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© 2003 American Society for Clinical Oncology Single Center Experience of a New Intensive Induction Therapy for Ewing’s Family of Tumors: Feasibility, Toxicity, and Stem Cell Mobilization PropertiesFrom the Meyerstein Institute of Oncology, Middlesex Hospital, University College London Hospitals National Health Service Trust, London, United Kingdom; and Royal National Orthopaedic Hospital, Stanmore, London, United Kingdom. Address reprint requests to J.S. Whelan, MD, Meyerstein Institute of Oncology, Middlesex Hospital, University College London Hospitals National Health Service Trust, Mortimer St, London W1T 3AA; email: jeremy.whelan{at}uclh.org.
Purpose: To examine the feasibility, tolerability, and toxicity of an intensified induction regimen (vincristine, ifosfamide, doxorubicin, and etoposide [VIDE]) in patients with newly diagnosed Ewing’s family of tumors (EFT); to assess ability to maintain dose-intensity, and predictability of peripheral-blood stem cell mobilization. Patients and Methods: Thirty patients were treated with vincristine 1.4 mg/m2 (maximum 2 mg) on day 1, doxorubicin 20 mg/m2, ifosfamide 3 g/m2 plus mesna and etoposide 150 mg/m2 on days 1 to 3. Cycles were given every 21 days for up to six cycles. Results: One-hundred and seventy cycles of VIDE were given. The median treatment interval was 21 days (21 to 42) and nadir count: hemoglobin 8.3 (6.3 to 11.9), neutrophils 0.045 (0.0 to 2.1), and platelets 45 (3 to 343). There were 96 episodes of infection requiring hospitalization (56%). Growth factor support reduced infectious complications by 34%. Etoposide dose was reduced, or omitted, in 24% of cycles. Four patients did not complete six cycles due to unacceptable toxicity and one patient progressed on treatment. Twenty patients underwent peripheral-blood stem cell harvesting, 15 after cycle 3, and five after cycle 4. Median CD34+ yield was 4.6 x 106/kg per patient (1.8 to 14.5). Overall response to treatment, measured in 24 patients, was 88%. Seven of 11 patients undergoing surgery achieved greater than 90% necrosis of tumor (64%). Conclusion: VIDE is an effective induction regimen with substantial but acceptable toxicity that allows predictable mobilization of stem cells. Maintenance of dose-intensity is feasible in the majority of patients. Growth factors play a role in maintaining dose-intensity and reduce infectious complications.
IN 1921, James Ewing described a small round cell tumor arising in bone, which principally occurred in children and teenagers.1 His accurate description of the clinical features of the disease that carries his name has now been expanded to include extraosseous and peripheral neuroectodermal tumors (PNET), which are histologically similar to Ewing’s sarcoma of bone2 and demonstrate the same rearrangement of chromosome 22 in more than 95% of tumors, most commonly as t(11;22).3,4 Because they share many clinical and pathological features, these tumors are classified as the Ewing’s family of tumors (EFT). Before the use of chemotherapy, the long-term outlook for patients with Ewing’s sarcoma was poor with a 5-year survival of less than 20% despite good local control of disease.5 The use of chemotherapy has improved prognosis, and with aggressive multimodality treatment, overall long-term survival now approaches 60%.6–9 Initial trials using vincristine, doxorubicin, dactinomycin, and cyclophosphamide showed improved survival in studies in Europe ET-1,8 CESS-819 and the United States IESS-1.7 Single agent data show alkylating agents and anthracyclines to be the most effective chemotherapeutic drugs. Doxorubicin is the most widely used anthracycline and has a steep dose-response curve. In a review of drugs active against Ewing’s sarcoma, doxorubicin dose-intensity was found to be the single most important determinant to influence survival.10 The dose of doxorubicin varies between regimens, with up to 90 mg/m2 being used.11 In most, however, the anthracycline is alternated with actinomycin-D, thereby reducing dose-intensity. In IESS-II, patients receiving higher doxorubicin dose-intensity showed a significantly better outcome when compared with patients treated with alternating courses of doxorubicin and actinomycin-D.12 Ifosfamide and cyclophosphamide show the highest activity among the alkylating agents, and their use at higher doses has been aided by the availability of mesna to prevent urothelial toxicity.13 The addition of ifosfamide to standard regimens, including cyclophosphamide, has been shown to be beneficial, particularly when given early in treatment.14,15 In ET-2,16 substitution of ifosfamide for cyclophosphamide and an increase in dose-intensity of