenia and grade 3 to 4 thrombocytopenia occurred in 81% and 85% of cycles, respectively. Thirty-five patients (66%) completed all therapy, only 13 without significant delays; three developed secondary myeloid malignancies. The toxicity and time to therapy completion were similar in both CTX arms. Estimated 3-year survival and event-free survival were 72% ± 8% and 60% ± 9%, respectively. CONCLUSION: Although intensifying therapy seems feasible for 25% of patients on this study, toxicity was considerable. Therefore, the noninvestigational use of dose-intensification in patients with EFT should await assessment of its impact on disease-free survival.
THE PROGNOSIS FOR PATIENTS with Ewing's sarcoma of bone was poor before the advent of effective chemotherapy, with 5-year survivals of 10% to 20% despite good local disease control.1-5 The consistent use of multimodality therapy has dramatically improved the outcome for these patients, yielding 5-year disease-free survivals (DFS) in the range of 40% to 50%.6-9 The two most effective agents are cyclophosphamide and doxorubicin, which have produced complete responses as single agents10-13; but vincristine and dactinomycin are also active. These four drugs have become the standard therapy. Ifosfamide and etoposide have recently been identified as having significant activity in sarcomas14 and improving the DFS for patients with nonmetastatic Ewing's sarcoma of bone.15 Therefore, they have been incorporated into current treatment strategies. Extraosseous Ewing's sarcoma and peripheral primitive neuroectodermal tumor (pPNET) are histologically similar to Ewing's sarcoma16 and share the same chromosomal translocation t(11;22)(q24;q12), which fuses the EWS and FLI-1 genes.17,18 On the basis of their similarities to Ewing's sarcoma of bone, these tumors have recently been included in the Ewing's family of tumors (EFT). A less common tumor, desmoplastic small round-cell tumor (DSRCT),19 also has a t(11;22), which fuses the EWS gene with WT1 rather than with the FLI-1 gene.20,21 Preliminary data suggest that patients with DSRCT respond to Ewing's-directed therapy, and therefore, they have been included in Ewing's protocols at St. Jude Children's Research Hospital (SJCRH) and other centers.22 Because a significant proportion of patients with Ewing's relapse despite the use of effective multimodality therapy,9 identification of new, effective therapeutic strategies is important to improve the prognosis of these patients. The use of dose-intensification seems to be of value in retrospective studies of some adult malignancies and childhood neuroblastoma23-25 and has been evaluated in a study of 36 patients with EFT.26 This approach seems attractive because these tumors are very sensitive to alkylating agents,10-12,14 which have a steep dose-response curve.
The overall survival and prognosis of patients with Ewing's treated at SJCRH27-29are similar to those of patients in other reported series.30 Patients with large tumors27 and/or the presence of metastases29 have a poor outcome. However, analysis of the pattern of failure reveals a predominance of local failures,27 particularly in high-risk patients (tumors > 8 cm),27 and is in contrast to a predominance of metastatic failures among patients treated in the Intergroup Ewing's Sarcoma Studies.30,31 Therefore, the current Ewing's study was designed with two aims. The first aim was to estimate the proportion of patients receiving all therapy without significant dosage reductions or delays, delivering induction within 8 weeks and maintenance therapy within 28 weeks. At study entry, patients were randomized to two different cyclophosphamide (CTX) schedules, stratified by the percentage of bone marrow to be irradiated (determined by the radiation oncologist,
Patients Between February 1992 and June 1996, previously untreated patients with EFT or DSRCT were enrolled on our institutional Ewing's protocol. Eligibility included age younger than 25 years, adequate performance status (Eastern Cooperative Oncology Group score of 0 or 1), and the presence of a central venous access device. Patients were also required to have normal renal, hepatic, and bone marrow function (in the absence of bone marrow metastases), defined as WBC count greater than 3.0 x 109/L, absolute neutrophil count (ANC) greater than 0.5 x 109/L, and platelets greater than 100 x 109/L. Signed informed consent was obtained from the patient, parent, or legal guardian, and the hospital's institutional review board approved the study.
Pathology
Diagnostic Imaging
Response Evaluation
Treatment Plan
Surgery.
Chemotherapy. Induction therapy was followed by local control measures along with weekly vincristine 1.5 mg/m2/dose IV x 8 and biweekly dactinomycin 1.5 mg/m2/dose IV x 4. Maintenance therapy consisted of four cycles each of ifosfamide 2 g/m2/d and etoposide 150 mg/m2/d IV on days 1 to 5, alternating with CTX (SD or HD) and doxorubicin 60 mg/m2/d infused immediately after the second CTX dose by continuous intravenous infusion over 24 hours. Twenty-four hours after each cycle, patients resumed G-CSF administration. Cycles were repeated every 21 days or as soon as the ANC was at least 0.5 x 109/L and the platelet count was at least 50 x 109/L. The planned length of therapy was 41 weeks.
