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Journal of Clinical Oncology, Vol 23, No 1 (January 1), 2005: pp. 105-112 © 2005 American Society of Clinical Oncology. DOI: 10.1200/JCO.2005.05.108 Randomized Phase II Evaluation of 6 g/m2 of Ifosfamide Plus Doxorubicin and Granulocyte Colony-Stimulating Factor (G-CSF) Compared With 12 g/m2 of Ifosfamide Plus Doxorubicin and G-CSF in the Treatment of Poor-Prognosis Soft Tissue SarcomaFrom the Departments of Internal Medicine, Biostatistics, Orthopedic Surgery, Surgery, and Radiation Oncology, Division of Hematology/Oncology, and Clinical Trials Office, University of Michigan Comprehensive Cancer Center, Ann Arbor, MI Address reprint requests to Laurence H. Baker, DO, 1500 E Medical Center Dr, Ann Arbor, MI 48109-0922; e-mail: bakerl{at}umich.edu
PURPOSE: The relative value of increasing ifosfamide dose in combination chemotherapy for patients with soft tissue sarcoma (STS) is unclear. The purpose of this study was to compare the efficacy and toxicity of doxorubicin with high-dose (HD) ifosfamide or standard-dose (SD) ifosfamide in patients with STS. PATIENTS AND METHODS: Chemotherapy-naive patients with STS were randomly assigned to receive doxorubicin 60 mg/m2 and either SD ifosfamide (1.5 g/m2/d, days 1 through 4) or HD ifosfamide (3.0 g/m2, days 1 through 4) every 21 days. Patients were stratified by the presence or absence of metastatic disease. End points were overall survival (OS), 1-year disease-free survival (DFS), and toxicity. RESULTS: The study group consisted of 79 patients (52 patients with localized disease and 27 patients with metastases). Both groups were well-balanced with respect to known prognostic factors. There was no significant difference in 1-year DFS comparing SD ifosfamide with HD ifosfamide (55% v 52%; P = .81). For SD ifosfamide, 2- and 3-year OS were 73% and 52% versus 57% and 49% for HD ifosfamide (P = .34). The incidence of grade 3/4 neutropenia, anemia, and thrombocytopenia were 49%, 23%, and 10%, respectively, on the SD ifosfamide arm, compared with 88%, 58%, and 63%, respectively, on the HD ifosfamide arm. There were five early deaths, all on the HD ifosfamide arm. CONCLUSION: When combined with doxorubicin, HD ifosfamide did not improve 1-year DFS and OS. Toxicity was clearly greater with the HD ifosfamide arm, and lack of outcome differences might be explained by toxicities with HD ifosfamide. These results suggest that HD ifosfamide combination regimens should not be used as first-line therapy for patients with STS.
Ifosfamide and doxorubicin are the principle cytotoxic agents used in patients with soft tissue sarcoma (STS). As single agents, they have similar response rates of approximately 26% for doxorubicin and approximately 27% for ifosfamide.1 When combined, doxorubicin and ifosfamide are associated with response rates of up to 35%.2-5 Although increased response rates are observed with combination regimens, survival is not significantly longer as compared with single-agent doxorubicin.5 Efforts to intensify the dosage of doxorubicin in combination with ifosfamide have been made.6-8 A European Organization for Research and Treatment of Cancer study reported improved progression-free survival but no improvement in overall survival (OS) with doxorubicin 75 mg/m2 as compared with doxorubicin 50 mg/m2, both arms in combination with ifosfamide 5 g/m2. Ifosfamide therapy yields clinical benefit in patients who have previously experienced treatment failure with doxorubicin-based regimens.9 Evidence supporting a dose-response relationship with ifosfamide was shown in sequential studies. In these trials, sarcoma patients previously treated with doxorubicin received single-agent ifosfamide in escalating doses. The response rate at 6 g/m2 was 10%, at 8 g/m2 was 14%, and at 10 g/m2 was 21%.10 A follow-up phase II study at a higher dose (14 g/m2) confirmed this dose-response relationship.11 To date, there are no published, randomized trials comparing doxorubicin in combination with a standard-dose (SD) ifosfamide regimen with doxorubicin in combination with a high-dose (HD) ifosfamide regimen as first-line therapy for patients with STS. One published study12 compared single-agent ifosfamide at a higher dose (3 g/m2 over 3 days) to a more standard regimen (5 g/m2 over 24 hours) as first- and second-line chemotherapy. Survival did not differ and toxicity was greater with the higher-dose arm. We designed a randomized phase II study to compare 1-year disease-free survival (DFS), OS, and toxicities of two combination regimens using equivalent doses of doxorubicin with SD ifosfamide versus HD ifosfamide as first-line therapy.