doxorubicin, was associated with a 20% improvement in survival in patients treated with combination induction therapy. Etoposide has been shown to be an active agent in Ewing’s sarcoma17 and has been used successfully in combination with ifosfamide, initially in patients with recurrent disease,18 and with higher activity in patients with newly diagnosed disease.19 The contribution of etoposide when added to doxorubicin and ifosfamide is as yet undetermined but has been addressed in the EICESS 92 study.20 Results of these trials have identified a number of factors that indicate an adverse prognosis.11,21,22 Most important is the presence of distant metastases as diagnosis, with bone metastases and bone marrow involvement conferring a worse prognosis than the presence of pulmonary metastases. Also, the site of disease is important with pelvic and axial tumors faring worse than extremity limb tumors. In addition, the size of the tumor at diagnosis alters outcome with smaller tumors (< 100 mL), although unusual, conferring a better outcome. Histological response to chemotherapy is increasingly recognized as another factor providing powerful prognostic information.9,23–25 A number of strategies have been used to improve outcome in patients with poor prognosis. These have included intensive induction regimens and the use of high-dose myeloablative chemotherapy with stem cell support.26–30 All the trials, however, are nonrandomized with small numbers of patients. Further information from larger trials is necessary. Thus, important questions in the development of new therapeutic strategies in EFT include whether more intensive treatments will improve outcome for those with metastatic or poorly responsive disease, and whether such factors can be used prospectively to adjust therapy. The purpose of this report is to describe the feasibility of an intensified induction regimen of vincristine, ifosfamide, doxorubicin, and etoposide (VIDE), in preparation for its use in a cooperative group randomized study. Ifosfamide and doxorubicin are given in 3-weekly cycles at doses based on previous European trials. The addition of etoposide intensifies the regimen with greater risk of significant toxicity due to increased myelosupression, thus tolerability and ability to maintain dose-intensity needs to be assessed. In addition, the phase III study addresses the role of high-dose chemotherapy in patients with poor prognostic features. Therefore, the efficacy and predictability of VIDE for mobilization of peripheral-blood stem cells was also assessed.
Patient Selection Between January 1998 and June 1999, thirty patients aged 7 to 36 years with previously untreated EFT were treated with VIDE chemotherapy at the London Bone and Soft Tissue Tumour Service (London, UK). Patients over 13 years of age were treated by a medical oncologist, with patients between 13 and 20 years of age being treated on a specialist adolescent unit. Children under 13 years of age were cared for by pediatric oncologists.
Histological Diagnosis
Staging Staging investigations included a plain chest radiograph, thoracic CT scan with 1-cm intervals, and whole body technetium (99mTc) bone scan. If equivocal areas of increased uptake were found on bone scanning, the presence of metastases was confirmed by MRI. Bilateral iliac crest bone marrow aspiration and trephine were taken (distant from the site of the primary tumor or known metastases). These underwent routine cytological and histological analysis.
Pretreatment Investigations
Treatment
Further Treatment
Patients with metastatic disease at presentation were considered for high-dose chemotherapy with busulphan 600 mg/m2 (150 mg/m2 days -6 to -3) and melphalan 140 mg/m2 (day 2) with peripheral-blood stem cell rescue (day 0) after one or more cycles of VAI chemotherapy (Fig 1
Monitoring During Chemotherapy All patients routinely had a complete blood count performed 10 days after chemotherapy to assess for nadir hematological toxicity, and complete blood count and renal function measured on the day before next treatment cycles. In patients who had additional blood counts performed because of toxicity, results were incorporated into assessment of toxicity. Duration of neutropenia was not routinely assessed.
Local Therapy In patients with metastatic disease undergoing high-dose chemotherapy, radiotherapy was administered when appropriate to the primary site 2 months after recovery from high-dose treatment.
Peripheral-Blood Stem Cell Harvesting Patients with bone marrow involvement at diagnosis had a repeat bone marrow aspirate and trephine before cycle 3. Harvesting was only performed if no evidence of tumor cells were demonstrated by histological or cytological analysis.