Postinduction surgery.
Radiation therapy.
Statistical Methods
Summary statistics were calculated using standard methods. The distribution of patient demographics between the two CTX schedules was compared using the Fisher's exact, exact
Toxicity and adjusted toxicity were compared between CTX schedules for all patients and for patients who completed all treatment using the exact Wilcoxon rank sum test. Because many patients did not receive all treatment, toxicity outcomes were adjusted for the time at risk (in days) for each patient. For example, if a patient had 112 days of grade 4 neutropenia and the duration of maintenance therapy was 199 days, then the patient's number of days of grade 4 neutropenia adjusted for time at risk was 112 of 199, or 0.56. Because some patients were withdrawn from this study for toxicity and persisted with decreased blood counts for prolonged periods, the ratios of neutropenia or thrombocytopenia adjusted for time at risk could be 1 or more. All tests comparing toxicity were stratified by the volume of marrow irradiated (< 25% or
Survival and event-free survival (EFS) distributions were estimated using the method of Kaplan and Meier35; associated standard errors were calculated by the method of Peto and Pike.36 Survival was defined as the time interval from study entry to death, whereas EFS was defined as the interval from study entry to disease progression, relapse, second malignancy, or death. Differences in survival distributions between CTX schedules were compared using the stratified Mantel-Haenszel test. The effects of tumor size ( To obtain the standardized incidence ratio (SIR) of second cancers, the number of person-years of observation was compiled for subgroups defined by age and sex using Epilog Plus (Epicenter Software, Pasadena, CA). Rates of incidence of cancers obtained from the registry of the Surveillance, Epidemiology, and End Results Program of the National Institutes of Health39 were used to calculate the expected number of cases of cancer. The SIR was calculated as the ratio of observed to expected cases; 95% confidence intervals (CI) were estimated using Byar's approximation.40
Patients Fifty-four patients with EFT/DSRCT were entered onto the study; one patient was not randomized at study entry and was excluded from the final analysis. Thus, 53 eligible patients were assessable for toxicity and 51 were assessable for response (after exclusion of the two patients with DSRCT). Table 2 lists the clinical characteristics of the patients. Median age was 13.4 years (range, 4.5 to 24.9 years); 34 patients were male and 43 patients were white. Twenty-nine patients had primary tumors measuring greater than 8 cm in maximum diameter, 19 patients had metastatic disease at diagnosis, and 26 patients had primary bone tumors. Therefore, two thirds of the patients (35 of 53) had high-risk features. Histologically, 14 patients were diagnosed as having Ewing's sarcoma (all primary bone tumors), two were diagnosed as having DSRCT, and the remaining 37 were diagnosed as having pPNET. Twenty-five (47%) patients were randomized to HD and 28 (53%) to SD maintenance. There were no significant differences in the age distribution, sex, tumor size, histology, bone versus soft tissue primary, or extent of disease among patients in the two CTX schedules, but there was a significant difference in the distribution of race (white v nonwhite, P = .034). The median follow-up for survivors in the cohort was 3.8 years (range, 1.6 to 6.0 years).
Induction Therapy Hematologic toxicity during this phase of treatment, although significant, was tolerable (see Table 3). Overall, 91% of the cycles resulted in grade 4 neutropenia (ANC < 0.5 x 109/L) lasting a median of 17 days; 74% of these patients experiencing neutropenic episodes required hospital admission for febrile neutropenia. Grades 3 to 4 thrombocytopenia (platelets < 50,000/µL) occurred in 68% of cycles and lasted a median of 9 days.
Maintenance Therapy Table 4 lists the number of patients who participated in this study and those who completed induction and maintenance, along with the reasons for not completing therapy or withdrawal from study. During maintenance, 49 patients received 357 maintenance cycles (154 HD, 203 SD). Twenty of 28 (71%) SD patients received all planned maintenance therapy, compared with 15 of 25 (60%) HD patients. Therefore, only 35 patients (66%) received all planned maintenance therapy. For patients who completed all eight maintenance cycles, the median duration (first to eighth cycles) was 184 days (range, 144 to 244 days); 178 days (range, 145 to 244 days) for SD patients and 194 days (range, 144 to 238 days) for HD patients. Sixteen SD patients who completed therapy recovered their blood counts at a median of 196 days (range, 157 to 282 days), but only eight (28%) of these recovered within 28 weeks. Thirteen HD patients who completed therapy recovered their blood counts at a median of 219 days (range, 155 to 280 days); only five (20%) recovered within 28 weeks. There was no evidence of an effect of CTX schedule on successful completion of maintenance therapy stratified by volume of marrow irradiated (P = .99). There was no evidence suggesting that the proportions of patients who completed maintenance therapy differed between the two CTX schedules (P = .54, Fisher's exact test).