Eligibility Patients with documented American Joint Committee on Cancer stage IIIB STS (grade G3, > 5 cm in diameter), stage IIB STS (grade G2, > 5 cm in diameter and deep to initial fascia), or measurable, metastatic, high-grade (> G2 lesions) STS previously untreated with chemotherapy were eligible. Patients having had primary surgical resection received adjuvant chemotherapy, whereas patients having had unresected primary disease received neoadjuvant chemotherapy. Patients with distant metastases received palliative treatment. Participants were required to be at least 16 years of age with a Zubrod performance status of less than 2. Further eligibility requirements included granulocyte count of greater than 1,500 cells/µL, platelet count of greater than 100,000 cells/µL, total bilirubin less than 1.5 times the upper limit of normal (ULN), and a serum creatinine less than 1.2x the ULN. Patients were required to have two functioning kidneys and an estimated creatinine clearance of greater than 50 mL/min. Osteosarcoma, Ewing’s sarcoma, rhabdomyosarcoma, undifferentiated small cell sarcoma, and Kaposi’s sarcoma patients were not eligible. Patients with unstable angina pectoris, uncontrolled ventricular arrhythmias, and decreased cardiac function were ineligible, as were patients with other active systemic malignancy within 1 year of enrollment. No concurrent radiation, hormonal, or biologic therapies were permitted. All patients provided written informed consent.
Treatment Plan
Treatment Evaluations and Dose Modifications
National Cancer Institute Common Toxicity Criteria (version 1.0) were used to classify adverse events. Filgrastim was continued until absolute neutrophil counts were
Response Criteria
Statistical Design
Statistical Analysis
Patient Characteristics From January 1999 to November 2002, 86 patients were registered. Four patients (5%) were ineligible: two patients had rhabdomyosarcoma, one patient had a serum creatinine level greater than 1.2x the ULN, and one patient was unable to complete prestudy evaluations. Of the 82 eligible patients, three patients (4%) were nonassessable: one patient withdrew, one patient was noncompliant, and one patient received an incorrect dosage of doxorubicin. All further analyses were performed on the 79 remaining patients. Patient characteristics are listed in Table 1. A total of 41 women and 38 men were enrolled. The median age was 53 years (range, 18 to 78 years); most had a Zubrod performance status of zero. None had received prior chemotherapy. Most patient characteristics were well-balanced between the treatment arms. However, because stratification for neoadjuvant or adjuvant therapy did not occur before randomization, more patients treated with adjuvant chemotherapy received SD ifosfamide, whereas more patients treated with neoadjuvant chemotherapy received HD ifosfamide. Histologic tumor types and disease sites are listed in Table 2.
Treatment and Tolerance Forty-four of 52 patients with localized disease completed four cycles of therapy (Table 3). In those with metastatic disease, however, only seven of 13 patients who received SD ifosfamide and four of 14 patients who received HD ifosfamide completed all six cycles. Eight patients (10%) failed to complete chemotherapy because of disease progression on chemotherapy (six patients assigned to SD ifosfamide and two patients assigned to HD ifosfamide). Fifteen patients (19%) discontinued therapy because of toxicity (three patients assigned to SD ifosfamide and 12 patients assigned to HD ifosfamide). Of those receiving HD ifosfamide, there were five early deaths, each within 120 days from randomization (two deaths from neutropenic sepsis and three deaths from tumor progression). Each of these five patients was older than 65 years of age.