Modifications for Toxicity
Radiological Response Evaluation
Radiological Response Criteria
Histological Response
Assessment of Toxicity Written informed consent was obtained from all patients undergoing treatment. For patients younger than 16 years of age, written informed consent was obtained from parents or legal guardian and verbal assent obtained from the patient.
Patient Characteristics Median age at diagnosis was 17 years (range 7 to 36). Male to female ratio was 2:1. Disease was localized in 19 patients (63%) and metastatic in 11 patients (37%). Three of 11 patients with metastatic disease had involvement of two or more sites. Nine of 24 (38%) patients assessable for tumor volume had primary tumors less than 100 mL (Table 1  ).
Treatment One-hundred and seventy cycles of VIDE chemotherapy were given to 30 patients. Twenty-five patients received six cycles. Treatment was terminated before six cycles in five patients, four due to unacceptable toxicity and one due to progressive disease. Toxicity data was available for 170 cycles, and nadir data at day 10 available in 160 cycles.
Treatment Interval
Treatment Duration
Dose Reduction
Toxicities
Mucositis was observed in 77 cycles (45%) of treatment; 38 cycles had grade 1, 23 grade 2, 5 grade 3 and 11 grade 4. Other toxicity included mild peripheral sensory neuropathy; 16 patients had grade 1 symptoms, and three patients had grade 2 symptoms. In all patients, symptoms resolved. There were no episodes of encephalopathy.
Growth Factors
Overall, the use of growth factor support had a significant effect on infectious complications with a reduction in infection requiring hospitalization of 34%. Grade 4 thrombocytopenia was more frequent in cycles treated with growth factor support. This may in part be explained by their greater use later on in treatment when cumulative toxicity is more significant (Table 3
Cardiac and Renal Toxicity Twenty two patients were evaluable for cardiac toxicity after completion of induction treatment. Fifteen patients (68%) experienced grade 1 toxicity (< 20% decrease from baseline) and one patient grade 2 toxicity (more than 20% decrease of baseline). No patients were symptomatic. Evaluation of glomerular filtration rate after completion of induction treatment was carried out on 22 patients. Four patients (18%) experienced grade 1 toxicity and two patients (9%) grade 3 toxicity.
Collection of Peripheral-Blood Stem Cells
Three patients with bone marrow involvement at diagnosis had a repeat aspirate and trephine performed after cycle 3. No evidence of residual tumor was visible by light microscopy and immunohistochemical analysis in any of the patients, and they were deemed fit for harvesting.
Details of Harvesting
Fifteen patients were successfully harvested over 1 day, with a median WBC of 17.3 x 109/L (3.8 to 41.3), yielding a median CD34+ count of 6.2 x 106/kg (1.8 to 14.5). Ten of these patients were harvested on day 14 (67%), two on day 15, two on day 16, and one on day 19. Four patients were harvested over 2 days (one starting on day 14, two on day 15, and one on day 16), and one patient who failed harvest over 2 days after cycle 3 was successfully harvested over 3 days with cycle 4. Apart from one patient who was harvested on day 19, harvests carried out on day 14 yielded the highest median CD34+ count (Table 5
In all 20 patients considered for mobilization, the procedure was successful. Nine patients with metastatic disease underwent harvesting, seven over 1 day, one patient over 2 consecutive days, and one patient over 3 days. There was no difference in predictability of mobilization between patients with localized and metastatic disease.
Local Treatment
Radiotherapy. Eight patients had hyperfractionated split course radiotherapy given concurrently with chemotherapy for treatment of the primary site. This was given with cycles 5 and 6 (one patient), 6 and 7 (two patients), 7 and 8 (four patients), and 10 and 11 (one patient). Four further patients underwent radical radiotherapy to the site of primary tumor. Two patients underwent radiotherapy 2 months after completion of high-dose chemotherapy, and two patients underwent radical radiotherapy after chemotherapy had been terminated due to toxicity. Four patients did not undergo local treatment. This was due to progression of disease while undergoing consolidation treatment in two patients, and renal toxicity preventing further treatment in one patient. The fourth patient had multiple sites of metastases from a primary tumor arising in C5 to T1 vertebrae and underwent high-dose treatment. One additional patient who progressed on VIDE underwent surgery after second line treatment.