Hematologic toxicity during maintenance therapy was considerable (see Table 5). The distributions of the number of days of grade 4 neutropenia adjusted for time at risk and stratified by volume of marrow irradiated for all patients seemed to differ between the maintenance arms (P = .046). The median number of days of grade 4 neutropenia adjusted for time at risk for the SD and HD groups were 0.33 days (range, 0.08 to 5.09 days) and 0.24 days (range, 0 to 1.25 days), respectively. There was no evidence that the distributions of other toxicities differed between the treatment arms (P > .5). Results of this analysis are difficult to interpret, as some patients stopped therapy early because of treatment-related toxicity. Although the results would be biased, we compared the toxicity distributions between the maintenance schedules using only the 35 patients who completed all treatment. Stratified by volume of marrow irradiated, there were no differences in the distributions of any of the toxicity outcomes by CTX schedule.
Response to Therapy and Local Control
Fourteen patients developed disease progression (n = 4) or recurrent disease (n = 10) a median of 1.4 years (range, 0.04 to 2.2 years) after study entry; 10 of these have subsequently died. Eight patients developed distant failures, and three each had local and both local/distant failure. There were only six local failures (three per arm), resulting in an estimated 3-year cumulative incidence of 12.2% ± 4.7% (SD, 10.9% ± 6.1%; HD, 13.7% ± 7.6%). Because of the small number of local failures, we lack statistical power to detect a difference in cumulative incidences of local failure between maintenance arms. However, there was no evidence of a difference in cumulative incidences of local failure between the treatment arms stratified by volume of marrow irradiated (P = .8).
Nonhematologic Toxicities and Subsequent Events As part of their local therapy, 40 patients had radiotherapy (32 also had surgery) at a median dose of 36 Gy (range, 36 to 68.4 Gy). Seventeen patients (42.5%) developed toxicity related to radiotherapy, including severe esophagitis (n = 5), radiation pneumonitis (n = 5), pulmonary fibrosis (n = 2), and severe skin reactions (n = 3; one required hydrotherapy). Additionally, one patient each developed pharyngitis/mucositis and radiation proctitis (requiring oxygen therapy and a colostomy) related to large unresectable tumor encompassing almost the entire pelvis. Other nonhematologic toxicities included decreased shortening fraction (n = 2), hemorrhagic cystitis (n = 7), veno-occlusive disease of the liver (n = 2), bronchiolitis obliterans organizing pneumonia (n = 1), and subclinical acute hepatitis (n = 1). Fourteen patients (26%) required nutritional support either with total parenteral nutrition or gastrostomy feedings. Three patients required amputations after primary local therapy with limb-salvage (n = 2) or radiotherapy (n = 1). Infectious complications were quite significant. Fourteen patients (26%) developed 16 episodes of bacteremia/line infections; six of these were associated with septic shock. Other infectious complications included skin infections (n = 10, 18.9%), documented fungal infections (n = 5), herpes zoster (n = 5), and recurrent varicella (n = 1). One additional patient received amphotericin B for a presumed fungal pneumonia. Four patients died before developing disease progression (all SD) at a median of 0.8 years (range, 0.6 to 1.2 years) after study entry (all during maintenance therapy). Two of these experienced toxic events during maintenance therapy, whereas the other two died of unknown causes (one may have been a toxic death). Three additional patients developed secondary myeloid malignancies (myelodysplastic syndrome) at 1.4, 2.6, and 3.9 years after diagnosis, resulting in a 4-year cumulative risk of 7.8% ± 4.7%. The expected number of cases of second cancers was 0.029, and the number of person-years of follow-up was 170.5 years, yielding an SIR of 103.4 (range, 20.8 to 302.3). Although the 95% confidence interval is wide, it does not include 1, suggesting that the cohort experienced significantly more cancers than would be expected from an age- and sex-matched cohort from the general population. Because of small numbers, we lack statistical power to determine whether there are significantly more second malignancies among patients in a particular treatment arm.