Hematologic toxicities are listed in Table 4. This table reflects the nadir hematologic values and most severe toxicity observed during the entire course of treatment. Grade 3/4 neutropenia was documented in 49% and 87% of patients on the SD ifosfamide and HD ifosfamide arms, respectively. Similarly, anemia and thrombocytopenia were also more pronounced on the HD ifosfamide arm. Grade 3/4 anemia occurred in 23% of patients who received SD ifosfamide and 57% of patients who received HD ifosfamide. Overall, seven patients on the SD ifosfamide arm required blood transfusions versus 30 patients on the HD ifosfamide arm. Ten percent of patients developed grade 3/4 thrombocytopenia while receiving SD ifosfamide versus 62% of patients receiving HD ifosfamide.
Grade 3/4 neurotoxicity, noted in four patients, was only observed on the HD ifosfamide arm. Renal toxicity, as described by a decline in creatinine clearance, is shown in Table 5. All patients had baseline creatinine clearances of  50 mL/min. After one or more courses of chemotherapy, only two patients (5%) who received SD ifosfamide had a decline in creatinine clearance, both of which were to less than 20 mL/min. Ten patients on the HD ifosfamide arm had reductions in creatinine clearance, nine patients to 20 to 50 mL/min and one patient to less than 20 mL/min.
Response to Treatment Response to therapy is detailed in Table 6. Responses were characterized in a post hoc analysis because this was not an original objective of this proposal. Patients who received neoadjuvant or adjuvant chemotherapy were not stratified before randomization, thus the groups were imbalanced. All patients who received SD ifosfamide as neoadjuvant therapy had stable disease. In the HD ifosfamide arm, three (18%) of 17 patients achieved objective responses, whereas 11 patients had stable disease. There were no complete responses in either arm. In patients with metastatic disease treated with SD ifosfamide, three (23%) of 13 patients attained an objective response, including two complete responses. In the HD ifosfamide arm, three (25%) of 12 patients had an objective response, including one complete response.
Survival is tabulated in Table 7. No significant survival benefit was observed in either arm. In the SD ifosfamide arm, the 2- and 3-year survival rates were higher, 73% and 52%, respectively, as compared with 57% and 49% in the HD ifosfamide arm. The relative hazard ratio of death for the HD ifosfamide group compared with the SD ifosfamide group was 1.39 (95% CI, 0.70 to 2.77; P = .34; Fig 1). The 1-year DFS was 55% for all patients in the SD ifosfamide arm compared with 52% for all patients in the HD ifosfamide arm (Fig 2). The relative hazard ratio of disease recurrence after treatment with HD ifosfamide versus SD ifosfamide was 1.08 (95% CI, 0.56 to 2.09; P = .81).
Both treatment arms were analyzed according to the presence or absence of metastatic disease. Overall survival and DFS were higher in patients with localized disease, regardless of the treatment arm. The 3-year OS was 60% in the nonmetastatic group and 35% in the metastatic group. In the nonmetastatic patient population, 1-year DFS was 75% in the SD ifosfamide arm compared with 65% in the HD ifosfamide arm (Table 7). At 2 years, OS was 88% in the SD arm compared with 64% in the HD arm. The relative hazard ratio of death for the HD ifosfamide arm versus the SD ifosfamide arm was 1.64 (95% CI, 0.62 to 4.31). In patients with metastatic disease, 1-year DFS was slightly lower in the SD ifosfamide arm versus the HD ifosfamide arm (15% v 29%). However, the 2-year OS rate was 46% in both treatment arms. The relative hazard ratio of death for the HD ifosfamide arm versus the SD ifosfamide arm was 1.18 (95% CI, 0.44 to 3.14).