Additional Therapy High-dose treatment. Patients with metastatic disease at diagnosis were considered for high-dose chemotherapy if in complete remission or with minimal stable disease based on CT or MRI after induction therapy. Six of 11 patients with metastatic disease at diagnosis underwent treatment with busulphan/melphalan supported by peripheral-blood stem cells. One patient with a large localized chest wall tumor that was treated with primary surgery also underwent high-dose treatment. Three patients who presented with metastatic disease terminated treatment early due to toxicity, and two patients progressed while undergoing consolidation therapy. In seven patients undergoing high-dose treatment, recovery of hematopoesis was with a median neutrophil recovery to more than 0.5 x 109/L of 11 days (11 to 13 days), and platelet recovery to more than 50 x 109/L of 16 days (15 to 44 days). The most frequent toxicity was grade 4 mucositis and febrile neutropenia lasting a median of 7 days (range 5 to 10 days). There were no toxic deaths.
Radiological Response Evaluation
Histological Response
Ahead of a cooperative European study examining the role of VIDE in all patients and contribution of high-dose busulphan/melphalan with peripheral-blood stem cell support in patients with high risk disease, we undertook a nonrandomized pilot study to examine the feasibility and tolerance of an intensive induction regimen with a particular emphasis on ability to maintain dose/time intensity, the role of growth factors, and collection of peripheral-blood stem cells. The toxicity encountered with VIDE chemotherapy was substantial but, in almost all situations, predictable and manageable. The most common toxicity was hematological with 97% cycles documenting grade 3 or 4 neutropenia. This was complicated by febrile neutropenia requiring admission in 56% of cycles, grade 3 to 4 anemia in 36% of cycles and grade 4 thrombocytopenia in 27% of cycles. These toxicities are manageable but require close liaison with the local multidisciplinary team and good local supportive care facilities. Ready access to inpatient and outpatient facilities in a population comprising pediatric and adult patients is essential. The regimen was generally well tolerated by patients with both localized and metastatic disease, but infectious complications were more frequent in those with primary pelvic disease. Other common toxicities included mild peripheral neuropathy (up to grade 2) in six patients (20%), which was reversible on dose reduction or termination of vincristine. There were no toxic deaths. Twenty-five patients (83%) completed 6 cycles of VIDE. Treatment interval was maintained without significant delay (up to 3 days) in 80% and up to 1 week in 95% of cycles. The use of growth factor support enabled maintenance of dose-intensity in 82 cycles (48%). Growth factors were shown to be useful in reducing infective complications, if used with the first cycle of treatment and with ongoing treatment. There was, however, an increased incidence of thrombocytopenia requiring platelet support. Dose reduction due to hematological toxicity was necessary in 15 patients. Because anthracyclines and alkylating agents are of such importance in EFT, the aim was to maintain doses of doxorubicin and ifosfamide as long as possible. The results show that this was feasible, with doxorubicin dose maintained in 98% of cycles and ifosfamide dose maintained in 97% of cycles. A recent experience at St Jude’s Children’s Hospital (Memphis, TN) showed that a dose-intensive induction regimen produced favorable response rates and was feasible for three cycles of treatment before local therapy with radiotherapy.33 The induction regimen consisted of ifosfamide 2 g/m2 (day 1 to 3), etoposide 150 mg/m2 (day 1 to 3), cyclophosphamide 1.5 g/m2 (day 5), and doxorubicin 45 mg/m2 (day 5) given three weekly. The VIDE regimen uses higher doses of doxorubicin (60 mg/m2) and ifosfamide (9 g/m2) but no cyclophosphamide and equivalent etoposide doses. The hematological toxicity experienced with VIDE was comparable to that of the St Jude induction regimen. We found it was feasible to prolong an intensive induction regimen to 6 cycles with little increase in toxicity, with 83% of patients tolerating 6 cycles of treatment. At St Jude, after treatment of the primary tumor with