Analyses of Prognostic Factors
There was no evidence that tumor size was a statistically significant predictor of survival or EFS (P = .55 for survival, P = .67 for EFS). These tests were not stratified by the amount of marrow irradiated. Three-year EFS estimates for patients with tumors greater than 8 cm and 8 cm or less in diameter were 56.9% ± 11.3% and 63.2% ± 12.1%, respectively. Three-year survival estimates were 69.2% ± 10.3% and 75.1% ± 10.4% for patients with tumors greater than 8 cm in diameter and those with tumors 8 cm or less in diameter, respectively. We also looked at the survival and EFS among the subgroup of patients with localized disease by size of tumor. Three-year estimates of EFS among localized patients were 74.5% ± 12.5% and 81.1% ± 11.2% for patients with tumors greater than 8 cm and those with tumors 8 cm or less, respectively.
There were too few events for us to study tumor size and stage of disease as predictors of local failure. However, the local failures were evenly divided between the groups (three local failures in each group of patients with tumors > 8 cm and
The prognosis for patients with Ewing's has improved dramatically with the advent of combined modality therapy.6-9 Despite this improvement in outcome and their excellent response to therapy, a significant proportion of these patients develop disease recurrence and eventually succumb to their disease. Therefore, investigation of new treatment strategies is important to improve the outcome for these patients. In an effort to explore strategies with potential efficacy, both the Pediatric Oncology Group and the Children's Cancer Group use investigational up-front windows in patients with metastatic disease at diagnosis. Dose-intensification is another strategy that seems useful in retrospective studies of some adult malignancies and childhood neuroblastoma.23-25 Although to date, the use of dose-intensification has not been demonstrated to improve DFS in Ewing's, it seems to be an attractive alternative because these tumors are very sensitive to alkylating agents,10-12,14 which have a steep dose-response curve. In this instance, increasing the total doses of drugs administered over time should theoretically result in a greater cell kill and, potentially, a better cure rate. One of the goals of the present study was to evaluate the feasibility of dose-intensifying both induction and maintenance therapy for patients with newly diagnosed EFT using G-CSF as compared with the doses used on our prior study.28 Prior studies using growth factors suggested it would be feasible and tolerable to administer these agents over prolonged periods. However, although growth factors have been used in controlled trials, both on newly diagnosed patients41-43 and relapsed patients,44,45 the duration of growth factor support has been somewhat limited, and the use of radiotherapy (for local control) along with dose-intensification has not been adequately investigated.26,42,43,45 Therefore, before this study, the feasibility of chronic G-CSF administration to dose-intensify therapy in the context of multimodality therapy that includes high-dose radiotherapy had only been addressed, to our knowledge, in a limited number of pediatric patients. Although it seemed likely that dose-intensification would be feasible, there were significant concerns that our attempts would be limited by the development of prolonged marrow suppression. The results of our study suggest that during induction, it is feasible to dose-intensify therapy using G-CSF, because 94% of patients were able to receive their induction therapy within the planned 8 weeks. These patients received 1.4 (minimum increase for ifosfamide) to 3.0 (maximum increase for doxorubicin) times the dose-intensity prescribed on our prior study.28 However, during maintenance therapy (after administering radiotherapy for local control), dose-intensification (as defined herein) is feasible for only a minority of patients (25%). Although 60% to 70% of the patients in our cohort received all scheduled therapy, they were unable to complete it as planned and required either dose reductions or a more prolonged period for therapy completion. In fact, one third of the patients were unable to receive the planned therapy, and there were four early deaths. Therefore, with the current doses and schedule, it was not feasible to dose-intensify maintenance therapy, suggesting that dose-intensification is limited by the patient's ability to recover from toxicity, especially after administration of local therapy including radiotherapy regardless of the percentage of marrow irradiated. Our study design provided for the use of cyclophosphamide at two different dosage schedules. Patients on the SD arm received 1 g/m2/d x 2 days, similar to the dose received by patients on the Intergroup Rhabdomyosarcoma Study Group,46 whereas patients on the HD arm received 1.5 g/m2/d x 2 days. Our results suggest that both these doses produce equivalent toxicity when administered after local therapy in the setting of a prolonged maintenance schedule. Additionally, three patients in our cohort developed secondary myeloid malignancies, resulting in a 4-year cumulative incidence of 8% ± 5%. All three patients had small primary tumors and received 36 Gy to local fields. This number may increase with longer follow-up and is higher than that reported for Ewing's patients treated with standard therapy,47 but not as high as that reported for metastatic patients treated with a dose-intensive regimen.48 Although we chose to increase cyclophosphamide doses in hopes that its toxicities would be tolerable and would therefore permit dose-intensification, it seems that in the current schedule, hematologic toxicity is dose-limiting