Clinical activity of ifosfamide in STS has been demonstrated for the past three decades.14 Increasing ifosfamide dosage from 5 g/m2 to 14 g/m2 is associated with improved response rates using short-term infusions versus prolonged infusion schedules11 (Table 8). Most commonly, HD regimens ( 10 g/m2) have been used in patients who have experienced treatment failure with regimens containing doxorubicin.11 Some studies suggest that a dose-response relationship to ifosfamide exists.21 Le Cesne et al22 reported that HD ifosfamide led to partial responses in patients who had failed to respond to SD regimens. Doxorubicin, on the contrary, does not increase response rates when given at higher doses beyond a threshold dose.7,16 The combination of doxorubicin and ifosfamide produces response rates that are higher than doxorubicin alone, despite little impact on OS.6,15 Epirubicin and ifosfamide combination regimens have efficacy similar to combinations of doxorubicin and ifosfamide; however, these regimens have never been directly compared.17-19 Although these drugs are similar, epirubicin is not more efficacious than doxorubicin in the treatment of STS. When compared in equimolar doses, doxorubicin and epirubicin produced similar response rates, slightly favoring doxorubicin.20,23
Despite improvements in response rates with combination chemotherapy, these multidrug regimens provide no OS benefit in comparison with single-agent doxorubicin.3,5 However, improved efficacy with combination regimens when used as neoadjuvant and adjuvant treatment may be expected. When administered as single agents, both doxorubicin and ifosfamide have response rates of approximately 25%, and response rates are generally improved when these agents are combined.3,6,11,24,25 The dosage of doxorubicin was limited in our study to 60 mg/m2, given the difficulty in administering 75 mg/m2 or greater with 12 g/m2 of ifosfamide. Published data fail to show a survival benefit from dose escalation of doxorubicin beyond 60 mg/m2 in the treatment of patients with STS.4,16 Similarly, new data from the breast cancer literature also report no improvement in OS with the administration of 75 mg/m2 of doxorubicin versus 60 mg/m2.26 This is the first randomized trial comparing an SD ifosfamide regimen with an HD ifosfamide regimen, with each arm receiving identical doses of doxorubicin. The results of this study show no improvement in 1-year DFS or OS in patients receiving HD ifosfamide and suggest a worse overall outcome with the higher dosage. Furthermore, when analyzed separately, neither patients with localized disease nor metastatic disease seem to have benefited from HD chemotherapy. An argument can be made that this study was underpowered. We were looking for an improvement in 1-year DFS from 40% with SD ifosfamide/doxorubicin to 70% with the HD ifosfamide/doxorubicin having an 80% power, using a one-sided test to detect that difference with 80 patients. In our study design, we estimated that approximately 70% of the patients would have nonmetastatic disease and 30% would have metastatic disease. We accrued 79 assessable patients, 52 patients (65%) with localized, nonmetastatic disease and 27 patients (35%) with metastatic disease. To detect a smaller difference from 40% to 60%, 86 patients in each study arm would be required, and 325 patients would be needed to detect a difference from 40% to 50%. Initiatives to collaborate with other institutions were made in an attempt to accrue larger numbers of patients. However, strong prior opinions on whether HD or SD ifosfamide should be administered as first-line therapy for STS forced us to conduct this trial as a single-institution, phase II study. We chose to include patients with poor prognosis (high grade, > 5 cm) tumors with both localized and metastatic disease to have a large enough patient population to conduct a single-institution, randomized trial. We recognize that histologic subtypes may have different responses to various systemic therapies. For example, gastrointestinal stomal tumors (GIST), formally thought of as epithelioid leiomyosarcomas of the gastrointestinal tract, were quite refractory to cytotoxic regimens, with response rates of less than 5%. The tyrosine kinase inhibitor, imatinib, has now revolutionized the treatment of GIST, with nearly 80% of patients with metastatic GIST having clinical benefit.27,28 In our study, we excluded the known histologic subtypes that had better response rates to specific cytotoxic regimens (ie, childhood rhabdomyosarcoma) or subtypes with known records of failure to doxorubicin and/or ifosfamide (ie, alveolar soft part sarcoma). The problem with clinical trials in STS without attention to the importance of histologic subtypes remains chronic and recurrent. It is possible that we may have missed the