radiotherapy, an attempt was made to increase dose-intensity with ifosfamide 2 g/m2 (day 1 to 5) with etoposide 150 mg/m2 (day 1 to 5), and cyclophosphamide 1.0 or 1.5 g/m2 (day 1 and 2) with doxorubicin 60 mg/m2 (day 1) alternating three weekly. This was only feasible in 25% of patients and lends support to the idea that if dose-intensity is to be attempted, it should be undertaken on commencement of chemotherapy before cumulative bone marrow and local treatment toxicity makes it difficult. Local treatment was scheduled to begin on completion of the induction regimen. When surgery was used as the treatment of the primary tumor, we found it was feasible to plan this to occur after the sixth cycle of treatment. The logistics of planning of concurrent radiotherapy were more complex, and the timing of radiotherapy commencement more variable. In the majority of patients, it was given concurrently with consolidation therapy. Mobilization and harvesting of stem cells is possible and predictable in patients treated with VIDE. The procedure was successful in all patients in whom it was attempted and equally practical in those with localized and metastatic disease. This is important because long-term survival of patients with adverse prognostic factors remains poor with conventional chemotherapy. There is some evidence of efficacy of high-dose busulphan/melphalan treatment with stem cell support in patients with EFTs.29 These trials, however, are nonrandomized and involve only small numbers of patients. A large European multinational randomized study to assess the role of high-dose treatment in patients with high-risk disease has now begun. It is thus important that the induction regimen allows predictable mobilization of peripheral-blood stem cells so that practical considerations do not interfere with treatment. Radiological response evaluation assessed by MRI in 24 patients showed an overall response rate of 88% to induction therapy, and histological response in 11 patients undergoing surgery showed greater than 90% necrosis in the 7 of 11 evaluable resection specimens (64%). In conclusion, VIDE is a dose-intense induction regimen that has substantial but acceptable toxicity. Maintenance of dose-intensity is feasible in the majority of patients for six cycles of treatment, and the treatment interval is sustainable. Growth factors play a role in maintaining dose-intensity, reduce the incidence of infectious complications, and enable consistent mobilization of peripheral-blood stem cells in all patients. Preliminary results show good radiological and histological response rates. Complex and intensive regimens such as this require familiarity, and good supportive care facilities are essential. Care must be taken if considering administration outside specialist centers.
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4. Delattre O, Zucman J, Melot T, et al: The Ewing family of tumors—a subgroup of small-round-cell tumors defined by specific chimeric transcripts. N Engl J Med 331:294–299, 1994 5. Rosen G, Caparros B, Mosende C, et al: Curability of Ewing’s sarcoma and considerations for future therapeutic trials. Cancer 41:888–899, 1978[CrossRef][Medline] 6. Kinsella TJ, Miser JS, Waller B, et al: Long-term follow-up of Ewing’s sarcoma of bone treated with combined modality therapy. Int J Radiat Oncol Biol Phys 20:389–395, 1991[Medline] 7. 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. J Clin Oncol 8:1664–1674, 1990[Abstract] 8. Craft AW, Cotterill SJ, Bullimore JA, et al: Long-term results from the first UKCCSG Ewing’s Tumour Study (ET-1). United Kingdom Children’s Cancer Study Group (UKCCSG) and the Medical Research Council Bone Sarcoma Working Party. Eur J Cancer 33:1061–1069, 1997[CrossRef][Medline] 9. 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 61:23–32, 1988[CrossRef][Medline]