and secondary myeloid malignancies are increased when results are compared with those of patients treated with more standard doses of chemotherapy.47 This phenomenon has also been observed in prior studies using dose-intensity for patients with metastatic Ewing's.48 Thus, it would seem that attempts at dose-intensification using alkylating agents will be limited by these toxic events. We would therefore suggest that because the value of dose-intensity for patients with Ewing's is uncertain, we should not submit patients to the greater toxicity of more intensive regimens unless such intensification leads to an improved outcome. The Intergroup Ewing's Sarcoma Study Group is currently investigating the impact of dose-intensification on outcome for patients with localized Ewing's. Although prior SJCRH studies demonstrated survivals comparable to those of other published series, there was a predominance of local failures.27 Therefore, in the current study we instituted earlier local control measures, performed surgical procedures in more patients, and used higher-dose hyperfractionated radiotherapy for high-risk patients. We hoped that all those measures would improve our local control and lead to an improved overall outcome. The results of the current study suggest that our approach to local control improved our local failure rate, because the 2- and 3-year cumulative incidences are 8% ± 4% and 12% ± 5%, respectively, with only six of 51 EFT patients having a local failure. This figure compares favorably with the 22 of 27 local failures on our prior two studies.27,28 However, it does not seem that improving our local failure rate translated into an improved overall outcome, because our 3-year EFS is only 60% ± 9%. It is possible that increasing the dose of radiotherapy for high-risk patients led to decreased tolerance of our dose-intensive systemic treatment and increased the number of distant failures. If this was the case, delaying radiotherapy might help to improve EFS. This approach has been used with success at Memorial Sloan-Kettering,26 and our current results would suggest that to administer prolonged, dose-intensive treatment, local therapy should be delayed. However, our prior experience using delayed radiotherapy resulted in a high local failure rate in the context of less intensive systemic therapy.27 The evolution of histologic diagnosis in children with SRCT of bone or soft tissues is also of interest. Using the previously defined diagnostic criteria including the presence of two or more neural markers to diagnose pPNET,49 the majority of the patients on this study were diagnosed with this entity. There is probably little clinical significance to this change, but it makes comparison with other studies difficult. Our study would suggest that with the use of newer diagnostic techniques, the majority of patients with bone or soft tissue SRCT who were previously diagnosed as having Ewing's sarcoma have subtle evidence of neural differentiation. Although it has been suggested that the presence of neural differentiation does not have prognostic importance,50 it would be of interest to evaluate its significance in the setting of a prospective collaborative group study. It would also be important for pediatric pathologists to develop consistent histologic criteria and methodology to diagnose Ewing's sarcoma and pPNET, so that results among studies may be compared. In conclusion, our study suggests that dose-intensifying treatment before administration of local therapy is feasible. Once radiotherapy is administered, dose-intensification is successful in only a minority of patients. In this setting, delaying local therapy might make dose-intensification feasible in a larger number of patients. However, because the toxicity of dose-intensification is high, it will be important to determine its impact on disease-free survival before deciding whether patients should receive these regimens. The current Intergroup Ewing's Sarcoma Study will likely answer this question for patients with localized Ewing's tumor.
Recently, Kushner et al (J Clin Oncol 9:3016-3020, 1998) reported an 8% cumulative incidence of treatment-related myelodysplasia/leukemia at 40 months from the start of the intensive P-6 chemotherapy. This therapy comprised repetitive high-dose alkylating agents (cyclophosphamide and ifosfamide) and topoisomerase-II inhibitors (etoposide and doxorubicin). Although the schedules and total dosages of chemotherapeutic agents in the reported dose-intensity trials for the Ewing's family of tumors vary, many such trials are associated with the development of secondary leukemias. In most settings, this complication is fatal, raising greater concern about the routine application of this treatment strategy for children with these tumors.
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Copyright © 1999 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
or < 25%). The intent of randomization was to decrease patient selection bias in evaluating the feasibility of prolonged CTX intensification during maintenance therapy. We hypothesized that administering a higher CTX dose might result in improved responses, but we had concerns regarding the higher toxicity of such intensification. The proposed dose-intensity in this study was 1.5 (minimum increase in ifosfamide) to 2.5 times (maximum increase for CTX) higher than that delivered on our prior Ewing's sarcoma study.
2, and the exact Wilcoxon tests. Zelen's exact test of homogeneity of the odds ratios
8 cm or > 8 cm) and the presence of metastases at diagnosis on survival and EFS were investigated using unstratified Mantel-Haenszel tests. To estimate the local control rate, we calculated estimates of the cumulative incidence of local failure.