impact of ifosfamide dose-intensity in one or more of the subtypes. However, from studies in metastatic patients, there is no evidence of such an impact. Clearly, new methodologies in clinical trial design are warranted. Equally as clear is the need for new methods of collaboration among institutions with relatively large populations of these patients so that these important clinical questions can be addressed. The role of adjuvant chemotherapy in the treatment of STS for localized disease remains controversial. However, data from a meta-analysis from 14 trials comparing surgery alone to surgery followed by adjuvant chemotherapy demonstrated a 7% improvement in OS at 10 years (P = .029).29 More recent data from Italy also indicate a benefit to adjuvant chemotherapy with regard to improvement in both DFS and OS in patients with high-grade sarcomas of the extremities.30 The role of neoadjuvant chemotherapy in the treatment of STS is not yet well documented.31 The overall response rate in patients treated with the HD regimen was 21% versus 15% in the SD regimen (Table 6). Although our findings are consistent with the response rates of HD and SD ifosfamide currently reported in the literature, it must be noted that the arms were not equally balanced in the subgroup analysis. Nineteen of the 27 patients treated neoadjuvantly were randomly assigned to the HD arm, and the majority of patients treated adjuvantly were randomly assigned to the SD arm. This was a chance occurrence, as patients were not stratified by neoadjuvant versus adjuvant status. We do not believe that this imbalance had any impact on the overall outcomes of our study in terms of DFS and OS.
The lack of difference in OS and 1-year DFS may be explained in part by a decline in renal function and increased toxicities, which prevented patients from completing planned courses of treatment or which led to early deaths. Before treatment, the patient population was considered fit, with only one patient having a Zubrod performance status of 2. Additionally, all registered patients had two functioning kidneys with adequate renal function. Of those patients with metastatic disease, fewer than one half who were randomly assigned to receive HD ifosfamide completed treatment. Toxicity and early death were the two contributing factors. All five patients with early death were It is well known that HD ifosfamide regimens are more toxic than lower-dose regimens.11,24,32 The results of our study are no exception. Although granulocyte colony-stimulating factor was required in both arms, grade 3/4 myelosuppression were greater with the HD group (Table 4). The toxic effects of ifosfamide were cumulative with subsequent chemotherapy cycles. Anemia was common in both arms but was worse in the HD ifosfamide arm. The HD ifosfamide treatment group also experienced more thrombosuppressive toxicity. Renal toxicity with HD ifosfamide was similar in our study as in other reports.11 Ten patients on the HD arm developed worsening of their renal function. All but one recovered full function, and no patients required dialysis. Neurotoxicity was noted in four patients treated with 12 g/m2 of ifosfamide. No toxic deaths were attributed to CNS events. Findings from this study confirm that HD ifosfamide is more toxic. Clearly, patients must be counseled about the potential severity of this approach, even if they are in excellent general health and have a good performance status. In conclusion, we attempted to explore the relative value of incorporating HD ifosfamide in combination with doxorubicin as first-line therapy for STS. Our findings, based on a combination of increased toxicity and lack of apparent benefit, do not support its routine use. Rather, standard doses of ifosfamide in combination with doxorubicin should be considered.
The following authors or their immediate family members have indicated a financial interest. No conflict exists for drugs or devices used in a study if they are not being evaluated as part of the investigation. Performed contract work within the last 2 years: Cornelius J. McGinn, Eli Lilly. Received more than $2,000 per year from a company for either of the last 2 years: Cornelius J. McGinn, Eli Lilly; Laurence H. Baker, Amgen, Ascentia, Kenisa.
We thank Yolanda Tra, PhD, of the Department of Biostatistics, for her support with biostastical analysis, and Monica Orians, of the Clinical Trials Office, for her support with data management.
Supported by Amgen Inc, Thousand Oaks, CA. Presented in part at the 38th Annual Meeting of the American Society of Clinical Oncology, Orlando, FL, May 18-21, 2002, and the 39th Annual Meeting of the American Society of Clinical Oncology, Chicago, IL, May 31-June 3, 2003. Authors’ disclosures of potential conflicts of interest are found at the end of this article.