10. Smith MA, Ungerleider RS, Horowitz ME, et al: Influence of doxorubicin dose intensity on response and outcome for patients with osteogenic sarcoma and Ewing’s sarcoma. J Natl Cancer Inst 83:1460–1470, 1991 11. Miser JS, Kinsella TJ, Triche TJ, et al: Preliminary results of treatment of Ewing’s sarcoma of bone in children and young adults: six months of intensive combined modality therapy without maintenance. J Clin Oncol 6:484–490, 1988[Abstract] 12. Burgert EO Jr, Nesbit ME, Garnsey LA, et al: Multimodal therapy for the management of nonpelvic, localized Ewing’s sarcoma of bone: intergroup study IESS-II. J Clin Oncol 8:1514–1524, 1990[Abstract] 13. Skinner R, Sharkey IM, Pearson AD, et al: Ifosfamide, mesna, and nephrotoxicity in children. J Clin Oncol 11:173–190, 1993[Abstract] 14. Rosito P, Mancini AF, Rondelli R, et al: Italian Cooperative Study for the treatment of children and young adults with localized Ewing sarcoma of bone: a preliminary report of 6 years of experience. Cancer 86:421–428, 1999[CrossRef][Medline] 15. Bacci G, Picci P, Ferrari S, et al: Neoadjuvant chemotherapy for Ewing’s sarcoma of bone: no benefit observed after adding ifosfamide and etoposide to vincristine, actinomycin, cyclophosphamide, and doxorubicin in the maintenance phase—results of two sequential studies. Cancer 82:1174–1183, 1998[CrossRef][Medline] 16. Craft A, Cotterill S, Malcolm A, et al: Ifosfamide-containing chemotherapy in Ewing’s sarcoma: The Second United Kingdom Children’s Cancer Study Group and the Medical Research Council Ewing’s Tumor Study. J Clin Oncol 16:3628–3633, 1998[Abstract] 17. Kung F, Hayes FA, Krischer J, et al: Clinical trial of etoposide (VP-16) in children with recurrent malignant solid tumors. A phase II study from the Pediatric Oncology Group. Invest New Drugs 6:31–36, 1988[Medline]
18. Miser JS, Kinsella TJ, Triche TJ, et al: Ifosfamide with mesna uroprotection and etoposide: an effective regimen in the treatment of recurrent sarcomas and other tumors of children and young adults. J Clin Oncol 5:1191–1198, 1987
19. Meyer WH, Kun L, Marina N, et al: Ifosfamide plus etoposide in newly diagnosed Ewing’s sarcoma of bone. J Clin Oncol 10:1737–1742, 1992 20. Paulussen M, Craft AW, Lewis I, et al: Ewing tumor of bone—updated report of the European Intergroup Cooperative Ewing’s Sarcoma Study EICESS 92. Proc Am Soc Clin Oncol 21:1568, 2002 21. Gobel V, Jurgens H, Etspuler G, et al: Prognostic significance of tumor volume in localized Ewing’s sarcoma of bone in children and adolescents. J Cancer Res Clin Oncol 113:187–191, 1987[CrossRef][Medline] 22. Sauer R, Jurgens H, Burgers JM, et al: Prognostic factors in the treatment of Ewing’s sarcoma. The Ewing’s Sarcoma Study Group of the German Society of Paediatric Oncology CESS 81. Radiother Oncol 10:101–110, 1987[Medline]
23. Paulussen M, Ahrens S, Craft AW, et al: Ewing’s tumors with primary lung metastases: survival analysis of 114 (European Intergroup) Cooperative Ewing’s Sarcoma Studies patients. J Clin Oncol 16:3044–3052, 1998 24. Picci P, Bohling T, Bacci G, et al: Chemotherapy-induced tumor necrosis as a prognostic factor in localized Ewing’s sarcoma of the extremities. J Clin Oncol 15:1553–1559, 1997[Abstract]
25. Bacci G, Ferrari S, Bertoni F, et al: Prognostic factors in nonmetastatic Ewing’s sarcoma of bone treated with adjuvant chemotherapy: analysis of 359 patients at the Istituto Ortopedico Rizzoli. J Clin Oncol 18:4–11, 2000
26. Burdach S, Jurgens H, Peters C, et al: Myeloablative radiochemotherapy and hematopoietic stem-cell rescue in poor-prognosis Ewing’s sarcoma. J Clin Oncol 11:1482–1488, 1993 27. Madero L, Munoz A, Sanchez de Toledo J, et al: Megatherapy in children with high-risk Ewing’s sarcoma in first complete remission. Bone Marrow Transplant 21:795–799, 1998[CrossRef][Medline] 28. Pinkerton CR: Intensive chemotherapy with stem cell support—experience in pediatric solid tumours. Bull Cancer 82:61s–65s, 1995 (suppl 1) 29. Atra A, Whelan JS, Calvagna V, et al: High-dose busulphan/melphalan with autologous stem cell rescue in Ewing’s sarcoma. Bone Marrow Transplant 20:843–846, 1997[CrossRef][Medline]
30. Meyers PA, Krailo MD, Ladanyi 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 31. Cancer Therapy Evaluation Program: Common Toxicity Criteria, Version 2.0. DCTD, NCI, NIH, DHHS. March, 1998 32. Malcolm AJ, Pringle J, Misdorp W, et al: A Reproducible method of assessing the post-chemotherapy changes in high-grade clinical osteosarcoma, J Pathol, 155:342A, 1988 (abstr)
33. Marina NM, Pappo AS, Parham DM, et al: 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 Hospital. J Clin Oncol 17:180–190, 1999 Submitted April 24, 2000; accepted May 2, 2003. This article has been cited by other articles:
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Copyright © 2003 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