1. Biermann JS, Baker LH: The future treatment of sarcoma. Semin Oncol 24:592-597, 1997[Medline] 2. Keohan ML, Taub RN: Chemotherapy for advanced sarcoma: Therapeutic decisions and modalities. Semin Oncol 24:572-579, 1997[Medline] 3. Antman KH, Crowley J, Balcerzak S, et al: An intergroup phase III randomized study of doxorubicin and dacarbazine with or without ifosfamide and mesna in advanced soft tissue and bone sarcomas. J Clin Oncol 11:1276-1285, 1993 4. Edmonson JH, Ryan LM, Blum RH, et al: Randomized comparison of doxorubicin alone versus ifosfamide plus doxorubicin or mitomycin, doxorubicin and cisplatin against advanced tissue sarcomas. J Clin Oncol 11:1269-1275, 1993 5. Santoro A, Tursz T, Mouridsen H, et al: Doxorubicin versus CYVADIC versus doxorubicin plus ifosfamide in first line treatment of advanced soft tissue sarcomas: A randomized study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 13:1537-1545, 1995 6. Steward WP, Verweiji J, Somers R, et al: Granulocyte-macrophage colony-stimulating factor allows safe escalation of dose-intensity of chemotherapy in metastatic adult soft tissue sarcomas: A study of the European Organization for Research and Treatment of Cancer Soft Tissue and Bone Sarcoma Group. J Clin Oncol 11:15-21, 1993[Abstract] 7. Le Cesne A, Judson I, Crowther D, et al: Randomized phase III study comparing conventional-dose doxorubicin plus ifosfamide versus high-dose doxorubicin plus ifosfamide plus recombinant human granulocyte-macrophage colony-stimulating factor in advanced soft tissue sarcomas: A trial of the European Organization for Research and Treatment of Cancer/Soft Tissue and Bone Sarcoma Group. J Clin Oncol 18:2676-2684, 2000 8. O’Bryan RM, Baker LH, Gottlieb JE, et al: Dose response evaluation of adriamycin in human neoplasia. Cancer 39:1940-1948, 1977[CrossRef][Medline] 9. Antman KH, Ryan L, Elias AD, et al: Response to ifosfamide and mesna: 124 previously treated patients with metastatic or unresectable sarcoma. J Clin Oncol 7:126-131, 1989[Abstract] 10. Benjamin RS, Legha SS, Patel SR, et al: Single-agent ifosfamide studies in sarcomas of soft-tissue and bone: The M.D. Anderson experience. Cancer Chemother Pharmacol 31:S174-S179, 1993 11. Patel SR, Vadhan-Raj S, Papadopolous N, et al: High-dose ifosfamide in bone and soft tissue sarcomas: Results of phase II and pilot studies—Dose-response and schedule dependence. J Clin Oncol 15:2378-2384, 1997 12. van Ooserom AT, Mouridsen HT, Nielsen OS, et al: Results of randomised studies of the EORTC Soft Tissue and Bone Sarcoma Group (STBSG) with two different ifosfamide regimens in first- and second-line chemotherapy in advanced soft tissue sarcoma patients. Eur J Cancer 38:2397-2406, 2002 13. Therasse P, Arbuck S, Eisenhauer E, et al: New guidelines to evaluate the response to treatment in solid tumors: European Organization for Research and Treatment of Cancer, National Cancer Institute of the United States, National Cancer Institute of Canada. J Natl Cancer Inst 92:205-216, 2000 14. Zalupski M, Baker LH: Ifosfamide. J Natl Cancer Inst 80:556-566, 1988 15. Schutte J, Dombernowsky P, Mouridsen HT, et al: Ifosfamide plus adriamycin in previously untreated patients with advanced STS: Final results of a phase II trial of the EORTC/STBSG. Eur J Cancer 26:558-561, 1990 16. Patel SR, Vadhan-Raj S, Burgess MA, et al: Results of two consecutive trials of dose-intensive chemotherapy with doxorubicin and ifosfamide in patients with sarcomas. Am J Clin Oncol 21:317-321, 1998[CrossRef][Medline] 17. Toma S, Palumbo R, Canavese G, et al: Ifosfamide plus epirubicin at escalating doses in the treatment of locally advanced and/or metastatic sarcomas. Cancer Chemother Pharmacol 31:S222-S227, 1993 (suppl 2) 18. Chevallier B, Leyvraz S, Olivier JP, et al: Epirubicin and ifosfamide in advanced soft tissue sarcoma: A phase II study. Cancer Invest 11:135-139, 1993[Medline] 19. Palumbo R, Neumaier C, Cosso M, et al: Dose-intensive first-line chemotherapy with epirubicin and continuous infusion ifosfamide in adult patients with advanced soft tissue sarcomas: A phase II study. Eur J Cancer 35:66-72, 1999 20. Mouridsen HT, Bastholt L, Somers R, et al: Adriamycin versus epirubicin in advanced STS: A randomized phase II/III study of the EORTC/STBSG. Eur J Cancer 33:220-225, 1995[CrossRef] 21. Palumbo R, Palmeri S, Antimi M, et al: Phase II study of continuous-infusion high-dose ifosfamide in advanced and/or metastatic pretreated soft tissue sarcomas. Ann Oncol 8:1159-1162, 1997 22. Le Cesne A, Antoine E, Spielman M, et al: High dose ifosfamide: Circumvention of resistance to standard dose ifosfamide in advanced soft tissue sarcomas. J Clin Oncol 13:1600-1608, 1995 23. Nielsen OS, Dombernowsky P, Mouridsen H, et al: High-dose epirubicin is not an alternative to standard-dose doxorubicin in the treatment of advanced soft tissue sarcomas: A study of the EORTC Soft Tissue and Bone Sarcoma Group. Br J Cancer 78:1634-1639, 1998[Medline] 24. Nielsen OS, Judson I, van Hoesel Q, et al: Effect of high-dose ifosfamide in advanced soft tissue sarcomas: A multicentre phase II study of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 36:61-67, 2000 25. Borden EC, Amato DA, Rosenbaum CH, et al: Randomized comparison of three Adriamycin regimens for metastatic soft tissue sarcomas. J Clin Oncol 5:840-850, 1987 26. Henderson IC, Berry DA, Demetri GD, et al: Improved outcomes from adding sequential paclitaxel but not from escalating doxorubicin dose in an adjuvant chemotherapy regimen for patients with node-positive primary breast cancer. J Clin Oncol 21:976-983, 2003 27. Heinrich M, Corless C, Demetri G, et al: Kinase mutations and imatinib response in patients with metastatic gastrointestinal stromal tumor. J Clin Oncol 21:4342-4349, 2003 28. van Oosterom A, Judson I, Verweij J, et al: Update of phase I study of imatinib (STI571) in advanced soft tissue sarcomas and gastrointestinal stromal tumors: A report of the EORTC Soft Tissue and Bone Sarcoma Group. Eur J Cancer 38:83-87, 2002 29. Sarcoma Meta-Analysis Collaboration: Adjuvant chemotherapy for localized resectable soft-tissue sarcoma of adults: Meta-analysis of individual data. Lancet 350:1647-1654, 1997[CrossRef][Medline] 30. Frustaci S, Gherlinzoni F, De Paoli A, et al: Adjuvant chemotherapy for adult soft tissue sarcomas of the extremities and girdles: Results of the Italian randomized cooperative trial. J Clin Oncol 19:1238-1247, 2001 31. Gortzak E, Azzarelli A, Buesa J, et al: A randomised phase II study on neo-adjuvant chemotherapy for ‘high-risk’ adult soft-tissue sarcoma. Eur J Cancer 37:1096-1103, 2001 32. Buesa J, Lopez-Pousen A, Anton A, et al: Phase II trial of first line HD-IF in advanced STS. Proc Am Soc Clin Oncol 16:498a, 1998 (abstr 1793) Submitted May 19, 2004; accepted October 1, 2004.
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Copyright © 2005 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
error of .05 and a ß error of .80. A one-sided 5% level test comparing proportions provided at least 80% power of detecting this difference or greater, with 40 patients per treatment arm. 
